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Published: 19 May 2021

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Eric Legius ORCID: orcid.org/0000-0003-2410-6996 1 na1 ,
Ludwine Messiaen 2 na1 ,
Pierre Wolkenstein 3 na1 ,
Patrice Pancza 4 na1 ,
Robert A. Avery 5 ,
Yemima Berman 6 ,
Jaishri Blakeley 7 ,
Dusica Babovic-Vuksanovic 8 ,
Karin Soares Cunha 9 ,
Rosalie Ferner 10 ,
Michael J. Fisher 11 ,
Jan M. Friedman 12 ,
David H. Gutmann 13 ,
Hildegard Kehrer-Sawatzki 14 ,
Bruce R. Korf 2 ,
Victor-Felix Mautner 15 ,
Sirkku Peltonen 16 , 17 ,
Katherine A. Rauen 18 ,
Vincent Riccardi 19 ,
Elizabeth Schorry 20 ,
Anat Stemmer-Rachamimov 21 ,
David A. Stevenson 22 ,
Gianluca Tadini 23 ,
Nicole J. Ullrich 24 ,
David Viskochil 25 ,
Katharina Wimmer 26 ,
Kaleb Yohay 27 ,
International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC) ,
Susan M. Huson 28 na1 ,
D. Gareth Evans 29 na1 &
Scott R. Plotkin 30 na1

Genetics in Medicine volume 23 , pages 1506–1513 ( 2021 ) Cite this article

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By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS).

We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups.

We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended.

The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types

Natural history of NF1 c.2970_2972del p.(Met992del): confirmation of a low risk of complications in a longitudinal study

An integrated clinical and molecular study of a cohort of Turkish patients with Marfan syndrome harboring known and novel FBN1 variants

Introduction, nomenclature and history.

Neurofibromatosis type 1 (NF1; OMIM 613113), inherited in an autosomal dominant pattern, is characterized by multiple café-au-lait macules (CALMs), skinfold freckling (more correctly termed lentiginous macules since they occur in non–sun exposed areas), iris Lisch nodules, tumors of the nervous system, and other features. 1 , 2 Disease manifestations can occur in any body system. There is a significantly increased risk of certain cancers, including female breast cancer <50 years, malignant peripheral nerve sheath tumors (MPNSTs), and brain tumors. 3 The modern history of nomenclature of neurofibromatosis started in 1987 with the National Institutes of Health (NIH) Consensus Development Conference on Neurofibromatosis. 4 Until that time there had been confusion in the literature as to whether bilateral vestibular schwannomas (previously termed acoustic neuromas) were a feature of NF1 or a distinct entity. Riccardi laid the groundwork for the NIH consensus criteria by proposing a numerical classification system based on the presence/absence of CALMs and skinfold freckling, specific eye signs, neurofibromas, and complications specific to each type. 5 The mapping of the NF1 gene to chromosome 17 6 and the NF2 gene to chromosome 22 7 allowed the consensus conference to establish diagnostic criteria for the two conditions (Table S1 ). The 1988 panel recognized that “[p]atients who do not fit into the NF1 or NF2 group by clinical or genetic criteria may, in the future, constitute the basis for establishing additional types of NF.” 4

The NIH criteria include the most frequent disease manifestations (CALMs, freckling, neurofibromas, and Lisch nodules) alongside disease complications typical of NF1. Since 1987 there has been one formal review of the NF1 criteria by the Clinical Care Advisory Board of the National Neurofibromatosis Foundation (now the Children’s Tumor Foundation). 8 No criteria alterations were suggested.

The NF1 gene was cloned in 1990. 9 , 10 Subsequent cell biology studies have found that neurofibromin, the NF1 gene product, largely operates as a GTPase-activating protein (GAP) that negatively regulates the RAS/MAPK pathway activity by accelerating the hydrolysis of RAS-bound GTP. 1 Cell biology advances and animal models have led to the identification of MEK inhibitors as a treatment for plexiform neurofibromas. 11 In April 2020, selumetinib was approved by the US Food and Drug Administration for treatment of children with NF1-related symptomatic plexiform neurofibroma. 11

NF1 was the first human condition mapped to the RAS pathway but subsequently other conditions have been shown to be caused by pathogenic variants (PVs) in RAS pathway genes, including Noonan, Costello, and cardiofaciocutaneous syndromes. 12 Together, this group of conditions is referred to as RASopathies. Legius syndrome (LGSS; OMIM 611431) is the RASopathy with the most overlap to NF1. 13 LGSS, inherited in an autosomal dominant pattern, is characterized by multiple CALMs similar to NF1 with or without skinfold freckling, caused by heterozygous PVs in SPRED1 , located on chromosome 15. 13 , 14 Further studies have shown that SPRED1 PVs account for 1% of sporadic cases and 19% of familial cases with pigmentary features of NF1 (CALMs and freckling) only. 14 No individuals with LGSS have developed Lisch nodules, neurofibromas, or other complications of NF1. LGSS could be clinically diagnosed as NF1 using the NIH criteria (50% satisfy the criteria 14 ) but it has a different natural history. The condition is less frequent than NF1 with an estimated birth prevalence of 1/46,000–1/75,000 (4% of individuals followed at a neurofibromatosis clinic), 15 compared to 1/2,000–1/3,000 for NF1. 16

The identification of LGSS highlights an important limitation of the NIH NF1 clinical diagnostic criteria. In addition, other conditions with overlapping phenotypes but distinct natural histories have been identified or better defined (e.g., segmental/mosaic NF1 17 and constitutional mismatch repair deficiency [CMMRD] syndrome 18 ) and new potential criteria for NF1 have been identified (e.g., choroidal anomalies 19 and nevus anemicus 20 ). Finally, NF1 genetic testing has become clinically available with a high detection rate 21 and clinically useful genotype–phenotype correlations have been identified. 22 With sponsorship from the Children’s Tumor Foundation (CTF), an international panel of neurofibromatosis and schwannomatosis experts was assembled in 2017 and charged with reviewing diagnostic criteria for NF1, NF2, and schwannomatosis. The work on NF2 and schwannomatosis is presented in another paper.

MATERIALS AND METHODS

A modified Delphi process was used to reach consensus on revised diagnostic criteria (Supplementary Fig. 1 ). A steering committee (seven experts) reviewed the literature and generated the statements for the two rounds of the Delphi process (data S1, S2, S3, S4, S5, and Supplemental Material and Methods ) regarding potential changes to NF1 diagnostic criteria. The Steering Committee actively sought input from patients, families, and advocates regarding the proposed criteria and the new diagnostic criteria were finalized in January 2020. All clinical images are used with consent from the patient/patient’s parent.

Development of initial proposals to revision of NF1 diagnostic criteria

The steering committee evaluated the literature for clinical and/or genetic features that could reliably identify and distinguish NF1, mosaic NF1, LGSS, and mosaic LGSS. Among the clinical features considered were presence of characteristic tumors such as neurofibromas or gliomas; presence of cutaneous findings including CALMs, skinfold freckling, juvenile xanthogranulomas, 23 and nevus anemicus; 20 presence of characteristic ophthalmologic findings such as Lisch nodules and choroidal abnormalities; 24 presence of characteristic osseous lesions such as sphenoid wing dysplasia, scoliosis, anterolateral bowing of the lower leg, pseudarthrosis; 25 presence of focal areas of signal intensity (FASI) detected by brain magnetic resonance image (MRI), 26 and presence of a family history. Among the molecular features considered were identification of an NF1 and SPRED1 pathogenic variant (PV) in unaffected tissue.

Modified Delphi process

Sixty-seven of 76 NF experts (89%) participated in the first Delphi process by rating the 13 NF1 diagnostic criteria statements (Supplementary Fig. 2 ). There was very high consensus (median score = 10/10) for four proposed changes: revising criteria to clearly define mosaic NF1; adding genetic diagnosis, without implying that genetic testing is required or recommended for diagnosis; replacing thinning of a long bone by anterolateral bowing of the lower limb; and retaining the specified criteria regarding neurofibromas, optic glioma, and Lisch nodules with minor wording changes for the latter two criteria. There was high consensus (median score = 7–9/10) for seven proposed changes: revising the nomenclature to clearly distinguish NF1/LGSS from NF2/schwannomatosis; clarifying which first-degree relatives meet criteria for family history; combining CALMs and skinfold freckling into a single criterion; naming individual long bones commonly affected by congenital bowing and/or pseudarthrosis; and adding juvenile xanthogranulomas, choroidal abnormalities, and dystrophic scoliosis to the revised criteria. There was no consensus (median score = 4–6/10) for two proposed changes: adding nevus anemicus and FASI to the revised criteria.

At the 2018 meeting in New York, working groups developed nine revised statements concerning diagnostic criteria for discussion, including discussion about changing the format of the diagnostic criteria into a tiered system with A and B features. Fifty-eight of 76 NF experts (76%) participated by rating the nine revised statements (Supplementary Fig. 3 ). There was very high consensus (more than 80% agreement) for four proposed changes: adding a new criterion of genetic diagnosis, and recommending genetic testing for patients with segmental clinical findings, for families with two affected siblings and clinically unaffected parents, and for children who meet the criteria based on pigmentary findings alone. There was high consensus (agreement 60–80%) for three proposed changes: considering genetic testing for individuals with multiple bilateral spinal nerve neurofibromas without other features of NF1, requiring use of slit lamp or indirect ophthalmoscopy for identification of Lisch nodules, and including choroidal abnormalities as a diagnostic criterion. Finally, there was more agreement to retain the current format as opposed to selecting A/B criteria (71% agreement). In total, 74/76 NF experts (97%) were involved in the revision process (data S4).

Nine of 12 (75%) non-NF specialists responded to the survey (data S5) and strongly agreed with the proposed changes to the NF1 diagnostic criteria. The experts agreed that nonspecialists would be able to use the revised criteria.

Proposed new diagnostic criteria for NF1 and LGSS

Ultimately, consensus was reached on the minimal clinical and genetic criteria for diagnosing NF1 and LGSS. Final recommendations for NF1 are listed in Table 1 and for LGSS in Table 2 .

Proposed diagnostic criteria for mosaic NF1 and mosaic LGSS

The final recommendations for diagnostic criteria for mosaic NF1 are listed in Table 3 , and for mosaic LGSS in Table 4 . The criteria allow for both a molecular and clinical diagnosis of mosaic NF1 and mosaic LGSS, although mosaic LGSS is very rare. 27

In this paper, the results of an international, multispecialty effort to revise the diagnostic criteria for NF1 and LGSS are presented. The process extended over three years, reflecting the commitment to involve a wide array of specialists, nonspecialists, patient advocacy groups, patients, and family members into the process. The goal was to incorporate clinical and genetic discoveries made since the initial consensus conference into the revised criteria. We used a modified Delphi approach to reach maximum consensus among stakeholders with the understanding that complete agreement was not a reasonable goal. A recurring theme during the process was the challenge of balancing the expectations of different medical specialties for diagnostic criteria. For example, some specialists emphasized the importance of diagnosing children at a young age to screen for important medical features (i.e., high sensitivity) while others emphasized the need to avoid potential misdiagnosis (i.e., high specificity). Ultimately, the group attempted to choose criteria that balanced the needs of high sensitivity and specificity. The Delphi process worked well in both reaching consensus in some areas and highlighting the issues with varying opinion for discussion at the meeting in New York.

Pigmentary findings alone are not specific for NF1

The current clinical diagnostic criteria have low sensitivity in children since diagnostic signs appear progressively over time. 1 Participants considered, but did not ultimately recommend, combining pigmentary criteria (CALMs/skinfold freckling) into a single criterion. Although combining would mean patients with LGSS would not meet the criteria for NF1, it could potentially delay diagnosis in children without access to molecular testing. To alert clinicians to the differential diagnosis, an asterisk was added to the diagnostic criteria for NF1 stating that if only pigmentary findings are present, clinicians should consider alternative diagnoses, including, but not limited to, LGSS, Noonan syndrome with multiple lentigines, and CMMRD.

The challenge of distinguishing NF1 from LGSS based on pigmentary findings was demonstrated by Messiaen et al. 14 who studied an anonymous cohort of 2,432 individuals referred for NF1 molecular diagnosis. An NF1 PV was identified in 1,114 individuals and a SPRED1 PV in 33 (2.9% of PV-positive individuals). In the subset of 1,098 individuals (45%) younger than seven years of age, the NIH criteria showed sensitivity of 58.2% and specificity of 88.6% for the diagnosis of a PV in NF1 or SPRED1 (groups lumped together). The positive predictive value (PPV) for the NIH criteria was 80.5%, and the negative predictive value (NPV) 71.5%. At ≥7 years, the sensitivity of the NIH criteria increased to 85.3%, specificity was 74.3%, PPV 75.8% and NPV 84.3%. To increase the diagnostic rate in the age group <7 years and in the subgroup with only CALMs and skinfold freckling (with or without a family history) and no other clinical criteria, molecular diagnosis could be considered to confirm a diagnosis of NF1 or LGSS.

Clinicians should attend closely to typical pigmentary findings to help distinguish between NF1 and mosaic NF1. Participants recommended adding a clarification to the revised criteria indicating that at least one of the two pigmentary findings (CALM/freckling) should be bilateral. This should help reduce, but will not completely eliminate, the misdiagnosis of NF1 in an individual with segmental or generalized mosaic NF1. However, it highlights the possibility of mosaic NF1 when pigmentary findings are localized to one side of the body. In addition, CALMs or freckling may not be seen in older individuals, in those with many cutaneous neurofibromas, or in individuals with spinal neurofibromatosis. 28 The diagnosis is confirmed by genetic testing or the finding of Lisch nodules/choroidal anomalies.

Choroidal abnormalities

Choroidal abnormalities were added as an ophthalmologic criterion because of the high specificity and sensitivity for NF1 19 , 29 and for the ability to differentiate NF1 from LGSS. 19 In the revised diagnostic criteria, either Lisch nodules or choroidal abnormalities is sufficient for this criterion; choroidal abnormalities were not included as a separate criterion since isolated ophthalmologic findings, even if bilateral (e.g., an individual with only two Lisch nodules and two choroidal abnormalities) are likely to reflect mosaic NF1 rather than constitutional NF1.

Affected siblings and offspring no longer qualify as criterion for NF1

Participants recommended changing “A first-degree relative (parent, sibling, or offspring) with NF1 by the above criteria” to “a parent with NF1 by the above criteria." Sibling was deleted because if only siblings are affected, one should consider a diagnosis of CMMRD. 30 Offspring was omitted because if an adult person only has one criterion aside from an offspring fulfilling diagnostic criteria, then mosaic NF1 should be suspected in this individual. Having a parent with NF1 by the above criteria will correctly diagnose most offspring presenting with one of the other diagnostic criteria as having NF1, although, occasional co-occurrence of more than one distinct NF1/SPRED1 pathogenic variant in a family has been reported. 31

Genetic concepts of importance for revised diagnostic criteria

Criteria for pathogenicity of variants.

Per recommendations by the Human Genome Variation Society (HGVS), the term “mutation” has been replaced by the more neutral term “variant.” 32 These variants and interpretation of variants are classified following criteria as established by their professional society. The standards and guidelines developed by the American College of Medical Genetics and Genomics (ACMG), the Association for Molecular Pathology (AMP), and the College of American Pathologists (CAP) have now been implemented widely in laboratories offering clinical molecular testing. 33 Variants can be classified as benign (B), likely benign (LB), of uncertain clinical significance (VUS), likely pathogenic (LP), or pathogenic (P). 33 This framework improves the interlaboratory consistency of classification and allows for re classification of a variant once more data have become available. The term likely pathogenic refers to those variants considered to have greater than 90% certainty to be disease causing. It is expected, as our understanding of NF1 genetic variants increases, that the algorithms to classify the variants will further be improved and refined, which is especially important for those variants currently classified as VUS.

Pathogenic NF1 variants

NF1 PVs can be located across the entire coding region as well as across noncoding regions and include microdeletions spanning the NF1 gene and multiple flanking genes; smaller intragenic copy-number variants; frameshift, nonsense and missense variants; splice site, exonic, and deep intronic variants affecting normal splicing; in-frame deletions or duplications of one to several codons; variants affecting the translational start codon; complex insertion/deletion variants; (balanced) translocations; and Alu/LINE insertions. 34

A comprehensive approach, using dosage analysis to detect copy-number variants, and DNA -based sequencing, detects a PV in ~90% of classic (i.e., having pigmentary features as well as neurofibromas) well characterized nonfounder (i.e., second generation) NF1 patients. Detection rate and specificity is increased to 95–97% when an RNA-based sequencing approach, in addition to dosage analysis, is applied. 34 Detection rates will vary in oligosymptomatic individuals or individuals with atypical presentation. 14 , 35 Since genetic testing for NF1 PV is heavily biased toward individuals with some aspect of the known NF1 phenotype we might be missing individuals with very atypical presentations. No NF1 inactivating variants have been reported in the alternatively spliced exons of NF1 because these might be associated with no or a different phenotype. Scrutiny of genome or exome sequencing data in large cohorts of carefully phenotyped patients might shed light on this issue.

NF1 PV alone is not sufficient for diagnosis

Diagnosis of NF1 is confirmed when an NF1 PV is identified in an individual/fetus having either one or more of the other diagnostic criteria fulfilled. As panel testing by next-generation sequencing and exome/genome sequencing analysis is ordered with increasing frequency in individuals with a variable set of clinical features, some individuals have been found to carry an NF1 variant (P, LP,VUS) in unaffected tissue such as blood, although NF1 was not clinically suspected. NF1 experts agreed that identification of an NF1 variant alone does not suffice to make a diagnosis of NF1 but does require further clinical and genetic evaluation: the variant must be confirmed as pathogenic using an orthogonal method; further genetic analysis is required to verify if the variant is present as a constitutional (germline), mosaic (which may result in a mild phenotype), or somatic variant (e.g., due to clonal expansion in the hematopoietic stem and progenitor cells of indeterminate potential or secondary to therapy, hematological malignancy, premalignancy, or circulating tumor cells 36 ). Since only one other criterion is required for a diagnosis of NF1 the NF1 variant has to be pathogenic to fulfill the second criterion for diagnosis. Including likely pathogenic variants in the diagnostic criteria will unnecessarily reduce specificity.

Somatic second hit NF1 PVs are typically identified in every NF1 -associated tumor such as cutaneous and plexiform neurofibromas as well as in tissues from distinctive nontumor lesions such as CALMs, 37 thereby resulting in biallelic NF1 activation (Supplementary Fig. 4 ).

Genetic mosaicism: mechanism, phenotypes, and implications for genetic testing

As many as 30–50% of NF1 patients are sporadic or founder patients, meaning they did not inherit the disorder from an affected parent. 1 , 2 , 8 It is important to raise awareness that a proportion of founder patients will have the disorder due to an NF1 variant acquired in a specific cell after fertilization.

These mosaic patients therefore carry the first hit NF1 variant only in a subpopulation, as opposed to all body cells, unlike in patients with constitutional NF1 where the NF1 variant is present in the fertilized egg. The risk for transmission to the next generation is <50% for an individual with mosaic NF1; however, if the NF1 variant is transmitted to the next generation, offspring will carry the variant in the germline and the overall clinical presentation will usually be more severe. Depending on the timing and types of progenitor cells affected externally visible features may include pigmentary features only, cutaneous or plexiform neurofibromas only, or a combination of both, and affected body regions may range from multiple body regions crossing the midline that may resemble a generalized phenotype, to a single segment of the body not crossing the midline. 38 Pure gonadal mosaicism, with the somatic NF1 PVs present only in the gonads, is, however, rare. 39

Mosaic NF1 in a patient is confirmed when an individual with features of NF1 carries a heterozygous NF1 PV in an unaffected tissue such as blood but in significantly less than 100% of cells (variant allele fraction [VAF] < 50%). Mosaic NF1 is also confirmed if an identical first hit pathogenic NF1 variant is identified in two or more anatomically unrelated affected lesions in the absence of this PV in unaffected tissue such as blood.

Detection of the causal NF1 PVs in individuals with a mosaic/segmental phenotype requires special attention to (1) the sensitivity of the technology used to detect variants, as well as (2) the type of cells to be analyzed in affected tissue if the variant is not detectable in blood, i.e., melanocytes (but not keratinocytes or fibroblasts) from CALMs 37 or Schwann cells from the cutaneous or plexiform neurofibromas. 40

It is the responsibility of the laboratories to define and report the criteria used for the orthogonal confirmation of the variants as either constitutional/germline or mosaic.

Orthopedic criteria

In the 1987 criteria, the orthopedic criteria included “thinning of the long bone cortex with or without pseudarthrosis.” In 2007, rewording of this criterion was suggested 25 since thinning of long bone cortex is not the primary lesion. Rather, most children present with anterolateral bowing of the lower limb and on X-ray have medullary canal narrowing and cortical thickening at the apex of the curve in the tibia and/or fibula. 25 The bowing may or may not progress to fracture and pseudarthrosis. Other long bones have been reported with pseudarthrosis but this is rare.

Proposed features that were not included in the revised criteria

Some possible diagnostic criteria were not incorporated into the revised criteria because of insufficient data on specificity and/or sensitivity or other reasons. These criteria include FASI detected by MRI (given concerns about their specificity and their disappearance over time in some patients, the potential complications of anesthesia in children in scans done for diagnostic evaluation), nevus anemicus, and juvenile xanthogranuloma (Supplementary Fig. 5 ; both features difficult to diagnose clinically for nondermatologists and xanthogranuloma only present transiently). In addition, participants decided not to include a comment on different possible locations of skinfold freckling or comments on spinal neurofibromas. Moving forward, it will be important to collect prospective data on the diagnostic sensitivity and specificity of these clinical findings for diagnosis.

Using the revised diagnostic criteria

It should be emphasized that clinicians do not necessarily need to search for each of the clinical features described in the criteria. For example, it is not recommended to perform biopsies or examinations under general anesthesia only to confirm diagnostic criteria. In the absence of molecular testing, serial observation will confirm whether NF1 is present in most affected individuals. In addition, one should be cautious to diagnose NF1 if neither CALMs nor neurofibromas are present, because that would be suggestive of mosaic NF1 or another unusual situation.

Revising the nomenclature of NF1

The term “neurofibromatosis” was derived from “neurofibroma,” the term used by von Recklinghausen to describe the benign nerve sheath tumor that is the hallmark of NF1. 2 In 2007, an NF1-like syndrome was linked to SPRED1 PVs. 13 Subsequent authors were concerned that any reference to NF1 in the name may confuse parents and proposed the eponymous name Legius syndrome, which has been widely adopted. During the discussions, we considered having it as a NF1 subtype but, in the absence of neurofibromas, it is inappropriate to consider it a type of neurofibromatosis.

The aim of the revision process was to help professionals distinguish between NF1 and LGSS early in life. Experts did not endorse renaming NF1 since virtually all individuals with NF1 develop neurofibromas and since the name is established by use and history. Ultimately for the syndrome associated with SPRED1 , experts agreed that nomenclature based on nosology or pathogenesis did not improve understanding of the condition and suggested retaining the name Legius syndrome since the term is established and not misleading. We understand that a more appropriate nomenclature is needed to rename neurofibromatosis type 1, Legius syndrome, neurofibromatosis type 2, and schwannomatosis. This will be one of the future tasks of the steering committee.

Continued revision of the diagnostic criteria

The proposed criteria for diagnosis of NF1 and LGSS represent the first coordinated attempt by our community to update the diagnostic criteria since 1987. Given the challenge in organizing the input of multiple experts, patients, and advocacy groups in this process, it is unlikely that a major revision to the criteria will be proposed in the near future. However, it is likely that refinement of these diagnostic criteria will be necessary in the future. For this reason, the CTF will sponsor an ongoing initiative to evaluate and recommend proposed changes to the diagnostic criteria for NF1 and LGSS. We anticipate that this group of experts will meet periodically to solicit input from the community, to review data relevant to diagnostic criteria, and will publish its consensus recommendations periodically for use by the larger community.

Data availability

The data from the modified Delphi process are available in the supplementary data and figure section.

Gutmann, D. H., Ferner, R. E., Listernick, R. H., Korf, B. R., Wolters, P. L. & Johnson, K. J. Neurofibromatosis type 1. Nat. Rev. Dis. Primers. 3 , 17004 (2017).

Article Google Scholar

Riccardi, V. M. Von Recklinghausen neurofibromatosis. N. Engl. J. Med. 305 , 1617–1627 (1981).

Article CAS Google Scholar

Uusitalo, E. et al. Distinctive cancer associations in patients with neurofibromatosis type 1. J. Clin. Oncol. 34 , 1978–1986 (2016).

Neurofibromatosis conference statement. National Institutes of Health Consensus Development Conference. Arch. Neurol. 45 , 575–578 (1988).

Riccardi, V. M. Neurofibromatosis: clinical heterogeneity. Curr. Probl. Cancer. 7 , 1–34 (1982).

Barker, D. et al. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science. 236 , 1100–1102 (1987).

Seizinger, B. R., Martuza, R. L. & Gusella, J. F. Loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma. Nature. 322 , 644–647 (1986).

Gutmann, D. H. et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 278 , 51–57 (1997).

Viskochil, D. et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 62 , 187–192 (1990).

Wallace, M. R. et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 249 , 181–186 (1990).

Gross, A. M. et al. Selumetinib in children with inoperable plexiform neurofibromas. N. Engl. J. Med. 382 , 1430–1442 (2020).

Rauen, K. A. The RASopathies. Annu. Rev. Genomics Hum. Genet. 14 , 355–369 (2013).

Brems, H. et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat. Genet. 39 , 1120–1126 (2007).

Messiaen, L. et al. Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. JAMA. 302 , 2111–2118 (2009).

Pasmant, E. et al. Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations? Eur. J. Hum. Genet. 23 , 596–601 (2015).

Kallionpaa, R. A., Uusitalo, E., Leppavirta, J., Poyhonen, M., Peltonen, S. & Peltonen, J. Prevalence of neurofibromatosis type 1 in the Finnish population. Genet. Med. 20 , 1082–1086 (2018).

Ruggieri, M. & Huson, S. M. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology. 56 , 1433–1443 (2001).

Wimmer, K., Rosenbaum, T. & Messiaen, L. Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1. Clin. Genet. 91 , 507–519 (2017).

Cassiman, C. et al. Choroidal abnormalities in cafe-au-lait syndromes: a new differential diagnostic tool? Clin. Genet. 91 , 529–535 (2017).

Tadini, G., Brena, M., Pezzani, L., Gelmetti, C., Santagada, F. & Boldrini, M. P. Anemic nevus in neurofibromatosis type 1. Dermatology. 226 , 115–118 (2013).

Messiaen, L. M. et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum. Mutat. 15 , 541–555 (2000).

Koczkowska, M. et al. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype–phenotype study in neurofibromatosis type 1. Hum. Mutat. 41 , 299–315 (2020).

Fenot, M., Stalder, J. F. & Barbarot, S. Juvenile xanthogranulomas are highly prevalent but transient in young children with neurofibromatosis type 1. J. Am. Acad. Dermatol. 71 , 389–390 (2014).

Viola, F. et al. Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology. 119 , 369–375 (2012).

Stevenson, D. A. et al. The use of anterolateral bowing of the lower leg in the diagnostic criteria for neurofibromatosis type 1. Genet. Med. 9 , 409–412 (2007).

DeBella, K., Poskitt, K., Szudek, J. & Friedman, J. M. Use of “unidentified bright objects” on MRI for diagnosis of neurofibromatosis 1 in children. Neurology. 54 , 1646–1651 (2000).

Jobling, R. K. et al. Mosaicism for a SPRED1 deletion revealed in a patient with clinically suspected mosaic neurofibromatosis. Br. J. Dermatol. 176 , 1077–1078 (2017).

Ruggieri, M. et al. The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin. Genet. 87 , 401–410 (2015).

Vagge, A. et al. Choroidal abnormalities in neurofibromatosis type 1 detected by near-infrared reflectance imaging in paediatric population. Acta Ophthalmol. 93 , e667–671 (2015).

Suerink, M. et al. Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy. J. Med. Genet. 56 , 53–62 (2019).

Upadhyaya, M. et al. Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1. Hum. Genet. 112 , 12–17 (2003).

den Dunnen, J. T. et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum. Mutat. 37 , 564–569 (2016).

Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17 , 405–424 (2015).

Messiaen, L. in Multidiscipilinary Approach to Neurofibromatosis 1. (eds Tadini, G., Legius, E. & Brems, H.). Molecular diagnosis of NF1 (Springer, Cham, Switzerland, 2020).

Castellanos, E. et al. Mutational spectrum by phenotype: panel-based NGS testing of patients with clinical suspicion of RASopathy and children with multiple cafe-au-lait macules. Clin. Genet. 97 , 264–275 (2020).

Shlush, L. I. Age-related clonal hematopoiesis. Blood. 131 , 496–504 (2018).

De Schepper, S., Maertens, O., Callens, T., Naeyaert, J. M., Lambert, J. & Messiaen, L. Somatic mutation analysis in NF1 cafe au lait spots reveals two NF1 hits in the melanocytes. J. Invest. Dermatol. 128 , 1050–1053 (2008).

Messiaen, L. & Xie, J. in Neurofibromatosis Type 1. (ed Cooper, M.U.D.) NF1 germline and somatic mosaicism (Springer, Berlin, 2012).

Lazaro, C., Ravella, A., Gaona, A., Volpini, V. & Estivill, X. Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N. Engl. J. Med. 331 , 1403–1407 (1994).

Serra, E. et al. Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Hum. Mol. Genet. 9 , 3055–3064 (2000).

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Acknowledgements

The authors particularly thank the Children’s Tumor Foundation and Annette Bakker for supporting the revision process both financially and administratively. The authors would also like to thank the patients and foundations, particularly the members of the NF Collective for their attendance at informational webinars and for providing critical input. D.G.E. is supported by the all Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007).

Author information

These authors contributed equally: Eric Legius, Ludwine Messiaen, Pierre Wolkenstein, Patrice Pancza, Susan M. Huson, D. Gareth Evans, Scott R. Plotkin.

Authors and Affiliations

Department of Human Genetics, KU Leuven and University Hospital, Leuven, Belgium

Eric Legius

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA

Ludwine Messiaen, Bruce R. Korf & Alicia Gomes

Assistance Publique-Hôpital Paris (AP-HP), Hôpital Henri-Mondor, UPEC, Service de Dermatologie, Créteil, France

Pierre Wolkenstein

Children’s Tumor Foundation, New York, NY, USA

Patrice Pancza

Division of Ophthalmology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Robert A. Avery

Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia and University of Sydney, Sydney, Australia

Yemima Berman

Johns Hopkins Comprehensive Neurofibromatosis Center, Baltimore, MD, USA

Jaishri Blakeley

Department of Clinical Genomics, Mayo Clinic College of Medicine, Rochester, MN, USA

Dusica Babovic-Vuksanovic

Department of Pathology, Universidade Federal Fluminense, Niteroi, Brasil

Karin Soares Cunha

Neurology, Guy’s and St. Thomas’ Hospital and NHS Trust, London, UK

Rosalie Ferner

Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Michael J. Fisher

Medical Genetics, University of British Columbia, Vancouver, BC, Canada

Jan M. Friedman

Neurology, Washington University, St. Louis, MO, USA

David H. Gutmann

Institute of Human Genetics, University of Ulm, Ulm, Germany

Hildegard Kehrer-Sawatzki

Neurology, University Hospital of Hamburg-Eppendorf, Hamburg, Germany

Victor-Felix Mautner & Victor Mautner

Dermatology, University of Turku and Turku University Hospital, Turku, Finland

Sirkku Peltonen

Department of Dermatology and Venereology, University of Gothenburg, Gothenburg, Sweden

Pediatrics, University of California Davis, Sacramento, CA, USA

Katherine A. Rauen

The Neurofibromatosis Institute, La Crescenta, CA, USA

Vincent Riccardi

Medical Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Elizabeth Schorry

Neuropathology, Massachusetts General Hospital, Boston, MA, USA

Anat Stemmer-Rachamimov

Medical Genetics, Stanford University, Stanford, CA, USA

David A. Stevenson & David Stevenson

Pediatric Dermatology, University of Milan, Milan, Italy

Gianluca Tadini

Department of Neurology, Boston Children’s Hospital, Boston, MA, USA

Nicole J. Ullrich

Medical Genetics, University of Utah, Salt Lake City, UT, USA

David Viskochil

Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria

Katharina Wimmer

NYU Langone Health, New York, NY, USA

Kaleb Yohay

Clinical Genetics, (Formerly) Manchester Center for Genomic Medicine, Manchester University Hospitals, NHS Foundation Trust, Manchester, UK

Susan M. Huson

Department of Genomic Medicine, St Mary’s Hospital, Manchester Academic Health Sciences Centre (MAHSC), Division of Evolution and Genomic Science, University of Manchester, Manchester, UK

Miriam J. Smith & D. Gareth Evans

Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA

Justin T. Jordan, Vanessa L. Merker & Scott R. Plotkin

Department of Neurology, Maastricht University Medical Center, Maastricht, Netherlands

Monique Anten

Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

Arthur Aylsworth

Department of Human Development and Health, University of Southampton, Southampton, UK

Diana Baralle

Centre Hospitalier Universitaire de Nantes, Nantes, France

Sebastien Barbarot

Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

Fred Barker II

Clalit Research Institute, & Schneider Children’s Medical Center, Ramat-Gan, Israel

Shay Ben-Shachar

Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA

Amanda Bergner

Department of Dermatology, Centre Hospitalier Universitaire de Montpellier, Montpellier, France

Didier Bessis

Department of Clinical Genetics, Hospital Universitari Germans Trias I Pujol, Badalona, Spain

Ignacio Blanco

Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium

Catherine Cassiman

Department of Neurosurgery, Hospital de Clinicas Gral San Martin, San Martin, Argentina

Patricia Ciavarelli

Department of Clinical Genetics, University of Padova, Padova, Italy

Maurizio Clementi & Eva Trevisson

Department of Genetics, University Hospital Rouen, Rouen, France

Thierry Frébourg

Department of Head and Neck Surgery, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, CA, USA

Marco Giovannini

Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

Dorothy Halliday

Department of Ophthalmology, King’s College London, London, UK

Chris Hammond

Institute of Translational and Stratified Medicine, Peninsula Medical School, University of Plymouth, Plymouth, UK

C. O. Hanemann

Department of Genetics, St George’s University Hospitals, London, UK

Helen Hanson

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

Arvid Heiberg

Department of Dermatology, University Hospital Rouen, Rouen, France

Pascal Joly

Department of Neurosurgery, Hôpital Pitié Salpêtrière, Paris, France

Michel Kalamarides

Department of Pediatrics and Otolaryngology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Matthias Karajannis

Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA

Daniela Kroshinsky

Department of Dermatology, Hospital Aleman, Buenos Aires, Argentina

Margarita Larralde

Institut Català d’Oncologia (ICO-IDIBELL-CIBERONC), Hospitalet de Llobregat, Barcelona, Spain

Conxi Lázaro

Department of Dermatology, University of Texas, Southwestern, Dallas, TX, USA

Department of Neurosurgery and Otolaryngology, Mayo Clinic, Rochester, MN, USA

Michael Link

Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA

Robert Listernick

Bend, OR, USA

Mia MacCollin

Department of Neurosurgery, Alder Hey Children’s Hospital NHS, Liverpool, UK

Conor Mallucci

Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

Christopher Moertel

Cancer Genetics, Massachusetts General Hospital, Boston, MA, USA

Amy Mueller

Lee Kong Chian School of medicine, Nanyang Technological University, Singapore and Cancer Genetics Service, National Cancer Center, Singapore, Singapore

Joanne Ngeow

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands

Rianne Oostenbrink

The Brain Tumor Institute, Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, Washington, DC, USA

Roger Packer

Department of Experimental and Clinical Biomedical Science “Mario Serio”, University of Florence, Florence, Italy

Department of Neurology, John Radcliff Hospital, Oxford, UK

Allyson Parry

Institute of Biomedicine, University of Turku and Turku University Hospital, Turku, Finland

Juha Peltonen

National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA

Dominique Pichard

Department of Medical Genetics, University Hospital Ghent, Ghent, Belgium

Bruce Poppe

School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil

Nilton Rezende

Department of Neurology, Children’s Hospital Los Angeles, Los Angeles, CA, USA

Luiz Oswaldo Rodrigues & Tena Rosser

Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy

Martino Ruggieri

The Institute for Health Science Research Germans Trias i Pujol (IGTP), Barcelona, Spain

Eduard Serra

Center of Medical Genetics, Munich, Germany

Verena Steinke-Lange

Division of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, UK

Stavros Michael Stivaros

Clinical Genetics Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

Department of Pediatrics, University Hospital Leuven, Leuven, Belgium

Jaan Toelen

Department of Pediatrics and Neurology, University of Chicago Medicine, Chicago, IL, USA

James Tonsgard

Institute of Cancer Genetics, Cardiff University, Cardiff, UK

Meena Upadhyaya

Department of Pediatric Oncology, Hacettepe University, Ankara, Turkey

Department of Clinical Genetics, Children’s Hospital Westmead, Sydney, Australia

Meredith Wilson

Shanghai Ninth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shangai, China

Princess Margaret Cancer Centre, Toronto Western Hospital, Toronto, ON, Canada

Gelareh Zadeh

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International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC)

, Ludwine Messiaen
, Pierre Wolkenstein
, Patrice Pancza
, Susan M. Huson
, D. Gareth Evans
, Scott R. Plotkin
, Robert A. Avery
, Dusica Babovic-Vuksanovic
, Yemima Berman
, Jaishri Blakeley
, Karin Soares Cunha
, Rosalie Ferner
, Michael J. Fisher
, Jan M. Friedman
, Alicia Gomes
, David H. Gutmann
, Justin T. Jordan
, Hildegard Kehrer-Sawatzki
, Bruce R. Korf
, Victor Mautner
, Vanessa L. Merker
, Sirkku Peltonen
, Katherine A. Rauen
, Vincent Riccardi
, Elizabeth Schorry
, Miriam J. Smith
, Anat Stemmer-Rachamimov
, David Stevenson
, Gianluca Tadini
, Nicole J. Ullrich
, David Viskochil
, Katharina Wimmer
, Kaleb Yohay
, Monique Anten
, Arthur Aylsworth
, Diana Baralle
, Sebastien Barbarot
, Fred Barker II
, Shay Ben-Shachar
, Amanda Bergner
, Didier Bessis
, Ignacio Blanco
, Catherine Cassiman
, Patricia Ciavarelli
, Maurizio Clementi
, Thierry Frébourg
, Marco Giovannini
, Dorothy Halliday
, Chris Hammond
, C. O. Hanemann
, Helen Hanson
, Arvid Heiberg
, Pascal Joly
, Michel Kalamarides
, Matthias Karajannis
, Daniela Kroshinsky
, Margarita Larralde
, Conxi Lázaro
, Michael Link
, Robert Listernick
, Mia MacCollin
, Conor Mallucci
, Christopher Moertel
, Amy Mueller
, Joanne Ngeow
, Rianne Oostenbrink
, Roger Packer
, Laura Papi
, Allyson Parry
, Juha Peltonen
, Dominique Pichard
, Bruce Poppe
, Nilton Rezende
, Luiz Oswaldo Rodrigues
, Tena Rosser
, Martino Ruggieri
, Eduard Serra
, Verena Steinke-Lange
, Stavros Michael Stivaros
, Amy Taylor
, Jaan Toelen
, James Tonsgard
, Eva Trevisson
, Meena Upadhyaya
, Ali Varan
, Meredith Wilson
& Gelareh Zadeh

Contributions

Conceptualization: E.L., L.M., P.W., P.P., R.A.A., Y.B., J.B., D.V.-B., K.S.C., R.F., M.J.F., J.M.F., D.H.G., H.K.S., B.R.K., V.F.-M., S.P., K.A.R., V.R., E.S., A.S.R., D.A.S., G.L., N.J.U., D.V., K.W., K.Y., I.N.F.D.C., S.M.H., D.G.E., S.R.P. Data curation: E.L. Formal analysis: E.L. Funding acquisition: P.P. Investigation: E.L., L.M., P.W., S.M.H., D.G.E., S.R.P. Methodology: E.L., L.M., P.W., S.M.H., D.G.E., S.R.P. Project administration: E.L., L.M., P.W., S.M.H., D.G.E., S.R.P., P.P. Visualization: E.L., L.M., P.W., S.M.H., D.G.E., S.R.P. Writing—original draft: E.L., L.M., P.W., S.M.H., D.G.E., S.R.P. Writing—review & editing: E.L., L.M., P.W., P.P., R.A.A., Y.B., J.B., D.V.-B., K.S.C., R.F., M.J.F., J.M.F., D.H.G., H.K.S., B.R.K., V.F.-M., S.P., K.A.R., V.R., E.S., A.S.R., D.A.S., G.L., N.J.U., D.V., K.W., K.Y., S.M.H., D.G.E., S.R.P.

Corresponding author

Correspondence to Eric Legius .

Ethics declarations

Ethics declaration.

All clinical images are used with consent from the patient/patient’s parent.

Competing interests

D.V.-B. is a scientific advisor for AstraZeneca Pharmaceuticals, LP, and receives grant support for the Department of Defense and SpringWorks Therapeutics. J.B. and M.J.F. are members of the Children’s Tumor Foundation Medical Advisory Committee. D.G.E., E.L., V.-F.M., S.P. are members of the Children’s Tumor Foundation Clinical Care Advisory Board-Europe. R.F. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board-Europe and is a medical advisor for AstraZeneca. J.M.F. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board. B.R.K. is a member of the Children’s Tumor Foundation Medical Advisory Committee (Chair) and is on the medical advisory boards of Genome Medicine and Infixion Bioscience. L.M. is director of the Medical Genomics Laboratory at University of Alabama, Birmingham, which specializes in genetic testing for all forms of the neurofibromatoses. P.P. is employed by the Children’s Tumor Foundation. S.R.P. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board (Chair, US) and Europe, and is co-founder of NFlection Therapeutics; is consultant for AstraZeneca and SonalaSense. E.S. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board and receives Department of Defense funding as a site for NF Clinical Trials Consortium. N.J.U. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board and serves on the board of NF Northeast. D.V. is member of the Children’s Tumor Foundation and Medical Advisory Committee, is a member of the AstraZeneca speakers bureau, and is on Sanofi-Genzyme–MPS Board of Advisors. P.W. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board–Europe (Chair). K.Y. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board; received a consultant fee from AstraZeneca Pharmaceuticals; is on the Scientific Advisory Board for Infixion Bioscience; and is a member of the Programmatic Review Committee for the Department of Defense, Congressionally Directed Medical Research Program, NF Research Program. The other authors declare no competing interests.

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Legius, E., Messiaen, L., Wolkenstein, P. et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med 23 , 1506–1513 (2021). https://doi.org/10.1038/s41436-021-01170-5

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Published : 19 May 2021

Issue Date : August 2021

DOI : https://doi.org/10.1038/s41436-021-01170-5

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Cancer and Neurofibromatosis Type 1—Confirming What We Knew and Telling Us Something New

1 Gerald Bronfman Department of Oncology, McGill University, Cedars Cancer Center, McGill University Health Centre, Montreal, Quebec, Canada
Original Investigation Cancer Prevalence in Patients With Neurofibromatosis Type 1 vs General Population Jace P. Landry, MD; Kelsey L. Schertz, BS; Yi-Ju Chiang, MSPH; Angela D. Bhalla, PhD; Min Yi, MD, PhD; Emily Z. Keung, MD; Christopher P. Scally, MD; Barry W. Feig, MD; Kelly K. Hunt, MD; Christina L. Roland, MD; Ashleigh Guadagnolo, MD; Andrew J. Bishop, MD; Alexander J. Lazar, MD, PhD; John M. Slopis, MD, MPH; Ian E. McCutcheon, MD; Keila E. Torres, MD, PhD JAMA Network Open

It has been known for decades that patients with neurofibromatosis type 1 (NF1) are at an increased risk of tumors, both benign and malignant. 1 Tumorigenesis is caused by activation of the RAS pathway by an aberrant neurofibromin, itself encoded by an altered NF1 gene. 2 Patients with NF1 also have a life expectancy 10 to 15 years shorter than the general population. 3 Many articles have documented the effects of NF1 on cancer in terms of epidemiological and clinical features, resulting in recommendations for screening and treatment of affected patients. However, the association of these measures with outcomes is unclear because the baseline risk of cancer in patients with NF1 is not well known, given the relatively small population size in many of these reports. Another area of uncertainty is the types of tumors that can be seen in patients with NF1. The article by Landry et al 4 helps to fill some of these knowledge gaps.

The study by Landry et al 4 confirms previous notions about cancer in patients with NF1. It also shows that the variety of associated malignant neoplasms is broader than previously suspected and that the outcomes of these cancers are worse than those in the general population. Of particular note is the discovery that multiple sarcomas, in addition to malignant peripheral nerve sheath tumors and gastrointestinal stromal tumors, are associated with NF1, especially undifferentiated pleomorphic sarcoma, genitourinary embryonal rhabdomyosarcoma, and osteosarcoma, and that ovarian cancer, melanoma, and neuroendocrine tumors should also be on the list of NF1-associated malignant neoplasms. It is unclear whether the poorer prognosis of NF1-associated cancers is because of delayed diagnosis or a different pathogenesis from their sporadic counterparts, but this worrisome outcome should trigger special vigilance from clinicians caring for patients with NF1. Such important findings by Landry et al 4 were made possible by their judicious analysis of a large and well-kept single-institution database spanning 35 years. The results of this analysis were compared with the data from the Surveillance, Epidemiology, and End Results Cancer Statistics Review and Participants Database. This is a remarkable effort for which the authors should be congratulated.

Where do we go from here? From a clinical standpoint, questions remain about the appropriate age and methods for screening patients with NF1 for a range of malignant neoplasms. Just as importantly, a high index of suspicion of cancer is appropriate in any patient with NF1 presenting with symptoms or signs different or worsening from baseline. The clinical approach to NF1-associated cancers is also challenging. Their reported poorer outcome suggests that an aggressive management is justified, although this finding would ideally need to be confirmed by multi-institutional studies comparing patients with NF1-associated cancer with well-matched controls. It would also require extensive data mining from large reference centers.

From a research standpoint, data are emerging about specific variant-phenotype correlations 5 , 6 ; there is no doubt that, when validated, they will refine screening in clinical practice. However, such information is scant, and therefore, general guidelines should remain in place at present, with updates as our knowledge progresses. Efforts should continue to investigate the molecular pathogenic mechanisms involved in NF1-associated cancers to identify possible biologically targeted therapies. 2 Discoveries in NF1 molecular pathogenesis could also lead to cancer prevention and restore the longevity of affected patients to that of the general population.

In summary, reading the article by Landry et al 4 on NF1 and cancers brings us information we want from a good study. It confirms what we knew, tells us something new, and potentially informs our practice.

Published: March 18, 2021. doi:10.1001/jamanetworkopen.2021.1061

Corresponding Author: Thierry Alcindor, MD, MSc, Gerald Bronfman Department of Oncology, McGill University, Cedars Cancer Center, McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada ( [email protected] ).

Conflict of Interest Disclosures: None reported.

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Alcindor T. Cancer and Neurofibromatosis Type 1—Confirming What We Knew and Telling Us Something New. JAMA Netw Open. 2021;4(3):e211061. doi:10.1001/jamanetworkopen.2021.1061

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A new era for myelin research in Neurofibromatosis type 1

Affiliations.

1 Department of Pediatrics, The Cure Starts Now Brain Tumor Center, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
2 Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA.
3 Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, Texas, USA.
PMID: 37382486
PMCID: PMC10592420 (available on 2024-12-01 )
DOI: 10.1002/glia.24432

Evidence for myelin regulating higher-order brain function and disease is rapidly accumulating; however, defining cellular/molecular mechanisms remains challenging partially due to the dynamic brain physiology involving deep changes during development, aging, and in response to learning and disease. Furthermore, as the etiology of most neurological conditions remains obscure, most research models focus on mimicking symptoms, which limits understanding of their molecular onset and progression. Studying diseases caused by single gene mutations represents an opportunity to understand brain dys/function, including those regulated by myelin. Here, we discuss known and potential repercussions of abnormal central myelin on the neuropathophysiology of Neurofibromatosis Type 1 (NF1). Most patients with this monogenic disease present with neurological symptoms diverse in kind, severity, and onset/decline, including learning disabilities, autism spectrum disorders, attention deficit and hyperactivity disorder, motor coordination issues, and increased risk for depression and dementia. Coincidentally, most NF1 patients show diverse white matter/myelin abnormalities. Although myelin-behavior links were proposed decades ago, no solid data can prove or refute this idea yet. A recent upsurge in myelin biology understanding and research/therapeutic tools provides opportunities to address this debate. As precision medicine moves forward, an integrative understanding of all cell types disrupted in neurological conditions becomes a priority. Hence, this review aims to serve as a bridge between fundamental cellular/molecular myelin biology and clinical research in NF1.

Keywords: Neurofibromatosis type 1; RASopathies; White matter; myelin; oligodendrocytes.

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PdB: paid consultant on pediatric oncology advisory board, Alexion Pharmaceuticals. AN and ALJ do not disclose any conflict of interest

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New Research Offers More Options to People with Neurofibromatosis Type 1

Substantial research funding and new medications are providing more options—and hope—for people with neurofibromatosis type 1..

Woman opening curtains to reveal sunny skies and butterflies

A week after Deniro Bruno was born in 2007, his pediatrician noted several tan birthmarks on his skin that she called “café au lait” spots. Although the doctor seemed unconcerned, Deniro's mother, Jessica, researched that description on her computer when she got home and was frightened by what she saw. “I read about the connection of those markings to a condition called neurofibromatosis type 1 [NF1]—deformity, tumors, cancer,” she says. “It was terrifying.”

Jessica was able to suppress her fears until Deniro started exhibiting cognitive and speech delays around the time he turned 1. He was evaluated and enrolled in an early intervention program, and Jessica once again pushed away thoughts about NF1. “There were other possible explanations for Deniro's problems, so I stayed positive and did everything in my power to not think about it,” says the mother of four, who lives in Boston.

When her son was nearly 2, Jessica noticed that his left eye and face seemed puffy. Their pediatrician referred her to a neurologist, who first suggested the puffiness could be caused by Deniro sleeping on the left side of his face. That explanation didn't feel right to Jessica, especially combined with Deniro's developmental delays and tan spots, so she pressed for him to get an MRI. The scan revealed abnormalities on Deniro's brain, which the doctor said could be harmless but were also a common feature of NF1. Deniro was referred to a clinic at Children's Hospital in Boston so specialists could monitor his symptoms. A year later, one of the neurologists ordered a second MRI because the left side of Deniro's face had started to droop. Jessica and her husband also requested genetic testing.

The MRI revealed a plexiform neurofibroma, a nonmalignant tumor arising from the cells that surround nerves, in his left cheek, and the genetic blood test results confirmed what Jessica had long feared: Deniro had a change in the NF1 gene. At age 3, he was officially diagnosed with neurofibromatosis 1.

Andres Lessing, 43, was diagnosed with NF1 when he was 8 months old, and for most of his childhood his symptoms were mild. That changed when he was 27 and doctors discovered a malignant tumor on a peripheral nerve sheath, which covers and protects peripheral nerves. He underwent chemotherapy, surgery, and radiation, but the tumor came back twice, and he received more treatment to resolve it. “I'm lucky to be alive,” he says. Between 25 and 50 percent of people with this kind of tumor also have NF1, and 8 to 13 percent of people with NF1 will develop the tumor in their lifetime, according to the National Cancer Institute.

Originally called von Recklinghausen disease after the physician who first described the lesions, NF1 is a rare genetic disorder that occurs in about 1 in 3,000 births. The disease is caused by a change in the NF1 gene that results in underproduction of neurofibromin (a protein necessary for regulating cell growth) and increases the risk of multiple tumors, called neurofibromas. “When the gene is altered, cell growth is uninhibited,” says Justin T. Jordan, MD, MPH, FAAN, clinical director of the Stephen E. and Catherine Pappas Center for Neuro-Oncology and director of the Family Center for Neurofibromatosis at Massachusetts General Hospital in Boston. Most of the tumors are not malignant, although some can be cancerous, he adds. Between 30 and 50 percent of cases are from noninherited changes of the NF1 gene. NF1 is genetically distinct from (and more common than) the two types of schwannomatosis: NF2-related schwannomatosis and SMARCB1-related schwannomatosis. Recently, an international group of experts updated diagnostic criteria for all three diseases and divided them into more accurate clinical features, says Scott Plotkin, MD, PhD, executive director of the Pappas Center.

Distinguishing these conditions should result in less confusion, fewer misdiagnoses, and improved care for all patients, Dr. Plotkin adds. Different genes on different chromosomes cause these three conditions, he says. The two kinds of schwannomatosis—both characterized by schwannomas, painful tumors that grow on the sheaths of peripheral nerves—were renamed to reflect their associated gene changes.

Diverse Symptoms

Among patients with NF1, the course of the disease can vary widely, and the prognosis is difficult to predict even within families, says Dr. Jordan. Common symptoms include changes in skin coloring, freckling in the armpits or groin, and learning disabilities. Otherwise, symptoms differ from patient to patient in part because tumors can develop on any nerve in the body, says Dr. Plotkin. One person with the disease might get a tumor on a nerve leading to the right arm, while another might develop one on a nerve to the left calf.

For Deniro, who is now 15, an inoperable neurofibroma on the left side of his face affects his speech, says his mother, who sometimes finds it difficult to understand her son. “That's hard. When people don't understand him, he often says, ‘Never mind.’ I worry that he's becoming afraid to speak up.” Because his tumor is in the trigeminal nerve region, Deniro also has intense facial pain, says Jessica. “Typical kids might feel pain when they get hit or bumped in the face, but for Deniro the slightest touch hurts.”

In addition to internal neurofibromas, people with the disease often have neurofibromas on their skin—sometimes hundreds or thousands of them. They range in size and are non-cancerous but can be disfiguring, which can affect patients' social lives and quality of life. Other common health problems include scoliosis, difficulty sleeping, and learning disabilities.

Some NF1 symptoms develop early in childhood; others may develop later in life. Deniro's uncertain future is both a challenge and a blessing, says Jessica. While many people with NF1 live a normal life span, the likelihood of developing other cancers can reduce life expectancy by 10 to 15 years, compared to the general population. “The phrase we hear most often is ‘wait and see,’ because Deniro's doctors can't predict how he will be affected,” Jessica says. “I can manage what we have now, but I don't know whether things will stay the same or if it will be harder down the road when and if Deniro develops more tumors.”

Treating Symptoms

No cure exists for NF1, but physicians can treat symptoms in several ways, including through surgery, medication, and occupational and physical therapies. “Even if you can make patients feel only 2 percent better, you can substantially improve their quality of life,” says Dr. Jordan.

Over the years, Deniro has had speech and occupational therapy and adopted strategies to compensate for his limitations, says Jessica. For example, she says, “it's hard for him to turn a doorknob, so he's learned not to be the first person to the door.”

Jessica and her husband are also helping their son to become a better advocate for himself.

When Deniro was 9, a tumor on his eyelid grew so heavy it started affecting his peripheral vision. He underwent surgery to correct the problem. When he was 12, surgeons removed part of his jawbone because the neurofibroma had grown into the bone and affected his bite. “The tumor is like a ball of elastics that wraps itself around the nerves,” says Jessica, “and we can't have it removed or dissected neatly because it's entangled.”

Without a cure, physicians have historically focused on optimizing surgical therapies for tumors, improving screening to identify problems early, and providing supportive care, says Dr. Plotkin. “We were pretty good at that, and if we followed people closely and caught things early, we could improve lives.”

In 1996, advocacy efforts led to congressional appropriation of $300 million for NF1 research—an investment that led to the approval of selumetinib (Koselugo), a targeted forms of chemotherapy that inhibits the MEK enzyme, slowing cell growth, says Dr. Jordan.

In an attempt to shrink Deniro's neurofibroma, Jessica enrolled her son in a two-year clinical trial for binimetinib (Mektovi), another MEK inhibitor that is not yet approved by the US Food and Drug Administration. Deniro was considered a “responder” because the tumor shrank 32 percent. “You could actually see the difference,” says Jessica. The medication, however, caused uncomfortable side effects like hair loss and nausea, and about six months after the trial ended and Deniro stopped treatment, the tumor grew back to its original size.

Deniro was later readmitted to the trial and started taking binimetinib at a lower dose. His side effects are more manageable, but the tumor has shrunk just 12 percent. “Still, the tumor isn't growing, and that's a major goal,” says his mother.

“There is great breadth of research right now,” says Dr. Jordan. “We finally have a foothold, approved drugs, and promising trials.” Advances in treatment and new approaches to gene therapy are generating much hope in the NF1 community, Dr. Plotkin says. “There is so much exciting research in progress that we hope will become a reality” and result in new treatment options, he says. Drugs under development include a topical medication for the disfiguring neurofibromas that appear on the skin.

Jessica and her family actively lobby Congress to keep funding for NF1 a priority. “I am still hopeful for a cure,” she says. “I am grateful for the things Deniro can do, because I know many kids are worse off.”

Neurofibromatosis Clinical Trials

The federal government's Neurofibromatosis Research Program (NFRP) lists at least 15 trials on its website. To find other studies, visit clinicaltrials.gov and type “neurofibromatosis” in the search field. In addition to contacting members of Congress to encourage continued funding, here are two ways to get involved in research.

NF1 Biospecimen Repository

What: Researchers at Johns Hopkins University and Stanford University are recruiting people 40 years and older who have neurofibromatosis to establish a biobank that can be used to identify genetic variants, understand the pathogenesis of the disease better, and provide more personalized treatment and management.
For more information: Email Carlos Romo, MD, at [email protected] or Ekshika Patel at [email protected] .

Antioxidant Therapy

What: Cincinnati Children's Hospital Medical Center is enrolling children between the ages of 8 and 16 in an on-site trial to assess the safety and clinical benefit of N-acetylcysteine (NAC) for patients with cognitive, behavioral, and motor impairments.
For more information: Email Lindsey Aschbacher-Smith at [email protected] or Laurie Bailey at [email protected] .

Resources for Neurofibromatosis Type 1

American Academy of Neurology: BrainandLife.org
Children's Tumor Foundation: ctf.org ; 800-323-7938
National Institute of Neurological Disorders and Stroke: ninds.nih.gov ; 800-352-9424
National Organization for Rare Disorders: rarediseases.org ; 617-249-7300
Neurofibromatosis Consortium: uab.edu ; 205-934-5140
Neurofibromatosis Network: nfnetwork.org ; 800-942-6825
Neurofibromatosis Research Program: cdmrp.health.mil ; 301-619-7071
NF Registry: ctf.org/nf-registry

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Person with a cafe-au-lait birthmark on stomach

Neurofibromatosis Type 1 (NF1)

What you need to know.

Neurofibromatosis type 1 (NF1) is a condition caused by a change in a specific gene, and therefore can be inherited and passed on.
Not all people with NF1 inherit the disease. It can also develop spontaneously.
Most people with NF1 have recognizable symptoms often affecting the skin, eyes and nervous system, commonly before age 10.
NF1 affects males and females equally, and shows no preference for race or ethnicity.
NF1 is a progressive disease. Symptoms are evaluated and addressed, but presently, there is no way to eradicate NF1.

What is NF1?

Neurofibromatosis type 1 (also called Von Recklinghausen’s disease, Von Recklinghausen neurofibromatosis and peripheral NF) is one of the most commoninherited disorders and affects about one in every 3,000 people. NF1 ranges from mild to severe, and can cause more symptoms in some people than in others. It can affect many organs and systems, but primarily the skin, nervous system and eyes.

NF1 Symptoms and Diagnosis

Neurofibromatosis type 1 symptoms can involve many different parts of the body. A doctor with expertise in NF1 can provide an accurate diagnosis based on the symptoms, family history, as well as genetic testing and other imaging tests or biopsy.

For a definite diagnosis, a person has:

Two or more of the following signs
Six or more cafe-au-lait spots . These light brown skin patches are sometimes called cafe au lait birthmarks because they are frequently present at birth.
Two or more benign tumors called neurofibromas that appear on the skin surface or just under it, or at least one plexiform neurofibroma that typically develops deeper inside the body. In severe cases, multiple skin tumors can appear as lumps under the skin all over the body. Sometimes, a neurofibroma can become malignant (cancerous).
Freckles under the arms or in the groin area. These can appear in childhood.
A distinctive bone lesion, usually in the long bones or a bone of the skull
A mutation in the NF1 gene that is found by performing genetic testing and is known to cause neurofibromatosis type 1
Two or more Lisch nodules, which are benign findings in the iris (the colored part of the eye)
Optic pathway glioma , which is a tumor that originates from the optic nerve behind the eye

Bone Deformities Associated with NF1

NF1 can affect the bones. Skeletal NF issues that may need to be treated by an orthopaedic specialist include:

Osseous (bony) lesions and malformations
Pseudoarthrosis (a false joint or unhealed fracture) affecting the tibia (a bone in the lower leg)
Bowing of the tibia
Sphenoid wing dysplasia (abnormal bone growth in the base of the skull)
Short stature
Osteoporosis

Cardiovascular Conditions Related to NF1

Coarctation of the aorta
Hypertension (high blood pressure)
Moyamoya disease
Renal artery stenosis

Nervous System Conditions Associated with NF1

About 15% of people with NF1 develop brain tumors called gliomas , usually during childhood. The most common gliomas associated with NF1 are astrocytoma, brain stem glioma and optic pathway glioma.

Other tumors associated with NF1 are malignant peripheral nerve sheath tumors .

Other manifestations of NF1 include:

Attention-deficit/hyperactivity disorder (ADHD) and learning disabilities (affecting about 65% of people with NF1)
Macrocephaly (an unusually large head)
Numbness or weakness
Problems with self-image

NF1 Gene — What causes neurofibromatosis type 1?

Neurofibromatosis type 1 is caused by a change in the NF1 gene, which is found on chromosome 17.

Some people with NF1 have signs and symptoms only on one part of their body. This is called mosaic (or segmental) NF1. Genetic testing for this form of NF1 can be more complex than for a nonmosaic form of the condition.

Can neurofibromatosis type 1 be passed on in families?

Yes. Some people with neurofibromatosis type 1 have inherited a change in the NF1 gene from one of their parents. Others with NF1 are the first person in their family to be affected with this condition, and are thought to have a new change in the NF1 gene.

Whether the NF1 gene change was inherited from a parent or is new, every person with an NF1 gene change has a 50% chance of passing this change on each time they have a child. When planning for pregnancy, an evaluation by a prenatal counselor may be beneficial, and could include a conversation about in vitro fertilization with pre-implantation genetic testing.

Is there a genetic test for the NF1 gene?

Genetic testing for the NF1 gene is available and may be appropriate for people with questions about inheriting neurofibromatosis type 1 or passing it on to a child. Consulting a specialized neurofibromatosis or genetics clinic can provide more guidance.

NF Care at Johns Hopkins

Smiling patient is evaluated by Dr. Blakeley.

The Johns Hopkins Comprehensive Neurofibromatosis Center is one of the few specialized centers in the world helping patients with NF1, NF2 and schwannomatosis. Our multi-specialty team uses the latest treatment approaches that aim to address all aspects of living with NF.

Neurofibromatosis Type 1 Treatment

While there is no treatment that can reverse NF1, its signs and symptoms can be addressed. Tumors, in particular, may warrant chemotherapy, radiation, surgery or a combination of treatments. In about 60% of people with NF1, symptoms are mild and can be monitored without the need for treatment.

Addressing NF1 Symptoms

Expert evaluation and a multispecialty approach at a specialized clinic can help a person with NF1 manage symptoms and improve quality of life, and in some cases can provide opportunities for participation in clinical trials. Treatment options include the following.

For ADHD: medications, behavioral therapy
For bone deformities: observation, bracing and/or surgery to straighten and align bones in the spine or legs
For learning disabilities: individualized education programs, medications
For malignant peripheral nerve sheath tumors: surgery, chemotherapy, radiation therapy
For neurofibromas: observation, surgery, drug therapy is under clinical investigation
For optic glioma: observation, chemotherapy, radiation
For pain: medication, acupuncture, behavioral intervention, surgery, interventional treatment
For plexiform tumors: medication, surgery, new drug therapies are under clinical investigation
For vascular complications: observation, medication, surgery

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Specializing In:

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Comprehensive Neurofibromatosis Center
Neurocutaneous Disorders Clinic (Johns Hopkins All Children's Hospital)

Find Additional Treatment Centers at:

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Neurofibromatosis Type 2 (NF2)

Schwannomatosis

Neurofibromatosis

What is neurofibromatosis.

Neurofibromatosis is not a single medical disorder. It refers to three different conditions involving the development of tumors that may affect the brain, spinal cord, and the nerves that send signals between the brain and spinal cord and all other parts of the body. Most tumors are non-cancerous (benign), although some may become cancerous (malignant).

The conditions are:

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease
Neurofibromatosis type 2 (NF2)
Schwannomatosis (SWN)

Neurofibromatosis 1 (NF1) is the most common of the three conditions. Although many people with NF1 inherit the gene that causes the condition, between 30 and 50 percent of cases arise from a spontaneous genetic mutation in the NF1 gene. Once this mutation has occurred, the abnormal gene can be inherited. Each child of an affected parent has a 50 percent chance of inheriting the gene mutation.

Children and adults with NF1 can have a variety of symptoms and medical problems that can change across a lifespan. Most people with NF1 have an average life expectancy. Because many of the other clinical features of NF1 develop as an individual ages, getting the correct diagnosis may take several years.

To diagnose NF1, a doctor looks for some of the following:

Six or more flat, light brown spots on the skin (“café au lait” spots), which are the most common feature of NF1. These multiple birthmarks measure more than five millimeters in diameter in children or more than 15 millimeters across in adolescents and adults. They are seen at birth or develop during the first few years of life. Café-au-lait spots are not dangerous but indicate the possible presence of an NF1 gene change in the person. These skin marks also occur in other conditions, such as Legius syndrome, a genetic condition that affects how cells in the body communicate.
Two or more soft, pea-sized bumps involving the skin (cutaneous neurofibromas), or one larger neurofibroma that involves multiple nerves (plexiform neurofibroma). Neurofibromas are tumors that originate from nerve cells. Plexiform neurofibromas are nerve-associated tumors involving nerves outside of the brain and spinal cord. They can be present at birth or may not become noticeable for many years. Although some cutaneous neurofibromas arise in childhood, most start appearing during or after the teenage years.
Freckling in the armpits or the groin. This usually appears by 3 to 5 years of age. Freckles are similar in appearance to café-au-lait spots but are smaller in size. Freckling can occur in other conditions, but not with the other symptoms and concerns of NF1.
Two or more growths on the iris of the eye (known as Lisch nodules or iris hamartomas). These nodules are harmless, not typically present until adolescence, do not affect vision, and do not require monitoring or treatment.
A tumor of the optic pathway (optic pathway glioma). These tumors typically first appear by age 6, rarely in late childhood and adolescence, and almost never in adults. Although they can affect vision, most do not become symptomatic.
Bone deformities. Abnormal development of the eye socket (sphenoid) or the tibia (one of the long bones of the shin).
A parent, sibling, or child with NF1.

Additional signs and symptoms of NF1 include:

Children with NF1 are usually shorter than average and have larger heads.
Cardiovascular complications, such as congenital heart defects, high blood pressure (hypertension), and constricted, blocked, or damaged blood vessels.
Poor visuospatial skills and poor performance on academic achievement tests, including those that measure reading and math skills.
Behavioral challenges, such as attention deficit hyperactivity disorder (ADHD) and social skills, are commonly seen in children with NF1.
Although common in all people, headaches, pain, and seizures happen more often in people with NF1.
Tumors that may become cancerous. An estimated 10 percent of plexiform neurofibromas may become malignant, requiring aggressive treatment. Cutaneous neurofibromas are not known to become malignant.
Malignant glioma is a type of tumor that can occur (although rarely) in adults with NF1.
Adult young women with NF1 are at a higher risk for breast cancer arising before the age of 50 years than women in the general public.
There is an increased risk of gastrointestinal stromal tumors (GIST) and neuroendocrine tumors, like pheochromocytoma. There also is an increased incidence of benign nerve tumors called glomus tumors.
Scoliosis, or curvature of the spine, can be more common and aggressive in people with NF1.

Neurofibromatosis 2 (NF2) is less common than NF1. Approximately 50 percent of affected people inherit the gene (familial); in others, however, the condition is caused by a spontaneous genetic mutation in the NF2 gene. Each child of an affected parent has a 50 percent chance inheriting the abnormal NF2 gene.

Signs and symptoms of NF2 result from the development of:

Schwannomas are tumors made up of Schwann cells, or the cells that produce the myelin that covers and protects peripheral nerves throughout the body. They often occur on the eighth cranial nerve, which has two branches: The acoustic branch carries the signals for hearing to the brain and the vestibular branch carries signals for sense of position and balance. Vestibular schwannomas (also known as acoustic neuromas) are the most recognized form of schwannoma in people with NF2, but schwannomas can involve any of the cranial or peripheral nerves in someone with NF2. Schwannomas also can occur in the skin and appear as bumps under the skin or on the skin surface. Most tumors are benign, although, very rarely, they may become cancerous. Schwannomas may or may not progress over time and many never require treatment.
Meningioma is the second most common tumor type in people who have NF2. Meningiomas form in the tissue covering that surrounds the brain and spinal cord. People with NF2 have both a higher rate of meningiomas than the general population and can develop multiple meningiomas within the skull and along the spinal column.
Ependymoma tumors occur more frequently in people with NF2 than in the general population. Ependymomas arise within the spinal cord (as opposed to on the surface) and arebenign. In many individuals, these tumors prooduce or show no symptoms.
People with NF2 may develop vision problems like cataracts at an earlier age or have changes in the retina that can affect vision.
Individuals with NF2 may develop peripheral neuropathy, or problems with nerve function, usually numbness and weakness on both sides of the body (with or without muscle loss) in the arms and legs.

While teenagers and adults often are first seen for hearing and balance problems, young children with NF2 more commonly seek initial medical attention due to vision problems and meningiomas.

Signs of NF2 may be present in childhood but can be overlooked, especially in children who do not have a family history of NF2. Children are often first seen by a doctor because of schwannomas in the skin, vision loss from retinal abnormalities or tumors, seizures, or weakness related to spinal cord compression. More commonly, symptoms of NF2 are first noticed in the second decade of life.

The most common first symptom is hearing loss or ringing in the ears (tinnitus) related to vestibular schwannomas. Less often, the first visit to a doctor will be because of disturbances in balance, visual impairment, focal weakness in an arm or leg, seizures, or skin tumors.

To diagnose NF2, a doctor will look for the following:

Vestibular schwannomas
A parent, sibling, or child with NF2

They will also look for a unilateral vestibular schwannoma (on one side of the body) before age 30; or any of the following:

Schwannoma of non-vestibular nerves
Juvenile cataract or retinal abnormalities

Schwannomatosis (SWN) is the rarest form of the three conditions and is genetically and clinically distinct from NF1 and NF2. In many cases, mutation of the SMARCB or LZTR1 genes is associated with the disease; however, the genetic cause of SWN in some people is unknown.

Signs and symptoms of SWN significantly overlap with those of NF2 since they result from the development of slow-growing schwannomas of the cranial, spinal, and peripheral nerves and in some cases meningiomas of the brain and spinal cord. About one-third of individuals with schwannomatosis have tumors limited to a single part of the body, such as an arm, leg, or a segment of the spine. Some people develop many tumors, while others develop only a few. Schwannomas or meningiomas in the setting of schwannomatosis sometimes show no symptoms.

Other symptoms of SWN a doctor may look for are:

Chronic pain anywhere on the body. Chronic pain affects many people with SWN; this pain may or may not be associated with a specific schwannoma
Numbness, tingling, or weakness in the fingers and toes and/or loss of muscle function

Who is more likely to get neurofibromatosis?

Neurofibromatosis occurs in both biological sexes and in all races and ethnic groups. Why tumors develop in these conditions isn't completely known, but it appears to be caused in part by mutations in genes that play key roles in suppressing growth in nervous system cells. These mutations keep the genes—identified as NF1, NF2, SMARCB1, and LZTR1—from making normal proteins that control the ability of the cells to function properly. Without the normal function of these proteins, cell growth increases, leading to the formation of tumors.

How is neurofibromatosis diagnosed and treated?

Diagnosing neurofibromatosis

It may be impossible to distinguish someone with NF2 from SWN based on clinical features alone. Genetic testing may be needed to correctly diagnose individuals with features of these conditions who lack a known family history or bilateral vestibular schwannomas (those that occur on both sides of the body). Genetic testing can be useful in some situations, such as for prenatal testing or when the clinical diagnosis is inconclusive.

Detailed imaging of the brain and spinal cord by MRI are necessary and additional imaging based on symptoms may reveal schwannomas on peripheral nerves.

Treating neurofibromatosis

NF1 cannot be cured, but treatments can help manage signs and symptoms. Many people with NF1 will not require any prolonged treatment for any manifestation (disease signs or development) during their lives. People with NF1 should be evaluated periodically by an NF1 specialist, even if they are not experiencing symptoms, to evaluate for signs or symptoms that may indicate a need for treatment and to provide reassurance that treatment is not needed when appropriate.

The U.S. Food and Drug Administration (FDA) approved selumetinib (Koselugo) as a treatment for children ages 2 years and older with NF1. The drug helps to stop tumor cells from growing.

Surgery may be used to remove tumors that develop symptoms or are of concern for cancer, as well as for tumors that cause significant discomfort. Several surgical options exist for many of the manifestations of NF1, but there is no general agreement among doctors about when surgery should be performed, or which surgical option is best. Some bone malformations, such as scoliosis, can be corrected surgically or by stabilizing the spine with a brace. Some malformations that affect blood vessels can be successfully addressed with surgery or non-surgical procedures.

Chemotherapy may be used to treat optic pathway or other brain gliomas. The drug selumetinib (Koselugo®) has been approved by the FDA to treat children older than 2 years of age who have symptoms but inoperable plexiform neurofibromas. Chemotherapy regimens are a core part of treating cancers that may arise in the setting of NF1, including malignant peripheral nerve sheath tumor (MPNST) and breast cancer.

Treatments for other conditions associated with NF1 are aimed at controlling or relieving symptoms. Headache and seizures are treated with medications. Because children with NF1 have a higher-than-average risk for a variety of learning disabilities, ADHD, motor delays, and autism, they should be evaluated by a care team knowledgeable in NF1, and may be advised to have formal neuropsychological assessments to assist in creating individualized educational plans for school.

NF2 is best managed at a specialty clinic with an initial screening and annual follow-up evaluations (more frequent if the disease is severe). Improved diagnostic technologies, such as magnetic resonance imaging (MRI), can reveal tumors of the vestibular nerve as small as a few millimeters in diameter. Vestibular schwannomas grow slowly, but they can grow large enough to engulf one of the eight cranial nerves as well as cause brain stem compression and damage to surrounding cranial nerves.

Surgical options depend on tumor size and the extent of hearing loss. There is no general agreement among doctors about when surgery should be performed or which surgical option is best. Individuals considering surgery should carefully weigh the risks and benefits of all options to determine which treatment is right for them.

There is no currently accepted medical treatment or drug for schwannomatosis. Surgery may help some people with growing tumors or symptoms that are directly referred to individual schwannomas. However, the potential risk of nerve damage must be weighed carefully against potential benefits of surgery.

What are the latest updates on neurofibromatosis?

The mission of the National Institute on Neurological Disorders and Stroke ( NINDS ) is to seek fundamental knowledge about the brain and nervous system and use that knowledge to reduce the burden of neurological disease. NINDS, a component of the National Institutes of Health ( NIH ), conducts and supports research aimed at understanding normal and abnormal development of the brain and nervous system, as well as clinical trials to improve the diagnosis and treatment of neurological disorders, including NF. Other NIH institutes, the Department of Defense, and private foundations have provided critical support for NF research and clinical trials.

Current basic and clinical research is not only aimed at understanding how genetic defects cause the diverse conditions and medical problems encountered people with NF, but also how to predict which clinical features will arise in any given person (personalized or precision medicine). In addition, studies in NF1, NF2, and SWN have revealed numerous important insights for investigators working in other fields, including brain cancer, sarcoma, autism, learning disabilities, nerve regeneration, chronic pain, and targeted therapies.

Genetic studies

The gene for NF1 is located on chromosome 17. The NF1 gene makes a protein called neurofibromin, which regulates cell division in the nervous system and functions as a kind of molecular brake to keep cells from growing out of control. Ongoing NINDS-sponsored research continues to discover additional genes and molecular pathways that may play a role in NF-related tumor suppression or growth. Continuing research is starting to reveal how this novel family of growth regulators controls how and where tumors form and grow, which may lead to the development of new drugs and therapies for NF.

Clinical trials

NINDS supports clinical trials aimed at understanding tumor growth and cognitive impairments in children, including:

Studying the natural history of tumors in NF2 can help scientists determine possible factors that may regulate their growth. NINDS-supported researchers are using a variety of tests, including diagnostic imaging, eye examinations, hearing and balance tests, neurologic examinations, blood and genetic testing, and quality of life assessments to characterize the impact of NF2 on individuals and better understand disease progression.
NINDS supports clinical trials involving a large group of children with NF1 to find associations between brain abnormalities and specific cognitive disabilities. Finding these links could help doctors anticipate cognitive impairments and inform early intervention programs.

NINDS also encourages research to develop improved methods to diagnose the neurofibromatoses and identify factors that contribute to the wide variations of symptoms and severity of the disorders.

Several options have been tested or are under investigation for treating NF tumors. Ongoing clinical studies on drugs that block the enzyme mitogen-activated protein kinase (that affects how some cells grow and develop) show great promise in treating NF1-associated tumors, especially in children. Because schwannomas are particularly hard to treat tumors, NINDS researchers are developing and testing a new treatment option, which uses a virus to kill tumor cells. Researchers are also testing chemotherapy drugs as treatments for NF2-related schwannomas.

How can I or my loved one help improve care for people with neurofibromatosis?

Consider participating in a clinical trial so clinicians and scientists can learn more about NF and related disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.

All types of volunteers are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research visit NIH Clinical Research Trials and You . Learn about clinical trials currently looking for people with NF at Clinicaltrials.gov .

Donate brain tissue

NINDS supports the Human Brain and Spinal Fluid Resource Center . This bank supplies investigators around the world with tissue from individuals with neurological and other disorders. Tissue from those with NF1, NF2, or Schwannomatosis is needed to help scientists study these disorders more effectively.

Where can I find more information about neurofibromatosis?

Information may be available from the following organizations and resources:

Children's Tumor Foundation Phone: 800-323-7938 or 212-344-6633

Department of Defense Neurofibromatosis Research Program

Human Brain and Spinal Fluid Resource Center Phone: 310-268-3536

Neurofibromatosis Clinical Trials Consortium

Neurofibromatosis Network Phone: 630-510-1115 or 800-942-6825

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Neurofibromatosis 1

Jan M Friedman , MD, PhD.

Initial Posting: October 2, 1998 ; Last Update: April 21, 2022 .

Estimated reading time: 1 hour

Clinical characteristics.

Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease.

Diagnosis/testing.

The diagnosis of NF1 is established in a proband with two or more of the characteristic clinical features or one characteristic clinical feature and a heterozygous NF1 pathogenic variant .

Management.

Treatment of manifestations: Referral to specialists for treatment of abnormalities of the eye, central or peripheral nervous system, cardiovascular system, lungs, endocrine system, spine, or long bones; surgical removal of disfiguring or uncomfortable discrete cutaneous or subcutaneous neurofibromas. Surgical treatment of diffuse or large plexiform neurofibromas is possible but may be associated with damage to involved nerves or adjacent tissues and stimulate growth of residual tumor. Complete surgical excision, when possible, of malignant peripheral nerve sheath tumors is the treatment of choice; chemotherapy may be beneficial in some individuals. Treatment of optic gliomas is generally unnecessary as they are usually asymptomatic and clinically stable. Dystrophic scoliosis often requires surgical management, whereas nondystrophic scoliosis can usually be treated conservatively. Individualized developmental and educational interventions may be beneficial, and methylphenidate treatment often benefits individuals with attention-deficit/hyperactivity disorder.

Surveillance: Annual physical examination by a physician familiar with the disorder; ophthalmologic examination annually in children, and regularly but less frequently in adults; developmental assessment of children; regular blood pressure monitoring; MRI for identification and follow up of clinically suspected intracranial or other tumors that are not apparent on physical examination. Begin annual mammography in women at age 30 years with consideration of annual breast MRI in women between ages 30 and 50 years. Individuals with NF1 whole- gene deletions, large or growing plexiform neurofibromas or intracranial tumors, symptomatic vascular disease, progressive osseous lesions, or other serious disease manifestations require more frequent targeted follow up.

Genetic counseling.

NF1 is inherited in an autosomal dominant manner. Approximately half of affected individuals have NF1 as the result of a de novo NF1 disease-causing variant. Each child of an individual with NF1 has a 50% chance of inheriting the disease-causing variant. Penetrance is close to 100%; thus, a child who inherits an NF1-causing variant is expected to develop features of NF1, but the features may be considerably more (or less) severe in an affected child than in his or her affected parent. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the disease-causing variant in a family is known.

Suggestive Findings

Neurofibromatosis 1 (NF1) should be suspected in individuals who have any one of the following clinical features:

Six or more café au lait macules (CALMs; Figure 1 ) >5 mm in greatest diameter in prepubertal individuals and >15 mm in greatest diameter in postpubertal individuals
Freckling in the axillary or inguinal regions
Two or more neurofibromas ( Figure 2 ) of any type or one plexiform neurofibroma ( Figure 3 )
Optic pathway glioma
Two or more Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities (bright, patchy nodules imaged by optical coherence tomography/near-infrared reflectance imaging)
A distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone
A parent who meets the diagnostic criteria for NF1
A germline NF1 pathogenic variant

Café au lait macules

Neurofibromas

Plexiform neurofibroma

Establishing the Diagnosis

The diagnosis of NF1 is established in a proband with two or more of the features described in Suggestive Findings [ Legius et al 2021 ].

About half of individuals with Legius syndrome (see Differential Diagnosis ) have skin pigmentary features that meet the diagnostic criteria of NF1 (i.e., ≥6 CALMs and axillary or inguinal freckling), but individuals with Legius syndrome do not have neurofibromas, optic pathway gliomas, Lisch nodules, or typical osseous lesions of NF1 [ Legius et al 2021 ]. Moreover, Legius syndrome is much rarer than NF1, and children with Legius syndrome almost always have an affected parent with only CALMs and intertriginous freckling (see Differential Diagnosis ).

CALMs, intertriginous freckling, cutaneous neurofibromas, and Lisch nodules are usually bilateral in NF1. A diagnosis of mosaic NF1 should be considered if such lesions are present only on one side or in one segment of the body.

Sphenoid wing dysplasia is not a separate criterion in those with ipsilateral orbital plexiform neurofibromas.

A germline NF1 pathogenic variant must be identified for genetic testing to serve as a criterion for diagnosis [ Legius et al 2021 ]. The criterion is not met by identification of an NF1 variant only in tumor tissue or identification of a germline likely pathogenic variant or variant of uncertain significance .

Negative NF1 molecular testing does not rule out a diagnosis of NF1 [ Accetturo et al 2020 ]. Some individuals diagnosed with NF1 based on clinical criteria do not have a pathogenic variant detectable by current technology. Many clinical features of NF1 increase in frequency with age, and some individuals who have unequivocal NF1 as adults cannot be diagnosed in early childhood, before these features become apparent.

If the phenotypic findings suggest the diagnosis of NF1 , single- gene testing may be considered. Sequence analysis of NF1 genomic DNA ( gDNA ) and/or cDNA (complementary DNA, copied from mRNA ) is performed in association with gene-targeted deletion analysis. Because of the frequency of pathogenic variants that affect splicing (22%-30%, more than 1/3 of which are not detected by gDNA sequencing of protein-coding regions), methods that include cDNA sequencing have higher detection rates than methods based solely on analysis of gDNA ( Table 1 ).

If an NF1 variant is not detected, sequence analysis and deletion/duplication analysis of SPRED1 (see Differential Diagnosis ) may be considered in individuals with only pigmentary features of NF1 .

Chromosomal microarray analysis (CMA) may be performed instead of sequence analysis to detect NF1 whole- gene deletions if the NF1 microdeletion phenotype is suspected clinically (see Genotype-Phenotype Correlations ).

A karyotype may be considered to look for a translocation or complex cytogenetic abnormality if a clinical diagnosis of NF1 is certain, but no pathogenic variant is found on sequence analysis of NF1 gDNA or cDNA and gene -targeted deletion analysis.

If the phenotype is indistinguishable from other disorders characterized by hyperpigmentation, tumors, and/or other overlapping features, a multigene panel that includes NF1 , SPRED1 , and other genes of interest (see Differential Diagnosis ) may be considered. A rasopathy multigene panel is usually most appropriate. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Many multigene panels include genes not associated with the condition discussed in this GeneReview ; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis , deletion/duplication analysis , and/or other non-sequencing-based tests.

For an introduction to multigene panels click here . More detailed information for clinicians ordering genetic tests can be found here .

If the phenotype is nonspecific (e.g., developmental delay and hypotonia in a young child) comprehensive genomic testing ( exome sequencing or genome sequencing ) may be considered. Note: Identification of one or more characteristic clinical features (see Suggestive Findings ) is required to establish the diagnosis in an individual with an NF1 pathogenic variant .

For an introduction to comprehensive genomic testing click here . More detailed information for clinicians ordering genomic testing can be found here .

Molecular Genetic Testing Used in Neurofibromatosis 1

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Gene	Method	Proportion of Probands with a Disease-Causing Variant Detectable by Method
	&	>95%
		~60%-90%
	Gene-targeted	~13%
	CMA	~5%-11%
	Karyotype	<1%

See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on variants detected in this gene .

Sequence analysis detects variants that are benign, likely benign , of uncertain significance , likely pathogenic , or pathogenic. Variants may include small intragenic deletions/insertions and missense , nonsense , or splice site variants. Deletion/ duplication analysis is often included in NF1 molecular analysis; If exome sequencing is used, confirm that deletion /duplcaiton analysis is included (usually performed by read-depth analysis of next generation sequencing data). For issues to consider in interpretation of sequence analysis results, click here .

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. If deletion/duplication analysis is not performed with sequence analysis (e.g., read-depth analysis), alternate methods may include quantitative PCR , multiplex ligation-dependent probe amplification (MLPA), or FISH .

Evans et al [2010] , Sabbagh et al [2013] , Giugliano et al [2019]

Maruoka et al [2014] , van Minkelen et al [2014] , Pasmant et al [2015] , Zhang et al [2015] , Calì et al [2017] , Bianchessi et al [2020]

Whole- gene deletions occur in 5%-11% of individuals with NF1 [ Kehrer-Sawatzki et al 2020 ].

Stenson et al [2020]

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including NF1 ) that may not be detected by sequence analysis . The ability to determine the size of the deletion / duplication depends on the type of microarray used and the density of probes in the 17q11.2 region. CMA designs in current clinical use target the 17q11.2 region.

Clinical Characteristics

Clinical Description

Neurofibromatosis 1 (NF1) is an extremely variable multisystem disease; the progression and severity may differ throughout life in an affected individual as well as in affected family members with the same NF1 pathogenic variant [ Gutmann et al 2017 , Monroe et al 2017 , Gianluca et al 2020 ]. The cardinal clinical manifestations of NF1 include multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, subcutaneous or deep nodular neurofibromas, plexiform neurofibromas, and characteristic ocular signs. Problems with learning, behavior, and social adaptation are unusually common among people with NF1. Optic or non-optic gliomas occur much more often than expected, but most of these tumors exhibit a benign course. Individuals with NF1, especially those with plexiform or deep nodular neurofibromas in large numbers or of large size, are at high risk of developing malignant peripheral nerve sheath tumors, which tend to occur at a much younger age and have a worse prognosis than in the general population. Women with NF1 are at increased risk of developing breast cancer and have complications of pregnancy more often than expected. Hypertension is frequent in people with NF1, and NF1 vasculopathy may cause stroke or other cardiovascular complications in affected children and young adults. Vertebral or tibial dysplasia can cause major disability in some individuals, and NF1-associated gastrointestinal, endocrine, or pulmonary disease – although less frequent – may be quite serious.

Neurofibromatosis 1: Frequency of Select Features

Feature	% of Persons w/Feature	Typical Age of Onset	Comment
Café au lait macules	>99%	Infancy & childhood	↑ in number & size during 1st few yrs of life; macules fade in older persons.
Intertrigenous freckling	85%	Infancy & early childhood	Frequency ↑ w/age during childhood.
Lisch nodules	>95%	Early childhood	Frequency ↑ w/age during childhood.
Choroidal abnormalities	82%-98%	Early childhood	↑ in number & size during childhood
Optic pathway glioma	15%-20%	Birth - 6 yrs	Frequency lower in adults
Non-optic glioma	2%-5%	Any age	Frequency lower in children than adults
Cutaneous neurofibromas	99%	Adolescence-adulthood	Infrequent in childhood; variably ↑ in size & number throughout life
Nodular neurofibromas (subcutaneous or deep)	~15%	Adolescence	Frequency shown is on clinical exam; frequency is 2-3x higher on whole-body MRI.
Plexiform neurofibroma(s)	~30%	Infancy (sometimes ) or childhood	Frequency shown is on clinical exam; frequency is ~50% on whole-body MRI.
Malignant peripheral nerve sheath tumor	8%-13%	Adolescence - adulthood	Cross-sectional prevalence 2%-5% after mid-childhood
Intellectual disability	4%-8%	Childhood	Persists throughout life
Learning difficulties	50%-60%	Childhood	Persist throughout life
Behavior issues	30%-67%	Childhood	Persist throughout life
Seizures	6%-7%	Any age
Long bone dysplasia	2%	Infancy ( )
Dystrophic scoliosis	5%	6-10 yrs	Rapidly progressive scoliosis due to vertebral dysplasia
Nondystrophic scoliosis	5%	Adolescence	Milder scoliosis w/o vertebral anomalies
Osteoporosis	~20%	Mid-adulthood	Osteopenia is frequent at all ages; osteoporosis occurs earlier than in general population but is rare in children & uncommon in young adults
Hypertension	≥15%-20%	Any age	Prevalence greater in adults than children

Many of the features listed in this table have different frequencies at different ages. The table gives life-time cumulative incidence figures that may be higher, and sometimes much higher, than the prevalence at any given age. Most frequencies in this table are from Ferner & Gutmann [2013] or DeBella et al [2000] . References for more recently defined features are given in the discussion of individual features below.

Cutaneous Features

Café au lait macules (CALMs). Typically, CALMs in individuals with NF1 are ovoid in shape with well-defined borders, uniform in color (a little darker than the background pigmentation of the individual's skin), and about 1-3 cm in size; however, they may be smaller or much larger, lighter or darker, or irregular in shape [ Ozarslan et al 2021 , Albaghdadi et al 2022 ]. The pigmentation may also be irregular, with freckling or a more deeply pigmented smaller CALM within a larger, more typically colored lesion. They usually appear in infancy and early childhood, and once established remain stable in number and size (except for growth of the skin itself). They may be difficult to see in older adults with NF1 because of the wrinkling and diffuse pigmentation that often occur with aging.

CALMs are flat and flush with the surrounding skin; if the skin of the lesion is raised or has an unusually soft or irregular texture in comparison to the surrounding skin, an underlying plexiform neurofibroma is likely. The darker pigmentation of CALMs may be difficult to see in people with very fair skin or very dark skin, where the color of the lesions is similar to that of the rest of the skin. A Wood's light is useful in such individuals to demonstrate the pigmented macules. CALMs are not seen on the palms or soles in people with NF1 but can occur almost anywhere else on the body.

Freckling. Clusters of freckles are frequent in sun-exposed areas and may also be seen diffusely over the trunk, proximal extremities, and neck in people with NF1. Individuals with NF1 also develop freckles in areas where skin rubs against skin – in the axilla, groin, and under the breasts in women [ Ozarslan et al 2021 , Albaghdadi et al 2022 ].

Neurofibromas. See Other Tumors .

Other skin findings. Juvenile xanthogranuloma and nevus anemicus are more common than expected in people with NF1 and may be useful in supporting the diagnosis in young children who do not meet the standard diagnostic criteria [ Miraglia et al 2020 , Ozarslan et al 2021 ]. Juvenile xanthogranulomas are small, tan- or orange-colored papules that may occur in clusters. Nevus anemicus is an irregularly shaped macule that is paler than surrounding skin and does not get red when rubbed, as the skin surrounding it does.

Ocular Findings

Lisch nodules are innocuous iris hamartomas that can be demonstrated on slit lamp examination in almost all adults with NF1, but in fewer than half of children with NF1 younger than age five years. They can be distinguished from iris freckles by their three-dimensional nodular appearance.

Choroidal freckling cannot be seen on standard ophthalmologic examination but can be visualized by scanning laser ophthalmoscopy with infrared or near-infrared light, infrared reflectance imaging, or optical coherence tomography [ Vagge et al 2016 , Moramarco et al 2018 ]. The lesions, which are Schwann cell proliferations arrayed in concentric rings around an axon, occur in the majority of people with NF1 of all ages and increase in prevalence, number, and size with age during childhood [ Touzé et al 2021 ].

Other findings frequently seen on ophthalmologic examination of individuals with NF1 include microvascular abnormalities of the retina [ Parrozzani et al 2018 , Moramarco et al 2019 ] and hyperpigmented spots of the fundus [ Moramarco et al 2021 ].

Optic pathway gliomas in individuals with NF1 are usually asymptomatic and remain so throughout life [ Di Nicola & Viola 2020 , Shofty et al 2020 ]. The clinical course in individuals with optic pathway gliomas tends to be milder in individuals with NF1 than in those who do not have NF1. Optic pathway gliomas in NF1 are frequently stable for many years or only very slowly progressive [ Sellmer et al 2018 , Kinori et al 2021 ]. In addition, the majority of optic pathway gliomas appear to regress spontaneously – their prevalence declines from approximately 20% in young children to less than 5% in older adults with NF1 [ Sellmer et al 2018 ]. Symptomatic optic pathway gliomas in individuals with NF1 usually present before age six years with loss of visual acuity, proptosis, or strabismus, but these tumors may not become symptomatic until later in childhood or adulthood [ Friedrich & Nuding 2016 , Kinori et al 2021 ].

Increased tortuosity of the optic nerve can be seen on brain MRI in children with NF1, but optic nerve tortuosity is not associated with the occurrence of optic pathway glioma among individuals with NF1 [ Ji et al 2013 ].

Other Tumors

Neurofibromas are benign Schwann cell tumors that can affect virtually any nerve in the body [ Brena et al 2020 , Serra et al 2020 , Ozarslan et al 2021 ]. Cutaneous neurofibromas are discrete, well-circumscribed masses, usually ranging in size from 1-2 mm to a few centimeters. Their consistency varies from soft to rubbery to firm. They may be sessile or pedunculated, and the involved skin may be the same color and tone as adjacent uninvolved skin or may be pinker or browner or bluer. Most are asymptomatic, but they may itch or be tender to touch. Cutaneous neurofibromas are rare in children but present in almost all adults with NF1.

Subcutaneous neurofibromas lie under the skin (the skin can be moved over them). Most feel rubbery and are nodular, but they may be diffuse, with indistinct borders, and of soft or heterogeneous consistency. The skin overlying a superficial diffuse neurofibroma may exhibit unusual pigmentation or hair patterning. Subcutaneous neurofibromas may be isolated or occur in clusters or continuously like beads on a string along a nerve. Most are small, but subcutaneous neurofibromas can grow to be 5 cm in diameter or more. They may be tender and are sometimes painful. Subcutaneous neurofibromas are uncommon in children but present in about 15% of adults with NF1 on clinical examination.

Cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year. The total number of neurofibromas seen on clinical examination in adults with NF1 varies from a few to hundreds or even thousands. Some women experience a rapid increase in the number and size of neurofibromas during pregnancy, but this does not appear to produce a persistent increase in the tumor burden in comparison to those of child-bearing age with NF1 who have not been pregnant [ Well et al 2020 ].

Plexiform neurofibromas. About half of people with NF1 have plexiform neurofibromas. Most of these tumors are internal, and thus not apparent on clinical examination. They can, however, be seen on MRI (see Imaging ). Plexiform neurofibromas tend to grow in childhood and adolescence and then remain stable throughout adulthood [ Nguyen et al 2012 ]. Although most plexiform neurofibromas are asymptomatic, they may cause pain, grow to cause disfigurement, produce overgrowth or erosion of adjacent tissue, or impinge on the function of nerves and other structures.

Superficial diffuse plexiform neurofibromas are soft and irregular; they are often associated with thickening, hypertrophy, and/or hyperpigmentation of the associated skin. More extensive diffuse plexiform neurofibromas may have a characteristic “bag of worms” feel on palpation, indicating involvement of multiple nerves and branches. Plexiform neurofibromas may also be firm and nodular, occurring singly or extending for some distance or even along the entire extent of a nerve, producing a “beads on a string” feel on palpation. Deeper plexiform neurofibromas that are not apparent on clinical examination may also be diffuse or nodular, and singular or clustered on any nerve, nerve root, or nerve plexus.

Malignant peripheral nerve sheath tumors (MPNST) are the most common malignant neoplasms associated with NF1. In comparison to the general population, MPNST tend to occur at a younger age and be associated with a poorer prognosis in people with NF1 [ Martin et al 2020 , Sharma et al 2021 ]. Most, if not all, MPNST arise in preexisting diffuse or nodular plexiform neurofibromas. The most frequent clinical sign of malignant change is persistent pain, either as a new symptom or as exacerbation of existing pain. This pain may be accompanied by rapid growth or change in texture of the tumor clinically or on MRI.

Individuals with NF1 who have a type 1 whole-gene deletion or benign subcutaneous neurofibromas, or whose burden of benign internal plexiform neurofibromas is high, appear to be at greater risk of developing MPNST than people with NF1 who do not have these features [ Nguyen et al 2014 ]. Individuals with atypical neurofibromas also appear to be at unusually high risk of developing MPNST [ Higham et al 2018 ].

Brain tumors. Non-optic gliomas in people with NF1 are usually asymptomatic, and most are discovered as incidental findings on head MRI done as a routine screen or for other indications. These are usually low-grade tumors that grow slowly or not at all over many years [ Sellmer et al 2017 ], although symptomatic and/or high-grade brain tumors are seen occasionally [ Byrne et al 2017 , Glombova et al 2019 ].

At least 20% of people with NF1 who have one non-optic glioma have two or more of these tumors [ Sellmer et al 2017 , Glombova et al 2019 ]. Second central nervous system (CNS) gliomas occur in 17%-20% of individuals with NF1 who have optic pathway gliomas [ Sharif et al 2006 , Sellmer et al 2018 ].

Breast cancer. Women with NF1 are at substantially increased risk of developing breast cancer before age 50 years [ Uusitalo et al 2016 ] and of dying of breast cancer [ Evans et al 2020 ]. The cumulative risk of developing contralateral breast cancer is greater than expected among women with NF1 [ Evans et al 2020 ]. Breast cancers in women with NF1 are more likely to be HER2-positive and to have other unfavorable tumor markers [ Evans et al 2020 ].

Hematologic malignancies. Although still rare, juvenile myelomonocytic leukemia (JMML) is hundreds of times more frequent in children with NF1 than in other children [ Niemeyer & Flotho 2019 ]. The usual clinical features at presentation are splenomegaly, hepatomegaly, and leukemic infiltrates of the lung in association with a peripheral blood smear that shows myelocytes, meta-myelocytes, and sometimes nucleated red cells. Juvenile xanthogranulomas may be seen in children with NF1 and JMML but do not appear to be more frequent than expected in other children with NF1 [ Liy-Wong et al 2017 ]. It is not clear whether lymphoreticular malignancies occur more frequently than expected in adults with NF1 [ Bergqvist et al 2021 ].

Additional tumors. A variety of other tumors may also be seen more often than expected in individuals with NF1, including rhabdomyosarcomas [ Crucis et al 2015 ], pheochromocytomas [ Gruber et al 2017 ], paragangliomas [ Gruber et al 2017 ], gastrointestinal stromal tumors [ Nishida et al 2016 ], and glomus tumors [ Kumar et al 2014 ]. People with NF1 may also be at increased risk for some other cancers [ Seminog & Goldacre 2013 , Varan et al 2016 , Landry et al 2021 ].

Other Neurologic Manifestations

Motor function. Hypotonia and impairments in coordination, balance, and fine motor function are frequent in children with NF1 [ Iannuzzi et al 2016 , Haas-Lude et al 2018 , Pardej et al 2022 ]. Children with NF1 also have less muscle strength than unaffected children of the same age, sex, and weight [ Summers et al 2015 ].

Intellectual and learning disabilities. Deficits in visual-spatial performance are most common in individuals with NF1, but specific learning disorders and problems with executive function, memory, and language are also frequent [ Vogel et al 2017 ]. The average IQ of people with NF1 is ~1 SD lower than individuals in the general population, and frank intellectual disability (IQ <70) occurs in 4%-8% of individuals with NF1, a frequency about twice that in the general population [ Vogel et al 2017 , Al-Farsi et al 2022 ]. Intellectual disability is more frequent among individuals whose NF1 is caused by a whole- gene deletion .

Behavioral issues include problems with social competence and attention. Both children and adults with NF1 report increased social difficulties such as isolation and reduced peer acceptance and exhibit fewer social skills and prosocial behaviors [ Chisholm et al 2018 , Payne et al 2020 ]. Attention-deficit/hyperactivity disorder is present in 30%-50% of children and adolescents with NF1 [ Vogel et al 2017 , Chisholm et al 2018 , Domon-Archambault et al 2018 ] and may persist into adulthood [ Mautner et al 2015 ]. Symptoms of autism are frequent in children with NF1, and 25% of children with NF1 meet standard diagnostic criteria for autism spectrum disorder [ Vogel et al 2017 , Chisholm et al 2018 , Domon-Archambault et al 2018 , Payne et al 2020 , Chisholm et al 2022 ]. Autistic symptoms appear to be less common among adults than children with NF1 [ Morris et al 2016 ]. Sleep disturbance is frequent in individuals with NF1 at all ages [ Domon-Archambault et al 2018 , Fjermestad et al 2018 ]. Psychiatric diseases such as mood disorders, anxiety disorders, and emerging personality disorders may also occur more often than expected among adults with NF1 [ Domon-Archambault et al 2018 , Kenborg et al 2021 ].

Polyneuropathy. A few percent of people with NF1 develop a diffuse polyneuropathy, often (though not always) in association with multiple nerve root tumors [ Barnett et al 2019 , Bayat & Bayat 2020 ]. NF1 polyneuropathy may be asymptomatic or produce sensory deficits, pain, or itching. The risk for MPNST appears to be higher in individuals who have polyneuropathy than in those who do not.

Seizures occur in about 5% of individuals with NF1, with a slightly higher prevalence in adults than in children [ Bernardo et al 2020 , Sorrentino et al 2021 ]. The seizures may be generalized but more often are focal, occurring in association with a brain tumor, area of infarction, or mesial temporal sclerosis [ Pecoraro et al 2017 , Bernardo et al 2020 , Sorrentino et al 2021 ]. Neurodevelopmental abnormalities are more common in individuals with NF1 and epilepsy [ Sorrentino et al 2021 ].

The approach to treating epilepsy in individuals with NF1 is similar to that used in those who do not have NF1 [ Bernardo et al 2020 , Sorrentino et al 2021 ]. Control of focal seizures may require the use of more than one anti-seizure drug or surgical removal of the affected part of the brain.

Headaches occur in at least half of individuals with NF1 and are more frequent in adults than children [ Fjermestad et al 2018 , Hirabaru & Matsuo 2018 , Kongkriangkai et al 2019 ]. Migraine headaches are most common in NF1, but other kinds of headaches may occur. NF1-associated lesions are often seen on head MRI in people with headaches, but the frequency is similar to that found in those without headaches [ Afridi et al 2015 ].

Neuroimaging. Hyperintense lesions (unidentified bright objects [UBOs] or focal areas of high signal intensity [FASI]) are seen on T 2 -weighted brain MRI in more than half of children with NF1 [ Sellmer et al 2018 ]. These may occur in the optic tracts, basal ganglia, brain stem, cerebellum, or cortex, and they usually show no evidence of a mass effect. Typical UBOs are not seen on T 1 -weighted MRI imaging or on CT scan. UBOs correspond pathologically to areas of spongiform myelinopathy [ DiPaolo et al 1995 ]. They peak in number and size at about age seven years and then tend to regress, but some persist into adulthood [ Sellmer et al 2018 , Calvez et al 2020 ]. The presence of UBOs does not appear to be related to the occurrence of seizures in children with NF1 [ Hsieh et al 2011 ]. Some studies have suggested that the presence, number, volume, location, or disappearance of UBOs over time correlates with learning disabilities or behavioral abnormalities in children with NF1, but findings have not been consistent across investigations [ Payne et al 2014 , Roy et al 2015 , Parmeggiani et al 2018 , Eby et al 2019 , Baudou et al 2020 ].

Enlargement of the corpus callosum is seen in some children with NF1 and has been associated with learning disabilities [ Pride et al 2010 , Aydin et al 2016 ].

MRI is the imaging method of choice for demonstrating optic gliomas, brain tumors, and neurofibromas of cranial, spinal, or peripheral nerves, as well as diffuse or nodular neurofibromas anywhere in the body. Positron emission tomography is useful in recognizing MPNST [ Nishida et al 2021 ], and high-resolution ultrasound examination can be used to characterize dermal and superficial plexiform neurofibromas [ Winter et al 2020 ].

Musculoskeletal Features

Long bone, sphenoid wing, or vertebral dysplasia. Osseous dysplasia may occur as a primary abnormality in individuals with NF1 (typical of long-bone dysplasia), or in association with an adjacent plexiform neurofibroma or dural ectasia (vertebral or sphenoid wing dysplasia). Healing of fractured or defective bone in any of these focal lesions is often unsatisfactory [ Elefteriou et al 2009 ]. Surgical treatment of osseous dysplasia and its associated deformities of the long bones, craniofacies, and spine is frequently difficult and best accomplished by experienced specialists [ Mladenov et al 2020 ].

Dysplasia of the long bones, most often the tibia and fibula, is an infrequent but characteristic feature of NF1 [ Elefteriou et al 2009 ]. The lesion is congenital and almost always unilateral. It usually presents in infancy with anteriolateral bowing of the lower leg. Early recognition of tibial dysplasia permits bracing, which may prevent fracture. The initial radiographic changes are narrowing of the medullary canal with cortical thickening at the apex of the bowing [ Stevenson et al 2007 ].

Sphenoid wing dysplasia typically presents with asymmetry of the orbits, but it is sometimes found incidentally on cranial imaging. Sphenoid wing dysplasia is often static but may be progressive, occasionally disrupting the integrity of the orbit and producing pulsating enophthalmos [ Chauvel-Picard et al 2020 ].

Vertebral dysplasia usually presents as dystrophic scoliosis, which typically develops between ages six and eight years, much earlier than common adolescent scoliosis. Dystrophic scoliosis, which is characterized by acute angulation of the spine over a short segment, may be rapidly progressive within a few months after becoming apparent [ Kaspiris et al 2022 ].

Nondystrophic scoliosis, which is not usually associated with vertebral abnormalities in individuals with NF1, resembles common adolescent scoliosis in its age at onset and more benign course [ Elefteriou et al 2009 ].

Osteoporosis. Generalized osteopenia is more common than expected in people with NF1 [ Rodari et al 2018 , Filopanti et al 2019 , Jalabert et al 2021 , Kaspiris et al 2022 ], and fractures occur more often than expected [ Heervä et al 2012 ]. Adults with NF1 develop osteoporosis more frequently and at a younger age than in the general population [ Filopanti et al 2019 , Kaspiris et al 2022 ]. The pathogenesis of these bony changes is not fully understood, but individuals with NF1 often have lower-than-expected serum 25-hydroxy vitamin D concentrations, elevated serum parathyroid hormone levels, and evidence of increased bone resorption [ Riccardi et al 2020 , Tezol et al 2021 , Kaspiris et al 2022 ]. The function of both osteoblasts and osteoclasts appears to be abnormal in bone from people with NF1 [ Riccardi et al 2020 , Kaspiris et al 2022 ].

Vascular Involvement

Arterial hypertension occurs in at least 15%-20% of individuals with NF1 [ Dubov et al 2016 , Sivasubramanian & Meyers 2021 ]. It may develop at any age but is more frequent in adults than children. Often no specific cause is found, but hypertension may be caused by renal artery stenosis or mid-aortic syndrome, usually as a manifestation of NF1 vasculopathy, especially in children [ Celik et al 2021 , Sivasubramanian & Meyers 2021 ]. Hydronephrosis and other structural abnormalities of the urinary tract are frequent in individuals with NF1-related hypertension but are also seen in those without hypertension [ Dubov et al 2016 , Celik et al 2021 ].

Although much more frequent in people with NF1 than in the general population, pheochromocytomas or paragangliomas are found in fewer than 1% of adults with NF1. These tumors are usually asymptomatic, but they can cause arterial hypertension [ Al-Sharefi et al 2019 ].

Pulmonary hypertension is a rare but very serious complication of NF1 in older adults [ Jutant et al 2018 , Jutant et al 2020 ]. It is usually associated with parenchymal lung disease, which itself may be a manifestation of NF1 vasculopathy affecting vessels in the lungs [ Jutant et al 2018 ].

Stroke is more common and often occurs at a younger age among people with NF1 than in the general population [ Terry et al 2016 ]. Anatomically variant stenotic or ectatic cerebral arteries and intracranial aneurysms occur more frequently in individuals with NF1 than in the general population [ Bekiesińska-Figatowska et al 2014 , D'Arco et al 2014 , Barreto-Duarte et al 2021 ]. The internal carotid, middle cerebral, or anterior cerebral artery are most often affected. Small telangiectatic vessels form around the stenotic area and appear as a "puff of smoke" (moya moya) on cerebral angiography. Moya moya vasculopathy develops about three times more often than expected in children with NF1 after cranial irradiation for primary brain tumor [ Murphy et al 2015 ].

Cardiac Issues

Congenital anomalies of the circulatory system were observed 3.35 times (95% confidence interval 1.64-6.83x) more often than expected among children with NF1 in a study performed through Finnish population-based registries [ Leppävirta et al 2018 ]. Pulmonary valve stenosis and mitral valve anomalies are the most frequent cardiac defects seen in individuals with NF1 [ Lin et al 2000 , Pinna et al 2019 ]. Congenital heart defects and hypertrophic cardiomyopathy may be especially frequent among persons with NF1 whole- gene deletions [ Nguyen et al 2013 , Pinna et al 2019 ]. Intracardiac neurofibromas may also occur [ Nguyen et al 2013 ].

Pulmonary Disease

NF1-associated diffuse lung disease occurs in 10%-20% of adults [ Jutant et al 2018 , Alves Júnior et al 2019 ]. Symptoms are usually nonspecific and may include dyspnea on exertion, shortness of breath, chronic cough, or chest pain. Symptoms do not usually appear until the third or fourth decade of life, although characteristic signs may be found on imaging studies in children with NF1 [ Spinnato et al 2019 ]. Chest CT is the method of choice for identifying NF1-associated diffuse lung disease, which typically is characterized by upper-lobe cystic and bullous disease and basilar interstitial disease. NF1 pulmonary disease is often poorly responsive to available medical treatments.

Individuals with NF1 tend to be below average in height and above average in head circumference for age [ Zessis et al 2018 ]. However, very few individuals with NF1 have height more than 3 SD below the mean or head circumference more than 4 SD above the mean.

In contrast, individuals with whole- gene NF1 deletions have overgrowth (especially in height) between ages two and six years [ Ning et al 2016 , Kehrer-Sawatzki et al 2020 ]. The clinical features in some of these individuals resemble those of Weaver syndrome (see Genotype-Phenotype Correlations ).

Pubertal development is usually normal, although decreased pubertal growth velocity occurs in both girls and boys [ Zessis et al 2018 ]. However, delayed puberty is common [ Virdis et al 2003 ], and precocious puberty and/or growth hormone excess may also occur in children with NF1, especially in those with tumors of the optic chiasm [ Cambiaso et al 2017 , Hannah-Shmouni & Stratakis 2019 ].

Life Expectancy

The median life expectancy of individuals with NF1 is at least eight years lower than in the general population [ Evans et al 2011 , Wilding et al 2012 ]. Even higher excess mortality has been identified in females [ Uusitalo et al 2015 ]. Malignancy (MPNST) and vasculopathy are the most important causes of early death in individuals with NF1 [ Evans et al 2011 , Masocco et al 2011 , Uusitalo et al 2015 ].

Quality of Life

Quality of life assessments are lower in both children and adults with NF1 than in comparison groups [ Vranceanu et al 2015 ]. Cosmetic, medical, social, and behavioral features of NF1 all may compromise the quality of life in people with NF1, and clinical depression may impair their ability to function effectively [ Domon-Archambault et al 2018 ]. A population-based Danish registry study found that people with NF1 were more than twice as likely to be hospitalized and to have more frequent and longer hospitalizations at all ages in comparison to the general population [ Kenborg et al 2020 ].

NF1 Phenotypic Variants

Mosaic NF1 (i.e., somatic mosaicism for an NF1 pathogenic variant ) may present as clinical features of NF1 localized to one or more segments of the body or as typical (generalized) NF1 [ Ejerskov et al 2021 ]. Mosaic NF1 is usually milder than typical NF1 involving the same pathogenic variant, and some adults with mosaic NF1 have no clinical features of NF1 [ Kluwe et al 2020 , Yang et al 2020 ]. Mosaic NF1 involving just a single body segment is sometimes called "segmental NF1," but the term "localized mosaic NF1" is preferred because it is more informative and because non-mosaic NF1 may sometimes involve just one part of the body by chance, especially in young children. Adults with mosaic NF1 may have children with typical (i.e., non-mosaic) NF1 [ Legius & Brems 2020 ] (see Genetic Counseling ).

NF1-Noonan syndrome phenotype occurs in approximately 12% of individuals with NF1. The features may include ocular hypertelorism, downslanted palpebral fissures, ptosis, low-set ears, webbed neck, pectus anomaly, and pulmonic stenosis. Affected family members with NF1 may or may not have concomitant features of Noonan syndrome [ Chen et al 2014 , Ekvall et al 2014 ]. The NF1-Noonan syndrome phenotype is genetically heterogeneous. Some individuals have disease-causing variants of both NF1 and PTPN11 (the gene most often involved in Noonan syndrome) [ D'Amico et al 2021 ]. In other individuals, only an NF1 variant is identified [ De Luca et al 2005 ]. Watson syndrome , an overlapping phenotype characterized by pulmonary valvular stenosis, CALMs, short stature, and mild intellectual disability, is caused by NF1 variants [ Allanson et al 1991 ].

Familial spinal neurofibromatosis is characterized by neurofibromas of every spinal nerve root but few (if any) cutaneous manifestations of NF1 [ Bettegowda et al 2021 ]. Despite the name, this phenotype may also occur in simplex cases [ Ruggieri et al 2015 ].

Multiple spinal ganglioneuromas (rather than neurofibromas) and multiple subcutaneous tumors were reported in an adult with an NF1 pathogenic variant whose clinical features were not diagnostic of NF1 [ Bacci et al 2010 ].

Multiple lipomas have been observed in association with a pathogenic variant of NF1 but no other clinical features of NF1 [ Ramirez et al 2021 ].

Symptomatic optic glioma was reported in a male with an NF1 pathogenic variant and no other diagnostic features of NF1 at age 21 years [ Buske et al 1999 ].

Encephalocraniocutaneous lipomatosis was reported in one child with more than five CALMs and an NF1 pathogenic variant [ Legius et al 1995 ].

Genotype-Phenotype Correlations

Several allele - phenotype correlations have been observed in NF1:

1.4-Mb (type 1) deletion of the entire NF1 gene are associated with larger numbers and earlier appearance of cutaneous and plexiform neurofibromas, a higher risk of developing MPNST, more frequent and more severe cognitive abnormalities, somatic overgrowth, and large hands and feet [ Bettegowda et al 2021 , Kehrer-Sawatzki & Cooper 2021 , Pacot et al 2021 , Well et al 2021 ]. A recurrent pattern of dysmorphic features that includes coarse facial appearance, flat forehead, ocular hypertelorism, broad nasal tip, low-set ears, and broad neck is often observed among adolescents and adults [ Kehrer-Sawatzki & Cooper 2021 ].
An unusually severe phenotype with frequent plexiform or spinal neurofibromas, optic pathway gliomas, malignant neoplasms, and skeletal abnormalities has been observed in adults with missense variants of one of five codons between 844 and 848 [ NM_000267.3 ] that code for the cysteine-serine rich domain of neurofibromin [ Koczkowska et al 2018 , Bettegowda et al 2021 ].
p.Met992del is associated with typical pigmentary features of NF1 but no cutaneous, subcutaneous, or surface plexiform neurofibromas [ Bettegowda et al 2021 ]. One quarter of individuals with this variant lack the clinical features needed to meet NF1 diagnostic criteria, but brain tumors outside of the optic pathways, cognitive or learning disabilities, and Noonan syndrome features occur at frequencies similar to those seen in other individuals with NF1.
p.Arg1038Gly has been associated with mild pigmentary features of NF1 but a paucity of neurofibromas and frequent NF1-Noonan syndrome features [ Trevisson et al 2019 ].
Missense variants affecting p.Met1149 have been associated with a mild phenotype characterized by pigmentary features, frequent learning problems, and features of NF1-Noonan syndrome [ Koczkowska et al 2020 ]
Missense variants affecting p.Arg1276 have been associated with a higher-than-expected frequency of cardiovascular malformations, especially pulmonic stenosis, NF1-Noonan phenotype , and symptomatic spinal neurofibromas [ Koczkowska et al 2020 ].
Missense variants affecting p.Lys1423 have been associated with higher-than-expected frequencies of plexiform neurofibromas, as well as of learning problems, cardiovascular malformations (especially pulmonic stenosis), and NF1-Noonan phenotype [ Koczkowska et al 2020 ].
Several missense variants affecting p.Arg1809 are associated with multiple CALMs but absence of cutaneous neurofibromas or clinically apparent plexiform neurofibromas, although learning disabilities, short stature, and pulmonic stenosis often occur [ Pinna et al 2015 , Rojnueangnit et al 2015 , Bettegowda et al 2021 ].

Pedigree studies demonstrate that the penetrance of NF1 is nearly complete after childhood [ Rasmussen & Friedman 2000 ], but molecular testing has documented incomplete penetrance of pathogenic NF1 variants in a small number of individuals [ Bettegowda et al 2021 ].

Nomenclature

NF1 was previously referred to as peripheral neurofibromatosis, to distinguish it from NF2 (central neurofibromatosis) – although CNS involvement may also occur in NF1.

"Neurofibromatosis" without further specification is sometimes used in the literature to refer to NF1, but this usage is confusing because other authors employ the term "neurofibromatosis" to designate a group of conditions that includes (in addition to NF1) Legius syndrome, NF2, and schwannomatosis .

A Finnish register-based total population study estimated the prevalence of NF1 at 1:2,052 between ages 0 and 74 years [ Kallionpää et al 2018 ]. The prevalence was highest in the youngest cohort and lower in older cohorts, reflecting the increased mortality (see Life Expectancy ). The incidence at birth in this study was estimated at 1:1,871 [ Uusitalo et al 2015 ], making NF1 one of the most common autosomal dominant genetic disorders. The prevalence and birth incidence were higher than previous estimates [ Evans et al 2010 ] – likely the result of the diagnosis of more mildly affected individuals rather than differences in the actual incidence and prevalence in the populations studied.

Almost half of all affected individuals have the disorder as the result of de novo variants. If the Finnish estimate of the incidence of NF1 at birth is correct and fertility in affected individuals is reduced by half [ Huson et al 1989 ], the mutation rate for NF1 would be >1:8000, among the highest known for any gene in humans. The cause of the unusually high mutation rate is unknown.

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with germline pathogenic variants in NF1 .

Differential Diagnosis

More than 100 genetic conditions and multiple congenital anomaly syndromes that include café au lait macules (CALMs) or other individual features of neurofibromatosis 1 (NF1) have been described, but few of these disorders are ever confused with NF1. The conditions to consider in the differential diagnosis of NF1 are summarized in Table 3 .

Genes of Interest in the Differential Diagnosis of Neurofibromatosis 1

Disorder	MOI	Clinical Characteristics / Comment
	See footnote 1.	Hamartomatous overgrowth of multiple tissues, connective tissue nevi, epidermal nevi, & hyperostoses
(previously referred to as LEOPARD syndrome)	AD	Multiple lentigines, ocular hypertelorism, deafness, & heart disease
(NS)	AD (AR)	Short stature, heart defect, neck webbing, & characteristic facies. Persons w/NF1 may have NS-like facial features. Facial features of NS change w/age. Features found irrespective of age: low-set, posteriorly rotated ears w/fleshy helices, vivid blue or blue-green irides, hypertelorism, downslanted palpebral fissures, epicanthal folds, & ptosis.
(FD/MAS)	See footnote 3.	Large CALMs w/irregular margins & polyostotic fibrous dysplasia
Piebald trait (OMIM )	AD	Areas of cutaneous pigmentation & depigmentation w/hyperpigmented borders of the unpigmented areas, & white forelock
	AD	Predisposition to develop multiple schwannomas & (less often) meningiomas. Most common presenting feature: localized or diffuse pain or asymptomatic mass.
Constitutional deficiency (CMMRD; see .)	AR	Rare childhood cancer predisposition syndrome. Affected persons often have colorectal cancer or cancer of the small intestine prior to 2nd decade of life. Cutaneous is remarkably similar to NF1. CMMRD is distinguishable from NF1 in that the parents are often & 1 or both parents often have clinical findings &/or family history of Lynch syndrome due to at one of these loci. Typically, neither parent has clinical findings consistent w/NF1.
(NF2)	AD	Bilateral vestibular schwannomas, schwannomas of other cranial & peripheral nerves, cutaneous schwannomas, meningiomas, & juvenile posterior subcapsular cataract
Infantile myofibromatosis (OMIM )	AD	Multiple tumors of the skin, subcutaneous tissues, skeletal muscle, bones, & viscera
	AD	Multiple CALMs w/o neurofibromas, other tumors, or Lisch nodules. Addl features of Legius: freckling, lipomas, macrocephaly, & learning disabilities / ADHD / DDs. ~8% of children w/≥6 CALMs & no other features of NF1 have Legius syndrome.

AD = autosomal dominant ; ADHD = attention-deficit/hyperactivity disorder; AR = autosomal recessive ; CALMs = café au lait macules; DD = developmental delay; MOI = mode of inheritance ; NS = Noonan syndrome

A somatic mosaic AKT1 pathogenic variant has been identified in more than 90% of individuals meeting Proteus syndrome diagnostic criteria. There are no confirmed occurrences of vertical transmission or sib recurrence.

NS is most often inherited in an AD manner. NS caused by pathogenic variants in LZTR1 can be inherited in either an AD or an AR manner.

FD/MAS is the result of early embryonic postzygotic somatic activating mutation of GNAS . There are no verified instances of vertical transmission of FD/MAS.

Clinically distinguishing Legius syndrome from NF1 may be impossible in a young child because neurofibromas and Lisch nodules do not usually arise until later in childhood or adolescence in those with NF1. Examination of the parents for signs of Legius syndrome or NF1 may distinguish the two conditions, but in simplex cases, reevaluation of the individual after adolescence or molecular testing may be necessary to establish the diagnosis [ Legius et al 2021 ].

Other disorders with features of NF1

Isolated familial multiple CALMs (OMIM 114030 ). Among 253 individuals with familial multiple CALMs but no other clinical features of NF1, 86.6% had disease-causing variants of NF1 , 7.1% had disease-causing variants of SPRED1 , and 6.3% did not have an NF1 or SPRED1 disease-causing variant identified [ Messiaen et al 2009 ].
Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face, and marfanoid habitus [ Babovic-Vuksanovic et al 2012 ]

The American Academy of Pediatrics and American College of Medical Genetics and Genomics (ACMG) have published management guidelines for children with NF1 [ Miller et al 2019 ], and the ACMG has published management guidelines for affected adults [ Stewart et al 2018 ]. Similar recommendations have been made by the NF France Network [ Bergqvist et al 2020 ] and by other experts [ Ly & Blakeley 2019 , Baudou & Chaix 2020 ]. Referral to a neurofibromatosis clinic staffed by a variety of medical specialists with experience and particular interest in NF1 may benefit many individuals [ Toledano-Alhadef et al 2020 ].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with neurofibromatosis 1 (NF1), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Recommended Evaluations Following Initial Diagnosis in Individuals with Neurofibromatosis 1

System/Concern	Evaluation	Comment
	Clinical assessment for skin findings of neurofibromas &/or plexiform neurofibromas
	Ophthalmologic eval incl fundoscopy, slit lamp exam of the irides, infrared reflectance imaging or optical coherence tomography of the fundus, & vision assessment
	Neurologic exam; assessment for seizures, headaches, & pain	Note: Routine use of brain MRI in asymptomatic persons is controversial.
	Developmental assessment
	Neuropsychiatric assessment
	Clinical assessment for asymmetry, long bone dysplasia, sphenoid wing dysplasia, vertebral dysplasia &/or scoliosis, & recurrent fractures
	Blood pressure	Evaluate those w/hypertension for renovascular disease or midaortic syndrome, hydronephrosis or other structural renal anomalies, & pheochromocytoma or paraganglioneuroma [ ].
	History & clinical exam for signs/symptoms of heart defects &/or cardiomyopathy
	Plot height, weight, & head circumference on age-appropriate charts.
	By genetics professionals	To inform affected persons & their families re nature, MOI, & implications of NF1 to facilitate medical & personal decision making

MOI = mode of inheritance

Proponents state that brain MRI is useful to identify structural anomalies of the brain or skull, tumors, or vascular disease before it becomes clinically apparent. Those who oppose head MRI in asymptomatic individuals point to the uncertain clinical significance of unidentified bright objects (UBOs), increased cost, requirement for sedation in small children, and findings resulting in repeating imaging for reassurance.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Treatment of Manifestations in Individuals with Neurofibromatosis 1

Manifestation/Concern	Treatment	Considerations/Other
		].
	Surgical removal, laser, or electrocautery for neurofibromas that are disfiguring or in locations that result in discomfort (e.g., at belt or collar lines)	Laser ablation is rapid & effective for removing large numbers of neurofibromas w/satisfactory cosmetic results [ ].

	]. ].	Treatments for MPNST involving MEK inhibitors, immunotherapy, &/or radiation therapy are currently being evaluated in clinical trials [ ].
	Monitoring by brain MRI & mgmt per oncologist w/experience in NF1	]. , ]. Transformation of a pilocytic astrocytoma to a more malignant brain tumor may occur after radiation therapy in persons w/NF1 [ ].
	Although more aggressive breast cancer is reported in NF1, women w/NF1 should be treated in the same manner as others w/similar pathology & tumor markers.	Avoiding radiotherapy, if possible, is reasonable.
	Mgmt per oncologist w/experience in treatment of NF1
	Pain treatment: ];	Persons w/intractable pain that interferes w/ADL despite conventional treatment should be referred to pain specialist.
	Mgmt per developmental specialist [ ]
	Methylphenidate treatment may be beneficial in children w/ADHD [ ].
	Mgmt per neurologist w/experience in treatment of epilepsy
	Mgmt per neurologist w/experience in treatment of headaches
		Surgical treatment of tibial pseudarthrosis is difficult & often unsatisfactory [ ].
	Mgmt per craniofacial team w/experience in treatment of NF1	Mgmt recommendations for orbital/periorbital plexiform neurofibroma in children w/NF1 have been made by a multidisciplinary expert task force [ ].
	Mgmt per orthopedist & spine specialist w/experience in treatment of NF1	Often requires surgical mgmt, which may be complex & difficult [ ]
	Mgmt per orthopedist	Treatment similar to that of scoliosis.
	, ].	Hypovitaminosis D is common in persons w/NF1 of all ages.
	Treatment per nephrologist &/or cardiologist based on cause of hypertension [ ]
	]
	Mgmt per cardiologist & cardiac surgeon
	Mgmt per pediatric endocrinologist
	Mgmt per endocrinologist

ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; MPNST = malignant peripheral nerve sheath tumor

Gross et al [2020] , Galvin et al [2021] , Mukhopadhyay et al [2021] , Anderson et al [2022]

Treatments for plexiform neurofibromas involving other MEK inhibitors are currently being evaluated in clinical trials [ Marjanska et al 2020 , Solares et al 2021 ].

MRI is the method of choice for demonstrating the size and extent of plexiform neurofibromas [ Ahlawat et al 2016 ] and for monitoring their growth over time [ Nguyen et al 2012 ]. MRI is also useful in characterizing optic pathway gliomas, other brain tumors, structural abnormalities of the brain, and signs of cerebrovascular disease in people with NF1 [ Lin et al 2011 , Prada et al 2015 , Blanchard et al 2016 , Sellmer et al 2017 , Sellmer et al 2018 ]. MR angiography is valuable in assessing NF1 vasculopathy [ D'Arco et al 2014 ]. Conventional radiographic studies can demonstrate the skeletal anomalies that occur in people with NF1 [ Patel & Stacy 2012 ], but CT imaging or three-dimensional CT reconstructions may be necessary when surgical treatment of bony lesions is being planned. PET and CT/PET can help to distinguish benign and malignant peripheral nerve sheath tumors [ Chirindel et al 2015 , Salamon et al 2015 , Van Der Gucht et al 2016 ], but definitive differentiation can only be made by histologic examination of the tumor. CT/PET appears to be useful in guiding percutaneous biopsies of peripheral nerve sheath tumors suspected of being malignant [ Brahmi et al 2015 ].

Surveillance

Surveillance recommendations for children and adults with NF1 have been published by ACMG [ Stewart et al 2018 , Miller et al 2019 ]. The evaluations summarized in Table 6a (routine surveillance of children with NF1), and Table 6b (routine surveillance of affected adults) are based on these recommendations.

Recommended Surveillance for Children with Neurofibromatosis 1

System/Concern	Evaluation	Frequency
	Ophthalmologic exam	Annually until adolescence or as recommended by ophthalmologist; exam as needed in older children
	Physical exam for neurofibromas, new or changing plexiform neurofibromas, & other signs/symptoms of malignancy by a clinical provider familiar w/the patient	Annually
	Neurologic assessment for neurologic deficit, seizures, headaches, & pain	Annually . Note: brain MRI only as indicated based on clinically apparent signs or symptoms
		As needed
	Clinical assessment for asymmetry & scoliosis	Annually throughout childhood until growth is complete
	Assess for increased fractures.	Annually
		Annually & prior to surgical procedures
	Assess height & head circumference on NF1 specific growth charts.	Annually throughout childhood
	Assess pubertal development.	Annually throughout early childhood

Persons with NF1 whole- gene deletions, large or growing plexiform neurofibromas or intracranial tumors, symptomatic vascular disease, progressive osseous lesions, or other serious disease manifestations require more frequent targeted follow up.

Recommended Surveillance for Adults with Neurofibromatosis 1

System/Concern	Evaluation	Frequency
	Physical exam for neurofibromas, new or changing plexiform neurofibromas, & other signs/symptoms of malignancy by a clinical provider familiar w/the patient	Annually
	Mammography	Annually beginning at age 30 yrs
	Contrast-enhanced breast MRI	Consider annually btwn ages 30 & 50 yrs.
	Neurologic assessment for neurologic deficit, headaches, seizures, sleep disturbance, & pain	Annually. Note: brain MRI only as indicated based on clinically apparent signs or symptoms
	Assess for cognitive issues & depression.	Annually or as needed
	Clinical assessment for scoliosis & osteoporosis	Annually
	Serum vitamin D levels	As needed
		Annually

The efficacy and cost-effectiveness of such screening have not yet been demonstrated [ Howell et al 2017 ].

Agents/Circumstances to Avoid

Activity restrictions may be required in those with tibial dysplasia or dystrophic scoliosis if recommended by orthopedic specialist.

Radiotherapy of individuals with NF1 appears to be associated with a high risk of developing malignant peripheral nerve sheath tumors within the field of treatment [ Evans et al 2002 , Sharif et al 2006 , Tsang et al 2017 ].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although most pregnancies in individuals with NF1 are normal, preterm delivery, delivery by cæsarean section, hypertension, and placental abruptions are more common than expected [ Chetty et al 2011 , Terry et al 2013 , Leppävirta et al 2018 ]. Although many individuals with NF1 report a rapid increase in the number and size of neurofibromas during pregnancy, no ongoing difference in cutaneous or plexiform neurofibroma volume was observed on whole-body MRI between 13 persons with NF1 who had a pregnancy and 13 age-matched nulligravid persons with NF1 over an observation period that averaged 4.7 years and spanned the pregnancy [ Well et al 2020 ].

Therapies Under Investigation

Therapy of NF1-related MPNST by interfering with various critical cell signaling pathways is under active investigation in preclinical models and early clinical trials [ Brosseau et al 2020 , Foiadelli et al 2020 ].

Many preclinical and clinical investigations of NF1-related gliomas are underway [ Packer et al 2020 , Packer & Vezina 2020 ].

Gene therapy to correct the primary disease-causing NF1 variant is also being studied in model systems [ Cui et al 2020 , Leier et al 2020 ].

Clinical studies are in progress to assess treatments for NF1-associated leukemia, cutaneous neurofibromas, pain, constipation, and hypertension, as well as for cognitive, learning, behavioral, social, and motor impairments.

See NIH ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for list of current clinical trials for NF1.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional . —ED.

Mode of Inheritance

Neurofibromatosis 1 (NF1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Approximately 50% of individuals diagnosed with NF1 have an affected parent.
Approximately 50% of individuals diagnosed with NF1 have the disorder as the result of a de novo NF1 pathogenic variant .
Medical history and physical examination with particular attention to dermal and other features of NF1; and
Ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1.
If neither parent of an individual with NF1 has features that meet the clinical diagnostic criteria for NF1 [ Legius et al 2021 ] after detailed medical history, physical examination, and ophthalmologic examination, the proband most likely has NF1 as the result of a de novo pathogenic variant . Alternatively, the proband may have NF1 as the result of a disease-causing variant inherited from a parent who is mosaic or, rarely, from a heterozygous parent with incomplete penetrance . If the disease-causing variant has been identified in a child with NF1, targeted molecular testing of the parents can be performed to look for mosaicism and determine if a parent is heterozygous (but apparently unaffected due to incomplete penetrance). Note: Parental somatic and germline mosaicism may be present even if there are no clinical signs of NF1 and no evidence of the proband ’s disease-causing NF1 variant on standard molecular testing of either parent’s leukocyte DNA [ Lázaro et al 1995 , Bottillo et al 2010 , Trevisson et al 2014 , Yang et al 2020 ].
The family history may appear to be negative because of failure to recognize NF1 in family members or early death of a parent before the recognition of signs or symptoms. Therefore, an apparently negative family history cannot be confirmed unless both parents have undergone detailed clinical examination for signs of NF1.
Note: An individual in whom NF1 appears to have arisen as the result of de novo mutation may have somatic mosaicism associated with segmental or unusually mild manifestations of NF1 [ Messiaen et al 2011 , García-Romero et al 2016 , Kluwe et al 2020 ]. The risk of a parent with mosaicism for an NF1 pathogenic variant transmitting the disorder to his or her child is less than 50%, but if the pathogenic variant is transmitted, it will be present in every cell in the child's body and the child may be much more severely affected.

Sibs of a proband . The risk to the sibs of the proband depends on the clinical status of the proband's parents.

If a parent is affected, the risk to the sibs is 50%; a sib who inherits an NF1 pathogenic variant will develop features of NF1, but the features may be considerably more (or less) severe in an affected sib than in the proband .
If a parent of a proband has mosaicism for a disease-causing NF1 variant, the risk to sibs of having typical (usually more severe) NF1 is less than 50% and probably depends on the frequency of the NF1 variant in parental germ cells. The frequency of the NF1 variant in parental germ cells cannot be predicted from the frequency of the variant in parental blood or other somatic tissues.
If neither parent of an individual with NF1 meets the clinical diagnostic criteria for NF1 after careful medical history, physical examination, and ophthalmologic examination, the risk to the sibs of the affected individual of having NF1 is low but greater than that of the general population because of the possibility of parental germline mosaicism . Germline mosaicism for an NF1 pathogenic variant has been demonstrated by molecular testing in a few families in which affected sibs were born to unaffected parents [ Lázaro et al 1995 , Bottillo et al 2010 , Trevisson et al 2014 , Yang et al 2020 ].

Offspring of a proband

Each child of an individual with NF1 has a 50% chance of inheriting the NF1 pathogenic variant .
Penetrance is close to 100%; thus, a child who inherits an NF1 pathogenic variant is expected to develop features of NF1, but the features may be considerably more (or less) severe in an affected child than in the child's affected parent.

Other family members. The risk to other family members depends on the status of the proband 's parents: if a proband's parent is affected, other members of his or her family may be at risk.

Related Genetic Counseling Issues

Possibility of multiple de novo pathogenic variants in a single family. Upadhyaya et al [2003] reported the occurrence of three different NF1 pathogenic variants in one family and advised caution in assuming that the same pathogenic variant is present in all members of an affected family. Two different NF1 pathogenic variants have been reported in other families [ Klose et al 1999 , Pacot et al 2019 ].

Considerations in families with an apparent de novo pathogenic variant . When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo . However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption may also be considered.

Family planning

The optimal time for determination of genetic risk and discussion of the availability of prenatal/ preimplantation genetic testing is before pregnancy.
Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the NF1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Ultrasound examination. Prenatal diagnosis of exceptionally severe NF1 by prenatal ultrasound examination has been reported [ McEwing et al 2006 ], but ultrasound examination is unlikely to be informative in most instances.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing . While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here .

Children's Tumor Foundation Phone: 800-323-7938 Email: [email protected] www.ctf.org
Medical Home Portal Neurofibromatosis Type 1
MedlinePlus Neurofibromatosis 1
National Organization for Rare Disorders (NORD) Neurofibromatosis Type 1 (NF1)
Nerve Tumours UK United Kingdom www.nervetumours.org.uk
Neurofibromatosis Network Phone: 630-510-1115 Email: [email protected] www.nfnetwork.org
RASopathies Network Email: [email protected] www.rasopathiesnet.org
NF Registry The NF Registry is for all types of NF (including NF1, NF2, and schwannomatosis). Children’s Tumor Foundation Welcome to the NF Registry
Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. — ED.

Neurofibromatosis 1: Genes and Databases

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
	.2

Data are compiled from the following standard references: gene from HGNC ; chromosome locus from OMIM ; protein from UniProt . For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here .

OMIM Entries for Neurofibromatosis 1 ( View All in OMIM )

	NEUROFIBROMATOSIS, TYPE I; NF1
	NEUROFIBROMIN 1; NF1

Molecular Pathogenesis

NF1 encodes neurofibromin, which activates ras GTPase, thereby controlling cellular proliferation and acting as a tumor suppressor [ Rad & Tee 2016 , Bergoug et al 2020 ]. Neurofibromin has other functions as well, including involvement in somatic cell division and regulation of adenylyl-cyclase activity and intracellular cyclic-AMP generation [ Mo et al 2022 ].

NF1 is large, and more than 3000 different disease-causing variants have been described [ Bettegowda et al 2021 ]. Many pathogenic variants have been observed repeatedly, but none has been found in more than a very small proportion of families studied. Most disease-causing variants are novel, and about half are de novo . Most of the germline NF1 pathogenic variants described appear to cause severe truncation of the gene product , often by altering mRNA splicing .

Mechanism of disease causation. Loss of function

NF1 -specific laboratory technical considerations. Splice variants may not be demonstrable by standard gDNA sequencing alone.

Notable NF1 Pathogenic Variants

Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
.3 .1	c.2970_2972delAAT	p.Met992del	See .
	c.3112A>G	p.Arg1038Gly
	c.3445A>G	p.Met1149Val
	c.3446T>C	p.Met1149Thr
	c.3447G>A	p.Met1149Ile
	c.3447G>C	p.Met1149Ile
	c.3447G>T	p.Met1149Ile
	c.3826C>G	p.Arg1276Gly
	c.3826_3827delinsGA	p.Arg1276Glu
	c.3827G>A	p.Arg1276Gln
	c.3827G>C	p.Arg1276Pro
	c.3827G>T	p.Arg1276Leu
	c.4267A>C	p.Lys1423Gln
	c.4267A>G	p.Lys1423Glu
	c.4268A>C	p.Lys1423Thr
	c.4268A>T	p.Lys1423Met
	c.5425C>A	p.Arg1809Ser
	c.5425C>T	p.Arg1809Cys
	c.5426G>C	p.Arg1809Pro
	c.5426G>T	p.Arg1809Leu
.1	1.4-Mb	--

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society ( varnomen .hgvs.org ). See Quick Reference for an explanation of nomenclature.

Type 1 deletion of the entire NF1 gene

Cancer and Benign Tumors

Several kinds of tumors that occur with increased frequency among persons with NF1 may exhibit somatic (but not germline ) NF1 variants of one or both alleles in individuals who do not have clinical features of NF1 [ D'Angelo et al 2019 , Eoli et al 2019 , Dunnett-Kane et al 2020 , Fisher et al 2021 ]. Examples of sporadic tumors with NF1 somatic variants include malignant peripheral nerve sheath tumors, pheochromocytomas, juvenile myelomonocytic leukemia, gliomas, and breast cancer. Somatic NF1 pathogenic variants may also be found in liposarcomas, lung adenocarcinomas, ovarian carcinomas, colorectal carcinomas, bladder transitional cell carcinoma, neuroblastomas, melanomas, and adult acute myeloid leukemia, all of which are uncommon in individuals with NF1 [ Philpott et al 2017 , Dunnett-Kane et al 2020 ]. Cancers associated with somatic NF1 variants often have different mutational spectra than those seen in individuals with germline NF1 variants.

Chapter Notes

Revision History

21 April 2022 (sw) Comprehensive update posted live
6 June 2019 (ha) Revision: ACMG patient management guidelines for children with NF1 [ Miller et al 2019 ] and for affected adults [ Stewart et al 2018 ] added
17 May 2018 (ma) Revision: treatment of and surveillance for NF1-related breast cancer added to Management
11 January 2018 (ha) Revision: to diagnostic criteria; Wimmer et al 2017 added
2 November 2017 (ha) Comprehensive update posted live
4 September 2014 (me) Comprehensive update posted live
3 May 2012 (me) Comprehensive update posted live
2 June 2009 (me) Comprehensive update posted live
31 January 2007 (me) Comprehensive update posted live
5 October 2004 (me) Comprehensive update posted live
30 September 2002 (me) Comprehensive update posted live
2 October 1998 (pb) Review posted live
Spring 1996 (jmf) Original submission

Literature Cited

Accetturo M, Bartolomeo N, Stella A. In-silico analysis of NF1 missense variants in clinvar: translating variant predictions into variant interpretation and classification. Int J Mol Sci. 2020; 21 :721. [ PMC free article : PMC7037781 ] [ PubMed : 31979111 ]
Afridi SK, Leschziner GD, Ferner RE. Prevalence and clinical presentation of headache in a National Neurofibromatosis 1 Service and impact on quality of life. Am J Med Genet A. 2015; 167A :2282–5. [ PubMed : 26044068 ]
Ahlawat S, Fayad LM, Khan MS, Bredella MA, Harris GJ, Evans DG, Farschtschi S, Jacobs MA, Chhabra A, Salamon JM, Wenzel R, Mautner VF, Dombi E, Cai W, Plotkin SR, Blakeley JO. Whole Body MRI Committee for the REiNS International Collaboration; REiNS International Collaboration Members 2016. Current whole-body MRI applications in the neurofibromatoses: NF1, NF2, and schwannomatosis. Neurology. 2016; 87 :S31–9. [ PMC free article : PMC5578359 ] [ PubMed : 27527647 ]
Albaghdadi M, Thibodeau ML, Lara-Corrales I. Updated approach to patients with multiple café au lait macules. Dermatol Clin. 2022; 40 :9–23. [ PubMed : 34799039 ]
Al-Farsi FAH, Al-Alyani OBS, Al-Kumzari A, Al-Saadi T. Systemic review and meta-analysis of the intellectual integrity of children with neurofibromatosis type 1. World Neurosurg. 2022; 157 :69–74. [ PubMed : 34648986 ]
Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, et al. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet. 1991; 28 :752–6. [ PMC free article : PMC1017110 ] [ PubMed : 1770531 ]
Al-Sharefi A, Javaid U, Perros P, Ealing J, Truran P, Nag S, Kamaruddin S, Abouglila K, Cains F, Lewis L, James RA. Clinical presentation and outcomes of phaeochromocytomas/paragangliomas in neurofibromatosis type 1. Eur Endocrinol. 2019; 15 :95–100. [ PMC free article : PMC6785954 ] [ PubMed : 31616500 ]
Alves Júnior SF, Zanetti G, Alves de Melo AS, Souza AS Jr, Souza LS, de Souza Portes Meirelles G, Irion KL, Hochhegger B, Marchiori E. Neurofibromatosis type 1: State-of-the-art review with emphasis on pulmonary involvement. Respir Med. 2019; 149 :9–15. [ PubMed : 30885426 ]
Anderson MK, Johnson M, Thornburg L, Halford Z. A review of selumetinib in the treatment of neurofibromatosis type 1-related plexiform neurofibromas. Ann Pharmacother. 2022; 56 :716–26. [ PubMed : 34541874 ]
Ater JL, Xia C, Mazewski CM, Booth TN, Freyer DR, Packer RJ, Sposto R, Vezina G, Pollack IF. Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: a report from the Children's Oncology Group. Cancer. 2016; 122 :1928–36. [ PMC free article : PMC4892942 ] [ PubMed : 27061921 ]
Avery RA, Katowitz JA, Fisher MJ, Heidary G, Dombi E, Packer RJ, Widemann BC, et al. Orbital/periorbital plexiform neurofibromas in children with neurofibromatosis type 1: multidisciplinary recommendations for care. Ophthalmology. 2017; 124 :123–32. [ PMC free article : PMC5173440 ] [ PubMed : 27817916 ]
Aydin S, Kurtcan S, Alkan A, Guler S, Filiz M, Yilmaz TF, Sahin TU, Aralasmak A. Relationship between the corpus callosum and neurocognitive disabilities in children with NF-1: diffusion tensor imaging features. Clin Imaging. 2016; 40 :1092–5. [ PubMed : 27423006 ]
Babovic-Vuksanovic D, Messiaen L, Nagel C, Brems H, Scheithauer B, Denayer E, Mao R, Sciot R, Janowski KM, Schuhmann MU, Claes K, Beert E, Garrity JA, Spinner RJ, Stemmer-Rachamimov A, Gavrilova R, Van Calenbergh F, Mautner V, Legius E. Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face and marfanoid habitus: a new syndrome. Eur J Hum Genet. 2012; 20 :618–25. [ PMC free article : PMC3355267 ] [ PubMed : 22258529 ]
Bacci C, Sestini R, Ammannati F, Bianchini E, Palladino T, Carella M, Melchionda S, Zelante L, Papi L. Multiple spinal ganglioneuromas in a patient harboring a pathogenic NF1 mutation. Clin Genet. 2010; 77 :293–7. [ PubMed : 19863548 ]
Barnett C, Alon T, Abraham A, Kim RH, McCuaig JM, Kongkham P, Maurice C, Suppiah S, Zadeh G, Bril V. Evidence of small-fiber neuropathy in neurofibromatosis type 1. Muscle Nerve. 2019; 60 :673–8. [ PubMed : 31465118 ]
Barreto-Duarte B, Andrade-Gomes FH, Arriaga MB, Araújo-Pereira M, Cubillos-Angulo JM, Andrade BB. Association between neurofibromatosis type 1 and cerebrovascular diseases in children: a systematic review. PLoS One. 2021; 16 :e0241096. [ PMC free article : PMC7781472 ] [ PubMed : 33395412 ]
Baudou E, Chaix Y. The value of screening tests in children with neurofibromatosis type 1 (NF1). Childs Nerv Syst. 2020; 36 :2311–19. [ PubMed : 32524181 ]
Baudou E, Nemmi F, Biotteau M, Maziero S, Assaiante C, Cignetti F, Vaugoyeau M, Audic F, Peran P, Chaix Y. Are morphological and structural MRI characteristics related to specific cognitive impairments in neurofibromatosis type 1 (NF1) children? Eur J Paediatr Neurol. 2020; 28 :89–100. [ PubMed : 32893091 ]
Bayat M, Bayat A. Neurological manifestations of neurofibromatosis: a review. Neurol Sci. 2020; 41 :2685–90. [ PubMed : 32358705 ]
Bekiesińska-Figatowska M, Brągoszewska H, Duczkowski M, Romaniuk-Doroszewska A, Szkudlińska-Pawlak S, Duczkowska A, Mądzik J, Kowalska B, Pęczkowski P. Circle of Willis abnormalities in children with neurofibromatosis type 1. Neurol Neurochir Pol. 2014; 48 :15–20. [ PubMed : 24636765 ]
Bellampalli SS, Khanna R. Towards a neurobiological understanding of pain in neurofibromatosis type 1: mechanisms and implications for treatment. Pain. 2019; 160 :1007–18. [ PMC free article : PMC6478401 ] [ PubMed : 31009417 ]
Bergoug M, Doudeau M, Godin F, Mosrin C, Vallée B, Bénédetti H. Neurofibromin structure, functions and regulation. Cells. 2020; 9 :2365. [ PMC free article : PMC7692384 ] [ PubMed : 33121128 ]
Bergqvist C, Hemery F, Jannic A, Ferkal S, Wolkenstein P. Lymphoproliferative malignancies in patients with neurofibromatosis 1. Orphanet J Rare Dis. 2021; 16 :230. [ PMC free article : PMC8136208 ] [ PubMed : 34011343 ]
Bergqvist C, Servy A, Valeyrie-Allanore L, Ferkal S, Combemale P, Wolkenstein P, et al. Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966. Orphanet J Rare Dis. 2020; 15 :37. [ PMC free article : PMC6998847 ] [ PubMed : 32014052 ]
Bernardo P, Cinalli G, Santoro C. Epilepsy in NF1: a systematic review of the literature. Childs Nerv Syst. 2020; 36 :2333–50. [ PubMed : 32613422 ]
Bettegowda C, Upadhayaya M, Evans DG, Kim A, Mathios D, Hanemann CO, et al. Genotype-phenotype correlations in neurofibromatosis and their potential clinical use. Neurology. 2021; 97 :S91–S98. [ PMC free article : PMC8594005 ] [ PubMed : 34230207 ]
Bianchessi D, Ibba MC, Saletti V, Blasa S, Langella T, Paterra R, Cagnoli GA, Melloni G, Scuvera G, Natacci F, Cesaretti C, Finocchiaro G, Eoli M. Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 gene mutations by targeted NGS in an Italian cohort of suspected NF1 patients. Genes (Basel). 2020; 11 :671. [ PMC free article : PMC7349720 ] [ PubMed : 32575496 ]
Blanchard G, Lafforgue MP, Lion-François L, Kemlin I, Rodriguez D, Castelnau P, Carneiro M, Meyer P, Rivier F, Barbarot S, Chaix Y, et al. Systematic MRI in NF1 children under six years of age for the diagnosis of optic pathway gliomas. Study and outcome of a French cohort. Eur J Paediatr Neurol. 2016; 20 :275–81. [ PubMed : 26774135 ]
Bottillo I, Torrente I, Lanari V, Pinna V, Giustini S, Divona L, De Luca A, Dallapiccola B. Germline mosaicism in neurofibromatosis type 1 due to a paternally derived multi-exon deletion. Am J Med Genet A. 2010; 152A :1467–73. [ PubMed : 20503322 ]
Brahmi M, Thiesse P, Ranchere D, Mognetti T, Pinson S, Renard C, Decouvelaere AV, Blay JY, Combemale P. Diagnostic accuracy of PET/CT-guided percutaneous biopsies for malignant peripheral nerve sheath tumors in neurofibromatosis type 1 patients. PLoS One. 2015; 10 :e0138386. [ PMC free article : PMC4596851 ] [ PubMed : 26445379 ]
Brena M, Besagni F, Hernandez-Martin A, Tadini G. Clinical features of NF1 in the skin. In: Multidisciplinary Approach to Neurofibromatosis Type 1, in: Gianluca T, Legius E, Brems H (eds). Multidisciplinary approach to neurofibromatosis type 1. Cham, Switzerland : Springer, [2020]. pp. 46-70.
Brosseau JP, Liao CP, Le LQ. Translating current basic research into future therapies for neurofibromatosis type 1. Br J Cancer. 2020; 123 :178–86. [ PMC free article : PMC7374719 ] [ PubMed : 32439933 ]
Buske A, Gewies A, Lehmann R, Rüther K, Algermissen B, Nürnberg P, Tinschert S. Recurrent NF1 gene mutation in a patient with oligosymptomatic neurofibromatosis type 1 (NF1). Am J Med Genet. 1999; 86 :328–30. [ PubMed : 10494088 ]
Byrne S, Connor S, Lascelles K, Siddiqui A, Hargrave D, Ferner RE. Clinical presentation and prognostic indicators in 100 adults and children with neurofibromatosis 1 associated non-optic pathway brain gliomas. J Neurooncol. 2017; 133 :609–14. [ PMC free article : PMC5537330 ] [ PubMed : 28593402 ]
Calì F, Chiavetta V, Ruggeri G, Piccione M, Selicorni A, Palazzo D, Bonsignore M, Cereda A, Elia M, Failla P, Figura MG, Fiumara A, Maitz S, Luana Mandarà GM, Mattina T, Ragalmuto A, Romano C, Ruggieri M, Salluzzo R, Saporoso A, Schepis C, Sorge G, Spanò M, Tortorella G, Romano V. Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform. Eur J Med Genet. 2017; 60 :93–9. [ PubMed : 27838393 ]
Calvez S, Levy R, Calvez R, Roux CJ, Grévent D, Purcell Y, Beccaria K, Blauwblomme T, Grill J, Dufour C, Bourdeaut F, Doz F, Robert MP, Boddaert N, Dangouloff-Ros V. Focal areas of high signal intensity in children with neurofibromatosis type 1: expected evolution on MRI. AJNR Am J Neuroradiol. 2020; 41 :1733–9. [ PMC free article : PMC7583105 ] [ PubMed : 32816766 ]
Cambiaso P, Galassi S, Palmiero M, Mastronuzzi A, Del Bufalo F, Capolino R, Cacchione A, Buonuomo PS, Gonfiantini MV, Bartuli A, Cappa M, Macchiaiolo M. Growth hormone excess in children with neurofibromatosis type-1 and optic glioma. Am J Med Genet A. 2017; 173 :2353–8. [ PubMed : 28631895 ]
Celik B, Aksoy OY, Bastug F, Poyrazoglu HG. Renal manifestations in children with neurofibromatosis type 1. Eur J Pediatr. 2021; 180 :3477–82. [ PubMed : 34091747 ]
Chauvel-Picard J, Lion-Francois L, Beuriat PA, Paulus C, Szathmari A, Mottolese C, Gleizal A, Di Rocco F. Craniofacial bone alterations in patients with neurofibromatosis type 1. Childs Nerv Syst. 2020; 36 :2391–9. [ PubMed : 32583151 ]
Chen PC, Yin J, Yu HW, Yuan T, Fernandez M, Yung CK, Trinh QM, Peltekova VD, Reid JG, Tworog-Dube E, Morgan MB, Muzny DM, Stein L, McPherson JD, Roberts AE, Gibbs RA, Neel BG, Kucherlapati R. Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc Natl Acad Sci U S A. 2014; 111 :11473–8. [ PMC free article : PMC4128129 ] [ PubMed : 25049390 ]
Chetty SP, Shaffer BL, Norton ME. Management of pregnancy in women with genetic disorders: Part 2: Inborn errors of metabolism, cystic fibrosis, neurofibromatosis type 1, and turner syndrome in pregnancy. Obstet Gynecol Surv. 2011; 66 :765–76. [ PubMed : 22192461 ]
Chirindel A, Chaudhry M, Blakeley JO, Wahl R. 18F-FDG PET/CT qualitative and quantitative evaluation in neurofibromatosis type 1 patients for detection of malignant transformation: comparison of early to delayed imaging with and without liver activity normalization. J Nucl Med. 2015; 56 :379–85. [ PubMed : 25655626 ]
Chisholm AK, Anderson VA, Pride NA, Malarbi S, North KN, Payne JM. Social function and autism spectrum disorder in children and adults with neurofibromatosis type 1: a systematic review and meta-analysis. Neuropsychol Rev. 2018; 28 :317–40. [ PubMed : 30097761 ]
Chisholm AK, Haebich KM, Pride NA, Walsh KS, Lami F, Ure A, Maloof T, Brignell A, Rouel M, Granader Y, Maier A, Barton B, Darke H, Dabscheck G, Anderson VA, Williams K, North KN, Payne JM. Delineating the autistic phenotype in children with neurofibromatosis type 1. Mol Autism. 2022; 13 :3. [ PMC free article : PMC8729013 ] [ PubMed : 34983638 ]
Crucis A, Richer W, Brugières L, Bergeron C, Marie-Cardine A, Stephan JL, Girard P, Corradini N, Munzer M, Lacour B, Minard-Colin V, Sarnacki S, Ranchere-Vince D, Orbach D, Bourdeaut F. Rhabdomyosarcomas in children with neurofibromatosis type I: a national historical cohort. Pediatr Blood Cancer. 2015; 62 :1733–8. [ PubMed : 25893277 ]
Cui XW, Ren JY, Gu YH, Li QF, Wang ZC. NF1, neurofibromin and gene therapy: prospects of next-generation therapy. Curr Gene Ther. 2020; 20 :100–8. [ PubMed : 32767931 ]
D'Amico A, Rosano C, Pannone L, Pinna V, Assunto A, Motta M, Ugga L, Daniele P, Mandile R, Mariniello L, Siano MA, Santoro C, Piluso G, Martinelli S, Strisciuglio P, De Luca A, Tartaglia M, Melis D. Clinical variability of neurofibromatosis 1: A modifying role of cooccurring PTPN11 variants and atypical brain MRI findings. Clin Genet. 2021; 100 :563–72. [ PubMed : 34346503 ]
D'Angelo F, Ceccarelli M, Tala A, Garofano L, Zhang J, Frattini V, Caruso FP, Lewis G, Alfaro KD, Bauchet L, Berzero G, Cachia D, Cangiano M, Capelle L, de Groot J, DiMeco F, Ducray F, Farah W, Finocchiaro G, Goutagny S, Kamiya-Matsuoka C, Lavarino C, Loiseau H, Lorgis V, Marras CE, McCutcheon I, Nam DH, Ronchi S, Saletti V, Seizeur R, Slopis J, Suñol M, Vandenbos F, Varlet P, Vidaud D, Watts C, Tabar V, Reuss DE, Kim SK, Meyronet D, Mokhtari K, Salvador H, Bhat KP, Eoli M, Sanson M, Lasorella A, Iavarone A. The molecular landscape of glioma in patients with neurofibromatosis 1. Nat Med. 2019; 25 :176–87. [ PMC free article : PMC6857804 ] [ PubMed : 30531922 ]
D'Arco F, D'Amico A, Caranci F, Di Paolo N, Melis D, Brunetti A. Cerebrovascular stenosis in neurofibromatosis type 1 and utility of magnetic resonance angiography: our experience and literature review. Radiol Med. 2014; 119 :415–21. [ PubMed : 24297593 ]
De Luca A, Bottillo I, Sarkozy A, Carta C, Neri C, Bellacchio E, Schirinzi A, Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M, Marino B, Pizzuti A, Digilio MC, Tartaglia M, Dallapiccola B. NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. Am J Hum Genet. 2005; 77 :1092–101. [ PMC free article : PMC1285166 ] [ PubMed : 16380919 ]
DeBella K, Poskitt K, Szudek J, Friedman JM. Use of "unidentified bright objects" on MRI for diagnosis of neurofibromatosis 1 in children. Neurology. 2000; 54 :1646–51. [ PubMed : 10762507 ]
Di Nicola M, Viola F. Ocular manifestations of neurofibromatosis type 1. In: Tadini G, Legius E, Brems H, eds. Multidisciplinary Approach to Neurofibromatosis Type 1 . Cham, Switzerland: Springer; 2020:71-84.
DiPaolo DP, Zimmerman RA, Rorke LB, Zackai EH, Bilaniuk LT, Yachnis AT. Neurofibromatosis type 1: pathologic substrate of high-signal-intensity foci in the brain. Radiology. 1995; 195 :721–4. [ PubMed : 7754001 ]
Domon-Archambault V, Gagnon L, Benoît A, Perreault S. Psychosocial features of neurofibromatosis type 1 in children and adolescents. J Child Neurol. 2018; 33 :225–32. [ PubMed : 29318935 ]
Dubov T, Toledano-Alhadef H, Chernin G, Constantini S, Cleper R, Ben-Shachar S. High prevalence of elevated blood pressure among children with neurofibromatosis type 1. Pediatr Nephrol. 2016; 31 :131–6. [ PubMed : 26314566 ]
Dunnett-Kane V, Burkitt-Wright E, Blackhall FH, Malliri A, Evans DG, Lindsay CR. Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts. Ann Oncol. 2020; 31 :873–83. [ PMC free article : PMC7322396 ] [ PubMed : 32240795 ]
Eby NS, Griffith JL, Gutmann DH, Morris SM. Adaptive functioning in children with neurofibromatosis type 1: relationship to cognition, behavior, and magnetic resonance imaging. Dev Med Child Neurol. 2019; 61 :972–8. [ PubMed : 30659594 ]
Ejerskov C, Raundahl M, Gregersen PA, Handrup MM. Clinical features and disease severity in patients with mosaic neurofibromatosis type 1: a single-center study and literature review. Orphanet J Rare Dis. 2021; 16 :180. [ PMC free article : PMC8048193 ] [ PubMed : 33853649 ]
Ekvall S, Sjörs K, Jonzon A, Vihinen M, Annerén G, Bondeson ML. Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome. Am J Med Genet A. 2014; 164A :579–87. [ PubMed : 24357598 ]
Elefteriou F, Kolanczyk M, Schindeler A, Viskochil DH, Hock JM, Schorry EK, Crawford AH, Friedman JM, Little D, Peltonen J, Carey JC, Feldman D, Yu X, Armstrong L, Birch P, Kendler DL, Mundlos S, Yang FC, Agiostratidou G, Hunter-Schaedle K, Stevenson DA. Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options. Am J Med Genet A. 2009; 149A :2327–38. [ PubMed : 19764036 ]
Eoli M, Saletti V, Finocchiaro G. Neurological malignancies in neurofibromatosis type 1. Curr Opin Oncol. 2019; 31 :554–61. [ PubMed : 31436563 ]
Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002; 39 :311–4. [ PMC free article : PMC1735122 ] [ PubMed : 12011145 ]
Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010; 152A :327–32. [ PubMed : 20082463 ]
Evans DG, Kallionpää RA, Clementi M, Trevisson E, Mautner VF, Howell SJ, Lewis L, Zehou O, Peltonen S, Brunello A, Harkness EF, Wolkenstein P, Peltonen J. Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five country cohort study. Genet Med. 2020; 22 :398–406. [ PMC free article : PMC7000349 ] [ PubMed : 31495828 ]
Evans DG, O'Hara C, Wilding A, Ingham SL, Howard E, Dawson J, Moran A, Scott-Kitching V, Holt F, Huson SM. Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989. Eur J Hum Genet. 2011; 19 :1187–91. [ PMC free article : PMC3198144 ] [ PubMed : 21694737 ]
Ferner RE, Gutmann DH. Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol. 2013; 115 :939–55. [ PubMed : 23931823 ]
Filopanti M, Verga U, Ulivieri FM, Giavoli C, Rodari G, Arosio M, Natacci F, Spada A. Trabecular bone score (TBS) and bone metabolism in patients affected with type 1 neurofibromatosis (NF1). Calcif Tissue Int. 2019; 104 :207–13. [ PubMed : 30421324 ]
Fisher MJ, Jones DTW, Li Y, Guo X, Sonawane PS, Waanders AJ, Phillips JJ, Weiss WA, Resnick AC, Gosline S, Banerjee J, Guinney J, Gnekow A, Kandels D, Foreman NK, Korshunov A, Ryzhova M, Massimi L, Gururangan S, Kieran MW, Wang Z, Fouladi M, Sato M, Øra I, Holm S, Markham SJ, Beck P, Jäger N, Wittmann A, Sommerkamp AC, Sahm F, Pfister SM, Gutmann DH. Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1). Acta Neuropathol. 2021; 141 :605–17. [ PubMed : 33585982 ]
Fjermestad KW, Nyhus L, Kanavin ØJ, Heiberg A, Hoxmark LB. Health survey of adults with neurofibromatosis 1 compared to population study controls. J Genet Couns. 2018; 27 :1102–10. [ PubMed : 29429039 ]
Foiadelli T, Naso M, Licari A, Orsini A, Magistrali M, Trabatti C, Luzzi S, Mosconi M, Savasta S, Marseglia GL. Advanced pharmacological therapies for neurofibromatosis type 1-related tumors. Acta Biomed. 2020; 91 :101–14. [ PMC free article : PMC7975824 ] [ PubMed : 32608378 ]
Friedrich RE, Nuding MA. Optic pathway glioma and cerebral focal abnormal signal intensity in patients with neurofibromatosis type 1: characteristics, treatment choices and follow-up in 134 affected individuals and a brief review of the literature. Anticancer Res. 2016; 36 :4095–121. [ PubMed : 27466519 ]
Galvin R, Watson AL, Largaespada DA, Ratner N, Osum S, Moertel CL. Neurofibromatosis in the era of precision medicine: development of MEK inhibitors and recent successes with selumetinib. Curr Oncol Rep. 2021; 23 :45. [ PMC free article : PMC10859964 ] [ PubMed : 33721151 ]
García-Romero MT, Parkin P, Lara-Corrales I. Mosaic Neurofibromatosis Type 1: A Systematic Review. Pediatr Dermatol. 2016; 33 :9–17. [ PubMed : 26338194 ]
Gianluca T, Legius E, Brems H (eds). Multidisciplinary approach to neurofibromatosis type 1 Cham, Switzerland : Springer, [2020] 313 pages.
Giugliano T, Santoro C, Torella A, Del Vecchio Blanco F, Grandone A, Onore ME, Melone MAB, Straccia G, Melis D, Piccolo V, Limongelli G, Buono S, Perrotta S, Nigro V, Piluso G. Clinical and genetic findings in children with neurofibromatosis type 1, Legius syndrome, and other related neurocutaneous disorders. Genes (Basel). 2019; 10 :580. [ PMC free article : PMC6722641 ] [ PubMed : 31370276 ]
Glombova M, Petrak B, Lisy J, Zamecnik J, Sumerauer D, Liby P. Brain gliomas, hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1. Brain Dev. 2019; 41 :678–90. [ PubMed : 31000370 ]
Gross AM, Dombi E, Widemann BC. Current status of MEK inhibitors in the treatment of plexiform neurofibromas. Childs Nerv Syst. 2020; 36 :2443–52. [ PubMed : 32607696 ]
Gruber LM, Erickson D, Babovic-Vuksanovic D, Thompson GB, Young WF Jr, Bancos I. Pheochromocytoma and paraganglioma in patients with neurofibromatosis type 1. Clin Endocrinol (Oxf). 2017; 86 :141–9. [ PubMed : 27460956 ]
Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017; 3 :17004. [ PubMed : 28230061 ]
Haas-Lude K, Heimgärtner M, Winter S, Mautner VF, Krägeloh-Mann I, Lidzba K. Motor dysfunction in NF1: Mediated by attention deficit or inherent to the disorder? Eur J Paediatr Neurol. 2018; 22 :164–9. [ PubMed : 29111114 ]
Hannah-Shmouni F, Stratakis CA. Growth hormone excess in neurofibromatosis 1. Genet Med. 2019; 21 :1254–5. [ PubMed : 30283094 ]
Heervä E, Huilaja L, Leinonen P, Peltonen S, Peltonen J. Follow-up of six patients with neurofibromatosis 1-related osteoporosis treated with alendronate for 23 months. Calcif Tissue Int. 2014; 94 :608–12. [ PubMed : 24390519 ]
Heervä E, Koffert A, Jokinen E, Kuorilehto T, Peltonen S, Aro HT, Peltonen J. A controlled register-based study of 460 neurofibromatosis 1 patients: increased fracture risk in children and adults over 41 years of age. J Bone Miner Res. 2012; 27 :2333–7. [ PubMed : 22692994 ]
Higham CS, Dombi E, Rogiers A, Bhaumik S, Pans S, Connor SEJ, Miettinen M, Sciot R, Tirabosco R, Brems H, Baldwin A, Legius E, Widemann BC, Ferner RE. The characteristics of 76 atypical neurofibromas as precursors to neurofibromatosis 1 associated malignant peripheral nerve sheath tumors. Neuro Oncol. 2018; 20 :818–25. [ PMC free article : PMC5961015 ] [ PubMed : 29409029 ]
Hirabaru K, Matsuo M. Neurological comorbidity in children with neurofibromatosis type 1. Pediatr Int. 2018; 60 :70–5. [ PubMed : 28796925 ]
Howell SJ, Hockenhull K, Salih Z, Evans DG. Increased risk of breast cancer in neurofibromatosis type 1: current insights. Breast Cancer (Dove Med Press). 2017; 9 :531–6. [ PMC free article : PMC5573065 ] [ PubMed : 28860858 ]
Hsieh HY, Fung HC, Wang CJ, Chin SC, Wu T. Epileptic seizures in neurofibromatosis type 1 are related to intracranial tumors but not to neurofibromatosis bright objects. Seizure. 2011; 20 :606–11. [ PubMed : 21621428 ]
Huson SM, Compston DA, Clark P, Harper PS. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J Med Genet. 1989; 26 :704–11. [ PMC free article : PMC1015740 ] [ PubMed : 2511318 ]
Iannuzzi S, Albaret JM, Chignac C, Faure-Marie N, Barry I, Karsenty C, Chaix Y. Motor impairment in children with Neurofibromatosis type 1: effect of the comorbidity with language disorders. Brain Dev. 2016; 38 :181–7. [ PubMed : 26321374 ]
Jalabert M, Ferkal S, Souberbielle JC, Sbidian E, Mageau A, Eymard F, Le Corvoisier P, Allanore L, Chevalier X, Wolkenstein P, Guignard S. Bone status according to neurofibromatosis type 1 phenotype: a descriptive study of 60 women in France. Calcif Tissue Int. 2021; 108 :738–45. [ PubMed : 33558959 ]
Ji J, Shimony J, Gao F, McKinstry RC, Gutmann DH. Optic nerve tortuosity in children with neurofibromatosis type 1. Pediatr Radiol. 2013; 43 :1336–43. [ PMC free article : PMC3904184 ] [ PubMed : 23636538 ]
Jia F, Wang G, Sun J, Liu X. Combined anterior-posterior versus posterior-only spinal fusion in treating dystrophic neurofibromatosis scoliosis with modern instrumentation: a systematic review and meta-analysis. Clin Spine Surg. 2021; 34 :132–42. [ PubMed : 32969869 ]
Jutant EM, Girerd B, Jaïs X, Savale L, O'Connell C, Perros F, Sitbon O, Humbert M, Montani D. Pulmonary hypertension associated with neurofibromatosis type 1. Eur Respir Rev. 2018; 27 :180053. [ PMC free article : PMC9488681 ] [ PubMed : 30158278 ]
Jutant EM, Jaïs X, Girerd B, Savale L, Ghigna MR, Perros F, Mignard X, Jevnikar M, Bourlier D, Prevot G, Tromeur C, Bauer F, Bergot E, Dauphin C, Favrolt N, Traclet J, Soumagne T, De Groote P, Chabanne C, Magro P, Bertoletti L, Gueffet JP, Chaouat A, Goupil F, Moceri P, Borie R, Fadel E, Wolkenstein P, Brillet PY, Simonneau G, Sitbon O, Humbert M, Montani D. Phenotype and outcomes of pulmonary hypertension associated with neurofibromatosis type 1. Am J Respir Crit Care Med. 2020; 202 :843–52. [ PubMed : 32437637 ]
Kallionpää RA, Uusitalo E, Leppävirta J, Pöyhönen M, Peltonen S, Peltonen J. Prevalence of neurofibromatosis type 1 in the Finnish population. Genet Med. 2018; 20 :1082–6. [ PubMed : 29215653 ]
Kaspiris A, Savvidou OD, Vasiliadis ES, Hadjimichael AC, Melissaridou D, Iliopoulou-Kosmadaki S, Iliopoulos ID, Papadimitriou E, Chronopoulos E. Current aspects on the pathophysiology of bone metabolic defects during progression of scoliosis in neurofibromatosis type 1. J Clin Med. 2022; 11 :444. [ PMC free article : PMC8781800 ] [ PubMed : 35054138 ]
Kehrer-Sawatzki H, Cooper DN. Classification of NF1 microdeletions and its importance for establishing genotype/phenotype correlations in patients with NF1 microdeletions. Hum Genet. 2021; 140 :1635–49. [ PMC free article : PMC8553723 ] [ PubMed : 34535841 ]
Kehrer-Sawatzki H, Kluwe L, Salamon J, Well L, Farschtschi S, Rosenbaum T, Mautner VF. Clinical characterization of children and adolescents with NF1 microdeletions. Childs Nerv Syst. 2020; 36 :2297–310. [ PMC free article : PMC7575500 ] [ PubMed : 32533297 ]
Kenborg L, Andersen EW, Duun-Henriksen AK, Jepsen JRM, Doser K, Dalton SO, Bidstrup PE, Krøyer A, Frederiksen LE, Johansen C, Østergaard JR, Hove H, Sørensen SA, Riccardi VM, Mulvihill JJ, Winther JF. Psychiatric disorders in individuals with neurofibromatosis 1 in Denmark: A nationwide register-based cohort study. Am J Med Genet A. 2021; 185 :3706–16. [ PubMed : 34327813 ]
Kenborg L, Duun-Henriksen AK, Dalton SO, Bidstrup PE, Doser K, Rugbjerg K, Pedersen C, Krøyer A, Johansen C, Andersen KK, Østergaard JR, Hove H, Sørensen SA, Riccardi VM, Mulvihill JJ, Winther JF. Multisystem burden of neurofibromatosis 1 in Denmark: registry- and population-based rates of hospitalizations over the life span. Genet Med. 2020; 22 :1069–78. [ PubMed : 32107470 ]
Kinori M, Armarnik S, Listernick R, Charrow J, Zeid JL. Neurofibromatosis type 1-associated optic pathway glioma in children: a follow-up of 10 years or more. Am J Ophthalmol. 2021; 221 :91–6. [ PubMed : 32283094 ]
Kleinerman RA. Radiation-sensitive genetically susceptible pediatric sub-populations. Pediatr Radiol. 2009; 39 Suppl 1:S27–31. [ PMC free article : PMC2656401 ] [ PubMed : 19083227 ]
Klose A, Peters H, Hoffmeyer S, Buske A, Lüder A, Hess D, Lehmann R, Nürnberg P, Tinschert S. Two independent mutations in a family with neurofibromatosis type 1 (NF1). Am J Med Genet. 1999; 83 :6–12. [ PubMed : 10076878 ]
Kluwe L, Friedrich RE, Farschtschi SC, Hagel C, Kehrer-Sawatzki H, Mautner VF. Null phenotype of neurofibromatosis type 1 in a carrier of a heterozygous atypical NF1 deletion due to mosaicism. Hum Mutat. 2020; 41 :1226–31. [ PubMed : 32248581 ]
Koczkowska M, Callens T, Chen Y, Gomes A, Hicks AD, Sharp A, Johns E, Uhas KA, Armstrong L, Bosanko KA, Babovic-Vuksanovic D, Baker L, Basel DG, Bengala M, Bennett JT, Chambers C, Clarkson LK, Clementi M, Cortés FM, Cunningham M, D'Agostino MD, Delatycki MB, Digilio MC, Dosa L, Esposito S, Fox S, Freckmann ML, Fauth C, Giugliano T, Giustini S, Goetsch A, Goldberg Y, Greenwood RS, Griffis C, Gripp KW, Gupta P, Haan E, Hachen RK, Haygarth TL, Hernández-Chico C, Hodge K, Hopkin RJ, Hudgins L, Janssens S, Keller K, Kelly-Mancuso G, Kochhar A, Korf BR, Lewis AM, Liebelt J, Lichty A, Listernick RH, Lyons MJ, Maystadt I, Martinez Ojeda M, McDougall C, McGregor LK, Melis D, Mendelsohn N, Nowaczyk MJM, Ortenberg J, Panzer K, Pappas JG, Pierpont ME, Piluso G, Pinna V, Pivnick EK, Pond DA, Powell CM, Rogers C, Ruhrman Shahar N, Rutledge SL, Saletti V, Sandaradura SA, Santoro C, Schatz UA, Schreiber A, Scott DA, Sellars EA, Sheffer R, Siqveland E, Slopis JM, Smith R, Spalice A, Stockton DW, Streff H, Theos A, Tomlinson GE, Tran G, Trapane PL, Trevisson E, Ullrich NJ, Van den Ende J, Schrier Vergano SA, Wallace SE, Wangler MF, Weaver DD, Yohay KH, Zackai E, Zonana J, Zurcher V, Claes KBM, Eoli M, Martin Y, Wimmer K, De Luca A, Legius E, Messiaen LM. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. Hum Mutat. 2020; 41 :299–315. [ PMC free article : PMC6973139 ] [ PubMed : 31595648 ]
Koczkowska M, Chen Y, Callens T, Gomes A, Sharp A, Johnson S, Hsiao MC, Chen Z, Balasubramanian M, Barnett CP, Becker TA, Ben-Shachar S, Bertola DR, Blakeley JO, Burkitt-Wright EMM, Callaway A, Crenshaw M, Cunha KS, Cunningham M, D'Agostino MD, Dahan K, De Luca A, Destrée A, Dhamija R, Eoli M, Evans DGR, Galvin-Parton P, George-Abraham JK, Gripp KW, Guevara-Campos J, Hanchard NA, Hernández-Chico C, Immken L, Janssens S, Jones KJ, Keena BA, Kochhar A, Liebelt J, Martir-Negron A, Mahoney MJ, Maystadt I, McDougall C, McEntagart M, Mendelsohn N, Miller DT, Mortier G, Morton J, Pappas J, Plotkin SR, Pond D, Rosenbaum K, Rubin K, Russell L, Rutledge LS, Saletti V, Schonberg R, Schreiber A, Seidel M, Siqveland E, Stockton DW, Trevisson E, Ullrich NJ, Upadhyaya M, van Minkelen R, Verhelst H, Wallace MR, Yap YS, Zackai E, Zonana J, Zurcher V, Claes K, Martin Y, Korf BR, Legius E, Messiaen LM. Genotype-phenotype correlation in NF1: evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848. Am J Hum Genet. 2018; 102 :69–87. [ PMC free article : PMC5777934 ] [ PubMed : 29290338 ]
Kongkriangkai AM, King C, Martin LJ, Wakefield E, Prada CE, Kelly-Mancuso G, Schorry EK. Substantial pain burden in frequency, intensity, interference and chronicity among children and adults with neurofibromatosis Type 1. Am J Med Genet A. 2019; 179 :602–7. [ PMC free article : PMC6451830 ] [ PubMed : 30737893 ]
Krishnatry R, Zhukova N, Guerreiro Stucklin AS, Pole JD, Mistry M, Fried I, Ramaswamy V, Bartels U, Huang A, Laperriere N, Dirks P, Nathan PC, Greenberg M, Malkin D, Hawkins C, Bandopadhayay P, Kieran MW, Manley PE, Bouffet E, Tabori U. Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: a population-based study. Cancer. 2016; 122 :1261–9. [ PubMed : 26970559 ]
Kumar MG, Emnett RJ, Bayliss SJ, Gutmann DH. Glomus tumors in individuals with neurofibromatosis type 1. J Am Acad Dermatol. 2014; 71 :44–8. [ PubMed : 24685357 ]
Landry JP, Schertz KL, Chiang YJ, Bhalla AD, Yi M, Keung EZ, Scally CP, Feig BW, Hunt KK, Roland CL, Guadagnolo A, Bishop AJ, Lazar AJ, Slopis JM, McCutcheon IE, Torres KE. Comparison of cancer prevalence in patients with neurofibromatosis type 1 at an academic cancer center vs in the general population from 1985 to 2020. JAMA Netw Open. 2021; 4 :e210945. [ PMC free article : PMC7974640 ] [ PubMed : 33734413 ]
Lázaro C, Gaona A, Lynch M, Kruyer H, Ravella A, Estivill X. Molecular characterization of the breakpoints of a 12-kb deletion in the NF1 gene in a family showing germ-line mosaicism. Am J Hum Genet. 1995; 57 :1044–9. [ PMC free article : PMC1801366 ] [ PubMed : 7485153 ]
Legius E, Brems H. Genetic basis of neurofibromatosis type 1 and related conditions, including mosaicism. Childs Nerv Syst. 2020; 36 :2285–95. [ PubMed : 32601904 ]
Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, Blakeley J, Babovic-Vuksanovic D, Cunha KS, Ferner R, Fisher MJ, Friedman JM, Gutmann DH, Kehrer-Sawatzki H, Korf BR, Mautner VF, Peltonen S, Rauen KA, Riccardi V, Schorry E, Stemmer-Rachamimov A, Stevenson DA, Tadini G, Ullrich NJ, Viskochil D, Wimmer K, Yohay K, Huson SM, Evans DG, Plotkin SR, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021; 23 :1506–13. [ PMC free article : PMC8354850 ] [ PubMed : 34012067 ]
Legius E, Wu R, Eyssen M, Marynen P, Fryns JP, Cassiman JJ. Encephalocraniocutaneous lipomatosis with a mutation in the NF1 gene. J Med Genet. 1995; 32 :316–9. [ PMC free article : PMC1050386 ] [ PubMed : 7643367 ]
Leier A, Bedwell DM, Chen AT, Dickson G, Keeling KM, Kesterson RA, Korf BR, Marquez Lago TT, Müller UF, Popplewell L, Zhou J, Wallis D. Mutation-directed therapeutics for neurofibromatosis type i. Mol Ther Nucleic Acids. 2020; 20 :739–53. [ PMC free article : PMC7225739 ] [ PubMed : 32408052 ]
Leppävirta J, Kallionpää RA, Uusitalo E, Vahlberg T, Pöyhönen M, Peltonen J, Peltonen S. Congenital anomalies in neurofibromatosis 1: a retrospective register-based total population study. Orphanet J Rare Dis. 2018; 13 :5. [ PMC free article : PMC5769274 ] [ PubMed : 29335026 ]
Lin AE, Birch PH, Korf BR, Tenconi R, Niimura M, Poyhonen M, Armfield Uhas K, Sigorini M, Virdis R, Romano C, Bonioli E, Wolkenstein P, Pivnick EK, Lawrence M, Friedman JM. Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1. Am J Med Genet. 2000; 95 :108–17. [ PubMed : 11078559 ]
Lin N, Baird L, Koss M, Kopecky KE, Gone E, Ullrich NJ, Scott RM, Smith ER. Discovery of asymptomatic moyamoya arteriopathy in pediatric syndromic populations: radiographic and clinical progression. Neurosurg Focus. 2011; 31 :E6. [ PubMed : 22133171 ]
Lion-François L, Gueyffier F, Mercier C, Gérard D, Herbillon V, Kemlin I, Rodriguez D, Ginhoux T, Peyric E, Coutinho V, Bréant V, des Portes V, Pinson S, Combemale P, Kassaï B, et al. The effect of methylphenidate on neurofibromatosis type 1: a randomised, double-blind, placebo-controlled, crossover trial. Orphanet J Rare Dis. 2014; 9 :142. [ PMC free article : PMC4172829 ] [ PubMed : 25205361 ]
Liy-Wong C, Mohammed J, Carleton A, Pope E, Parkin P, Lara-Corrales I. The relationship between neurofibromatosis type 1, juvenile xanthogranuloma, and malignancy: A retrospective case-control study. J Am Acad Dermatol. 2017; 76 :1084–7. [ PubMed : 28189268 ]
Ly KI, Blakeley JO. The diagnosis and management of neurofibromatosis type 1. Med Clin North Am. 2019; 103 :1035–54. [ PubMed : 31582003 ]
Madden JR, Rush SZ, Stence N, Foreman NK, Liu AK. Radiation-induced gliomas in 2 pediatric patients with neurofibromatosis type 1: case study and summary of the literature. J Pediatr Hematol Oncol. 2014; 36 :e105–8. [ PubMed : 24136023 ]
Marjanska A, Galazka P, Wysocki M, Styczynski J. New frontiers in therapy of peripheral nerve sheath tumors in patients with neurofibromatosis type 1: latest evidence and clinical implications. Anticancer Res. 2020; 40 :1817–31. [ PubMed : 32234870 ]
Martin E, Coert JH, Flucke UE, Slooff WM, van de Sande MAJ, van Noesel MM, Grünhagen DJ, Wijnen MHWA, Verhoef C. Neurofibromatosis-associated malignant peripheral nerve sheath tumors in children have a worse prognosis: a nationwide cohort study. Pediatr Blood Cancer. 2020; 67 :e28138. [ PubMed : 31889416 ]
Maruoka R, Takenouchi T, Torii C, Shimizu A, Misu K, Higasa K, Matsuda F, Ota A, Tanito K, Kuramochi A, Arima Y, Otsuka F, Yoshida Y, Moriyama K, Niimura M, Saya H, Kosaki K. The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: a validation study. Genet Test Mol Biomarkers. 2014; 18 :722–35. [ PMC free article : PMC4216997 ] [ PubMed : 25325900 ]
Masocco M, Kodra Y, Vichi M, Conti S, Kanieff M, Pace M, Frova L, Taruscio D. Mortality associated with neurofibromatosis type 1: a study based on Italian death certificates (1995-2006). Orphanet J Rare Dis. 2011; 6 :11. [ PMC free article : PMC3079598 ] [ PubMed : 21439034 ]
Mautner VF, Granström S, Leark RA. Impact of ADHD in adults with neurofibromatosis type 1: associated psychological and social problems. J Atten Disord. 2015; 19 :35–43. [ PubMed : 22786884 ]
McEwing RL, Joelle R, Mohlo M, Bernard JP, Hillion Y, Ville Y. Prenatal diagnosis of neurofibromatosis type 1: sonographic and MRI findings. Prenat Diagn. 2006; 26 :1110–4. [ PubMed : 16981221 ]
Méni C, Sbidian E, Moreno JC, Lafaye S, Buffard V, Goldzal S, Wolkenstein P, Valeyrie-Allanore L. Treatment of neurofibromas with a carbon dioxide laser: a retrospective cross-sectional study of 106 patients. Dermatology. 2015; 230 :263–8. [ PubMed : 25662097 ]
Messiaen L, Vogt J, Bengesser K, Fu C, Mikhail F, Serra E, Garcia-Linares C, Cooper DN, Lazaro C, Kehrer-Sawatzki H. Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1). Hum Mutat. 2011; 32 :213–9. [ PubMed : 21280148 ]
Messiaen L, Yao S, Brems H, Callens T, Sathienkijkanchai A, Denayer E, Spencer E, Arn P, Babovic-Vuksanovic D, Bay C, Bobele G, Cohen BH, Escobar L, Eunpu D, Grebe T, Greenstein R, Hachen R, Irons M, Kronn D, Lemire E, Leppig K, Lim C, McDonald M, Narayanan V, Pearn A, Pedersen R, Powell B, Shapiro LR, Skidmore D, Tegay D, Thiese H, Zackai EH, Vijzelaar R, Taniguchi K, Ayada T, Okamoto F, Yoshimura A, Parret A, Korf B, Legius E. Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. JAMA. 2009; 302 :2111–8. [ PubMed : 19920235 ]
Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR, et al. Health supervision for children with neurofibromatosis type 1. Pediatrics. 2019; 19 :143. [ PubMed : 31010905 ]
Miraglia E, Moliterni E, Iacovino C, Roberti V, Laghi A, Moramarco A, Giustini S. Cutaneous manifestations in neurofibromatosis type 1. Clin Ter. 2020; 171 :e371–e377. [ PubMed : 32901776 ]
Mladenov KV, Spiro AS, Krajewski KL, Stücker R, Kunkel P. Management of spinal deformities and tibial pseudarthrosis in children with neurofibromatosis type 1 (NF-1). Childs Nerv Syst. 2020; 36 :2409–25. [ PMC free article : PMC8346390 ] [ PubMed : 32613421 ]
Mo J, Moye SL, McKay RM, Le LQ. Neurofibromin and suppression of tumorigenesis: beyond the GAP. Oncogene. 2022; 41 :1235–51. [ PMC free article : PMC9063229 ] [ PubMed : 35066574 ]
Monroe CL, Dahiya S, Gutmann DH. Dissecting clinical heterogeneity in neurofibromatosis type 1. Annu Rev Pathol. 2017; 12 :53–74. [ PubMed : 28135565 ]
Moramarco A, Giustini S, Nofroni I, Mallone F, Miraglia E, Iacovino C, Calvieri S, Lambiase A. Near-infrared imaging: an in vivo, non-invasive diagnostic tool in neurofibromatosis type 1. Graefes Arch Clin Exp Ophthalmol. 2018; 256 :307–11. [ PubMed : 29290016 ]
Moramarco A, Mallone F, Sacchetti M, Lucchino L, Miraglia E, Roberti V, Lambiase A, Giustini S. Hyperpigmented spots at fundus examination: a new ocular sign in Neurofibromatosis Type I. Orphanet J Rare Dis. 2021; 16 :147. [ PMC free article : PMC7986306 ] [ PubMed : 33757576 ]
Moramarco A, Miraglia E, Mallone F, Roberti V, Iacovino C, Bruscolini A, Giustolisi R, Giustini S. Retinal microvascular abnormalities in neurofibromatosis type 1. Br J Ophthalmol. 2019; 103 :1590–4. [ PubMed : 30705042 ]
Morris SM, Acosta MT, Garg S, Green J, Huson S, Legius E, North KN, Payne JM, Plasschaert E, Frazier TW, Weiss LA, Zhang Y, Gutmann DH, Constantino JN. Disease burden and symptom structure of autism in neurofibromatosis type 1: a study of the International NF1-ASD Consortium Team (INFACT). JAMA Psychiatry. 2016; 73 :1276–84. [ PMC free article : PMC5298203 ] [ PubMed : 27760236 ]
Mukhopadhyay S, Maitra A, Choudhury S. Selumetinib: the first ever approved drug for neurofibromatosis-1 related inoperable plexiform neurofibroma. Curr Med Res Opin. 2021; 37 :789–94. [ PubMed : 33683166 ]
Murphy ES, Xie H, Merchant TE, Yu JS, Chao ST, Suh JH. Review of cranial radiotherapy-induced vasculopathy. J Neurooncol. 2015; 122 :421–9. [ PubMed : 25670390 ]
Nguyen R, Dombi E, Widemann BC, Solomon J, Fuensterer C, Kluwe L, Friedman JM, Mautner VF. Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1. Orphanet J Rare Dis. 2012; 7 :75. [ PMC free article : PMC3524754 ] [ PubMed : 23035791 ]
Nguyen R, Jett K, Harris GJ, Cai W, Friedman JM, Mautner VF. Benign whole body tumor volume is a risk factor for malignant peripheral nerve sheath tumors in neurofibromatosis type 1. J Neurooncol. 2014; 116 :307–13. [ PubMed : 24166582 ]
Nguyen R, Mir TS, Kluwe L, Jett K, Kentsch M, Mueller G, Kehrer-Sawatzki H, Friedman JM, Mautner VF. Cardiac characterization of 16 patients with large NF1 gene deletions. Clin Genet. 2013; 84 :344–9. [ PubMed : 23278345 ]
Niemeyer CM, Flotho C. Juvenile myelomonocytic leukemia: who's the driver at the wheel? Blood. 2019; 133 :1060–70. [ PubMed : 30670449 ]
Ning X, Farschtschi S, Jones A, Kehrer-Sawatzki H, Mautner VF, Friedman JM. Growth in neurofibromatosis 1 microdeletion patients. Clin Genet. 2016; 89 :351–4. [ PubMed : 26111455 ]
Nishida T, Tsujimoto M, Takahashi T, Hirota S, Blay JY, Wataya-Kaneda M. Gastrointestinal stromal tumors in Japanese patients with neurofibromatosis type I. J Gastroenterol. 2016; 51 :571–8. [ PMC free article : PMC4880630 ] [ PubMed : 26511941 ]
Nishida Y, Ikuta K, Ito S, Urakawa H, Sakai T, Koike H, Ito K, Imagama S. Limitations and benefits of FDG-PET/CT in NF1 patients with nerve sheath tumors: a cross-sectional/longitudinal study. Cancer Sci. 2021; 112 :1114–22. [ PMC free article : PMC7935790 ] [ PubMed : 33415792 ]
Ozarslan B, Russo T, Argenziano G, Santoro C, Piccolo V. cutaneous findings in neurofibromatosis type 1. Cancers (Basel). 2021; 13 :463. [ PMC free article : PMC7865571 ] [ PubMed : 33530415 ]
Packer RJ, Iavarone A, Jones DTW, Blakeley JO, Bouffet E, Fisher MJ, Hwang E, Hawkins C, Kilburn L, MacDonald T, Pfister SM, Rood B, Rodriguez FJ, Tabori U, Ramaswamy V, Zhu Y, Fangusaro J, Johnston SA, Gutmann DH. Implications of new understandings of gliomas in children and adults with NF1: report of a consensus conference. Neuro Oncol. 2020; 22 :773–84. [ PMC free article : PMC7283027 ] [ PubMed : 32055852 ]
Packer RJ, Vezina G. New treatment modalities in NF-related neuroglial tumors. Childs Nerv Syst. 2020; 36 :2377–84. [ PubMed : 32601903 ]
Pacot L, Burin des Roziers C, Laurendeau I, Briand-Suleau A, Coustier A, Mayard T, Tlemsani C, Faivre L, Thomas Q, Rodriguez D, Blesson S, Dollfus H, Muller YG, Parfait B, Vidaud M, Gilbert-Dussardier B, Yardin C, Dauriat B, Derancourt C, Vidaud D, Pasmant E. One NF1 mutation may conceal another. Genes (Basel). 2019; 10 :633. [ PMC free article : PMC6769760 ] [ PubMed : 31443423 ]
Pacot L, Vidaud D, Sabbagh A, Laurendeau I, Briand-Suleau A, Coustier A, Maillard T, Barbance C, Morice-Picard F, Sigaudy S, Glazunova OO, Damaj L, Layet V, Quelin C, Gilbert-Dussardier B, Audic F, Dollfus H, Guerrot AM, Lespinasse J, Julia S, Vantyghem MC, Drouard M, Lackmy M, Leheup B, Alembik Y, Lemaire A, Nitschké P, Petit F, Dieux Coeslier A, Mutez E, Taieb A, Fradin M, Capri Y, Nasser H, Ruaud L, Dauriat B, Bourthoumieu S, Geneviève D, Audebert-Bellanger S, Nizon M, Stoeva R, Hickman G, Nicolas G, Mazereeuw-Hautier J, Jannic A, Ferkal S, Parfait B, Vidaud M, Wolkenstein P, Pasmant E, et al. Severe phenotype in patients with large deletions of NF1. Cancers (Basel). 2021; 13 :2963. [ PMC free article : PMC8231977 ] [ PubMed : 34199217 ]
Paley D. Congenital pseudarthrosis of the tibia: biological and biomechanical considerations to achieve union and prevent refracture. J Child Orthop. 2019; 13 :120–33. [ PMC free article : PMC6442511 ] [ PubMed : 30996736 ]
Pardej SK, Glad DM, Casnar CL, Janke KM, Klein-Tasman BP. Longitudinal investigation of early motor development in neurofibromatosis type 1. J Pediatr Psychol. 2022; 47 :180–8. [ PMC free article : PMC9020479 ] [ PubMed : 34664663 ]
Parmeggiani A, Boiani F, Capponi S, Duca M, Angotti M, Pignataro V, Sacrato L, Spinardi L, Vara G, Maltoni L, Cecconi I, Pastore Trossello M, Franzoni E. Neuropsychological profile in Italian children with neurofibromatosis type 1 (NF1) and their relationships with neuroradiological data: Preliminary results. Eur J Paediatr Neurol. 2018; 22 :822–30. [ PubMed : 29802023 ]
Parrozzani R, Pilotto E, Clementi M, Frizziero L, Leonardi F, Convento E, Miglionico G, Pulze S, Perrini P, Trevisson E, Cassina M, Midena E. Retinal vascular abnormalities in a large cohort of patients affected by neurofibromatosis type 1: a study using optical coherence tomography angiography. Retina. 2018; 38 :585–93. [ PubMed : 28248826 ]
Pasmant E, Parfait B, Luscan A, Goussard P, Briand-Suleau A, Laurendeau I, Fouveaut C, Leroy C, Montadert A, Wolkenstein P, Vidaud M, Vidaud D. Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations? Eur J Hum Genet. 2015; 23 :596–601. [ PMC free article : PMC4402624 ] [ PubMed : 25074460 ]
Patel NB, Stacy GS. Musculoskeletal manifestations of neurofibromatosis type 1. AJR Am J Roentgenol. 2012; 199 :W99-106. [ PubMed : 22733937 ]
Payne JM, Pickering T, Porter M, Oates EC, Walia N, Prelog K, North KN. Longitudinal assessment of cognition and T2-hyperintensities in NF1: an 18-year study. Am J Med Genet A. 2014; 164A :661–5. [ PubMed : 24357578 ]
Payne JM, Walsh KS, Pride NA, Haebich KM, Maier A, Chisholm A, Glad DM, Casnar CL, Rouel M, Lorenzo J, Del Castillo A, North KN, Klein-Tasman B. Social skills and autism spectrum disorder symptoms in children with neurofibromatosis type 1: evidence for clinical trial outcomes. Dev Med Child Neurol. 2020; 62 :813–19. [ PubMed : 32181506 ]
Pecoraro A, Arehart E, Gallentine W, Radtke R, Smith E, Pizoli C, Kansagra S, Abdelnour E, McLendon R, Mikati MA. Epilepsy in neurofibromatosis type 1. Epilepsy Behav. 2017; 73 :137–41. [ PubMed : 28633092 ]
Philpott C, Tovell H, Frayling IM, Cooper DN, Upadhyaya M. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics. 2017; 11 :13. [ PMC free article : PMC5480124 ] [ PubMed : 28637487 ]
Pinna V, Daniele P, Calcagni G, Mariniello L, Criscione R, Giardina C, Lepri FR, Hozhabri H, Alberico A, Cavone S, Morella AT, Mandile R, Annunziata F, Di Giosaffatte N, D'Asdia MC, Versacci P, Capolino R, Strisciuglio P, Giustini S, Melis D, Digilio MC, Tartaglia M, Marino B, De Luca A. Prevalence, type, and molecular spectrum of NF1 mutations in patients with neurofibromatosis type 1 and congenital heart disease. Genes (Basel). 2019; 10 :675. [ PMC free article : PMC6770533 ] [ PubMed : 31487937 ]
Pinna V, Lanari V, Daniele P, Consoli F, Agolini E, Margiotti K, Bottillo I, Torrente I, Bruselles A, Fusilli C, Ficcadenti A, Bargiacchi S, Trevisson E, Forzan M, Giustini S, Leoni C, Zampino G, Digilio MC, Dallapiccola B, Clementi M, Tartaglia M, De Luca A. p. Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas. Eur J Hum Genet. 2015; 23 :1068–71. [ PMC free article : PMC4795103 ] [ PubMed : 25370043 ]
Prada CE, Hufnagel RB, Hummel TR, Lovell AM, Hopkin RJ, Saal HM, Schorry EK. The use of magnetic resonance imaging screening for optic pathway gliomas in children with neurofibromatosis type 1. J Pediatr. 2015; 167 :851–6.e1. [ PMC free article : PMC9100836 ] [ PubMed : 26233602 ]
Pride N, Payne JM, Webster R, Shores EA, Rae C, North KN. Corpus callosum morphology and its relationship to cognitive function in neurofibromatosis type 1. J Child Neurol. 2010; 25 :834–41. [ PubMed : 20142468 ]
Rad E, Tee AR. Neurofibromatosis type 1: fundamental insights into cell signalling and cancer. Semin Cell Dev Biol. 2016; 52 :39–46. [ PubMed : 26860753 ]
Ramirez E, Morris SM, Turner TN, Gutmann DH. Familial lipomas without classic neurofibromatosis-1 caused by a missense germline NF1 mutation. Neurol Genet. 2021; 7 :e582. [ PMC free article : PMC8054955 ] [ PubMed : 33884301 ]
Rasmussen SA, Friedman JM. NF1 gene and neurofibromatosis 1. Am J Epidemiol. 2000; 151 :33–40. [ PubMed : 10625171 ]
Riccardi C, Perrone L, Napolitano F, Sampaolo S, Melone MAB. Understanding the biological activities of vitamin D in type 1 neurofibromatosis: new insights into disease pathogenesis and therapeutic design. Cancers (Basel). 2020; 12 :2965. [ PMC free article : PMC7602022 ] [ PubMed : 33066259 ]
Rodari G, Scuvera G, Ulivieri FM, Profka E, Menni F, Saletti V, Esposito S, Bergamaschi S, Ferrante E, Eller-Vainicher C, Esposito S, Arosio M, Giavoli C. Progressive bone impairment with age and pubertal development in neurofibromatosis type I. Arch Osteoporos. 2018; 13 :93. [ PubMed : 30151698 ]
Rojnueangnit K, Xie J, Gomes A, Sharp A, Callens T, Chen Y, Liu Y, Cochran M, Abbott MA, Atkin J, Babovic-Vuksanovic D, Barnett CP, Crenshaw M, Bartholomew DW, Basel L, Bellus G, Ben-Shachar S, Bialer MG, Bick D, Blumberg B, Cortes F, David KL, Destree A, Duat-Rodriguez A, Earl D, Escobar L, Eswara M, Ezquieta B, Frayling IM, Frydman M, Gardner K, Gripp KW, Hernández-Chico C, Heyrman K, Ibrahim J, Janssens S, Keena BA, Llano-Rivas I, Leppig K, McDonald M, Misra VK, Mulbury J, Narayanan V, Orenstein N, Galvin-Parton P, Pedro H, Pivnick EK, Powell CM, Randolph L, Raskin S, Rosell J, Rubin K, Seashore M, Schaaf CP, Scheuerle A, Schultz M, Schorry E, Schnur R, Siqveland E, Tkachuk A, Tonsgard J, Upadhyaya M, Verma IC, Wallace S, Williams C, Zackai E, Zonana J, Lazaro C, Claes K, Korf B, Martin Y, Legius E, Messiaen L. High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation. Hum Mutat. 2015; 36 :1052–63. [ PMC free article : PMC5049609 ] [ PubMed : 26178382 ]
Roy A, Barbarot S, Charbonnier V, Gayet-Delacroix M, Stalder JF, Roulin JL, Le Gall D. Examining the frontal subcortical brain vulnerability hypothesis in children with neurofibromatosis type 1: Are T2-weighted hyperintensities related to executive dysfunction? Neuropsychology. 2015; 29 :473–84. [ PubMed : 25365565 ]
Ruggieri M, Polizzi A, Spalice A, Salpietro V, Caltabiano R, D'Orazi V, Pavone P, Pirrone C, Magro G, Platania N, Cavallaro S, Muglia M, Nicita F. The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin Genet. 2015; 87 :401–10. [ PubMed : 25211147 ]
Sabbagh A, Pasmant E, Imbard A, Luscan A, Soares M, Blanché H, Laurendeau I, Ferkal S, Vidaud M, Pinson S, Bellanné-Chantelot C, Vidaud D, Parfait B, Wolkenstein P. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013; 34 :1510–8. [ PubMed : 23913538 ]
Salamon J, Papp L, Tóth Z, Laqmani A, Apostolova I, Adam G, Mautner VF, Derlin T. Nerve sheath tumors in neurofibromatosis type 1: assessment of whole-body metabolic tumor burden using F-18-FDG PET/CT. PLoS One. 2015; 10 :e0143305. [ PMC free article : PMC4666520 ] [ PubMed : 26625155 ]
Sellmer L, Farschtschi S, Marangoni M, Heran MK, Birch P, Wenzel R, Friedman JM, Mautner VF. Non-optic glioma in adults and children with neurofibromatosis 1. Orphanet J Rare Dis. 2017; 12 :34. [ PMC free article : PMC5312522 ] [ PubMed : 28202035 ]
Sellmer L, Marangoni M, Farschtschi S, Heran MK, Birch P, Wenzel R, Mautner VF, Friedman JM. Serial MRIs provide novel insight into natural history of optic pathway gliomas in patients with neurofibromatosis 1. Orphanet J Rare Dis. 2018; 13 :62. [ PMC free article : PMC5913802 ] [ PubMed : 29685181 ]
Seminog OO, Goldacre MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br J Cancer. 2013; 108 :193–8. [ PMC free article : PMC3553528 ] [ PubMed : 23257896 ]
Serra E, Gel B, Fernández-Rodríguez J, Lázaro C. Genomics of peripheral nerve sheath tumors associated with neurofibromatosis type 1. In: Tadini G, Legius E, Brems H, eds. Multidisciplinary Approach to Neurofibromatosis Type 1 . Cham, Switzerland: Springer; 2020:118-48.
Sharif S, Ferner R, Birch JM, Gillespie JE, Gattamaneni HR, Baser ME, Evans DG. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol. 2006; 24 :2570–5. [ PubMed : 16735710 ]
Sharma MR, Puj KS, Salunke AA, Pandya SJ, Gandhi JS, Parikh AR. Malignant peripheral nerve sheath tumor with analysis of various prognostic factors: a single-institutional experience. J Cancer Res Ther. 2021; 17 :106–13. [ PubMed : 33723140 ]
Shofty B, Ben Sira L, Constantini S. Neurofibromatosis 1-associated optic pathway gliomas. Childs Nerv Syst. 2020; 36 :2351–61. [ PubMed : 32524182 ]
Sivasubramanian R, Meyers KE. Hypertension in children and adolescents with turner syndrome (TS), neurofibromatosis 1 (NF1), and Williams syndrome (WS). Curr Hypertens Rep. 2021; 23 :18. [ PubMed : 33779870 ]
Solares I, Viñal D, Morales-Conejo M, Rodriguez-Salas N, Feliu J. Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review. ESMO Open. 2021; 6 :100223. [ PMC free article : PMC8363824 ] [ PubMed : 34388689 ]
Sorrentino U, Bellonzi S, Mozzato C, Brasson V, Toldo I, Parrozzani R, Clementi M, Cassina M, Trevisson E. Epilepsy in NF1: epidemiologic, genetic, and clinical features. A monocentric retrospective study in a cohort of 784 patients. Cancers (Basel). 2021; 13 :6336. [ PMC free article : PMC8699608 ] [ PubMed : 34944956 ]
Spinnato P, Facchini G, Tetta C, Lotrecchiano L, Colangeli M, Bazzocchi A, Albisinni U, Cutrera R, Tomà P, Bartoloni A. Neurofibromatosis type-1-associated diffuse lung disease in children. Pediatr Pulmonol. 2019; 54 :1760–4. [ PubMed : 31411009 ]
Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020; 139 :1197–207. [ PMC free article : PMC7497289 ] [ PubMed : 32596782 ]
Stevenson DA, Viskochil DH, Schorry EK, Crawford AH, D'Astous J, Murray KA, Friedman JM, Armstrong L, Carey JC. The use of anterolateral bowing of the lower leg in the diagnostic criteria for neurofibromatosis type 1. Genet Med. 2007; 9 :409–12. [ PMC free article : PMC3244139 ] [ PubMed : 17666887 ]
Stewart DR, Korf BR, Nathanson KL, Stevenson DA, Yohay K. Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018; 20 :671–82. [ PubMed : 30006586 ]
Summers MA, Quinlan KG, Payne JM, Little DG, North KN, Schindeler A. Skeletal muscle and motor deficits in neurofibromatosis type 1. J Musculoskelet Neuronal Interact. 2015; 15 :161–70. [ PMC free article : PMC5133719 ] [ PubMed : 26032208 ]
Terry AR, Barker FG 2nd, Leffert L, Bateman BT, Souter I, Plotkin SR. Neurofibromatosis type 1 and pregnancy complications: a population-based study. Am J Obstet Gynecol. 2013; 209 :46.e1–8. [ PubMed : 23535241 ]
Terry AR, Jordan JT, Schwamm L, Plotkin SR. Increased risk of cerebrovascular disease among patients with neurofibromatosis type 1: population-based approach. Stroke. 2016; 47 :60–5. [ PubMed : 26645253 ]
Tezol O, Balcı Y, Alakaya M, Gundogan B, Cıtak EC. Bone densitometry measurements in children with neurofibromatosis Type 1 using quantitative computed tomography. Singapore Med J. 2021. Epub ahead of print. [ PMC free article : PMC9678133 ] [ PubMed : 34005845 ]
Toledano-Alhadef H, Mautner VF, Gugel I, Zipfel J, Haas-Lude K, Constantini S, Schuhmann MU. Role, function and challenges of multidisciplinary centres for rare diseases exemplified for neurofibromatosis type 1 syndrome. Childs Nerv Syst. 2020; 36 :2279–84. [ PMC free article : PMC7276654 ] [ PubMed : 32514759 ]
Touzé R, Manassero A, Bremond-Gignac D, Robert MP. Long-term follow-up of choroidal abnormalities in children with neurofibromatosis type 1. Clin Exp Ophthalmol. 2021; 49 :516–9. [ PubMed : 33893699 ]
Trevisson E, Forzan M, Salviati L, Clementi M. Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism. Clin Genet. 2014; 85 :386–9. [ PubMed : 23621909 ]
Trevisson E, Morbidoni V, Forzan M, Daolio C, Fumini V, Parrozzani R, Cassina M, Midena E, Salviati L, Clementi M. The Arg1038Gly missense variant in the NF1 gene causes a mild phenotype without neurofibromas. Mol Genet Genomic Med. 2019; 7 :e616. [ PMC free article : PMC6503065 ] [ PubMed : 30843352 ]
Tsang DS, Murphy ES, Merchant TE. Radiation therapy for optic pathway and hypothalamic low-grade gliomas in children. Int J Radiat Oncol Biol Phys. 2017; 99 :642–51. [ PubMed : 29280458 ]
Uehara M, Nakamura Y, Takahashi J, Kamimura M, Isobe F, Yamaguchi T, Kosho T, Uchiyama S, Suzuki T, Kato H. Efficacy of denosumab therapy for neurofibromatosis type 1 with osteoporosis and history of fractures: a case report. Ther Clin Risk Manag. 2018; 14 :1243–6. [ PMC free article : PMC6052922 ] [ PubMed : 30038498 ]
Upadhyaya M, Majounie E, Thompson P, Han S, Consoli C, Krawczak M, Cordeiro I, Cooper DN. Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1. Hum Genet. 2003; 112 :12–7. [ PubMed : 12483293 ]
Uusitalo E, Leppävirta J, Koffert A, Suominen S, Vahtera J, Vahlberg T, Pöyhönen M, Peltonen J, Peltonen S. Incidence and mortality of neurofibromatosis: a total population study in Finland. J Invest Dermatol. 2015; 135 :904–6. [ PubMed : 25354145 ]
Uusitalo E, Rantanen M, Kallionpää RA, Pöyhönen M, Leppävirta J, Ylä-Outinen H, Riccardi VM, Pukkala E, Pitkäniemi J, Peltonen S, Peltonen J. Distinctive cancer associations in patients with neurofibromatosis type 1. J Clin Oncol. 2016; 34 :1978–86. [ PubMed : 26926675 ]
Vagge A, Nelson LB, Capris P, Traverso CE. Choroidal freckling in pediatric patients affected by neurofibromatosis type 1. J Pediatr Ophthalmol Strabismus. 2016; 53 :271–4. [ PubMed : 27637020 ]
Valentin T, Le Cesne A, Ray-Coquard I, Italiano A, Decanter G, Bompas E, Isambert N, Thariat J, Linassier C, Bertucci F, Bay JO, Bellesoeur A, Penel N, Le Guellec S, Filleron T, Chevreau C. Management and prognosis of malignant peripheral nerve sheath tumors: the experience of the French Sarcoma Group (GSF-GETO). Eur J Cancer. 2016; 56 :77–84. [ PubMed : 26824706 ]
Van Der Gucht A, Zehou O, Djelbani-Ahmed S, Valeyrie-Allanore L, Ortonne N, Brugières P, Wolkenstein P, Luciani A, Rahmouni A, Sbidian E, Itti E. Metabolic tumour burden measured by 18F-FDG PET/CT predicts malignant transformation in patients with neurofibromatosis Type-1. PLoS One. 2016; 11 :e0151809. [ PMC free article : PMC4795780 ] [ PubMed : 26987124 ]
van Minkelen R, van Bever Y, Kromosoeto JN, Withagen-Hermans CJ, Nieuwlaat A, Halley DJ, van den Ouweland AM. A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands. Clin Genet. 2014; 85 :318–27. [ PubMed : 23656349 ]
Varan A, Şen H, Aydın B, Yalçın B, Kutluk T, Akyüz C. Neurofibromatosis type 1 and malignancy in childhood. Clin Genet. 2016; 89 :341–5. [ PubMed : 26073032 ]
Virdis R, Street ME, Bandello MA, Tripodi C, Donadio A, Villani AR, Cagozzi L, Garavelli L, Bernasconi S. Growth and pubertal disorders in neurofibromatosis type 1. J Pediatr Endocrinol Metab. 2003; 16 Suppl 2:289–92. [ PubMed : 12729406 ]
Vogel AC, Gutmann DH, Morris SM. Neurodevelopmental disorders in children with neurofibromatosis type 1. Dev Med Child Neurol. 2017; 59 :1112–16. [ PubMed : 28845518 ]
Vranceanu AM, Merker VL, Park ER, Plotkin SR. Quality of life among children and adolescents with neurofibromatosis 1: a systematic review of the literature. J Neurooncol. 2015; 122 :219–28. [ PubMed : 25663248 ]
Well L, Döbel K, Kluwe L, Bannas P, Farschtschi S, Adam G, Mautner VF, Salamon J. Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth. PLoS Genet. 2021; 17 :e1009517. [ PMC free article : PMC8099117 ] [ PubMed : 33951044 ]
Well L, Jaeger A, Kehrer-Sawatzki H, Farschtschi S, Avanesov M, Sauer M, de Sousa MT, Bannas P, Derlin T, Adam G, Mautner VF, Salamon JM. The effect of pregnancy on growth-dynamics of neurofibromas in Neurofibromatosis type 1. PLoS One. 2020; 15 :e0232031. [ PMC free article : PMC7188260 ] [ PubMed : 32343738 ]
Wilding A, Ingham SL, Lalloo F, Clancy T, Huson SM, Moran A, Evans DG. Life expectancy in hereditary cancer predisposing diseases: an observational study. J Med Genet. 2012; 49 :264–9. [ PubMed : 22362873 ]
Winter N, Dohrn MF, Wittlinger J, Loizides A, Gruber H, Grimm A. Role of high-resolution ultrasound in detection and monitoring of peripheral nerve tumor burden in neurofibromatosis in children. Childs Nerv Syst. 2020; 36 :2427–32. [ PMC free article : PMC7575466 ] [ PubMed : 32561982 ]
Yang YD, Jiang F, Li DZ. Neurofibromatosis type 1 due to possible maternal mosaicism in a family with two affected siblings. Congenit Anom (Kyoto). 2020; 60 :156–7. [ PubMed : 32352596 ]
Zessis NR, Gao F, Vadlamudi G, Gutmann DH, Hollander AS. Height growth impairment in children with neurofibromatosis type 1 is characterized by decreased pubertal growth velocity in both sexes. J Child Neurol. 2018; 33 :762–6. [ PubMed : 30009646 ]
Zhang J, Tong H, Fu X, Zhang Y, Liu J, Cheng R, Liang J, Peng J, Sun Z, Liu H, Zhang F, Lu W, Li M, Yao Z. Molecular characterization of NF1 and neurofibromatosis type 1 genotype-phenotype correlations in a Chinese population. Sci Rep. 2015; 5 :11291. [ PMC free article : PMC4460887 ] [ PubMed : 26056819 ]

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Diseases & Conditions
Neurofibromatosis type 1

To diagnose neurofibromatosis type 1 (NF1), a healthcare professional begins with a review of your personal and family medical history and a physical exam.

Your child's skin is checked for cafe au lait spots, which can help diagnose NF1.

If other tests are needed to diagnose NF1, your child may need:

Eye exam. An eye exam can reveal Lisch nodules, cataracts and vision loss.
Imaging tests. X-rays, CT scans or MRIs can help identify bone changes, tumors in the brain or spinal cord, and very small tumors. An MRI might be used to diagnose optic gliomas.
Genetic tests. Genetic testing for NF1 can help support the diagnosis. Genetic tests also can be done in pregnancy before a baby is born. Ask a member of your healthcare team about genetic counseling.

For a diagnosis of NF1, at least two symptoms of the condition must be present. A child who has only one symptom and no family history of NF1 is likely to be monitored for any other symptoms. A diagnosis of NF1 is usually made by age 4.

Care at Mayo Clinic

Our caring team of Mayo Clinic experts can help you with your neurofibromatosis type 1-related health concerns Start Here

There isn't a cure for neurofibromatosis type 1 (NF1), but symptoms can be managed. Generally, the sooner someone is under the care of a specialist trained in treating NF1, the better the outcome.

If your child has NF1, often yearly age-appropriate checkups are recommended to:

Check your child's skin for new neurofibromas or changes in existing ones.
Check for signs of high blood pressure.
Check your child's growth and development. This includes measuring height, weight and head circumference to compare to growth charts for children who have NF1.
Look for signs of early puberty.
Look for any skeletal changes.
Check your child's learning development and progress in school.
Get a complete eye exam.

Contact your healthcare team right away if you notice any changes in symptoms between visits. Many complications of NF1 can be treated effectively if therapy starts early.

Selumetinib (Koselugo) is a treatment approved by the U.S. Food and Drug Administration for plexiform neurofibroma in children. The medicine can shrink the size of a tumor. Clinical trials of similar medicines are currently being done for children and adults.

Surgery and other procedures

Surgery to remove tumors may be needed to treat serious symptoms or complications of NF1. Symptoms can be relieved by removing all or part of tumors that are compressing nearby tissue or damaging organs.

Cancer treatment

Cancers related to NF1 are treated with standard cancer therapies, such as surgery, chemotherapy and radiation therapy. Early diagnosis and treatment are the most important factors for a good outcome.

Potential future treatments

Researchers are testing gene therapies for neurofibromatosis type 1 (NF1). Potential new treatments could include replacing the NF1 gene to restore the function of neurofibromin.

Coping and support

Caring for a child with a condition such as neurofibromatosis type 1 (NF1) can be a challenge. But many children with NF1 grow up to live healthy lives with few, if any, complications.

To help you cope:

Find a healthcare professional you can trust and who can coordinate your child's care with other specialists. The Children's Tumor Foundation has an online tool to help you find a specialist in your area.
Join a support group for parents who care for children who have NF1, ADHD, special needs or lifelong illnesses.
Accept help for daily needs such as cooking, cleaning or caring for your other children or simply to take a needed break.
Seek academic support for children who have learning disabilities.

Preparing for your appointment

You may be referred to a doctor who specializes in brain and nervous system conditions, known as a neurologist.

It's a good idea to be well prepared for your appointment. Here's some information to help you get ready and know what to expect.

What you can do

Write down a list of concerns, making a note of when you first noticed them.
Bring a complete medical and family history with you if your healthcare professional doesn't already have it.
Write down key personal information, including any major stresses or recent life changes.
Make a list of all medicines, vitamins or supplements that you or your child is taking.
Bring photographs of any family members — living or deceased — who may have had similar symptoms.
Write down questions to ask your healthcare professional.

Your time during your appointment is limited. Preparing a list of questions can help you make the most of your time. List your questions from most important to least important in case time runs out. For neurofibromatosis, some basic questions to ask include:

Do you suspect neurofibromatosis type 1?
What tests do you recommend?
What treatments are available?
How should the condition be monitored for changes?

In addition to the questions that you've prepared, don't hesitate to ask other questions that occur to you.

What to expect from your doctor

You're likely to be asked a number of questions. Being ready to answer them may allow time later to cover other points you want to address. Your healthcare professional may ask:

When did you first notice symptoms? Have they changed over time?
Is there a family history of neurofibromatosis type 1?

Neurofibromatosis type 1 care at Mayo Clinic

Ferri FF. Neurofibromatosis. In: Ferri's Clinical Advisor 2024. Elsevier; 2024. https://www.clinicalkey.com. Accessed Feb. 21, 2024.
Neurofibromatosis. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Neurofibromatosis-Fact-Sheet. Accessed Feb. 21, 2024.
Korf BR, et al. Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis. https://www.uptodate.com/contents/search. Accessed Feb. 21, 2024.
Saleh M, et al. Neurofibromatosis type 1 system-based manifestations and treatments: A review. Neurological Sciences. 2023; doi:10.1007/s10072-023-06680-5.
Neurofibromatosis. American Association of Neurological Surgeons. https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Neurofibromatosis. Accessed Feb. 21, 2024.
Neurofibromatosis. Merck Manual Professional Version. https://www.merckmanuals.com/professional/pediatrics/neurocutaneous-syndromes/neurofibromatosis. Accessed Feb. 21, 2024.
Jankovic J, et al., eds. Neurocutaneous syndromes. In: Bradley and Daroff's Neurology in Clinical Practice. 8th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed Feb. 21, 2024.
Armstrong AE, et al. Treatment decisions and the use of the MEK inhibitors for children with neurofibromatosis type 1-related plexiform neurofibromas. BMC Cancer. 2023; doi:10.1186/s12885-023-10996-y.
Zitelli BJ, et al., eds. Neurology. In: Zitelli and Davis' Atlas of Pediatric Physical Diagnoses. 8th ed. Elsevier; 2023. https://www.clinicalkey.com. Accessed Feb. 21, 2024.
Kellerman RD, et al. Neurofibromatosis (type 1). In: Conn's Current Therapy 2024. Elsevier; 2024. https://www.clinicalkey.com. Accessed Feb. 21, 2024.
Babovic-Vuksanovic D (expert opinion). Mayo Clinic. March 26, 2024.
Tamura R. Current understanding of neurofibromatosis type 1, 2 and schwannomatosis. International Journal of Molecular Sciences. 2021; doi:10.3390/ijms22115850.
Legius E, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: An international consensus recommendation. Genetics in Medicine. 2021; doi:10.1038/s41436-021-01170-5.
Find a doctor. Children's Tumor Foundation. https://www.ctf.org/understanding-nf/find-a-doctor/. Accessed Feb. 26, 2024.
Ami TR. Allscripts EPSi. Mayo Clinic. April 18, 2024.

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DOI: 10.1016/j.jid.2024.06.1109
Corpus ID: 271341134

LB936 NFX-179 topical gel for the treatment of cutaneous neurofibromas in neurofibromatosis type 1: A multicenter phase 2b study

K. Sarin , N. S. Team , +3 authors G. Webster
Published in Journal of Investigative… 1 August 2024

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IMAGES

Neurofibromatosis type 1
2: NF1 manifestations. The disease Neurofibromatosis Type 1 (NF1) has
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Diagnostic criteria for neurofibromatosis type 1.
Figure 1 from Neurofibromatosis type 1: diagnosis and recent advances
Neurofibromatosis Type-1 (NF1)

COMMENTS

Emerging therapeutic targets for neurofibromatosis type 1 (NF1)
Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited tumor predisposition syndrome with an incidence of one in 3000-4000 individuals with no currently effective therapies. ... Despite the NF1 gene having been identified in 1990, a multitude of factors have hampered research into the disease, for which there is still no ...
Current concepts of neurofibromatosis type 1: pathophysiology and
Neurofibromatosis type 1 is the most common tumor predisposition syndrome inherited in an autosomal dominant (100% penetrance) fashion with a wide variety of expressivity. ... Legius E, et al. Neurofibromatosis type 1-associated MPNST state of the science: outlining a research agenda for the future. J Natl Cancer Inst. 2017; 109:djx124. [PMC ...
Efficacy of Trametinib in Neurofibromatosis Type 1-Associated
Neurofibromatosis type 1 (NF1) or von Recklinghausen disease is the most common autosomal dominant inherited disorder in humans, affecting approximately 1 in 3,000 individuals. 1 The pathogenesis of this disease is based on genetic alterations in the neurofibromin 1 gene, NF1, located on chromosome 17q11.2, which encodes neurofibromin, a tumor suppressor protein. 2 Despite our molecular ...
Neurofibromatosis type 1: New developments in genetics and treatment
Neurofibromatosis type 1 is the most common neurocutaneous syndrome, with a frequency of 1 in 2500 persons. Diagnosis is paramount in the pretumor stage to provide proper anticipatory guidance for a number of neoplasms, both benign and malignant. Loss-of-function mutations in the NF1 gene result in truncated and nonfunctional production of neurofibromin, a tumor suppressor protein involved in ...
Translating current basic research into future therapies for
Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. Biallelic inactivation of the tumour-suppressor ...
Current Understanding of Neurofibromatosis Type 1, 2, and
1. Introduction. Neurofibromatosis (NF) is a genetic disorder that causes multiple tumors on nerve tissues, including brain, spinal cord, and peripheral nerves [1,2,3].There are three types in NF: NF1, NF2, and schwannomatosis (SWN) [].NF1 is the most prevalent, accounting for 96% of all cases and characterized by neurofibromas (peripheral nerve tumors) that induce skin changes and bone ...
Neurofibromatosis Clinical Trials
The objective of this study is to collect blood samples from living patients with neurofibromatosis type 1 (NF1) for future genomic, proteomic, metabolomic, and other research studies. A Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas Rochester, MN. The purpose of this study is to evaluate children ≥ 1 year of age ...
Neurofibromatosis type 1
In children and adolescents with neurofibromatosis type 1, research findings indicate reduced QOL relative to population norms 173,175-177, and parent-reported ratings tend to yield lower scores ...
Revised diagnostic criteria for neurofibromatosis type 1 and Legius
Neurofibromatosis type 1 (NF1; OMIM 613113), inherited in an autosomal dominant pattern, is characterized by multiple café-au-lait macules (CALMs), skinfold freckling (more correctly termed ...
A Systematic Review of Recent and Ongoing Clinical Trials in ...
Introduction: The neurofibromatoses comprise three different genetic conditions causing considerable morbidity and mortality: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). This review summarizes recent and ongoing clinical trials involving patients with neurofibromatoses to better understand the current state of clinical trial research centered ...
Neurofibromatosis Clinical Trials
Overview: This important research study is evaluating potential relations between gene variants (mutations) in the NF1 gene and the formation of neurofibromas in the skin (cutaneous neurofibromas) in people with neurofibromatosis type 1. In addition, we are evaluating the possibility for specific alterations in the NF1 gene may influence the ...
Neurofibromatosis type 1: a multidisciplinary approach to care
Neurofibromatosis type 1 is a relatively common inherited disorder. Patients have a high predisposition to develop both benign and malignant tumours. Although many manifestations of neurofibromatosis type 1 affect the nervous system, other organs and tissues can also be affected. Because of the varying features and clinical heterogeneity inherent to this disorder, patients can present to ...
Cancer and Neurofibromatosis Type 1
It has been known for decades that patients with neurofibromatosis type 1 (NF1) ... From a research standpoint, data are emerging about specific variant-phenotype correlations 5,6; there is no doubt that, when validated, they will refine screening in clinical practice. However, such information is scant, and therefore, general guidelines should ...
A new era for myelin research in Neurofibromatosis type 1
Here, we discuss known and potential repercussions of abnormal central myelin on the neuropathophysiology of Neurofibromatosis Type 1 (NF1). Most patients with this monogenic disease present with neurological symptoms diverse in kind, severity, and onset/decline, including learning disabilities, autism spectrum disorders, attention deficit and ...
Neurofibromatosis, Congressionally Directed Medical Research Programs
Neurofibromatosis (NF) is a group of three genetically distinct disorders that cause tumors to grow in the nervous system. It also produces other abnormalities in the skin and bones. There are three types of NF: 1) Neurofibromatosis Type 1 or NF1 affects 1 in 3500 people worldwide and is caused by a mutation in the neurofibromin gene, 2 ...
New Research Offers More Options to People with Neurofibromatosis Type 1
Substantial research funding and new medications are providing more options—and hope—for people with neurofibromatosis type 1. Illustration by Maria Hergueta A week after Deniro Bruno was born in 2007, his pediatrician noted several tan birthmarks on his skin that she called "café au lait" spots.
ERN GENTURIS tumour surveillance guidelines for individuals with
Geoffrey Jefferson Brain Research Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK ... Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder, predisposing development of benign and malignant tumours. Given the oncogenic potential, long-term surveillance is ...
Neurofibromatosis type 1
Neurofibromatosis type 1 (NF1) is an autosomal dominant, multisystem disorder affecting approximately 1 in 3500 people. ... Further research into genotype-phenotype correlations is needed before such predictions can be made. There is a paucity of available medical treatments but ongoing trials hold promise in treating both the cutaneous and non ...
Neurofibromatosis Type 1 (NF1)
Neurofibromatosis type 1 (NF1) is a condition caused by a change in a specific gene, and therefore can be inherited and passed on. Not all people with NF1 inherit the disease. It can also develop spontaneously. Most people with NF1 have recognizable symptoms often affecting the skin, eyes and nervous system, commonly before age 10.
Neurofibromatosis
Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease; Neurofibromatosis type 2 (NF2) ... conducts and supports research aimed at understanding normal and abnormal development of the brain and nervous system, as well as clinical trials to improve the diagnosis and treatment of neurological disorders, including NF. Other NIH ...
Neurofibromatosis 1
Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and ...
Neurofibromatosis type 1
Neurofibromatosis type 1 (NF1) is a genetic condition that causes changes in skin pigment and tumors on nerve tissue. Skin changes include flat, light brown spots and freckles in the armpits and groin. Tumors can grow anywhere in the nervous system, including the brain, spinal cord and nerves. NF1 is rare. About 1 in 2,500 is affected by NF1.
Neurofibromatosis Type 1
Neurofibromatosis type 1 (NF1) is a rare genetic disorder that can be passed down from parents to their children (inherited). People with NF1 have a higher risk of developing certain kinds of tumors. These tumors are usually non-cancerous (benign) but may sometimes be cancerous (malignant). NF1 can affect many areas of the body.
Neurofibromatosis type 1
To diagnose neurofibromatosis type 1 (NF1), a healthcare professional begins with a review of your personal and family medical history and a physical exam. Your child's skin is checked for cafe au lait spots, which can help diagnose NF1. If other tests are needed to diagnose NF1, your child may need: Eye exam.
LB936 NFX-179 topical gel for the treatment of cutaneous neurofibromas
Semantic Scholar extracted view of "LB936 NFX-179 topical gel for the treatment of cutaneous neurofibromas in neurofibromatosis type 1: A multicenter phase 2b study" by K. Sarin et al. ... AI-powered research tool for scientific literature, based at Ai2. Learn More. About About Us Meet the Team Publishers Blog (opens in a new tab) ...