GTS5:Neurofibromatosis type 1 (NF1)

Genetic Tumour Syndromes (Who Classification, 5th ed.)

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Primary Author(s)*

Ngonidzashe Faya, PhD, DABMGG

WHO Classification of Disease

Structure	Disease
Book	WHO Classification of Tumours (Genetic Tumour Syndromes, Soft Tissue and Bone; Central Nervous System Tumours)
Category	Genetic tumour syndromes
Family	RAS-MAPK pathway; Neurocutaneous syndromes
Type	Neurofibromatosis type 1 (NF1)
Subtype(s)	Mosaic NF1 (segmental NF1); Spinal NF1; Neurofibromatosis–Noonan syndrome; 17q11.2 microdeletion syndrome

Related Terminology

Acceptable	N/A
Not Recommended	Von Recklinghausen disease; peripheral neurofibromatosis

Definition/Description of Disease

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic tumour predisposition syndrome caused by heterozygous pathogenic variants in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin (PMID: 2134734; PMID: 1694727). NF1 is clinically diagnosed based on established essential or desirable diagnostic criteria requiring at least two characteristic clinical or molecular features, revised most recently in 2021 (PMID: 34012067; WHO 5^th ed of Genetic Tumour Syndromes):

(1) Six or more café-au-lait macules (CALM) (> 5 mm diameter in children, > 15 mm in adults)

(2) Axillary/inguinal freckling

(3) Two or more neurofibromas of any type or one plexiform neurofibroma (PN)

(4) Optic pathway glioma (OPG) / pilocytic astrocytoma

(5) Two or more iris hamartomas (Lisch nodules) or two or more choroidal abnormalities

(6) Distinctive bony abnormality (anterolateral bowing of the tibia, pseudarthrosis of a long bone, sphenoid dysplasia)

(7) Heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue

(8) Parent or first-degree relative with NF1 (by the above criteria).

NF1 is characterized by multisystem involvement with marked inter- and intrafamilial variable expressivity. Cardinal manifestations include pigmentary abnormalities, peripheral nerve sheath tumours, central nervous system neoplasms, skeletal dysplasia, vasculopathy, and neurocognitive impairment. Tumour manifestations range from benign cutaneous and plexiform neurofibromas to malignant peripheral nerve sheath tumours (MPNSTs) and gliomas. Conditions with overlapping features include Legius syndrome, Noonan syndrome, and constitutional mismatch repair deficiency (PMID: 30415209).

Epidemiology/Prevalence

NF1 has a birth incidence of approximately 1 in 2,500 to 3,000 live births worldwide (PMID: 25354145, 37710322) and approximately 50% of affected individuals have an affected parent, while the remaining cases result from de novo pathogenic variants.

Genetic Abnormalities: Germline

Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
NF1	Nonsense, frameshift, splice-site, missense; small indels	Loss of neurofibromin function with increased RAS signaling	Autosomal dominant; near-complete penetrance; highly variable expressivity	No mutational hotspots; extensive allelic heterogeneity
NF1	17q11.2 microdeletion	Haploinsufficiency of NF1 and contiguous genes	Autosomal dominant; fully penetrant	Associated with early-onset and severe disease, cognitive impairment, dysmorphism, and increased MPNST risk (PMID: 34230207; PMID: 34535841)

Genotype–phenotype correlations have been described for 17q11.2 microdeletion, a 3bp deletion (c.2970_2972del; p.Met992del), and missense variant p.Arg1809. Thus, individuals with a 17q11.2 microdeletion have earlier onset and more severe disease phenotype, including higher burden of neurofibromas and somatic overgrowth, more severe cognitive abnormalities and dysmorphic features, and lastly, higher risk of developing MPNST (PMID:34230207, PMID:34535841). Interestingly, patients with missense variants affecting codons 844-848 exhibit more severe disease phenotype, including visible PN, spinal nerve root neurofibromas, OPG, and MPNST (PMID:29290338), whereas patients with variants in codons 992 or 1809 do not develop neurofibromas or OPGs (PMID: 30190611; PMID:26178382).

Genetic Abnormalities: Somatic

Tumour development in NF1 follows a classic two-hit mechanism, with somatic inactivation of the remaining wild-type NF1 allele in affected tissues (PMID: 8499945). Additional recurrent somatic alterations drive tumour progression and malignant transformation.

Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
NF1	Biallelic inactivation (LOH, deletions, point mutations)	Complete loss of neurofibromin	N/A	Required for development of neurofibromas and NF1-associated gliomas
CDKN2A/CDKN2B	Deletions or inactivating variants	Cell cycle dysregulation	N/A	Common in atypical neurofibromas/ANNUBP and MPNST (PMID: 21987445)
SUZ12, EED	Inactivating variants	PRC2 complex dysfunction	N/A	Associated with loss of H3K27 trimethylation and malignant progression (PMID: 25119042; PMID: 25240281)
TP53, ATRX	Inactivating variants	Genomic instability	N/A	Observed in high-grade gliomas and MPNST (PMID: 30531922)

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
NF1 loss of function	RAS/MAPK; PI3K/AKT/mTOR	Increased cell proliferation and survival
CDKN2A/CDKN2B loss	Cell cycle regulation	Uncontrolled cell division
PRC2 complex genes (SUZ12, EED)	Epigenetic regulation	Loss of H3K27 trimethylation; malignant transformation
TP53, ATRX alterations	DNA damage response; chromatin remodeling	Aggressive tumour behaviour

Genetic Diagnostic Testing Methods

• Germline NF1 testing using next-generation sequencing (NGS) with comprehensive exon and intron coverage
• Copy number analysis (e.g., MLPA or NGS-based CNV detection) to identify exon-level deletions and 17q11.2 microdeletions
• RNA-based assays to improve detection of deep intronic and splice-altering variants
• Tumour sequencing to identify somatic second-hit events and alterations associated with malignant transformation

Additional Information

NF1 management requires lifelong, multidisciplinary surveillance due to the broad spectrum of associated complications. MEK inhibitors are approved for children aged 2–18 years with symptomatic, inoperable plexiform neurofibromas (PMID:32187457). Ongoing clinical trials are evaluating targeted therapies for additional NF1-associated tumours.

Links

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NF1 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

NF1 by COSMIC - sequence information, expression, catalogue of mutations

NF1 by CIViC - general knowledge and evidence-based variant specific information

NF1 by St. Jude ProteinPaint - mutational landscape and matched expression data.

NF1 by OncoKB - mutational landscape, mutation effect, variant classification

NF1 by NCBI Gene - brief gene overview

NF1 by My Cancer Genome  - brief gene overview

NF1 by UniProt - protein and molecular structure and function

NF1 by Pfam -  gene and protein structure and function information

NF1 by GeneCards - general gene information and summaries

NF1 by OMIM (162200) - compendium of human genes and genetic phenotypes

NF1 by LOVD (3.0) - Leiden Open Variation Database

GeneReviews – Neurofibromatosis Type 1

References

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Notes

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Prior Author(s):  

START OF OLD TEMPLATE MATERIAL!

Primary Author(s)*

Ngonidzashe Faya, PhD

Madina Sukhanova, PhD, FACMG

Cancer Category/Type

Genetic Tumour Syndromes (GTS)

Cancer Sub-Classification / Subtype

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Definition / Description of Disease

Neurofibromatosis type 1(NF1) is an autosomal dominant disorder caused by a pathogenic NF1 variant, characterized by at least two of eight diagnostic criteria.

Essential and desirable diagnostic criteria

Essential:

A clinical diagnosis of NF1 requires the presence of at least two of the following features:

(1) Six or more café-au-lait macules (CALM) (> 5 mm diameter in children, > 15 mm in adults)

(2) Axillary/inguinal freckling

(3) Two or more neurofibromas of any type or one plexiform neurofibroma (PN)

(4) Optic pathway glioma (OPG)

(5) Two or more iris hamartomas (Lisch nodules) or two or more choroidal abnormalities

(6) Distinctive bony abnormality (anterolateral bowing of the tibia, pseudarthrosis of a long bone, sphenoid dysplasia)

(7) Heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue

(8) Parent with NF1 (by the above criteria).

These criteria were revised in 2021. Of note, there are other conditions with features that overlap with NF1, including Legius syndrome (OMIM 611431), Noonan syndrome, and constitutive mismatch repair deficiency.

Synonyms / Terminology

Not recommended: Von Recklinghausen disease; peripheral neurofibromatosis

Epidemiology / Prevalence

NF1 is a common autosomal dominant disorder with a birth incidence of 1 per 3000

Clinical Features

Multiple café-au-lait macules (CALMs) are typically present at birth and increase in number during early childhood. Axillary and inguinal freckling occurs in >80% and Lisch nodules (iris hamartomas) in >90% of adults with NF1. Cutaneous neurofibromas (>85% of adults with NF1) frequently develop during puberty, whereas plexiform neurofibromas (PN) are likely congenital, arising in 30–50% of children with NF1. Individual PNs have variable growth rates, but exhibit the greatest growth during infancy and childhood. A subset of PNs transform into atypical neurofibroma/atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP), which can be premalignant lesions with increased risk of transformation into high-grade malignant peripheral nerve sheath tumours (MPNSTs). Possible ANNUBP or MPNST should be considered in patients with growing nodular PNs, PNs in which an isolated portion exhibits disproportionate growth, or adults with continued PN growth.

Specific NF1-associated bone abnormalities, including severe scoliosis, sphenoid wing dysplasia, non-ossifying fibromas, decreased bone mineral density, and congenital tibial bowing, are encountered. Progressive tibial bowing can result in pathological fracture and pseudarthrosis.

Many children exhibit learning disabilities, attention deficits, and problems with reciprocal social interactions. Children with NF1 can also develop vasculopathies, especially of the renal and CNS circulation. Macrocephaly, short stature, epilepsy, headache (including migraine), chronic pain, neuropathy and sleep disturbances are over-represented in people with NF1. Fifteen percent of children will develop an optic pathway glioma/pilocytic astrocytoma (OPG), which causes vision loss in 30-50% of affected individuals. Low-grade gliomas (LGG) are found in other locations, especially the brainstem. Adults with NF1 are prone to malignant gliomas. Brain MRI in children show focal areas of high signal intensity on T2-weighted sequences, which tend to disappear with age and are sometimes difficult to differentiate from LGGs, as well as larger grey matter and corpus callosum volumes. Other neoplasms observed at increased frequency are juvenile myelomonocytic leukaemia, rhabdomyosarcoma, glomus tumours of the digits, gastrointestinal stromal tumours, phaeochromocytoma, breast cancer in females, and duodenal neuroendocrine tumours (somatostatinomas).

Signs and Symptoms	EXAMPLE Asymptomatic (incidental finding on complete blood counts) EXAMPLE B-symptoms (weight loss, fever, night sweats) EXAMPLE Fatigue EXAMPLE Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE Cytopenias EXAMPLE Lymphocytosis (low level)

Sites of Involvement

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Morphologic Features

Café au lait macules

Neurofibromas

Plexiform neurofibroma

Immunophenotype

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Finding	Marker
Positive (universal)	EXAMPLE CD1
Positive (subset)	EXAMPLE CD2
Negative (universal)	EXAMPLE CD3
Negative (subset)	EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE t(9;22)(q34;q11.2)	EXAMPLE 3'ABL1 / 5'BCR	EXAMPLE der(22)	EXAMPLE 20% (COSMIC) EXAMPLE 30% (add reference)	Yes	No	Yes	EXAMPLE The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

Individual Region Genomic Gain/Loss/LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE 7	EXAMPLE Loss	EXAMPLE chr7:1- 159,335,973 [hg38]	EXAMPLE chr7	Yes	Yes	No	EXAMPLE Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:1-145,138,636 [hg38]	EXAMPLE chr8	No	No	No	EXAMPLE Common recurrent secondary finding for t(8;21) (add reference).

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

Gene Mutations (SNV/INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

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Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

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Familial Forms

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Additional Information

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Links

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References

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EXAMPLE Book

1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.