Neurofibromatosis Type 1

name: Neurofibromatosis Type 1
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-02-10T22:44:01Z'
description: >-
  Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome
  caused by germline pathogenic variants in the NF1 tumor suppressor gene encoding
  neurofibromin. It is characterized by cafe-au-lait macules, neurofibromas, Lisch
  nodules, skeletal abnormalities, and increased risk of malignancy including optic
  pathway gliomas and malignant peripheral nerve sheath tumors (MPNST). NF1 exemplifies
  the RASopathy spectrum, with neurofibromin functioning as a RAS-GAP that normally
  negatively regulates RAS-MAPK signaling.
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Neurocutaneous Syndrome
- RASopathy
parents:
- hereditary cancer-predisposing syndrome
pathophysiology:
- name: NF1 Tumor Suppressor Loss
  description: >-
    Germline heterozygous NF1 mutations result in haploinsufficiency for neurofibromin
    function. Somatic loss or mutation of the remaining wild-type allele (second hit)
    eliminates neurofibromin completely, resulting in loss of RAS negative regulation
    and driving tumorigenesis. This follows Knudson's two-hit hypothesis.
  biological_processes:
  - preferred_term: regulation of Ras protein signal transduction
    modifier: DECREASED
    term:
      id: GO:0046578
      label: regulation of Ras protein signal transduction
  genes:
  - preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  downstream:
  - target: RAS-MAPK Pathway Hyperactivation
    description: Loss of RAS-GAP activity results in constitutive RAS-GTP accumulation
- name: RAS-MAPK Pathway Hyperactivation
  description: >-
    Neurofibromin normally accelerates GTP hydrolysis on RAS proteins, promoting
    the inactive GDP-bound state. Loss of neurofibromin results in prolonged RAS-GTP
    accumulation and constitutive activation of the RAS-RAF-MEK-ERK cascade, driving
    cell proliferation and survival.
  biological_processes:
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  downstream:
  - target: Uncontrolled Neural Crest Cell Proliferation
    description: RAS-MAPK activation promotes proliferation of neural crest derivatives
  - target: Neurodevelopmental Circuit Dysfunction
    description: Dysregulated RAS signaling in neurons and glia perturbs cognition and learning networks.
  - target: Skeletal Dysplasia
    description: Aberrant MAPK activity in developing bone contributes to dystrophic skeletal growth.
- name: Uncontrolled Neural Crest Cell Proliferation
  description: >-
    Neural crest-derived cells (Schwann cells, melanocytes) show particular
    dependence on RAS-MAPK signaling. Loss of neurofibromin drives uncontrolled
    proliferation of these cell types, resulting in neurofibromas (Schwann cell
    tumors) and hyperpigmented skin lesions (cafe-au-lait macules from melanocyte
    hyperproliferation).
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Tumor Development
    description: Proliferating neural crest derivatives form benign and malignant tumors
  - target: Cafe-au-lait Macules
    description: Melanocyte hyperproliferation and melanin dysregulation produce hyperpigmented skin macules.
  - target: Lisch Nodules
    description: Melanocytic proliferation in iris stroma generates Lisch nodules.
  - target: Cutaneous Neurofibromas
    description: Schwann-cell-dominant peripheral nerve sheath overgrowth produces cutaneous neurofibromas.
- name: Tumor Development
  description: >-
    Biallelic NF1 loss in Schwann cells drives neurofibroma formation. Most
    neurofibromas remain benign, but plexiform neurofibromas have 8-13% lifetime
    risk of transformation to malignant peripheral nerve sheath tumors (MPNST),
    which require additional genetic events (TP53, CDKN2A loss).
  downstream:
  - target: Plexiform Neurofibromas
    description: Expanded Schwann cell clones in major nerves form plexiform tumors.
  - target: Optic Pathway Glioma
    description: Susceptible glial lineages in optic pathways develop low-grade gliomas.
  - target: Malignant Peripheral Nerve Sheath Tumor
    description: Additional hits in NF1-deficient tumors drive malignant transformation.
- name: Neurodevelopmental Circuit Dysfunction
  description: >-
    Constitutive RAS-MAPK signaling in developing brain circuits disrupts synaptic
    maturation, attention control, and executive function. This contributes to the
    common cognitive and learning phenotype in NF1.
  downstream:
  - target: Learning Difficulties
    description: Circuit-level dysregulation manifests as impaired learning and executive function.
- name: Skeletal Dysplasia
  description: >-
    NF1-related dysregulation of osteoblast and osteoclast signaling alters bone
    modeling and spinal structural integrity, predisposing to deformity.
  downstream:
  - target: Scoliosis
    description: Abnormal vertebral growth and bone remodeling promote progressive spinal curvature.
phenotypes:
- category: Dermatologic
  name: Cafe-au-lait Macules
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Flat, hyperpigmented skin lesions present in >99% of NF1 patients. Six or more
    cafe-au-lait macules >5mm (prepubertal) or >15mm (postpubertal) meet one of
    the NIH diagnostic criteria. Usually present at birth or develop in first years
    of life.
  phenotype_term:
    preferred_term: Multiple cafe-au-lait spots
    term:
      id: HP:0007565
      label: Multiple cafe-au-lait spots
- category: Neoplastic
  name: Cutaneous Neurofibromas
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Benign peripheral nerve sheath tumors arising from Schwann cells. Typically
    appear around puberty and increase in number with age. May cause cosmetic
    concerns but rarely become malignant.
  phenotype_term:
    preferred_term: Neurofibroma
    term:
      id: HP:0001067
      label: Neurofibroma
- category: Neoplastic
  name: Plexiform Neurofibromas
  frequency: FREQUENT
  description: >-
    Diffuse neurofibromas involving multiple nerve fascicles, often present at birth.
    Can cause significant morbidity through mass effect, disfigurement, and pain.
    Approximately 8-13% lifetime risk of malignant transformation to MPNST.
  phenotype_term:
    preferred_term: Plexiform neurofibroma
    term:
      id: HP:0009732
      label: Plexiform neurofibroma
  evidence:
  - reference: PMID:33395032
    supports: PARTIAL
    snippet: >-
      Given the potential of MEK inhibition as an effective and overall well
      tolerated medical treatment, the use of targeted agents in the NF1
      population is likely to increase considerably.
    explanation: >-
      Review confirms plexiform neurofibromas are a significant clinical problem
      in NF1 amenable to MEK inhibitor therapy.
- category: Ophthalmologic
  name: Lisch Nodules
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Melanocytic hamartomas of the iris, appearing as tan-brown dome-shaped elevations.
    Present in >90% of adults with NF1. Best visualized by slit-lamp examination.
    Pathognomonic for NF1 and do not affect vision.
  phenotype_term:
    preferred_term: Lisch nodules
    term:
      id: HP:0009737
      label: Lisch nodules
- category: Neoplastic
  name: Optic Pathway Glioma
  frequency: FREQUENT
  description: >-
    Low-grade gliomas of the optic nerve, chiasm, or tract occur in 15-20% of NF1
    patients. Usually pilocytic astrocytomas. Most are asymptomatic and nonprogressive,
    but can cause vision loss. Peak incidence in first 6 years of life.
  phenotype_term:
    preferred_term: Optic nerve glioma
    term:
      id: HP:0009734
      label: Optic nerve glioma
- category: Neoplastic
  name: Malignant Peripheral Nerve Sheath Tumor
  frequency: OCCASIONAL
  description: >-
    Aggressive sarcoma arising from peripheral nerves, often from transformation of
    plexiform neurofibromas. Lifetime risk 8-13% in NF1. Leading cause of NF1-related
    mortality. Presents with rapid growth, pain, or new neurologic deficits.
  phenotype_term:
    preferred_term: Neurofibrosarcoma
    term:
      id: HP:0100697
      label: Neurofibrosarcoma
  evidence:
  - reference: PMID:32234870
    supports: SUPPORT
    snippet: >-
      Almost all individuals with neurofibromatosis type 1 (NF1) develop peripheral
      nerve sheath tumors (PNSTs), mainly benign neurofibromas, however about 10%
      of PNSTs will undergo transformation to malignant peripheral nerve sheath
      tumors (MPNSTs).
    explanation: >-
      Review confirms approximately 10% of peripheral nerve sheath tumors in NF1
      undergo malignant transformation to MPNST.
- category: Skeletal
  name: Scoliosis
  frequency: FREQUENT
  description: >-
    Spinal curvature occurs in 10-30% of NF1 patients. Can be idiopathic-type or
    dystrophic (sharply angulated, short segment) forms. Dystrophic scoliosis may
    progress rapidly and require surgical intervention.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
- category: Neurologic
  name: Learning Difficulties
  frequency: FREQUENT
  description: >-
    Learning disabilities and attention deficits occur in 50-75% of children with NF1.
    Intelligence is usually normal but specific learning disabilities, ADHD, and
    executive function problems are common. Motor coordination difficulties may occur.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  notes: >-
    Most NF1 patients have normal IQ but specific learning disabilities. HP term
    for learning disability is used as closest match.
biochemical:
- name: NF1 Genetic Testing
  notes: >-
    Comprehensive NF1 testing identifies germline pathogenic variants including
    point mutations, small insertions/deletions, large deletions/duplications,
    and deep intronic variants. Approximately 50% are de novo mutations. Mutation
    detection rate exceeds 95% with comprehensive testing including deletion/duplication
    analysis.
genetic:
- name: NF1
  association: Germline Loss-of-Function Mutations
  inheritance:
  - name: Autosomal Dominant
  notes: >-
    NF1 (17q11.2) encodes neurofibromin, a large protein with RAS-GAP domain that
    negatively regulates RAS signaling. Germline mutations include truncating variants,
    missense mutations in the GAP domain, splice site variants, and large deletions
    (5% of cases, associated with more severe phenotype). De novo mutation rate is
    approximately 50%. Penetrance is essentially complete but expressivity is highly
    variable, even within families.
treatments:
- name: MEK Inhibitors
  description: >-
    Selumetinib is FDA-approved for symptomatic, inoperable plexiform neurofibromas
    in children aged 2 years and older. As a MEK inhibitor, it targets the downstream
    effector of hyperactive RAS signaling. Shrinkage of plexiform neurofibromas
    observed in clinical trials.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:33395032
    supports: SUPPORT
    snippet: >-
      The phase 2 trial (SPRINT) of selumetinib in pNF resulted in at least 20%
      reduction in the size of pNF from baseline in 71% of patients and was associated
      with clinically meaningful improvements. On the basis of this trial, selumetinib
      (Koselugo) received FDA approval for children 2 years of age and older with
      inoperable, symptomatic pNF.
    explanation: >-
      SPRINT trial demonstrated selumetinib efficacy in plexiform neurofibromas
      leading to FDA approval for pediatric NF1 patients.
- name: Surgical Management
  description: >-
    Surgery for symptomatic neurofibromas causing pain, functional impairment, or
    disfigurement. Complete resection of plexiform neurofibromas often impossible
    due to infiltrative nature. Surgery is primary treatment for operable MPNST.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Surveillance Protocol
  description: >-
    Annual clinical evaluation including skin, skeletal, neurologic, and ophthalmologic
    examination. Annual ophthalmologic evaluation in children (optic glioma screening).
    MRI for symptomatic lesions or suspected MPNST. Blood pressure monitoring for
    renovascular disease or pheochromocytoma.
  treatment_term:
    preferred_term: cancer screening
    term:
      id: MAXO:0000126
      label: cancer screening
- name: Genetic Counseling
  description: >-
    Genetic counseling for affected individuals and at-risk family members. Children
    of affected parents have 50% risk. High rate of de novo mutations means negative
    family history does not exclude NF1. Variable expressivity makes predicting
    severity difficult.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
disease_term:
  preferred_term: neurofibromatosis type 1
  term:
    id: MONDO:0018975
    label: neurofibromatosis type 1