Overview Of NF1

  • Incidence: ~1 in 3000 individuals
  • Inheritance: Autosomal dominant (approx. 50% of cases are de novo mutations)
  • Gene & Protein: NF1 gene on chromosome 17q11.2 encodes neurofibromin, a GTPase-activating protein that downregulates Ras
  • Main Clinical Features
    • Multiple café au lait spots
    • Axillary or inguinal freckling
    • Neurofibromas (cutaneous, subcutaneous, plexiform)
    • Lisch nodules (iris hamartomas)
    • Bone abnormalities (e.g., sphenoid dysplasia, long bone bowing)
    • Central nervous system tumors (optic gliomas, astrocytomas)
    • Increased risk of pheochromocytoma/paraganglioma (2% of individuals)
    • Macrocephaly, possible cognitive deficits

Diagnostic Criteria

At least two of the following must be present:

  1. Six or more café au lait macules larger than 5 mm in prepubertal individuals or larger than 15 mm in postpubertal individuals
  2. Two or more neurofibromas of any type or one plexiform neurofibroma
  3. Axillary or inguinal freckling
  4. Optic glioma
  5. Two or more Lisch nodules (iris hamartomas)
  6. Distinctive bony lesion, such as sphenoid dysplasia or thinning of the cortex of long bones
  7. First-degree relative with NF1 according to the above criteria

Key Clinical Manifestations

Skin Findings

  • Café au Lait Spots
    • Flat, hyperpigmented lesions
    • Appear in infancy or early childhood
    • Six or more suggests NF1
  • Freckling
    • Dense patches in the axilla or inguinal region (pathognomonic for NF1)

Neurofibromas

  • Cutaneous Neurofibromas
    • Soft, fleshy tumors on the skin surface
    • Commonly appear in adolescence; number increases with age
  • Subcutaneous Neurofibromas
    • Firm, tender nodules along peripheral nerves
  • Plexiform Neurofibromas (nodular or diffuse)
    • May cause disfigurement and, rarely, transform into malignant peripheral nerve sheath tumors

Lisch Nodules

  • Iris Hamartomas
    • Usually asymptomatic, identified by slit-lamp exam
    • Raised, pigmented spots on the iris

Skeletal Abnormalities

  • Sphenoid Wing Dysplasia → facial asymmetry
  • Long Bone Dysplasia → bowing, fractures
  • Vertebral Changes → scalloping from dural ectasia, scoliosis or kyphosis

Nervous System Tumors

  • Optic Pathway Gliomas
    • May present with vision loss, proptosis
  • Other Gliomas (astrocytomas, brainstem gliomas)
  • Hydrocephalus (rare) from aqueductal stenosis

Other

  • Pheochromocytoma/Paraganglioma
    • Occurs in ~2% of patients
    • Hypertension from catecholamine excess or renal artery stenosis
  • Learning Disabilities (mild), macrocephaly in some patients

Genetic & Molecular

  • NF1 Gene: Large gene on 17q11.2 with >95% mutation detection using advanced methods
  • Neurofibromin: A Ras GTPase-activating protein; loss causes increased Ras signaling
  • Inheritance: 50% familial; 50% de novo
  • Genotype-Phenotype:
    • Rarely a single known correlation: a 3-bp deletion (c.2970-2972 delAAT) is associated with few or no cutaneous neurofibromas

Management & Surveillance

  1. Clinical Evaluations
    • Annual blood pressure checks (pheochromocytoma risk)
    • Neurologic and skin exams
    • Eye exams to screen for optic gliomas
  2. Imaging
    • MRI of the brain or orbit if symptoms suggest optic pathway glioma or other CNS tumors
    • Imaging of suspicious neurofibromas or skeletal lesions
  3. Genetic Testing & Counseling
    • Helpful in uncertain cases or family planning
  4. Surgical Interventions
    • Resection of symptomatic or suspicious plexiform neurofibromas
    • Address skeletal deformities if severe
    • Resection or medical management of pheochromocytoma

Patients with NF1 require a multidisciplinary approach (neurologists, geneticists, ophthalmologists, orthopedic surgeons, oncologists) for lifelong monitoring to manage and promptly treat complications.

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