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:
- Six or more café au lait macules larger than 5 mm in prepubertal individuals or larger than 15 mm in postpubertal individuals
- Two or more neurofibromas of any type or one plexiform neurofibroma
- Axillary or inguinal freckling
- Optic glioma
- Two or more Lisch nodules (iris hamartomas)
- Distinctive bony lesion, such as sphenoid dysplasia or thinning of the cortex of long bones
- 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
- Clinical Evaluations
- Annual blood pressure checks (pheochromocytoma risk)
- Neurologic and skin exams
- Eye exams to screen for optic gliomas
- Imaging
- MRI of the brain or orbit if symptoms suggest optic pathway glioma or other CNS tumors
- Imaging of suspicious neurofibromas or skeletal lesions
- Genetic Testing & Counseling
- Helpful in uncertain cases or family planning
- 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.