What are the components of neurofibromatosis (NF)?

Components of Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is a multisystem disorder characterized by cutaneous, neurologic, ophthalmologic, skeletal, and oncologic manifestations that follow an autosomal dominant inheritance pattern with complete penetrance but variable expressivity. 1

Cutaneous Manifestations

• Café-au-lait macules are typically the initial clinical manifestation, measuring ≥5mm in prepubertal children or ≥15mm in postpubertal individuals, with ≥6 spots required for diagnosis 2, 3
• Axillary or inguinal freckling (Crowe's sign) develops as a diagnostic feature 1, 3
• Dermal neurofibromas protrude from the skin surface and typically appear in the second decade of life, becoming more frequent with age, with no risk of malignant transformation 1
• Subcutaneous neurofibromas present as firm nodules just below the skin surface 1
• Plexiform neurofibromas (PNs) are complex nerve sheath tumors affecting multiple nerve branches, likely congenital but growing during the first two decades, occurring in approximately 50% of NF1 patients 1, 4

Ophthalmologic Manifestations

• Lisch nodules (iris hamartomas) are diagnostic features that do not cause vision loss 1
• Choroidal nodules are present but do not typically result in visual impairment 1
• Optic pathway gliomas (OPGs) occur in approximately 20% of NF1 patients, presenting at median age 4-5 years, with 15-20% progressing and causing visual deterioration, strabismus, proptosis, or nystagmus 1, 4
• Orbital-periorbital plexiform neurofibromas (OPPNs) involve the eyelid, orbit, and facial structures, causing vision loss through deprivational or anisometropic amblyopia and glaucoma 1
• Glaucoma can develop as a complication of orbital involvement 1

Neurologic and Central Nervous System Manifestations

• Low-grade gliomas are the most common CNS tumor type, frequently affecting the optic pathway and presenting before age 8 years 1
• Focal brainstem enlargement from pilocytic or diffuse astrocytomas occurs in <10% of individuals, with mean presentation age of 7 years 1
• Focal areas of signal intensity (unidentified bright objects) appear on brain MRI 3
• Learning disabilities and intellectual disabilities are common neurocognitive manifestations 1, 5

Skeletal Manifestations

• Sphenoid wing dysplasia is a diagnostic bony lesion 3, 5
• Scoliosis develops as a characteristic skeletal abnormality 3, 5
• Other bony dysplasias including long bone abnormalities 5

Malignant Transformation and Associated Neoplasms

• Atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) are premalignant tumors typically developing within or near a known PN in the second to third decades 1, 6
• Malignant peripheral nerve sheath tumors (MPNSTs) arise from PNs with median diagnosis age 33-34 years, representing a leading cause of mortality in NF1 1, 6
• Gastrointestinal stromal tumors (GISTs) show established association with NF1, typically affecting the small intestine and presenting as multifocal lesions in adults 1
• Pheochromocytomas occur as endocrine neoplasms 1, 5
• Rhabdomyosarcoma affects pediatric patients, typically involving urogenital sites 1
• Juvenile myelomonocytic leukemia (JMML) can develop in early childhood 1
• Breast cancer shows 3-fold increased risk in all women with NF1, with 11-fold increased risk in women under age 40 1
• Neuroblastoma occurs at higher frequencies than in the general population during early childhood 1

Vascular Manifestations

• Vasculopathy affects small, medium, and large vessels (primarily arteries), with estimated incidence between 0.4% and 6.4% 1
• Cerebrovascular vasculopathy has an estimated incidence of 2-5%, including moyamoya arteriopathy, aneurysms, and arterial stenosis 1
• Renal artery stenosis causes hypertension in young adults, affecting up to 1% of individuals 1

Molecular and Genetic Features

• Autosomal dominant inheritance with approximately 50% of cases due to sporadic mutations in the NF1 tumor suppressor gene 1
• Neurofibromin deficiency results in loss of RAS pathway negative regulation, predisposing to tumor development 1
• Somatic mosaicism is well documented and may present with variable or few clinical features 1

Clinical Pitfalls

The diagnosis requires meeting specific clinical criteria, and when suspected but not confirmed, consider alternative diagnoses including Legius syndrome (SPRED1), other mosaic RASopathies (KRAS), CDKN2A-related melanoma-astrocytoma syndrome, and constitutional mismatch repair deficiency 1. Life expectancy is reduced by 8-15 years compared to the general population, primarily due to malignant neoplasms 6.