Neurofibromatosis type 1 (NF1), historically called von Recklinghausen disease, is a relatively common autosomal dominant tumor predisposition syndrome with prevalence approximately 1/3,000 to 1/4,000. It results from inactivating mutations in the NF1 gene on chromosome 17q11.2, encoding neurofibromin, a GTPase-activating protein (GAP) that downregulates Ras signaling. Loss of neurofibromin leads to constitutive Ras-MAPK pathway activation and tumor formation. Approximately 50% of cases are familial; the remainder arise from de novo mutations.
Cutaneous manifestations are central to diagnosis. Café-au-lait macules (CALM) are well-defined uniformly hyperpigmented macules typically present at birth or developing in infancy; the diagnostic threshold is 6 or more lesions exceeding 5 mm prepuberty or 15 mm postpuberty. Axillary or inguinal freckling (Crowe sign) appears in skin folds during early childhood. Cutaneous neurofibromas (CNFs) are soft, sessile, dome-shaped, or pedunculated tumors that develop during late childhood and increase in number through adulthood; women experience increased growth during pregnancy. Plexiform neurofibromas (PNFs, present in 50% by adulthood) are larger, deeper, and may involve nerve plexuses or internal organs, with 8-13% lifetime risk of malignant peripheral nerve sheath tumor (MPNST) transformation.
Diagnosis requires 2 or more of the 2021 revised NIH/NF1 diagnostic criteria: 6+ CALMs of appropriate size; freckling in axillary/inguinal/intertriginous areas; 2+ cutaneous neurofibromas or 1 plexiform; optic glioma; 2+ iris Lisch nodules or 2+ choroidal abnormalities; distinctive osseous lesion (sphenoid dysplasia, long bone bowing); first-degree relative with NF1; or heterozygous pathogenic NF1 variant. Surveillance includes annual physical examination, ophthalmologic assessment for optic glioma in children (annual until age 8), spine examination for scoliosis, blood pressure monitoring (renovascular hypertension, pheochromocytoma risk), and MRI for symptomatic plexiform or suspected MPNST. Breast cancer screening starts at age 30 in women (mammography + MRI). Selumetinib, an oral MEK1/2 inhibitor, was FDA-approved in 2020 for inoperable plexiform neurofibromas in children aged 2 and older. Cosmetic CNF removal can be performed by excision, electrodesiccation, or CO2 laser. Genetic counseling is recommended for affected families.