neurofibromatosis type 1
Summary
Neurofibromatosis type 1 (NF1, von Recklinghausen disease) is an autosomal dominant neurocutaneous disorder caused by loss-of-function mutations in the NF1 tumor suppressor gene (chromosome 17q11.2), which encodes neurofibromin, a negative regulator of Ras. Classic findings include café-au-lait macules, axillary/inguinal freckling, cutaneous neurofibromas, Lisch nodules, optic pathway gliomas, and sphenoid dysplasia. It has ~100% penetrance, variable expressivity, and ~50% of cases arise from de novo mutations.
Detail
**Genetics and pathophysiology** - Autosomal dominant; NF1 gene on chromosome 17q11.2. Remember "von Recklinghausen = 17 letters" (NF1 on chromosome 17) vs NF2 on chromosome 22. - The gene encodes neurofibromin, a GTPase-activating protein (GAP) that inactivates Ras by promoting Ras-GTP to Ras-GDP. Loss of function leads to constitutive Ras/MAPK (and PI3K/mTOR) activation, which drives uncontrolled cell growth. - Tumor suppressor gene, so tumors follow the two-hit hypothesis (germline mutation plus somatic loss of the second allele). - Complete penetrance but variable expressivity. About 50% of cases are de novo, and the mutation rate is high. Incidence is about 1 in 3,000.
**Diagnostic criteria (NIH; need ≥2)** - ≥6 café-au-lait macules (>5 mm prepubertal, >15 mm postpubertal) - ≥2 neurofibromas of any type, or 1 plexiform neurofibroma - Axillary or inguinal freckling (Crowe sign) - Optic pathway glioma - ≥2 Lisch nodules (pigmented iris hamartomas) - Distinctive osseous lesion (sphenoid dysplasia, or long-bone cortical thinning with or without pseudarthrosis, e.g., anterolateral tibial bowing) - First-degree relative with NF1 - Newer (2021) criteria add choroidal abnormalities (on OCT) to the list, and a pathogenic NF1 variant can also establish the diagnosis.
**Other clinical features** - Plexiform neurofibromas are pathognomonic and can undergo malignant transformation to malignant peripheral nerve sheath tumors (MPNST). - Pheochromocytoma (episodic hypertension, headache, sweating, palpitations) - Learning disabilities, ADHD, and macrocephaly are common. - Scoliosis and sphenoid wing dysplasia (may cause pulsatile exophthalmos) - Renal artery stenosis causes hypertension in children. - Other tumors: gastrointestinal stromal tumors (GIST), juvenile myelomonocytic leukemia (JMML), rhabdomyosarcoma, and breast cancer. - Astrocytomas and optic gliomas (usually pilocytic, in children <7 years)
**Management** - Surveillance includes annual physical exam, ophthalmologic exams in childhood, BP monitoring, and scoliosis screening. MRI is used for symptomatic lesions. - Selumetinib (MEK inhibitor) is FDA-approved for symptomatic, inoperable plexiform neurofibromas in children. Surgery is for symptomatic lesions.
**High-yield comparisons** - NF2 (chromosome 22, merlin/schwannomin): bilateral vestibular schwannomas, meningiomas, ependymomas, and juvenile cataracts. Remember "MISME" (Multiple Inherited Schwannomas, Meningiomas, Ependymomas). - NF1 has neurofibromas (mixed Schwann cells, fibroblasts, and mast cells that are S-100 positive), while NF2 has schwannomas. - Other neurocutaneous disorders: tuberous sclerosis (TSC1/TSC2, ash-leaf spots, angiofibromas, rhabdomyomas, SEGA), Sturge-Weber (GNAQ, port-wine stain, not inherited), and von Hippel-Lindau (VHL on 3p, hemangioblastomas, renal cell carcinoma).
**Exam pearls** - A child with multiple café-au-lait spots and axillary freckles, with a family history, points to NF1. - Lisch nodules are asymptomatic and seen on slit-lamp exam, and they do not affect vision. - Neurofibromas are benign peripheral nerve sheath tumors that arise from Schwann cells, and many cases also involve mast cells. - A sudden change in size or pain in a neurofibroma suggests MPNST.
Sources
- First Aid for the USMLE Step 1 (Neurocutaneous disorders; Genetics)
- Pathoma (Fundamentals of Pathology) - Nervous system tumors
- Robbins & Cotran Pathologic Basis of Disease - Neurofibromatosis
- Legius E, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome. Genet Med. 2021
- NIH Consensus Development Conference Statement on Neurofibromatosis, 1988
- Harrison's Principles of Internal Medicine - Neurocutaneous syndromes
- UpToDate - Neurofibromatosis type 1 (NF1): Clinical features and diagnosis
Reviewed by Medusa editorial — medical student review. Information here is for study reference only and is not medical advice. Spotted an error? Let us know.