A 16-year-old boy presents with multiple café-au-lait macules (CALMs), axillary freckling (Crowe's sign), and a soft, flesh-coloured pedunculated nodule on the back. Ophthalmological examination reveals small, pigmented hamartomas on the iris. His father has similar lesions. What is the mutation responsible for this autosomal dominant neurocutaneous syndrome?

• A TSC1/TSC2 mutation affecting hamartin/tuberin
• B PTCH1 mutation on chromosome 9q22 affecting the Hedgehog signalling pathway
• C VHL gene mutation on chromosome 3p affecting von Hippel-Lindau protein
• D NF1 gene mutation on chromosome 17q11.2 encoding neurofibromin (Ras-GAP protein) ✓

Explanation

Neurofibromatosis type 1 (NF1, von Recklinghausen's disease) is diagnosed by the NIH criteria (≥2 of: ≥6 CALMs ≥1.5 cm in adults, axillary/inguinal freckling — Crowe's sign, ≥2 neurofibromas, ≥1 plexiform neurofibroma, ≥2 Lisch nodules on iris, optic glioma, characteristic bony lesion, first-degree relative with NF1). It is caused by mutation in the NF1 tumour suppressor gene on chromosome 17q11.2, encoding neurofibromin, a Ras-GTPase activating protein. Loss of neurofibromin leads to unopposed Ras-MAP kinase signalling and tumour growth. TSC1/2 mutations cause tuberous sclerosis.

Reference: Neena Khanna Illustrated Synopsis of Dermatology & STD, 6th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.