A 6-year-old boy presents to pediatrics clinic with multiple brown macules on his trunk and axillae. On examination, the structure marked **B** in the diagram (axillary freckling) is noted. His mother reports similar lesions and has a history of multiple skin tumors. What is the most likely diagnosis, and which gene mutation is responsible for this condition?

Explanation

## Why Option 1 (NF1) is right The presence of axillary freckling (Crowe sign) marked as **B** in the diagram is highly specific and pathognomonic for Neurofibromatosis Type 1 (NF1, also called von Recklinghausen disease). This finding, combined with café-au-lait macules on the trunk and a positive family history, fulfills diagnostic criteria for NF1. The NF1 gene on chromosome 17q encodes neurofibromin, a RAS GTPase activator protein that functions as a tumor suppressor. Loss of neurofibromin function leads to uncontrolled RAS signaling and increased cell proliferation, explaining the predisposition to multiple neurofibromas and other malignancies. Axillary or inguinal freckling typically develops by age 5–7 years and is one of the major diagnostic criteria (Nelson 21e Ch 614; Robbins 10e Ch 28). ## Why each distractor is wrong - **Option 2 (NF2)**: NF2 is caused by mutations in the NF2 gene on chromosome 22 and presents with bilateral vestibular schwannomas (acoustic neuromas), meningiomas, and cataracts. Notably, NF2 does NOT feature café-au-lait spots or axillary/inguinal freckling, making it incompatible with this clinical presentation. - **Option 3 (FAP)**: Familial Adenomatous Polyposis is caused by APC gene mutations on chromosome 5q and presents with hundreds of colorectal polyps and increased colorectal cancer risk. It is not associated with café-au-lait macules, axillary freckling, or neurofibromas. - **Option 4 (TSC)**: Tuberous Sclerosis Complex (TSC1/TSC2 mutations) presents with cortical tubers, cardiac rhabdomyomas, renal angiomyolipomas, and facial angiofibromas (not café-au-lait spots). Axillary freckling is not a feature of TSC. **High-Yield:** Crowe sign (axillary or inguinal freckling) is pathognomonic for NF1 and develops early in childhood; it is absent in NF2, which instead features bilateral vestibular schwannomas. [cite: Nelson 21e Ch 614; Robbins 10e Ch 28]