A 35-year-old woman presents with multiple firm, dome-shaped pink-to-blue nodules confluent across the scalp, forming a characteristic "turban-like" appearance. Similar lesions have appeared on her face and trunk over the past 5 years. Her mother and maternal grandmother had identical presentations. The pedigree shown in the diagram (marked **A**) demonstrates autosomal dominant inheritance with female-predominant expression and vertical transmission across generations. Which of the following best explains the molecular basis of this condition?

Question

Accepted Answer

D. Germline loss-of-function mutation in CYLD gene causing dysregulated NF-κB signalling due to impaired deubiquitination of TRAF2 and TRAF6. ## Why option 1 is correct

The pedigree pattern marked **A** — autosomal dominant inheritance with female-predominant expression and vertical transmission across generations — is pathognomonic for familial cylindromatosis (Brooke-Spiegler syndrome). This condition is caused by germline loss-of-function mutations in the CYLD gene on chromosome 16q12-q13. CYLD encodes a deubiquitinating enzyme (DUB) that negatively regulates NF-κB and JNK signalling by removing K63-linked polyubiquitin chains from substrates including TRAF2, TRAF6, NEMO, and BCL3. Loss of CYLD function leads to dysregulated NF-κB activation in skin appendageal cells, predisposing to development of multiple cylindromas (the "turban tumors"), trichoepitheliomas, and spiradenomas following a two-hit Knudson mechanism. This is the established molecular pathophysiology per GeneReviews and Bignell et al. (Nature Genet 2000).

## Why each distractor is wrong

- **Option 2 (BRAF gain-of-function)**: BRAF mutations cause melanoma and other malignancies but do not produce the characteristic autosomal dominant pedigree with multiple benign adnexal tumors seen in familial cylindromatosis. BRAF is not implicated in Brooke-Spiegler syndrome.
- **Option 3 (p53 loss)**: While p53 mutations predispose to multiple cancers (Li-Fraumeni syndrome), they do not cause the specific pattern of benign cylindromas, trichoepitheliomas, and spiradenomas. p53 is not the primary gene defect in familial cylindromatosis.
- **Option 4 (NOTCH1 activation)**: Activating NOTCH1 mutations are associated with T-cell acute lymphoblastic leukaemia and some skin conditions, but not with the autosomal dominant syndrome of multiple benign skin appendageal tumors characteristic of Brooke-Spiegler syndrome.

**High-Yield:** Familial cylindromatosis = CYLD loss-of-function = dysregulated NF-κB = autosomal dominant with female predominance = "turban tumors" on scalp + trichoepitheliomas + spiradenomas.

[cite: Brooke-Spiegler syndrome; Bignell GR et al., Nature Genet 2000; GeneReviews]

Answer

A. Gain-of-function mutation in BRAF causing constitutive MAPK pathway activation in skin appendageal cells

Answer

B. Loss of function of p53 tumour suppressor gene leading to impaired cell cycle checkpoint control

Answer

C. Activating mutation in NOTCH1 causing aberrant Notch signalling in follicular epithelium

Explanation

Why option 1 is correct

Why each distractor is wrong

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