CYLD – familial cylindromatosis

Familial cylindromatosis is a rare, autosomal dominant predisposition to multiple benign skin appendage tumors, principally cylindromas, trichoepitheliomas, and spiradenomas. Affected individuals develop numerous nodules primarily on the scalp, face, and trunk, often beginning in adolescence with cumulative tumor burden affecting quality of life. Genetic counseling and early diagnosis are critical for management, surveillance, and consideration of future therapeutic trials.

The causative gene, CYLD, was identified by germline mutation analysis in 21 unrelated families, all harboring truncating or splice-site variants predicting loss of function. In the foundational study, germline CYLD mutations—including c.2469+1G>A and c.2272C>T (p.Arg758Ter)—were detected in 21 pedigrees with segregation of disease, establishing CYLD as a tumor suppressor (PMID:10835629).

Subsequent case reports reinforced the genotype-phenotype link. A familial study described a mild phenotype associated with an inherited R758X (c.2272C>T (p.Arg758Ter)) nonsense mutation, in which affected members developed multiple small cylindromas, the largest measuring 30 mm (PMID:15541090). No clear genotype–phenotype correlations have emerged, as truncating mutations throughout the ubiquitin-specific protease domain yield overlapping clinical spectra across Brooke–Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma.

Inheritance is autosomal dominant with high penetrance and variable expressivity. Segregation analysis in 21 families demonstrates robust co-segregation of CYLD variants with disease (affected relatives = 21). Over 90 distinct germline mutations have been reported, chiefly nonsense and frameshift changes leading to premature termination, and rare splice-site and missense mutations clustered in exons 9–20.

Functionally, CYLD encodes a deubiquitinase that negatively regulates NF-κB and JNK signaling. Experimental assays show that missense mutation p.Asp681Gly dramatically reduces cleavage of K63-linked polyubiquitin chains, impairing inhibition of TRAF2- and TRAF6-mediated NF-κB activation (PMID:17851586). Animal models and cell-based rescue experiments further support haploinsufficiency as the mechanism of tumor predisposition.

No conflicting genetic evidence disputes CYLD’s role; all reported germline variants are consistently associated with skin adnexal tumors. Anecdotal reports of additional phenotypes remain rare and unreplicated in familial cylindromatosis cohorts.

Overall, the CYLD–familial cylindromatosis association meets Definitive ClinGen criteria based on decades of reproducible genetic and functional data. Genetic testing for CYLD truncating variants informs diagnosis, allows at‐risk family screening, and may guide future targeted therapies against NF-κB pathway dysregulation. Key take-home: Heterozygous loss-of-function CYLD variants cause autosomal dominant familial cylindromatosis with high penetrance and a characteristic spectrum of skin appendage tumors.

References

• Nature Genetics • 2000 • Identification of the familial cylindromatosis tumour-suppressor gene PMID:10835629
• British Journal of Dermatology • 2004 • Mild phenotype of familial cylindromatosis associated with an R758X nonsense mutation in the CYLD tumour suppressor gene PMID:15541090
• Journal of Investigative Dermatology • 2008 • Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity PMID:17851586

Evidence Based Scoring (AI generated)