CYLD – Familial Multiple Trichoepithelioma

Familial multiple trichoepithelioma (MFT) is an autosomal dominant tumor predisposition characterized by multiple skin-colored papules on the central face. Germline CYLD mutations were first implicated through a single family exhibiting both MFT and familial cylindromatosis phenotypes, harboring a truncating c.2806C>T (p.Arg936Ter) variant in exon 17 (PMID:16922728).

Subsequent studies in three Chinese MFT pedigrees confirmed CYLD as the causative gene, identifying frameshift (c.1462del (p.Ile488SerfsTer10)), nonsense (c.2128C>T (p.Gln710Ter)), and missense (c.2822A>T (p.Asp941Val)) variants segregating with disease (PMID:15024746). A cohort analysis of two MFT families within broader Brooke-Spiegler syndrome phenotypes also revealed recurrent truncating mutations including c.2806C>T (p.Arg936Ter) (PMID:15854031).

Broader mutational screens in eight additional patients from German and Turkish origins identified two missense, two nonsense, two deletions, and two duplication variants without genotype–phenotype correlation, underscoring allelic heterogeneity in MFT (PMID:29974194). Large germline rearrangements such as c.-34111_*297858del378779 and c.914-6398_1769del13642ins20 have been reported but are rare (PMID:25347032).

CYLD encodes a lysine-63–specific deubiquitinase that negatively regulates NF-κB and JNK signaling. Functional assays of the catalytic USP domain demonstrate that p.Asp681Gly exhibits markedly reduced deubiquitinating activity on TRAF2 and TRAF6, driving NF-κB hyperactivation, while the p.Pro904Leu variant shows impaired regulatory control of NF-κB in inflammation models (PMID:17851586; PMID:31366726).

No significant genotype–phenotype correlations have been established across MFT, familial cylindromatosis, and Brooke-Spiegler syndrome phenotypes, suggesting variable expressivity of CYLD loss-of-function alleles (PMID:15854031; PMID:29974194). The E3 ligase MIB2 has emerged as a modulator of CYLD stability, enhancing NF-κB signaling via Lys-48–linked polyubiquitination and proteasomal degradation of CYLD p.Pro904Leu (PMID:31366726).

The wealth of genetic and experimental data provides definitive evidence that CYLD haploinsufficiency underlies autosomal dominant MFT. Comprehensive sequencing of CYLD should be integrated into diagnostic panels for patients presenting with multiple facial papules, facilitating early detection and management. Key Take-home: CYLD testing informs diagnosis and risk stratification in familial multiple trichoepithelioma.

References

• Clinical genetics • 2006 • CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. PMID:16922728
• Human mutation • 2004 • CYLD mutation causes multiple familial trichoepithelioma in three Chinese families. PMID:15024746
• The Journal of investigative dermatology • 2005 • Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. PMID:15854031
• Archives of dermatological research • 2018 • Phenotype variability in tumor disorders of the skin appendages associated with mutations in the CYLD gene. PMID:29974194
• The American Journal of dermatopathology • 2014 • Large germline deletions of the CYLD gene in patients with Brooke-Spiegler syndrome and multiple familial trichoepithelioma. PMID:25347032
• The 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
• The Journal of Biological Chemistry • 2019 • The E3 ubiquitin ligase MIB2 enhances inflammation by degrading the deubiquitinating enzyme CYLD. PMID:31366726

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