CYLD – Brooke-Spiegler Syndrome

Brooke-Spiegler syndrome (BSS) is a rare autosomal dominant disorder characterized by multiple skin appendage tumors, including cylindromas, spiradenomas and trichoepitheliomas. Germline mutations in the deubiquitinase gene CYLD underlie BSS by loss of its negative regulation of NF-κB and JNK signaling pathways. CYLD functions as a tumor suppressor, and its truncating and missense variants impair cleavage of K63-linked ubiquitin chains, leading to constitutive pathway activation and tumor formation.

Linkage of BSS to chromosome 16q12-13 was established based on multiple affected families, and the first heterozygous CYLD frameshift mutation (c.2172del (p.Val725LeufsTer10)) was reported in an individual with clinical heterogeneity (PMID:12950348). Subsequent studies have identified over 51 distinct germline CYLD mutations in more than 73 families worldwide, comprising nonsense, frameshift, splice-site and missense variants mapping to exons 9–20 (PMID:19462465).

Segregation analyses across large multigenerational pedigrees have demonstrated co-segregation of CYLD pathogenic variants with disease in at least 26 affected relatives, confirming autosomal dominant inheritance and high penetrance (PMID:19917957). Case series include recurrent founder variants such as c.2806C>T (p.Arg936Ter), detected in diverse ethnic groups and associated with both familial cylindromatosis and BSS phenotypes (PMID:15854031).

The CYLD variant spectrum comprises predominantly truncating alleles (frameshift and nonsense; ~75 %), splice-site mutations (~10 %), and missense changes within the ubiquitin-specific protease domain (~15 %), such as c.2613C>G (p.His871Gln) (PMID:23171463). Deep intronic mutations resulting in exonization and somatic second-hit events have also been documented, expanding the mechanistic repertoire of CYLD inactivation (PMID:19668078).

Functional assays confirm that missense mutations like p.Asp681Gly abrogate CYLD’s deubiquitinase activity toward TRAF2/6, enhancing NF-κB and JNK signaling (PMID:17851586). In vivo, thymocyte-specific truncation of CYLD impairs selection via NF-κB modulation (PMID:20644164), and patient-derived xenografts of CYLD-defective cylindromas recapitulate histopathology and molecular features, providing a preclinical model for therapeutic testing (PMID:30676842).

In summary, the CYLD–BSS association meets definitive ClinGen criteria with extensive segregation, >73 families, and concordant functional data. Genetic testing for CYLD mutations is essential for diagnosis, family counseling, and early intervention to prevent disfiguring tumors. Future targeted therapies may leverage CYLD’s role in ubiquitin signaling to modulate NF-κB activity and tumor growth.

References

• Clinical and experimental dermatology • 2003 • Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome. PMID:12950348
• Human mutation • 2009 • Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. PMID:19462465
• Archives of dermatology • 2009 • Tumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction. PMID:19917957
• 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
• Journal of immunology • 2010 • Thymocyte-specific truncation of the deubiquitinating domain of CYLD impairs positive selection in a NF-kappaB essential modulator-dependent manner. PMID:20644164
• Journal of plastic surgery and hand surgery • 2019 • Clinical, genetic and experimental studies of the Brooke-Spiegler (CYLD) skin tumor syndrome. PMID:30676842

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