<scp>CYLD</scp> Cutaneous Syndrome: Report of a New Splicing Pathogenic Variant and Additional Evidence Supporting the Absence of Genotype–Phenotype Correlation

CYLD cutaneous syndrome (CCS, OMIM #605041, #132700, #601606) is a rare autosomal dominant disorder caused by germline pathogenic variants in the CYLD gene, characterized by the development of multiple adnexal cutaneous tumors, including cylindromas, trichoepitheliomas, and spiradenomas. The syndrome has been described under different clinical designations: Brooke–Spiegler Syndrome (BSS), featuring both cylindromas and trichoepitheliomas; familial cylindromatosis (FC), predominantly characterized by cylindromas; and multiple familial trichoepithelioma (MFT), primarily presenting trichoepitheliomas [1]. These conditions represent a phenotypic spectrum of the same genetic disorder. Clinical manifestations typically emerge in early adulthood, with tumors predominantly affecting the head, neck, and extremities. Lesions tend to increase in size and number over time. Although generally benign, malignant transformations have been documented, including squamous cell carcinoma (SCC) and rare pulmonary cylindromas, particularly in longstanding tumors [2]. The CYLD gene encodes a deubiquitinase enzyme functioning as a tumor suppressor. CYLD negatively regulates key cellular signaling pathways, including NF-κB and Wnt/β-catenin [3, 4]. No genotype–phenotype correlations have been established for CCS phenotypic variants [1]. We report a novel CYLD splicing pathogenic variant identified in two families presenting with distinct clinical phenotypes of CCS, providing further evidence for the absence of genotype–phenotype correlation in CCS. In the first family, a 62-year-old man presented with numerous cylindromas on the scalp and arms, initially appearing at age 27 and increasing in number and size, and was diagnosed with FC. His twin brother, nephew, mother, and sister exhibited similar lesions (Figures 1a and 2a). In the second family, a 44-year-old woman was diagnosed with BSS, presenting with multiple cylindromas, trichoepitheliomas, and cylindrospiradenomas distributed on the face, scalp, and arms, first appearing at age 20. Similar cutaneous lesions were reported in her paternal aunts (Figures 1b and 2b). In both families, DNA sequencing revealed a heterozygous variant in intron 16 of CYLD (c.2241+5G>A) in all analyzed affected members (probands and available relatives). cDNA analysis from the BSS proband revealed an aberrant band by capillary electrophoresis, consistent with a deletion of exon 16. Sanger sequencing of the RT-PCR products confirmed the presence of two transcripts: the wild-type transcript containing exons 15–16-17 and a mutant transcript in which exon 16 was completely skipped. Finally, the c.2241+5G>A variant was classified as pathogenic as the deletion of exon 16 causes a frameshift in the reading frame, resulting in a premature termination codon: p.(His704Serfs*4) (NP_050662.1). A similar variant affecting the same splice site (c.2241_2242delAG) was reported in a Chinese family with MFT, also resulting in exon 16 deletion [5], reinforcing the absence of genotype–phenotype correlation in CCS. Previous mutational analyses have shown that CYLD pathogenic variants are distributed throughout the gene, with approximately 48% being frameshift mutations and 11% affecting splicing [1]. Most pathogenic variants cluster between exons 9 and 20, yet no mutational hotspots have been identified [3]. As the majority of these variants are frameshift, nonsense, or splice variants that often introduce a premature termination codon, they likely lead to mRNA degradation via the nonsense-mediated decay (NMD) pathway. This common mechanism resulting in a uniform loss of function could provide a plausible explanation for the absence of genotype–phenotype correlation. It is noteworthy that major genetic databases continue to classify BSS, FC, and MFT as three distinct entities. However, as demonstrated by our findings and supported by accumulating evidence in the literature, these represent variable phenotypic expressions of a single disorder, CYLD cutaneous syndrome, caused by pathogenic variants in the CYLD gene. Clinical presentation is independent of genotype and likely influenced by additional genetic, epigenetic, and environmental modifiers. This historical nomenclature should be updated in clinical databases to reflect current understanding of CCS as a unified disease entity with a broad phenotypic spectrum. Open access publication funding provided by COUPERIN CY26. Written informed consent was obtained from all individual participants included in the study for genetic testing and publication of clinical information and photographs. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.