# Case Report: CYLD cutaneous syndrome with malignant transformation to spiradenocarcinoma: cooperative effects of CYLD truncation and an MSH2 clamp-domain variant in an Ecuadorian patient

## TL;DR

A rare skin condition with cancer risk is reported in an Ecuadorian patient, revealing new genetic factors linked to tumor development.

## Contribution

First genetically confirmed case of CYLD cutaneous syndrome in Ecuador, revealing a novel MSH2 variant's potential role in malignant transformation.

## Key findings

- A CYLD truncation variant and an MSH2 missense variant were identified in a patient with CCS and spiradenocarcinoma.
- The MSH2 variant affects a conserved residue in the clamp domain, potentially destabilizing the MSH2–MSH6 complex.
- Genomic and protein analyses highlight cooperative mechanisms in malignant progression of CCS.

## Abstract

CYLD cutaneous syndrome (CCS) is a rare autosomal dominant disorder caused by germline CYLD variants and characterized by multiple skin adnexal tumors. Malignant transformation is uncommon, and cooperative genetic events remain poorly defined, particularly in underrepresented populations.

We report a 61-year-old Ecuadorian woman with multiple scalp cylindromas and spiradenomas, including one spiradenocarcinoma. Family history was notable for malignancies in first- and second-degree relatives. Whole-exome sequencing identified a heterozygous nonsense CYLD variant (c.1207C > T; p.Gln403Ter), classified as likely pathogenic, and a homozygous missense MSH2 variant (c.1609A > G; p.Lys537Glu) of uncertain significance. Histopathology confirmed malignant transformation, while immunohistochemistry showed preserved MSH2 expression with a microsatellite-stable phenotype. Nevertheless, a functional impact of the MSH2 variant cannot be excluded. Consistent with these observations, in silico modeling demonstrated that CYLD truncation eliminates the catalytic USP domain and regulatory motifs, abolishing deubiquitinase activity, whereas the MSH2 substitution affects a conserved residue in the clamp domain, likely destabilizing the MSH2–MSH6 complex despite intact nuclear localization.

This is the first genetically confirmed case of CCS in Ecuador and among the few reported in South America. Beyond expanding the geographic spectrum, our findings highlight the value of integrating genomic and protein analyses to uncover cooperative mechanisms of malignant progression. Such integrative genomic approaches refine diagnosis, enhance genotype–phenotype interpretation, and deepen understanding of malignant transformation in CCS, particularly in underrepresented populations.