Опубликована статья "Case report: Multiple facial trichoepitheliomas caused by p.Val835SerfsTer52 variant of CYLD gene" в журнале Frontiers in Medicine
Introduction
Genodermatosis is an extensive clinically heterogeneous group of hereditary diseases characterized primarily by lesions of the skin and dermal appendages. Dermatoscopy is an important diagnostic tool for genodermatoses, particularly when the symptoms are not pronounced (1). Clinical manifestations of genodermatosis depend on the type and location of the mutation in a particular gene. The CYLD gene is a tumor suppressor and encodes an ubiquitin-specific protease which main purpose is to activate apoptosis (2). Germline mutations in the heterozygous state of CYLD gene are described in following cases of patients with Brooke–Spiegler syndrome (BSS): the classic clinical variant, multiple familial trichoepithelioma, familial cylindromatosis (3). It is believed that all clinical variants comprise one phenotypically heterogeneous genodermatosis with an autosomal dominant inheritance (4, 5).
All clinically significant mutations of the CYLD gene debut during puberty, the average onset age is 16, sex ratio (number of women to men) varies from 0.33 to 4.00 (6). Clinically, CYLD gene mutations manifest by multiple benign tumors of the skin and its appendages. Although it is possible for tumors to become malignant and develop into adenocarcinoma, cylindrocarcinoma, sarcomatoid carcinoma, squamous cell skin cancer, trichoblast carcinoma, which reduces the life expectancy of patients (7). There is a case of development of a membranous type basal cell adenoma of the salivary gland in BSS, which is described in the literature (8). An annual dermatological examination is recommended for individuals diagnosed with BSS, with follow-up frequency adjusted based on patient needs—ranging from every few months for those needing repeated surgeries to as needed for stable cases. Patients should report any changes in tumors, such as rapid growth or bleeding, and undergo additional assessments if necessary; annual salivary gland exams and lung imaging are advised for those over 40 with new breathlessness (7).
According to the VarSome database, 65 pathogenic and 8 likely pathogenic variants of the CYLD gene (the most common mutation type is frameshift), as well as 145 variants with unknown clinical significance (mostly missense mutations) are registered at the moment (date of access 29 August 2024) (9). Literature contains reports on 107 mutations that are associated with skin pathology (10). There is no correlation between skin manifestations and genomic position of the variant, however, 99% of mutations occur between exon 9 and 20 (NM_015247).
This study presents a previously undescribed de novo variant c.2501dupC (p.Val835SerfsTer52) of the CYLD gene in a young woman with multiple trichoepitheliomas. This variant was detected by clinical exome sequencing and validated by Sanger sequencing.
Genodermatosis is an extensive clinically heterogeneous group of hereditary diseases characterized primarily by lesions of the skin and dermal appendages. Dermatoscopy is an important diagnostic tool for genodermatoses, particularly when the symptoms are not pronounced (1). Clinical manifestations of genodermatosis depend on the type and location of the mutation in a particular gene. The CYLD gene is a tumor suppressor and encodes an ubiquitin-specific protease which main purpose is to activate apoptosis (2). Germline mutations in the heterozygous state of CYLD gene are described in following cases of patients with Brooke–Spiegler syndrome (BSS): the classic clinical variant, multiple familial trichoepithelioma, familial cylindromatosis (3). It is believed that all clinical variants comprise one phenotypically heterogeneous genodermatosis with an autosomal dominant inheritance (4, 5).
All clinically significant mutations of the CYLD gene debut during puberty, the average onset age is 16, sex ratio (number of women to men) varies from 0.33 to 4.00 (6). Clinically, CYLD gene mutations manifest by multiple benign tumors of the skin and its appendages. Although it is possible for tumors to become malignant and develop into adenocarcinoma, cylindrocarcinoma, sarcomatoid carcinoma, squamous cell skin cancer, trichoblast carcinoma, which reduces the life expectancy of patients (7). There is a case of development of a membranous type basal cell adenoma of the salivary gland in BSS, which is described in the literature (8). An annual dermatological examination is recommended for individuals diagnosed with BSS, with follow-up frequency adjusted based on patient needs—ranging from every few months for those needing repeated surgeries to as needed for stable cases. Patients should report any changes in tumors, such as rapid growth or bleeding, and undergo additional assessments if necessary; annual salivary gland exams and lung imaging are advised for those over 40 with new breathlessness (7).
According to the VarSome database, 65 pathogenic and 8 likely pathogenic variants of the CYLD gene (the most common mutation type is frameshift), as well as 145 variants with unknown clinical significance (mostly missense mutations) are registered at the moment (date of access 29 August 2024) (9). Literature contains reports on 107 mutations that are associated with skin pathology (10). There is no correlation between skin manifestations and genomic position of the variant, however, 99% of mutations occur between exon 9 and 20 (NM_015247).
This study presents a previously undescribed de novo variant c.2501dupC (p.Val835SerfsTer52) of the CYLD gene in a young woman with multiple trichoepitheliomas. This variant was detected by clinical exome sequencing and validated by Sanger sequencing.