Abstract
Brooke-Spiegler syndrome (BSS, OMIM 605041) is a rare monogenic skin disease characterized by the development of skin appendage tumors caused by mutations in the cylindromatosis gene. We recently investigated a Hungarian and an Anglo-Saxon pedigrees affected by Brooke-Spiegler syndrome. Despite carrying the same disease-causing mutation (c.2806C>T, p.Arg936X) of the cylindromatosis (CYLD) gene, the affected family members of the two pedigrees exhibit striking differences in their phenotypes. To identify phenotype-modifying genetic factors, whole exome sequencing was performed and the data from the Hungarian and Anglo-Saxon BSS patients were compared. Three putative phenotype-modifying genetic variants were identified: the rs1053023 SNP of the signal transducer and activator of transcription 3 (STAT3) gene, the rs1131877 SNP of the tumor necrosis factor receptor-associated factor 3 (TRAF3) gene and the rs202122812 SNP of the neighbour of BRCA1 gene 1 (NBR1) gene. Our study contributes to the accumulating evidence for the clinical importance of phenotype-modifying genetic factors, which are potentially important for the elucidation of disease prognosis.
Highlights
Brooke-Spiegler syndrome (BSS; OMIM 605041) is a rare monogenic skin disease characterized by the development of skin appendage tumors caused by mutations in the cylindromatosis (CYLD) gene
Our study contributes to the accumulating evidence for the clinical importance of phenotype-modifying genetic factors, which are potentially important for the elucidation of genotype– phenotype correlations and disease prognosis
A significant challenge that exists is that patients with identical mutations of the CYLD gene can present with different phenotypic features, ranging from BSS to familial cylindromatosis (FC; OMIM 132700) and multiple familial trichoepithelioma type 1 (MFT1; OMIM 601606), suggesting additional genetic factors impact on the presentation of clinical variants of the CYLD mutation-caused spectrum [4, 5]
Summary
Brooke-Spiegler syndrome (BSS; OMIM 605041) is a rare monogenic skin disease characterized by the development of skin appendage tumors caused by mutations in the cylindromatosis (CYLD) gene. Despite the described phenotypes and reports of the underlying CYLD mutations, it has been difficult to establish genotype–phenotype correlations in BSS. CYLD cutaneous syndrome) is a rare monogenic skin disease characterized by the development of skin appendage tumors, such as cylindromas, trichoepitheliomas and spiradenomas [1, 2]. A significant challenge that exists is that patients with identical mutations of the CYLD gene can present with different phenotypic features, ranging from BSS to familial cylindromatosis (FC; OMIM 132700) and multiple familial trichoepithelioma type 1 (MFT1; OMIM 601606), suggesting additional genetic factors impact on the presentation of clinical variants of the CYLD mutation-caused spectrum [4, 5]
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