Large Germline Deletions of the CYLD Gene in Patients With Brooke–Spiegler Syndrome and Multiple Familial Trichoepithelioma

Abstract

Brooke-Spiegler syndrome (BSS) and its phenotypic variants, multiple familial trichoepithelioma (MFT) and familial cylindromatosis, are rare autosomal dominant hereditary diseases. They are characterized by the presence of multiple adnexal tumors, especially cylindromas, spiradenomas, spiradenocylindromas, and trichoepitheliomas. Implicated in the pathogenesis of the disease is the gene CYLD, which is localized on the long arm of chromosome 16. This gene encodes an evolutionarily conserved protein belonging to the deubiquitinating enzymes family, which plays a key role in many signaling pathways, especially in NF-κB, JNK, and Wnt. Less than 90 germline mutations of CYLD have been identified in patients with BSS/MFT. These mutations are mostly small alterations in the coding sequence and at exon-intron junction sites. One patient with an intronic mutation and another with a large CYLD deletion have also been recorded. In this study, the authors have analyzed a cohort of 14 patients with BSS/MFT from 13 families for large genome rearrangements by array comparative genome hybridization followed by confirmatory sequencing. We identified 2 large deletions, namely c.-34111_*297858del378779 and c.914-6398_1769del13642ins20 in patients with MFT and BSS, respectively. All other analyzable patients did not reveal any copy number alteration. It is concluded that the large rearrangements are relatively rare in patients without a germline CYLD mutation demonstrable by conventional sequencing. The pathogenetic mechanisms in patients with BSS/MFT lacking germline sequence alterations or large rearrangements in the CYLD gene remain to be clarified.

Spiradenoma of the breast and review of cases over 76-years

“…[5] The co-occurrence of these two tumors separately is frequently seen in Brooke-Spiegler syndrome, a condition where various adnexal neoplasms develop due to a CYLD tumor suppressor gene mutation located on 16q12-q13 normally interacting with the anti-apoptotic nuclear factor kappa B (NF-kB) pathway. [6,7] While this pathway has been identified for this syndromic condition the exact pathogenesis of solitary spiradenomas has not yet been elucidated.…”

“…The characteristics of both tumors in all reported cases in the literature over the past 76 years are displayed in Table 1. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]…”

Report of Three Novel Germline <b><i>CYLD</i></b> Mutations in Unrelated Patients with Brooke-Spiegler Syndrome, Including Classic Phenotype, Multiple Familial Trichoepitheliomas and Malignant Transformation

“…Mutations in introns leading to intronic exonization and large deletions have been reported in some of those ‘negative' cases [30,34]. So far, no genotype-phenotype correlation has been found [11,17,35].…”

Brooke-Spiegler Syndrome and Phenotypic Variants: An Update

“…There is no hotspot but most mutations have been detected in exons 9-20, whereas exons 4-8 are spared [27]. Reasons for the absence of a demonstrable CYLD mutation are being intensively investigated; large deletions in CYLD and mutations in intronic sequences leading to intronic exonization have been detected in a subset of those patients [28][29][30]. There appears to be no genotype-phenotype correlations with respect to the severity of the disease, the possibility of malignant transformation, and development of extracutaneous lesions.…”