Mutations in the CYLD gene in Brooke–Spiegler Syndrome, Familial Cylindromatosis, and Multiple Familial Trichoepithelioma: Lack of Genotype–Phenotype Correlation

Abstract

Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepithelioma (MFT), originally described as distinct entities, share overlapping clinical findings. Patients with BSS are predisposed to multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. FC, however, is characterized by cylindromas and MFT by trichoepitheliomas as the only tumor type. These disorders have recently been associated with mutations in the CYLD gene. In this report, we describe three families with BSS, one with FC, and two with MFT phenotypes associated with novel and recurrent mutations in CYLD. We provide evidence that these disorders represent phenotypic variation of a single entity and lack genotype-phenotype correlation.

Phenotype–genotype correlations for clinical variants caused by CYLD mutations

“…We performed haplotype analysis for these two geographically distant pedigrees and found that the mutations resulted from two independent mutational events, suggesting that is the mutations represent a mutational hotspot on the CYLD gene [Grossmann et al, 2013]. Our results correlate well with the data reported in the literature supporting the assumption that this is a mutational hotspot on the gene: the c.2806C>T, p.Arg936X nonsense mutation has been described in all three allelic variants in the disease spectrum caused by CYLD mutations 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 7 and results in different symptom severity as well as the development of different clinical variants [Bignell et al, 2000;Bowen et al, 2005;Grossmann et al, 2013;Saggar et al, 2008;Kazakov et al, 2009;Nagy et al, 2013]. [Bignell et al, 2000;Grossmann et al, 2013;Saggar et al, 2008;Nasti et al, 2009;Ying et al, 2012 …”

“…BSS, FC and MFT1 were originally described as distinct clinical entities, but due to their overlapping clinical symptoms and their manifestation within the same families, they are now considered as a clinical variants that represent a phenotypic spectrum of a single entity Welch et al, 1968;Young et al, 2006;Oranje et al, 2008]. [Bignell et al, 2000;Bowen et al, 2005;Grossmann et al, 2013;Linos et al, 2011;Lv et al, 2008;Kacerovska et al, 2013;Saggar et al, 2008;Van den Ouweland et al, 2011;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;Kazakov et al, 2011;Nagy et al, 2013]. Therefore, it has been hypothesized that BSS, FC and MFT1 are not different disease entities, but represent a phenotypic spectrum of the same disease.…”

Mutations in the NF-κB signaling pathway: implications for human disease

“…Most CYLD mutations identified in cylindromatosis are frameshift or nonsense mutations that remove all or part of the catalytic domain of CYLD (Bignell et al, 2000;Poblete-Gutie´rrez et al, 2002;Hu et al, 2003;Scheinfeld et al, 2003;Tobin et al, 2003;Bowen et al, 2005;Heinritz et al, 2006) (Figure 2). In addition, a few missense mutations have been identified, but how they affect CYLD function is unclear .…”

Morphologically low-grade spiradenocarcinoma: a clinicopathologic study of 19 cases with emphasis on outcome and MYB expression

“…1,2 Although typically observed sporadically as solitary neoplasms, they may rarely be multiple in the setting of the Brooke-Spiegler syndrome. 3,4 Similar to adenoid cystic carcinoma of the breast and salivary glands, the MYB-NFIB gene fusion product, due to a t(6;9)(q22 ∼ 23; p23 ∼ 24) translocation, has recently been demonstrated in a subset of dermal cylindromas, resulting in overexpression of the MYB protein. [5][6][7][8][9] MYB is a leucine zipper transcription factor and has an important role in cell proliferation, apoptosis and cell differentiation.…”