Kazakov Dmitry V, Vanecek Tomas, Zelger Bernhard, Carlson J Andrew, Spagnolo Dominic V, Schaller Jörg, Nemcova Jana, Kacerovska Denisa, Vazmitel Marina, Sangüeza Martin, Emberger Michael, Belousova Irena, Fernandez-Figueras Maria Tereza, Kempf Werner, Meyer Dale R, Rütten Arno, Baltaci Mehmet, Michal Michal
Sikl's Department of Pathology, Charles University Medical Faculty Hospital, Alej Svobody 80, Pilsen, Czech Republic.
Am J Dermatopathol. 2011 May;33(3):251-65. doi: 10.1097/DAD.0b013e3181f7d373.
Multiple familial trichoepitheliomas (MFT) constitute an autosomally inherited syndrome possibly related to Brooke-Spiegler syndrome (BSS). Although some early studies suggested a role for the PTCH gene on chromosome 9q22.3 in the etiopathogenesis of MFT, recent studies of occasional patients with the MFT clinical phenotype identified mutations in the CYLD gene on chromosome 16q12-q13, a gene responsible for BSS. A systematic investigation of PTCH and CYLD mutations in patients with MFT has never been performed. Our main objective was to collect a reasonably large series of patients with MFT to (1) study the clinicopathological spectrum of the disease, (2) determine whether the PTCH gene is implicated in the pathogenesis of MFT, and if so (3) determine the relative frequency of CYLD and PTCH mutations, (4) establish if there may be any possible genotype-phenotype correlations, and (5) study the spectrum of somatic mutations. Clinical analysis including family histories, histopathological investigations, and molecular genetic studies were performed. There were 9 female and 7 male patients ranging in age from 11 to 63 years. They presented with multiple, small, discrete and sometimes confluent, skin-colored to pink, asymptomatic nodules preferentially located on the face, being especially prominent and confluent in the nasolabial folds and inner aspects of the eyebrows. A total of 66 conventional trichoepitheliomas (TEs) were studied microscopically. Aside from typical features of TE, some also exhibited variant morphological patterns including areas reminiscent of other benign adnexal neoplasms and melanocytic hyperplasia. In none of the 9 patients tested was a germline mutation of the PTCH gene identified. Germline CYLD mutations were detected in 6 of 13 patients tested (identical in 2 unrelated patients) including 2 novel mutations, whereas the remaining 7 individuals showed wild-type alleles. Two patients with germline wild-type CYLD showed, however, a somatic mutation in the gene (1 duplication, 1 substitution mutation). Neither CYLD nor PTCH germline mutations were found in the 5 patients in whom both genes were analyzed. MFT seems to be a phenotypic variant of BSS. The PTCH gene is rarely, if ever, involved in the pathogenesis of MFT. Absence of a germline mutation of the CYLD gene in cases harboring a somatic mutation may be explained by large deletions in the gene or by mutation in intronic sequences or in the promoter region. Considering our 5 patients with no mutation in either gene, the final possibility is that another, as yet undescribed gene (neither CYLD nor PTCH) is implicated in the pathogenesis of some patients with MFT.
多发性家族性毛发上皮瘤（MFT）是一种常染色体显性遗传综合征，可能与布鲁克 - 施皮格勒综合征（BSS）相关。尽管一些早期研究表明9号染色体长臂22.3区的PTCH基因在MFT的发病机制中起作用，但最近对一些具有MFT临床表型患者的研究发现，16号染色体长臂12 - 13区的CYLD基因发生了突变，该基因也是导致BSS的原因。此前从未对MFT患者的PTCH和CYLD突变进行过系统研究。我们的主要目的是收集相当数量的MFT患者，以（1）研究该疾病的临床病理特征，（2）确定PTCH基因是否参与MFT的发病机制，如果是，（3）确定CYLD和PTCH突变的相对频率，（4）确定是否存在可能的基因型 - 表型相关性，以及（5）研究体细胞突变的特征。我们进行了包括家族史、组织病理学检查和分子遗传学研究在内的临床分析。共有9名女性和7名男性患者，年龄在11至63岁之间。他们表现为多发性、小的、离散的，有时融合的皮肤色至粉红色、无症状结节，主要位于面部，在鼻唇沟和眉毛内侧尤为突出且融合。共对66个传统毛发上皮瘤（TE）进行了显微镜检查。除了TE的典型特征外，一些还表现出变异的形态学模式，包括类似其他良性附属器肿瘤和黑素细胞增生的区域。在检测的9名患者中，均未发现PTCH基因的种系突变。在检测的13名患者中的6名（2名无关患者相同）检测到CYLD基因种系突变，包括2个新突变，而其余7名个体显示野生型等位基因。然而，2名CYLD基因种系野生型的患者在该基因中出现了体细胞突变（1个重复，1个替代突变）。在对两个基因都进行分析的5名患者中，未发现CYLD和PTCH基因种系突变。MFT似乎是BSS的一种表型变异。PTCH基因极少（如果有的话）参与MFT的发病机制。在存在体细胞突变的病例中未检测到CYLD基因种系突变，可能是由于该基因的大片段缺失或内含子序列或启动子区域的突变所致。考虑到我们有5名患者两个基因均无突变，最后的可能性是，另一个尚未描述的基因（既不是CYLD也不是PTCH）参与了一些MFT患者的发病机制。
