Gorlin-like phenotype in a patient with a PTCH2 variant of uncertain significance
Gorlin-like phenotype in a patient with a PTCH2 variant of uncertain significance
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DOI：
10.1016/j.ejmg.2020.103842
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发表时间：
2020-04-01
影响因子：
1.9
通讯作者：
Lacassie, Yves
中科院分区：
文献类型：
--
作者：
Casano, Kelsey;Meddaugh, Hannah;Lacassie, Yves
Gorlin综合征，也被称为新生基底细胞癌综合征(NBCCS)，是一种常染色体显性遗传性肿瘤易感综合征，早期表现为特征性的先天性畸形和肿瘤。这种综合征最常见的原因是ptch1抑癌基因的胚系突变，该基因表现出高外显性和很大的家族内和家族间表型变异，以及SUFU抑癌基因。最近，PTCH2基因也被认为是导致Gorlin综合征的原因之一。值得注意的是，当考虑到ptch1和SUFU相关疾病时，这些患者表现出较轻的Gorlin综合征表型。我们报告了一例从他父亲那里遗传的新的PTCH2突变的患者。先证者表现出戈林综合征的几个次要诊断特征，支持该基因的致病作用。先证者的特征包括巨头畸形，宽脸，突出的额头，远端畸形，大眼睛，唇腭裂，薄的垂直掌纹，阴茎阴囊内翻，以及阴茎上的色素沉着斑点。他的父亲表现出巨头畸形，背部和肩膀上有几个雀斑，左手只有一个掌凹，这引起了人们对戈林综合征的怀疑。全外显子序列(TRIO)发现先证者和父亲是PTCH2第21外显子NM_003738.4：C.3347C>；T；p.(Pro1116Leu)的杂合子，在其轻度患病的兄弟中也发现了该杂合子。这种半保守的氨基酸替代在文献中已有报道，但其意义尚不清楚。值得注意的是，先证者、兄弟和父亲不符合戈林综合征的临床标准。然而，该家系中描述的临床发现支持PTCH2突变和Gorlin样表型之间的关联。
Gorlin syndrome, also known as Nevoid Basal-Cell Carcinoma Syndrome (NBCCS), is an autosomal dominant tumor predisposition syndrome that presents early in life with characteristic congenital malformations and tumors. This syndrome most commonly results from germline mutations of the PTCH1 tumor suppressor gene, which shows high penetrance and great intra and interfamilial phenotypic variability, as well as the SUFU tumor suppressor gene. Recently, the PTCH2 gene has also been implicated as a cause of Gorlin syndrome. Notably, these patients displayed milder phenotypes of Gorlin syndrome when considered against PTCH1 and SUFU-related disease.We report a patient with a novel PTCH2 mutation inherited from his father. The proband displays several minor diagnostic features of Gorlin syndrome, supporting the pathogenic role of this gene. Features in the proband include macrocephaly, a wide face, prominent forehead, hypertelorism/telecanthus, large eyes, cleft lip and palate, thin vertical palmar creases, penoscrotal inversion, and a hyperpigmented spot on his penis. His father displays macrocephaly, several nevi on his back and shoulders, and a single palmar pit on his left hand, raising suspicion for Gorlin syndrome. Whole exome sequence (trio) found that the proband and father are heterozygous for NM_003738.4:c.3347C > T;p.(Pro1116Leu) in exon 21 of PTCH2, found also in his mildly affected brother. This semi-conservative amino acid substitution has been reported in the literature, but its significance is unclear. Notably, the proband, brother, and father do not meet clinical criteria for Gorlin syndrome. However, the clinical findings described in this family support the association between PTCH2 mutations and Gorlin-like phenotypes.