BACKGROUND Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. RESULTS The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. CONCLUSION This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

中文翻译：

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由 PTCH1 突变引起的具有嗅觉障碍和 Gorlin 特征的先天性低促性腺激素性腺功能减退症揭示了卡尔曼综合征的新候选基因。

背景 通过对 CHARGE 和 Waardenburg 综合征的临床和遗传分析，发现了卡尔曼综合征 (KS) 的两个潜在位点 (CHD7 和 SOX10)，包括嗅球 (CA/OB) 缺陷引起的先天性嗅觉丧失和先天性低促性腺激素性性腺功能减退症 (CHH)。我们假设可以通过分析出现这些迹象的罕见综合征来发现 KS 的其他候选基因。研究设计、规模、持续时间：我们首先调查了一个患有 Gorlin-Goltz 综合征 (GGS) 的家庭，其中受影响的成员表现出提示 KS 的临床症状。参与者/材料、方法：先证者和家庭成员进行了详细的临床评估。先证者接受了详细的神经内分泌评估。遗传分析包括在诊断时对 PTCH1 基因进行测序，然后对致病基因或候选 KS/CHH 基因进行外显子组分析，以排除对其他突变表型的贡献。在另外 124 名 KS/CHH 先证者中进行外显子组分析，没有额外的 GGS 征象。结果 先证者表现为 CA，磁共振成像上没有 OB，并且有 CHH 伴单侧隐睾，与 KS 一致。脉冲促性腺激素释放激素 (GnRH) 治疗使血清促性腺激素正常化并增加睾酮水平，支持 GnRH 缺乏症。遗传研究显示 3 名受影响的家庭成员携带 PTCH1 的新突变（c.838G> T；p.Glu280*）。这种未报告的无义有害突变导致推定的截断 Ptch1 蛋白或与无义介导的信使 RNA 衰变相关的翻译 Ptch1 蛋白缺失。这种杂合突变在 GGS 和 CA 的谱系中与 OB 发育不全/发育不全以及先证者中的 CHH 共分离，表明存在遗传连锁和常染色体显性遗传模式。在其他 KS/CHH 基因中没有与这些表型共分离的致病性罕见变异。在另外 124 名 KS/CHH 患者中，发现了另外 3 个杂合的、罕见的错义变异，并在计算机中预测为具有破坏性：p.Ser1203Arg、p.Arg1192Ser 和 p.Ile108Met。结论 该家族表明，与 PTCH1 突变相关的 GGS 可以包括 KS 的 2 个主要迹象。我们的数据与小鼠模型相结合表明 PTCH1 可能是 KS/CHH 的新候选基因，并加强了 Hedgehog 信号通路在 KS 和 GnRH 神经元迁移的病理生理学中的作用。