Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

Abstract

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.

Olfactory Malformations in Mendelian Disorders of the Epigenetic Machinery

“…Clinical presentation is extremely variable, with more than 100 minor criteria described ( Jawa et al, 2009 ). Among possible presentations, absent OBs and hypogonadotropic hypogonadism have been recently reported ( Barraud et al, 2020 ). Unlike GGS, to our knowledge, no olfactory malformation has ever been described in NF1 patients.…”

The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

“…The PTCH1 gene has been recently proposed as a CHH novel candidate gene [241], because four different variants were identified and predicted to be pathogenetic in a normosmic CHH/KS group of patients.…”

Recent advances in understanding and managing Kallmann syndrome

“…Again, the signalling pathway of the morphogenetic factor sonic hedgehog (Shh) could be another candidate in the defects of the olfactory and GnRH systems in KS 32 ; accordingly, a loss-of-function variant of GLI3, encoding a transcription factor involved in Shh signaling 33 , and mutations of WD Repeat Domain 11 (WDR11), which modulates the proteolytic processing of GLI3 34 , have also been identified in KS. Additionally, several semaphorins—from a large family of guidance molecules implicated in neuronal development and GnRH neuron migration and survival—have been found to be mutated in KS 35 , 36 .…”