Our data demonstrate the hypothalamic origin of the gonadotropin deficiency in these genetic forms of normosmic CHH. Neurokinin B and NK3R therefore both play a crucial role in hypothalamic GnRH release in humans.

Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women.However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation.These are genetic diseases that can be transmitted to patients' offspring. Importantly patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex, oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing, and is increasingly being used in medical practice. Thus it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission but also its role in incomplete penetrance and variable expresivity in a perspective of genetic counseling.

Pulsatile gonadotropin-releasing hormone (GnRH) is crucial to normal reproductive function and abnormalities in pulse frequency give rise to reproductive dysfunction. Kisspeptin and neurokinin B (NKB), neuropeptides secreted by the same neuronal population in the ventral hypothalamus, have emerged recently as critical central regulators of GnRH and thus gonadotropin secretion. Patients with mutations resulting in loss of signaling by either of these neuroendocrine peptides fail to advance through puberty but the mechanisms mediating this remain unresolved. We report here that continuous kisspeptin infusion restores gonadotropin pulsatility in patients with loss-of-function mutations in NKB (TAC3) or its receptor (TAC3R), indicating that kisspeptin on its own is sufficient to stimulate pulsatile GnRH secretion. Moreover, our findings suggest that NKB action is proximal to kisspeptin in the reproductive neuroendocrine cascade regulating GnRH secretion, and may act as an autocrine modulator of kisspeptin secretion. The ability of continuous kisspeptin infusion to induce pulsatile gonadotropin secretion further indicates that GnRH neurons are able to set up pulsatile secretion in the absence of pulsatile exogenous kisspeptin.

SEMA3A is therefore a new gene whose loss-of-function is involved in KS. These findings validate the specific role of semaphorin 3A in the development of the olfactory system and in neuronal control of puberty in humans.

Context TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway.ObjectiveTo evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations.ResultsFrom a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein.We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio.ConclusionThe gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations.

Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defective GNRH release, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmann's syndrome, a disorder in which CHH is related to abnormal GNRH neuron ontogenesis and is associated with anosmia or hyposmia.In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a nonendocrine disorder, other mutations affecting GNRH and/or gonadotropin secretion have been reported.Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affecting GNRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GNRH sensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmann's syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine.This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype-phenotype relationships.

Pseudohypoparathyroidism type 1A (PHP1A), pseudoPHP (PPHP), and PHP type 1B (PHP1B) are caused by maternal and paternal GNAS mutations, and abnormal methylation at maternal GNAS promoter(s), respectively. Adult PHP1A patients are reportedly obese and short, whereas most PPHP patients are born small. In addition to PTH resistance, PHP1A and PHP1B patients may display early-onset obesity. As early-onset and severe obesity and short stature are daily burdens for PHP1A patients, we aimed at improving knowledge on the contribution of the GNAS transcripts to fetal and postnatal growth and fat storage. Through an international collaboration, we collected growth and weight data from birth until adulthood for 306 PHP1A/PPHP and 220 PHP1B patients. PHP1A/PPHP patients were smaller at birth than healthy controls, especially PPHP (length z-score PHP1A: −1.1±1.8; PPHP: −3.0±1.5). Short stature is observed in 64% and 59% of adult PHP1A and PPHP patients. PHP1B patients displayed early post-natal overgrowth (height z-score at 1 year: 2.2±1.3 and 1.3±1.5 in autosomal dominant and sporadic PHP1B) followed by a gradual decrease in growth velocity resulting in normal adult height (z-score for both: −0.4±1.1). Early-onset obesity characterizes GNAS alterations and is associated to significant overweight and obesity in adults (BMI z-score: 1.4±2.6, 2.1±2.0, and 1.4±1.9 in PPHP, PHP1A, and PHP1B, respectively), indicating that reduced Gsα expression is a contributing factor.. The growth impairment in PHP1A/PPHP may be due to Gsα haploinsufficiency in the growth plates; the paternal XLαs transcript likely contributes to prenatal growth; for all disease variants, a reduced pubertal growth spurt may be due to accelerated growth plate closure. Consequently, early diagnosis and close follow-up is needed in patients with GNAS defects to screen and intervene in case of early-onset obesity and decreased growth velocity.

Description and analysis of this family of patients with mutant ERα provide additional clinical findings toward identification and characterization of what was previously thought to be a highly rare clinical condition.