European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

Abstract

| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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“…Selectively blocking miR-200/429 binding to the 3'UTR of the Zeb1 transcript in the hypothalamus during the infantile period (between P7 and weaning) suppresses GnRH promoter activity at the cellular level and leads to abnormalities in the onset of puberty. Interestingly, the microRNA-gene micronetworks that we have identified as sustaining the postnatal increase in GnRH expression also appear to be at work during These results raise the intriguing possibility that the microRNA-dependent epigenetic regulation of GnRH secretion could underlie the pathophysiology of human congenital hypogonadotropic hypogonadism (CHH) when no mutations are found in known CHH genes [8]. Exploring the putative contribution of mutations in these microRNA-gene networks could thus hold therapeutic potential for disorders of puberty and fertility of hypothalamic origin (e.g.…”

MANAGEMENT OF ENDOCRINE DISEASE: Diagnostic and therapeutic approach of tall stature

“…When it is congenital, cryptorchidism and micropenis can raise suspicion after birth. It is important to search for anosmia as a clue for Kallmann syndrome (MIM 308700), and affected relatives can present only with an impaired sense of smell (31). Aromatase deficiency (MIM 613546) is a rare autosomal recessive disorder.…”

FGFR1 disruption identified by whole genome sequencing in a male with a complex chromosomal rearrangement and hypogonadotropic hypogonadism

“…Indeed, since the t(8;9)(p11.2;q21.1) has caused haploinsufficiency of FGFR1, this is consistent with the development of an autosomal dominant form of HH (Boehm et al, 2015). In this regard, since FGFR1 disruption compromises fertility (Boehm et al, 2015), the t(8;9)(p11.2;q21.1) would have occurred as a de novo event,…”