20 research outputs found
A new variant in signal peptide of the human luteinizing hormone receptor (LHCGR) affects receptor biogenesis causing leydig cell hypoplasia
The human luteinizing hormone/chorionic gonadotropin receptor (LHCGR) plays a fundamental role in male and female reproduction. In males, loss-of-function mutations in LHCGR have been associated with distinct degrees of impairment in pre- and postnatal testosterone secretion resulting in a variable phenotypic spectrum, classified as Leydig cell hypoplasia (LCH) type 1 (complete LH resistance and disorder of sex differentiation) and type 2 (partial LH resistance with impaired masculinization and fertility).Here, we report the case of an adolescent who came to the pediatric endocrinologist at the age of 12 years old for micropenis and cryptorchidism. Testis biopsy showed profound Leydig cell hypoplasia and absent germinal line elements (Sertoli-only syndrome). The sequence analysis of the LHCGR gene showed the presence of a compound heterozygosity, being one variation, c.1847C>A p.S616Y, already described in association to Hypergonadotropic Hypogonadism (HH), and the other, c.29 C>T p.L10P, a new identified variant in the putative signal peptide of LHCGR. Functional and structural studies provide first evidence that LHCGR have a functional and cleavable signal peptide required for receptor biogenesis. Moreover, we demonstrate the pathogenic role of the novel p.L10P allelic variant, which has to be considered a loss-of-function mutation significantly contributing, in compound heterozygosity with p.S616Y, to the Leydig cell hypoplasia type 2 observed in our patient
Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism
Multiple metabolic and inflammatory mechanisms are considered the determinants of acquired functional isolated hypogonadotropic hypogonadism (IHH) in males, whereas classic IHH is a rare congenital condition with a strong genetic background. Since we recently uncovered a frequent familiarity for classic IHH among patients with mild adult-onset hypogonadism (AO-IHH), here we performed a genetic characterization by next generation sequencing of 160 males with classic or "functional" forms. The prevalence of rare variants in 28 candidate genes was significantly higher than in controls in all IHH patients, independently of the age of IHH onset, degree of hypogonadism or presence of obesity. In fact, it did not differ among patients with classic or milder forms of IHH, however particular genes appear to be more specifically associated with one or the other category of IHH. ROC curves showed that Total Testosterone <6.05 nmol/L and an age of onset <41 years are sensitive cutoffs to identify patients with significantly higher chances of harboring rare IHH gene variants. In conclusion, rare IHH genes variants can frequently predispose to AO-IHH with acquired mild hormonal deficiencies. The identification of a genetic predisposition can improve the familial and individual management of AO-IHH and explain the heritability of congenital IHH
The complex genetic basis of congenital hypogonadotropic hypogonadism
Congenital hypogonadotropic hypogonadism (CHH) is a rare disease characterized by delayed/absent puberty and infertility due to an inadequate secretion or action of gonadotrophin-releasing hormone (GnRH), with an otherwise structurally and functionally normal hypothalamic-pituitary-gonadal (HPG) axis. CHH is genetically heterogeneous but, due to the infertility of affected individuals, most frequently emerges in a sporadic form, though numerous familial cases have also been registered. In around 50-60% of cases, CHH is associated with a variety of non-reproductive abnormalities, most commonly anosmia/hyposmia, which defines Kallmann Syndrome (KS) by its presence. Broadly-speaking, genetic defects that directly impact on hypothalamic secretion, regulation, or action of GnRH result in a pure neuroendocrine phenotype, normosmic CHH (nCHH), whereas genetic defects that impact of embryonic migration of GnRH neurons to the hypothalamus most commonly result in KS, though nCHH can also arise. Hence, the description of several pedigrees, comprising subjects exhibiting KS and others with nCHH. Although more than 24 genes have been described to be involved in CHH, molecular variants of these do not presently explain more than 35-45% of reported cases. Therefore, numerous other unidentified genes (or conceivably, epigenetic mechanisms) remain to be described to fully understand the pathogenesis of CHH, explaining the emergent idea that CHH is a complex genetic disease characterized by variable expressivity and penetrance. This review summarizes the current state of knowledge on the complex genetic basis of congenital hypogonadotropic hypogonadism and aims to be accessible to both researchers and clinicians
Pubertal Delay. The challenge of a timely differential diagnosis between Congenital Hypogonadotropic Hypogonadism (CHH) and Constitutional Delay of Growth and Puberty (CDGP): a narrative review
Distinguishing between Constitutional Delay of Growth and Puberty (CDGP) and Congenital Hypogonadotropic Hypogonadism (CHH) may be challenging. CDGP and CHH appear to belong to the same clinical spectrum (with low sex hormones and low LH and FSH), although one is classically transient and known as a self-limited form of delayed puberty (CDGP) while the other is permanent (CHH). Thus, the clinical history and the outcomes of these two conditions require different approaches, and an adequate and timely management for the patients is mandatory. Since the initial presentation of CDGP and CHH is almost identical and given the similarities of CDGP and partial forms of CHH (i.e. patients with partial and early interrupted pubertal development) the scientific community has been struggling to find some diagnostic tests able to allow an accurate differential diagnosis between these two conditions in delayed puberty. In this review we provide an up to date insight on the tests available, their meanings and accuracy, as well as some clues to effectively differentiate between constitutional pubertal delay and pathologic CHH
P59 ACTIVE TREATMENT AND LOW IGM ARE ASSOCIATED WITH INFERIOR SARS-COV-2 SPIKE ANTIBODY RESPONSE TO THREE DOSES OF COVID-19 RNA VACCINATION IN PATIENTS WITH MULTIPLE MYELOMA
Defective Jagged1 signaling impacts GnRH development and contributes to congenital hypogonadotropic hypogonadism.
In vertebrate species, fertility is controlled by gonadotropin-releasing hormone (GnRH) neurons. GnRH cells arise outside the central nervous system, in the developing olfactory pit, and migrate along olfactory/vomeronasal/terminal nerve axons into the forebrain during embryonic development. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare genetic disorders characterized by infertility and they are associated with defects in GnRH neuron migration and/or altered GnRH secretion and signaling.Here, we documented the expression of Jagged 1/Notch signaling pathway in GnRH neurons and along the GnRH neuron migratory route both in zebrafish embryos and in human fetuses. Genetic knock-down of the zebrafish ortholog of JAG1 (jag1b) resulted in altered GnRH migration and olfactory axonal projections to the olfactory bulbs.Next-generation sequencing was performed in 467 CHH unrelated probands leading to the identification of heterozygous rare variants in JAG1. Functional in vitro validation of JAG1 mutants revealed that 7 out of the 9 studied variants exhibit reduced protein levels and altered subcellular localization.Altogether our data provide compelling evidence that Jag1/Notch signaling plays a prominent role in the development of GnRH neurons and we propose that JAG1 insufficiency may contribute to the pathogenesis of CHH in humans