Idiopathic Hypogonadotropic Hypogonadism Research Articles

A novel nonsense variant (p.Arg1293Ter) of the immunoglobulin superfamily 1 (IGSF1) associated with congenital hypogonadotropic hypogonadism and central hypothyroidism.

A novel nonsense variant (p.Arg1293Ter) of the immunoglobulin superfamily 1 (IGSF1) associated with congenital hypogonadotropic hypogonadism and central hypothyroidism.

Genetic Etiology of Idiopathic Hypogonadotropic Hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of rare developmental disorders characterized by low gonadotropin levels in the face of low sex steroid hormone concentrations. IHH is practically divided into two major groups according to the olfactory function: normal sense of smell (normosmia) nIHH, and reduced sense of smell (hyposmia/anosmia) Kallmann syndrome (KS). Although mutations in more than 50 genes have been associated with IHH so far, only half of those cases were explained by gene mutations. Various combinations of deleterious variants in different genes as causes of IHH have been increasingly recognized (Oligogenic etiology). In addition to the complexity of inheritance patterns, the spontaneous or sex steroid-induced clinical recovery from IHH, which is seen in approximately 10–20% of cases, blurs further the phenotype/genotype relationship in IHH, and poses challenging steps in new IHH gene discovery. Beyond helping for clinical diagnostics, identification of the genetic mutations in the pathophysiology of IHH is hoped to shed light on the central governance of the hypothalamo-pituitary-gonadal axis through life stages. This review aims to summarize the genetic etiology of IHH and discuss the clinical and physiological ramifications of the gene mutations.

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia.

The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

Evidence for Perinatal Steroid Influence on Human Sexual Orientation and Gendered Behavior.

In laboratory animals, exposure to gonadal steroid hormones before and immediately after birth can exert permanent effects on many behaviors, particularly reproductive behaviors. The extent to which such effects occur in humans remains an open question, but several lines of evidence indicate that perinatal levels of both androgens and estrogens may affect adult human psychology and behavior, including sexual orientation and gender nonconformity. Some putative indicators of prenatal androgen exposure, including the ratio of the length of the index finger to that of the ring finger (2D:4D), have repeatedly indicated that lesbians, on average, were exposed to more prenatal androgens than straight women, suggesting that sufficient fetal androgen exposure predisposes a fetus to gynephilia (attraction to women) at maturity. The digit ratios of gay men do not differ from those of straight men, suggesting that prenatal androgen levels are not responsible for their androphilia (attraction to men). However, evidence that gay men who prefer an insertive anal sex role (ASR) have more masculine digit ratios than those preferring a receptive ASR suggests that early androgens influence some sexual preferences in men. Furthermore, digit ratios among gay men have been found to correlate with recalled childhood gender nonconformity (CGN). People with isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) offer further insight into the effects of perinatal gonadal steroid exposure. In people with IGD, gonadal hormone production is low or absent after the first trimester of gestation. However, because placental gonadotropins drive gonadal hormone secretion during the first trimester when genitalia sexually differentiate, individuals with IGD are unambiguously male or female at birth, consistent with their chromosomal and gonadal sex. Men with IGD report greater CGN, again suggesting that perinatal androgen exposure contributes to male-typical behavioral patterns in humans. Interestingly, women with IGD report less androphilia and more bisexuality than control women, suggesting that perinatal ovarian steroids in females typically augment androphilia in adulthood. Taken together, these findings indicate that the perinatal hormonal milieu influences human sexual orientation and gender conformity.

Whole exome sequencing identifies deleterious rare variants in CCDC141 in familial self-limited delayed puberty

Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range of conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed to discover important underlying regulators of self-limited delayed puberty through interrogation of GnRH pathways. Whole exome sequencing (WES) data consisting of 193 individuals, from 100 families with self-limited delayed puberty, was analysed using a virtual panel of genes related to GnRH development and function (n = 12). Five rare predicted deleterious variants in Coiled-Coil Domain Containing 141 (CCDC141) were identified in 21 individuals from 6 families (6% of the tested cohort). Homology modeling predicted all five variants to be deleterious. CCDC141 mutant proteins showed atypical subcellular localization associated with abnormal distribution of acetylated tubulin, and expression of mutants resulted in a significantly delayed cell migration, demonstrated in transfected HEK293 cells. These data identify mutations in CCDC141 as a frequent finding in patients with self-limited delayed puberty. The mis-localization of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with heterozygous defects potentially impacting the timing of puberty.

Translational aspects of novel findings in genetics of male infertility—status quo 2021

IntroductionMale factor infertility concerns 7–10% of men and among these 40–60% remain unexplained.Sources of dataThis review is based on recent published literature regarding the genetic causes of male infertility.Areas of agreementScreening for karyotype abnormalities, biallelic pathogenic variants in the CFTR gene and Y-chromosomal microdeletions have been routine in andrology practice for >20 years, explaining ~10% of infertility cases. Rare specific conditions, such as congenital hypogonadotropic hypogonadism, disorders of sex development and defects of sperm morphology and motility, are caused by pathogenic variants in recurrently affected genes, which facilitate high diagnostic yield (40–60%) of targeted gene panel-based testing.Areas of controversyProgress in mapping monogenic causes of quantitative spermatogenic failure, the major form of male infertility, has been slower. No ‘recurrently’ mutated key gene has been identified and worldwide, a few hundred patients in total have been assigned a possible monogenic cause.Growing pointsGiven the high genetic heterogeneity, an optimal approach to screen for heterogenous genetic causes of spermatogenic failure is sequencing exomes or in perspective, genomes. Clinical guidelines developed by multidisciplinary experts are needed for smooth integration of expanded molecular diagnostics in the routine management of infertile men.Areas timely for developing researchDi−/oligogenic causes, structural and common variants implicated in multifactorial inheritance may explain the ‘hidden’ genetic factors. It is also critical to understand how the recently identified diverse genetic factors of infertility link to general male health concerns across lifespan and how the clinical assessment could benefit from this knowledge.

Age at diagnosis in patients with chronic congenital endocrine conditions: a regional cohort study from a reference center for rare diseases

BackgroundFor chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient’s age, but diagnosis is often late.ObjectiveTo evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development.Patients and MethodsThis observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases—non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)—included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening.ResultsMedian age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8–10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD.ConclusionThe early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes.

DLG2 Mutations in the Etiology of Pubertal Delay and Idiopathic Hypogonadotropic Hypogonadism

Introduction: Idiopathic hypogonadotropic hypogonadism (IHH) is caused by dysfunction of the hypothalamic-pituitary-gonadal axis. DLG2 was recently implicated as a gene associated with delayed puberty and which may also contribute to IHH. The confirmation of the candidate puberty genes in independent IHH cohorts has become crucial due to the lack of proper genotype-phenotype segregations in reported pedigrees. Therefore, we aimed to screen DLG2 in patient variants in a large cohort of IHH patients. Methods: The present study included a total of 336 IHH patients from 290 independent families. The coding and flanking regions of DLG2 were screened for potentially important variants in the WES data. Candidate variants were evaluated in the ­gnomAD and GME databases according to their allele frequencies, and only those with a frequency <0.0001 were considered rare. Detected variants were classified according to the ACMG/AMP criteria. Results: We found 1 homozygous and 2 heterozygous missense variants in 3 independent pedigrees. Identified variants were found extremely rare or not reported in gnomAD. Two variants were categorized as “uncertain significance,” and the other one was “likely pathogenic” according to the ACMG criteria. All patients were normosmic, and in 2 of the 3 families, there were no causal variants in other IHH-related genes. Conclusion: We detected 3 rare sequencing variants in DLG2 in 5 patients with IHH or delayed puberty in a large IHH cohort. Our results support the contention that the DLG2 mutations are associated with IHH in human puberty.

Discovery of a Novel Variant of SEMA3A in a Chinese Patient with Isolated Hypogonadotropic Hypogonadism.

Semaphorin (SEMA) has an important role in nerve development, organ formation, immune response, angiogenesis, and tumor growth. SEMA can regulate the growth and branching of axons, the morphology of dendrites, and the migration of neurons. The loss-of-function in SEMA and its receptors PLXNs and NRP affect the migration of GnRH neurons, leading to idiopathic hypogonadotropic hypogonadism (IHH). As a member of the SEMA family, SEMA3A has an important role in axonal rejection, dendritic branching, synaptic formation, and neuronal migration. There are more and more SEMA3A variants identified in IHH patients. In this study, we identified a novel SEMA3A variant (c.1369A > G (p.T457A)) in a male nIHH patient. Functional studies indicated that the T457A SEMA3A variant led to the defect of FAK phosphorylation and GN11 cell migration, which strongly argued in favor of its pathogenic effect in the nIHH patient. Our findings substantiated that the 435–457 position of SEMA3A might be very important for the secretion of SEMA3A. Haploin-sufficiency of SEMA3A in humans was sufficient to cause the IHH phenotype. SEMA3A variants might have a role in modifying the IHH phenotype, according to the variants at different positions of SEMA3A. SEMAs and its receptors formed a complex network, and other members of the SEMA-signaling pathway might also be involved in the pathogenesis of IHH.

Hormonal changes throughout puberty in boys: an observational study on the treatment outcome of congenital hypogonadotropic hypogonadism.

Hormonal changes throughout puberty in boys: an observational study on the treatment outcome of congenital hypogonadotropic hypogonadism.

Next-generation sequencing-based mutational analysis of idiopathic short stature and isolated growth hormone deficiency in Korean pediatric patients

We investigated the distribution of short stature-associated mutations in Korean pediatric patients with idiopathic short stature (ISS) and isolated growth hormone deficiency (IGHD) via targeted next-generation sequencing (TNGS). We employed a 96-gene TNGS panel for short stature in a total of 144 patients (5-19 years-old) previously diagnosed with ISS or IGHD and identified heterozygous pathogenic or likely pathogenic genetic variants in 14 (10%) patients. Of the mutated genes, PROKR2 (n = 3) is associated with gonadotropin-releasing hormone deficiency or hypopituitarism, while FGFR1 (n = 1) and NPR2 (n = 3) encode growth plate paracrine factors. FBN1 (n = 1), COL9A1 (n = 1), MATN3 (n = 1), and ACAN (n = 3) regulate the cartilage extracellular matrix, while PTPN11 (n = 1) controls intracellular pathways. Six patients had IGHD, and eight patients had ISS. The current findings highlight the utility of TNGS for determining the genetic etiology in these patients.

Analysis of PLXNA1, NRP1, and NRP2 variants in a cohort of patients with isolated hypogonadotropic hypogonadism.

BackgroundIsolated hypogonadotropic hypogonadism (IHH) is a clinical syndrome described by failure of gonadal function secondary to defects on the synthesis, secretion, or action of the gonadotropin‐releasing hormone (GnRH). The secreted glycoprotein SEMA3A binds its receptors NRP1 or NRP2 and PLXNA to participate in axonal projection, dendritic branching, synaptic formation, and neuronal migration. Deficiency in SEMA3A, NRP1, NRP2, and PLXNA1 have been related to abnormal GnRH neuron development in mice and IHH in humans.MethodsThe aim of this study was to examine the genotypic and phenotypic spectra of the NRP1, NRP2, and PLXNA1 genes in a large cohort of IHH probands from China. We screened NRP1, NRP2, and PLXNA1 variants in Chinese IHH patients by whole exome sequencing and pedigree analysis.ResultsWe identified 10 heterozygous missense variants in PLXNA1, five heterozygous missense variants in NRP1, and two heterozygous missense variants in NRP2. NRP1 variants were found only in IHH patients with defective olfaction (i.e., Kallmann syndrome, KS). In addition, 85% (17/20) of patients harbored variants in other IHH‐associated genes.ConclusionOur study greatly enriched the genotypic and phenotypic spectra of PLXNA1, NRP1, and NRP2 in IHH. It may be conducive to the genetic counseling, diagnosis, and treatment of IHH with mutations in the PLXNA1, NRP1, and NRP2 genes. Furthermore, our results indicated that NRP1 were strongly linked to hearing loss.

Enigmatic Neural Pathways: Potentiating Viral Neuroinvasion Into the CNS.

Enigmatic Neural Pathways: Potentiating Viral Neuroinvasion Into the CNS.

Congenital hypogonadotropic hypogonadism: from clinical characteristics to genetic aspects

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by a deficiency in gonadotropin-releasing hormone (GnRH). CHH is characterized by delayed puberty and/or infertility; this is because GnRH is the main component of the hypothalamic-pituitary-gonadal (HPG) axis, which is a key factor in pubertal development and reproductive function completion. However, since the development of sexual characteristics and reproduction begins in the prenatal period and is very complex and delicate, the clinical characteristics and involved genes are very diverse. In particular, the HPG axis is activated three times in a lifetime, and the symptoms and biochemical findings of CHH vary by period. In addition, related genes also vary according to the formation and activation process of the HPG axis. In this review, the clinical characteristics and treatment of CHH according to HPG axis activation and different developmental periods are reviewed, and the related genes are summarized according to their pathological mechanisms.

Evidence that perinatal ovarian hormones promote women’s sexual attraction to men

Ovarian estrogens may influence the development of the human brain and behavior, but there are few opportunities to test this possibility. Isolated GnRH deficiency (IGD) is a rare endocrine disorder that could provide evidence for the role of estrogens in organizing sexually differentiated phenotypes: Unlike typical development, development in individuals with IGD is characterized by low or absent gonadal hormone production after the first trimester of gestation. Because external genitalia develop in the first trimester, external appearance is nevertheless concordant with gonadal sex in people with IGD. We therefore investigated the effects of gonadal hormones on sexual orientation by comparing participants with IGD (n = 97) to controls (n = 1670). Women with IGD reported lower male-attraction compared with typically developing women. In contrast, no consistent sexuality differences between IGD and typically developing men were evident. Ovarian hormones after the first trimester appear to influence female-typical dimensions of sexual orientation.

A novel heterozygous mutation of CHD7 gene in a Chinese patient with Kallmann syndrome: a case report

BackgroundVariants of chromodomain helicase DNA binding protein 7 (CHD7) gene are commonly associated with Kallmann syndrome (KS) and account for 5–6% of idiopathic hypogonadotropic hypogonadism (IHH) cases. Here we report a novel mutation of CHD7 gene in a patient with KS, which may contribute to the better understanding of KS.Case presentationA 29-year-old male patient with KS and a chief complaint of delayed puberty for 13 years (Tanner B Stage< 4) was admitted to the Department of Endocrinology of the First Affiliated Hospital of Zhejiang University (Hangzhou, China) in September 2019. Dual-energy X-ray absorptiometry (DEXA) showed low bone density in both lumbar spine (L1 ~ L5 mean Z-score − 3.0) and femoral neck (Z-score − 2.7). Dynamic contrast-enhanced magnetic resonance imaging (MRI) of pituitary and contrast-enhanced computed tomography (CT) showed no abnormal findings. Ophthalmological evaluation showed that his both eyes showed exotropia, and no sight loss was noted. Heterozygous c.1619G > T mutation of TCD7 gene (p.G4856V) was detected, whereas none of his family members had this mutation. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) were injected for three times/week to treat idiopathic hypogonadotropic hypogonadism (IHH). After several months of therapy, the patient’s health condition improved. His testicles became larger, and his secondary sexual characteristics improved after treatment.ConclusionExploration of the novel splice-site mutation of CHD7 may further our current understanding of KS.

GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty

Hum Reprod. 2020 Oct 1;35(10):2312–2322. 10.1093/humrep/deaa185. PMID: 32862222. https://academic.oup.com/humrep/article/35/10/2312/5899242

Feedback-Related Beta-Band Power Predicts Risky Choices in a Probabilistic Gambling Task

SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders.Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population.Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD.SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.

Reproductive prognosis of patients with hypogonadotropic hypogonadism: Retrospective review of 16 cases with amenorrhea.

The aim of this study was to evaluate the general characteristics, menstruation status, and fertility outcomes of patients with hypogonadotropic hypogonadism (HH). We evaluated 16 patients with HH who visited our institution between April 2012 and March 2016 with a complaint of amenorrhea. Four (25%) patients had primary amenorrhea and the remaining 12 (75%) cases had secondary amenorrhea. Among the patients with primary amenorrhea, weight loss was considered to be the underlying cause in one (25%) patient, whereas the remaining three (75%) cases were idiopathic HH. Among HH cases with secondary amenorrhea, six (50%) developed amenorrhea following weight loss, whereas the remaining six cases were of unknown etiology. Among the 16 patients with HH, we observed the sporadic restart of the menstrual cycle in four (25%) women during follow-up. Infertility treatment was administered to nine patients with HH who wished to become pregnant. Clomiphene citrate was effective in four patients with secondary amenorrhea and induced follicular development. Seven of nine patients with HH (77.8%) became pregnant following infertility treatment. In some cases of HH, the serum levels of gonadotropin increased sporadically during follow-up, regardless of the recovery of menstruation. We followed one patient with HH for more than 20 years. Although her gonadotropin levels were generally low and sometimes fluctuated without spontaneous menstruation, they increased dramatically to menopausal levels at 50 years of age. However, they again decreased to hypogonadotropic levels. As the pathophysiology varied widely among patients, the etiologic factors underlying HH might also vary.

Oligogenic Inheritance Underlying Incomplete Penetrance of PROKR2 Mutations in Hypogonadotropic Hypogonadism

The role of the prokineticin 2 pathway in human reproduction, olfactory bulb morphogenesis, and gonadotropin-releasing hormone secretion is well established. Recent studies have highlighted the implication of di/oligogenic inheritance in this disorder. In the present study, we aimed to identify the genetic mechanisms that could explain incomplete penetrance in hypogonadotropic hypogonadism (HH). This study involved two unrelated Tunisian patients with HH, which was triggered by identifying a homozygous p.(Pro290Ser) mutation in the PROKR2 gene in a girl (HH1) with Kallmann syndrome (KS). The functional effect of this variant has previously been well demonstrated. Unexpectedly, her unaffected father (HH1P) and brother (HH1F) also carried this genetic variation at a homozygous state. In the second family, we identified a heterozygous p.(Lys205del) mutation in PROKR2, both in a male patient with normosmic idiopathic IHH (HH12) and his asymptomatic mother. Whole-exome sequencing in the three HH1 family members allowed the identification of additional variants in the prioritized genes. We then carried out digenic combination predictions using the oligogenic resource for variant analysis (ORVAL) software. For HH1, we found the highest number of disease-causing variant pairs. Notably, a CCDC141 variant (c.2803C > T) was involved in 18 pathogenic digenic combinations. The CCDC141 variant acts in an autosomal recessive inheritance mode, based on the digenic effect prediction data. For the second patient (HH12), prediction by ORVAL allowed the identification of an interesting pathogenic digenic combination between DUSP6 and SEMA7A genes, predicted as “dual molecular diagnosis.” The SEMA7A variant p.(Glu436Lys) is novel and predicted as a VUS by Varsome. Sanger validation revealed the absence of this variant in the healthy mother. We hypothesize that disease expression in HH12 could be induced by the digenic transmission of the SEMA7A and DUSP6 variants or a monogenic inheritance involving only the SEMA7A VUS if further functional assays allow its reclassification into pathogenic. Our findings confirm that homozygous loss-of-function genetic variations are insufficient to cause KS, and that oligogenism is most likely the main transmission mode involved in Congenital Hypogonadotropic Hypogonadism.