Normosmic Idiopathic Hypogonadotropic Hypogonadism Research Articles

Contributions of common genetic variants to constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism.

Constitutional delay of puberty (CDP) is highly heritable, but the genetic basis for CDP is largely unknown. Idiopathic hypogonadotropic hypogonadism (IHH) can be caused by rare genetic variants, but in about half of cases, no rare-variant cause is found. To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH. Case-control study. 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome; control genotyping data from unrelated studies. Polygenic scores (PGS) based on genome-wide association studies for timing of male pubertal hallmarks and age at menarche (AAM). The CDP cohort had higher PGS for male pubertal hallmarks and for AAM compared to controls (for male hallmarks, Cohen's d = 0.85, p = 1 × 10-16; for AAM, d = 0.67, p = 1 × 10-10). The normosmic IHH cohort also had higher PGS for male hallmarks compared to controls, but the difference was smaller (male hallmarks d = 0.20, p = 0.003; AAM d = 0.10, p = 0.055). No differences were seen for the KS cohort compared to controls (male hallmarks d = 0.04, p = 0.45; AAM d = -0.03, p = 0.86). Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, weakly to normosmic IHH, and potentially not at all to KS. These findings demonstrate that the common-variant genetics of CDP and normosmic IHH are largely but not entirely distinct.

Whole-Exome Sequencing Analysis of Idiopathic Hypogonadotropic Hypogonadism: Comparison of Varicocele and Nonobstructive Azoospermia

As a rare disease leading to male infertility, idiopathic hypogonadotropic hypogonadism (IHH) has strong heterogeneity of clinical phenotype and gene mutation. At present, there is no effective diagnosis and treatment method for this disease. This study is to explore the possible new pathogenic gene of idiopathic hypogonadotrophic hypogonadism and the pathological mechanism affecting its occurrence. We performed a whole-exome sequencing on 9 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), 19 varicocele patients with asthenospermia, oligospermia, or azoospermia, 5 patients with simple nonobstructive azoospermia, and 13 normal healthy adult males and carried out comparative analysis, channel analysis, etc. After preliminary sequencing screening, 309–431 genes harbouring variants, including SNPs and indels, were predicted to be harmful per single patient in each group. In genetic variations of nIHH patients’ analysis, variants were detected in 10 loci and nine genes in nine patients. And in co-analysis of the three patient groups, nine nIHH patients, 19 VC patients, and five SN patients shared 116 variants, with 28 variant-harbouring genes detected in five or more patients. We found that the NEFH, CCDC177, and PCLO genes and the Gene Ontology pathways GO:0051301: cell division and GO:0090066: regulation of anatomical structure size may be key factors in the pathogenic mechanism of IHH. Our results suggest that the pathogenic mechanism of IHH is not limited to the central nervous system effects of GnRH but may involve other heterogeneous pathogenic genetic variants that affect peripheral organs.

Clinical Manifestations, Genetic Variants and Therapeutic Evaluation in Sporadic Chinese Patients with Idiopathic Hypogonadotropic Hypogonadism.

Genetic factors account for a large proportion of idiopathic hypogonadotropic hypogonadism (IHH) etiologies, although not necessarily a complete genetic basis. This study aimed to characterize the clinical presentations, genetic variants, and therapeutic outcomes of patients with sporadic IHH, which may be helpful for genetic counseling and treatment decisions. Eleven Chinese patients with IHH were retrospectively analyzed. Rare genetic variants were evaluated using whole-exome sequencing and bioinformatics analysis and were further classified according to the ACMG-AMP guidelines. The therapeutic responses of patients were further evaluated. Six heterozygous variants of SOX10, WDR11, PROKR2, CHD7 and FGF17 were detected in five Kallmann syndrome (KS) patients, whereas two heterozygous variants of CHD7 and PROKR2 were detected in two normosmic IHH (nIHH) patients. Among these variants, a novel likely pathogenic variant in the SOX10 (c.429-1G>C) was considered to cause the KS phenotype in patient 02, and two potential variants of uncertain significance (VUS) in CHD7 (c.3344G>A and c.7391A>G) possibly contributed to the KS phenotype in patient 05 and the nIHH phenotype in patient 07, which need to be confirmed by further evidence. Additionally, long-term testosterone or estradiol replacement treatment effectively improved the development of sexual characteristics in patients with IHH. Next-generation sequencing is a powerful tool for identifying the molecular etiology and early diagnosis of IHH. Efficient therapeutic outcomes strongly indicate a need for timely treatment.

Clinical feature and genetic analysis of a patient with Idiopathic hypogonadotropic hypogonadism due to a novel variant of CHD7 gene

To explore the clinical feature and genetic etiology of a patient with normosmic idiopathic hypogonadotropic hypogonadism (nIHH) due to variant of CHD7 gene. A patient who had presented at Anhui Provincial Children's Hospital in October 2022 was selected as the study subject. Clinical data of the patient was collected. The patient and his parents were subjected to trio-whole exome sequencing. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. The patient had featured delayed development of secondary sexual characteristics but normal olfactory function. Genetic testing revealed that he has harbored a c.3052C>T (p.Pro1018Ser) missense variant of the CHD7 gene, for which both of his parents were of the wild type. The variant has not been recorded in the PubMed and HGMD databases. Analysis of amino acid sequences suggested that the variant site is highly conserved, and the variant may affect the stability of protein structure. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.3032C>T variant was classified as a likely pathogenic (PS2+PM2_Supporting+PP2+PP3+PP4). The delayed development of secondary sexual characteristics of the patient may be attributed to the c.3052C>T (p.Pro1018Ser) variant of the CHD7 gene. Above finding has expanded the variation spectrum of the CHD7 gene.

Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty.

The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Clinical Characteristics and Genetic Analyses of Patients with Idiopathic Hypogonadotropic Hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH) is classified into two groups-Kalman syndrome and normosmic IHH (nIHH). Half of all cases can be explained by mutations in >50 genes. Targeted gene panel testing with nexrt generation sequencing (NGS) is required for patients without typical phenotypic findings. The aim was to determine the genetic etiologies of patients with IHH using NGS, including 54 IHH-associated genes, and to present protein homology modeling and protein stability analyzes of the detected variations. Clinical and demographic data of 16 patients (eight female), aged between 11.6-17.8 years, from different families were assessed. All patients were followed up for a diagnosis of nIHH, had normal cranial imaging, were without anterior pituitary hormone deficiency other than gonadotropins, had no sex chromosome anomaly, had no additional disease, and underwent genetic analysis with NGS between the years 2008-2021. Rare variants were classified according to the variant interpretation framework of the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology. Changes in protein structure caused by variations were modeled using RoseTTAFold and changes in protein stability resulting from variation were analyzed. Half of the 16 had no detectable variation. Three (18.75%) had a homozygous (pathogenic) variant in the GNRHR gene, one (6.25%) had a compound heterozygous [likely pathogenic-variants of uncertain significance (VUS)] variant in PROK2 and four (25%) each had a heterozygous (VUS) variant in HESX1, FGF8, FLRT3 and DMXL2. Protein models showed that variants interpreted as VUS according to ACMG could account for the clinical IHH. The frequency of variation detection was similar to the literature. Modelling showed that the variant in five different genes, interpreted as VUS according to ACMG, could explain the clinical IHH.

ODP401 A new FGFR1 mutation causing Idiopathic Hypogonadotropic Hypogonadism and Polydactyly

Abstract Introduction Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a heterogeneous condition with unknown genetic basis in approximately 30% of patients. We describe a case with normosmic IHH and an unreported FGFR1 mutation. Case Report A 23-year-old hispanic man, with a history of polydactyly presented to our clinic for evaluation of delayed puberty. He had no facial hair and minimal pubic and axillary hair. He reported fatigue, low libido and scant ejaculation. He denied anosmia, eating disorders, learning disability, urological malformations, obesity, galactorrhea, testicular trauma, mumps, or use of androgenic steroids. Family history was significant for polydactyly in his mother. Physical exam findings showed normal vitals, height 185 cm, BMI 24 kg/m2, eunuchoid body habitus, bilateral gynecomastia, no facial hair, scant axillary and pubic hair, prepubertal 2 ml testicles within the scrotum and a micro-penis. Serum total testosterone was 7 ng/dl (250-1100 ng/dl), free testosterone 0.9 pg/ml (9.3-26.5 pg/ml), FSH 2.2 mIU/ml (1.6-8. 0 mIU/ml), LH 0.8 mIU/ml (1.5-9.3 mIU/ml), Prolactin 4.1 ng/ml (4-15.2 ng/ml), TSH 1.68 mIU/ml (0.4-5.5 mIU/ml), free t4 1.2 ng/dl (0.8-1.7 ng/dl), growth hormone 0.3 ng/ml (0. 0-10 ng/ml), IGF-1 175 ng/ml (155-432 ng/ml), ACTH 14.6 pg/ml (7.2-63 pg/ml), cortisol (not am) 3. 0 ug/dl (6.2-19.4 ug/dl). Pituitary MRI revealed no focal sellar/suprasellar lesions with normal enhancement of the pituitary gland . DXA scan showed a low bone density for his age with Z-scores below -2. 0 in all regions. Chromosome analysis revealed a normal male 46, XY karyotype. Genetic testing of both patient and mother, using Invitae test kit, revealed an heterozygous mutation in FGFR1 gene, exon 9, variant c.1231C>A (p. Gln411Lys), not described in medical literature. A diagnosis of normosmic idiopathic hypogonadotropic hypogonadism (nIHH) was made. Testosterone cypionate IM 100 mg once weekly was initiated and after 6 months he experienced improvement in energy, libido, muscle mass, facial and body hair, and virilization of his voice. Conclusions The heterogeneity in phenotypic presentation of IHH makes its diagnosis a challenge. Furthermore, the genetic basis for these multiple phenotypes are still not fully described. We report a new FGFR1 mutation causing hypogonadism. Reference: Ferreira Gontijo, L., Latronico, A. Approach to the Patient With Hypogonadotropic Hypogonadism. JES, Vol. 98, Issue 5, 1 May 2013, P. 1781–1788. Presentation: No date and time listed

Treatment of congenital hypogonadotropic hypogonadism in male patients.

Congenital hypogonadotropic hypogonadism (CHH) is characterized by complete or partial failure of pubertal development because of inadequate secretion of gonadotropic hormones. CHH consists of hypogonadotropic hypogonadism with anosmia or hyposmia, Kallmann syndrome, and the normosmic variation normosmic idiopathic hypogonadotropic hypogonadism. CHH is one of the few treatable diseases of male infertility, although men with primary testicular dysfunction have irreversibly diminished spermatogenic capacity. The approach to CHH treatment is determined by goals such as developing virilization or inducing fertility. This review focuses on the current knowledge of therapeutic modalities for inducing puberty and fertility in men with CHH.

Unilaterally disrupted structural and functional connectivity of the fronto-limbic system in idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) is rare and can either be associated with normal or defective olfactory sensation, classified as normosmic IHH (nIHH) or Kallmann syndrome (KS). We do not yet understand the central processing pathways in the olfactory system. We aimed to compare the resting-state structural and functional connectivity (FC) of olfactory neural pathways in patients with IHH. We hypotheses that alterations of structuralconnectivity and FC may exist in the olfactory cortex pathways in IHH patients. STRUCTURAL AND FUNCTIONAL CONNECTIVITY DATA RESULTS BETWEEN TWO GROUPS WERE ANALYZED: Patients: Twenty-five IHH patients (13 nIHH patients and 12 KS patients) were recruited from the Department of Endocrinology and were assessed. A total of 25 age-matched healthy male controls were recruited from the community. All subjects underwent diffusion tensor imaging and functional magnetic resonance imaging (fMRI) scans. Structural and functional connectivity data analyses were then performed. Pearson's correlation analyses were performed to investigate the correlations between the fractional anisotropy (FA) value and FC strength, showing significant differences among the three groups separately. Compared with the HC group, FA value in the right uncinate fasciculus (UF) decreased significantly in the IHH group. The olfactory cortex FC values of the right gyrus rectus, orbitofrontal cortex (OFC) and right middle temporal gyrus in the IHH group were decreased compared with those in the HC group. Moreover, there were significant negative correlations between right UF FA and olfactory cortex-FC to both the gyrus rectus and OFC within the HC group (p < .05). Our findings suggest that alterations of structural and FC support the presence of neurobiological disruptions in IHH patients, particularly a specific structural-functional asymmetry disruption may exist in the olfactory cortex pathways in IHH patients.

PLXNB1 mutations in the etiology of idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) comprises a group of rare genetic disorders characterized by pubertal failure caused by gonadotropin-releasing hormone (GnRH) deficiency. Genetic factors involved in semaphorin/plexin signaling have been identified in patients with IHH. PlexinB1, a member of the plexin family receptors, serves as the receptor for semaphorin 4D (Sema4D). In mice, perturbations in Sema4D/PlexinB1 signaling leads to improper GnRH development, highlighting the importance of investigating PlexinB1 mutations in IHH families. In total, 336 IHH patients (normosmic IHH, n=293 and Kallmann syndrome, n=43) from 290 independent families were included in the present study. Six PLXNB1 rare sequence variants (p.N361S, p.V608A, p.R636C, p.V672A, p.R1031H, and p.C1318R) are described in eight normosmic IHH patients from seven independent families. These variants were examined using bioinformatic modeling and compared to mutants reported in PLXNA1. Based on these analyses, the variant p.R1031H was assayed for alterations in cell morphology, PlexinB1 expression, and migration using a GnRH cell line and Boyden chambers. Experiments showed reduced membrane expression and impaired migration in cells expressing this variant compared to the wild-type. Our results provide clinical, genetic, molecular/cellular, and modeling evidence to implicate variants in PLXNB1 in the etiology of IHH.

Clinical, hormonal, and genetic characteristics of 25 Chinese patients with idiopathic hypogonadotropic hypogonadism

BackgroundIdiopathic hypogonadotropic hypogonadism (IHH) is a type of congenital disease caused by a variety of gene variants leading to dysfunction in the secretion of hypothalamic gonadotropin-releasing hormones (GnRHs). Clinically, IHH can be divided into Kallmann syndrome (KS) with dysosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH) according to the presence or absence of an olfactory disorder.MethodsWe retrospectively evaluated 25 IHH patients (8 KS and 17 nIHH) who were diagnosed at the Department of Endocrinology of Shanghai Children’s Hospital from 2015 to 2021. We analysed the patients’ clinical data, including their hormone levels and gene sequences.ResultsAll male patients exhibited small phalli, and 35% of them exhibited cryptorchidism. A significant difference was observed in the levels of dihydrotestosterone (DHT) after human chorionic gonadotropin (HCG) stimulation (P = 0.028) between the KS group and the nIHH group. Missense variants were the major cause of IHH, and the main pathogenic genes were FGFR1, PROKR2/PROK2, and KAl1. Nine reported and 13 novel variants of six genes were identified. De novo variants were detected in 16 IHH patients; eight patients inherited the variants from their mothers, while only three patients inherited variants from their fathers. One patient had both KAl1 and PROKR2 gene variants, and another patient had two different PROKR2 gene variants. These two patients both had the hot spot variant c.533G > C (p. Trp178Ser) of the PROKR2 gene.ConclusionIHH should be highly suspected in patients with a small phallus and cryptorchidism. Compared with nIHH patients, KS patients exhibited a higher level of DHT after HCG stimulation. Missense variants were the major cause of IHH, and most of the inherited variants were from their mothers who exhibited no obvious clinical symptoms. We identified 9 reported variants and 13 novel variants that led to IHH. A small proportion of patients were at risk of inheriting either the oligogenic variant or the compound heterozygous variant. The hot spot variant c.533G > C (p. Trp178Ser) of PROKR2 might be involved in oligogenic inheritance and compound heterozygous inheritance. These findings provide deeper insight into the diagnosis and classification of IHH and will contribute to its clinical assessment.

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.

Contribution of Copy Number Variation in Idiopathic Hypogonadotropic Hypogonadism

Introduction: While the role of single nucleotide variants (SNVs) in causal genes for Idiopathic Hypogonadotropic hypogonadism (IHH) is known, the contribution of copy number variants (CNVs) to IHH has not been systematically studied. Here, we examined the prevalence of CNVs in a large IHH cohort and their associated phenotypic spectrum. Methods: Exome sequencing (ES) from 1,441 IHH probands was analyzed using the GATK-gCNV pipeline to identify CNVs that spanned known IHH genes with a site frequency of <1%. ES data was also analyzed for rare SNVs in all IHH genes. IHH subjects were evaluated for reproductive and non-reproductive phenotypes (kidney, eye, cardiovascular, midline/ facial, bone and neurological abnormalities). Results: (i) CNV prevalence in IHH: Three percent of the IHH probands (46/1441 probands, 38 males and 8 females) harbored CNVs in 19/36 high confidence IHH genes (26 deletions 20 duplications). The vast majority of CNVs disrupted either the ANOS1 (26%) or FGFR1 (17%) genes. Intriguingly, CHD7 (a gene that carries SNVs in ~12% of our IHH subjects) did not harbor any CNVs. (ii) Phenotypic analysis: We found that CNVs were more common in IHH subjects with anosmia (Kallmann syndrome, N=33) compared to normosmic IHH (N=13). More than half of the subjects with CNVs affecting IHH genes carried at least 1 non-reproductive feature (26/46 IHH subjects, 56%). A syndromic presentation with multiple non-reproductive phenotypes was more common in IHH subjects harboring multigenic CNVs (IHH gene & additional genes) compared to IHH subjects with single IHH gene CNV or SNV in a single IHH gene (61% vs. 12% or 18%, respectively; p 0.0006). Conclusions: CNVs in known IHH genes contribute to 3% of the IHH genetic architecture in our cohort. IHH subjects with larger multigenic CNVs displayed phenotypes consistent with contiguous gene syndromes. The absence of genic CNVs in genes frequently found to carry SNVs, such as CHD7, requires additional analysis to establish the biologic or mechanistic reasons for their rarity.

Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants

Purpose:SOX10 mutations 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.Methods:Exome sequencing from 1309 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 & literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population.Results:Thirty-seven SOX10-associated IHH cases were identified: 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 vs. gnomAD.Conclusions:SOX10 mutations 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.

Clinicohormonal Parameters as a Primary Step to Differentiate Normosmic Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome in a Tertiary Care Hospital in Eastern India

Introduction: Idiopathic hypogonadotropic hypogonadism is a rare gonadal dysgenesis in which puberty does not take place naturally. It occurs due to insufficient pulsatile secretion of Gonadotrophin-Releasing Hormone (GnRH) and the resulting Follicle-Stimulating Hormone (FSH) and Luteinising Hormone (LH) deficiency leads to absence of or delayed sexual maturation. Kallmann syndrome is an uncommon genetic disorder characterised by hypogonadotropic hypogonadism associated with anosmia or hyposmia. When anosmia is absent, the same is referred as normosmic Idiopathic Hypogonadotropic hypogonadism (nIHH). Aim: To find out the significant differences between Kallmann syndrome and nIHH based on clinical features and biochemical assessment as a primary measure to initiate the treatment early. Materials and Methods: This hospital based cross-sectional observational cohort study was conducted in Department of Endocrinology, Nilratan Sircar Medical College and Hospital, Kolkata, India. The study was done on 55 cases of IHH presenting to the department with delayed secondary sexual characteristics. Results: Out of these 55 cases, 45 (81.8%) were of nIHH and only 10 (18.2%) cases were of Kallmann Syndrome. It was found that both the conditions show male predominance. Smell abnormalities were present only in Kallmann group. The level of serum testosterone was significantly higher (p&lt;0.05) in nIHH subjects (mean-35.59 ng/dL) than patients with Kallmann Syndrome (mean-14.90 ng/dL). Patients with Kallmann syndrome showed significantly reduced pubic and axillary hair development and absence of gonadal development. Conclusion: Absence of puberty with anosmia/hyposmia with low serum FSH and LH, drastically reduced serum testosterone, are factors that point towards the diagnosis of Kallmann syndrome even in absence of genetic study, which is helpful for initiation of hormone replacement therapy for treatment.

The Impact of LHR Gene Polymorphism Rs12470652 in Women with POF and Nihh, A Case-Control Study

The current study was designed to investigate the impact of the missense Single Nucleotide Polymorphism (SNP), Asn291Ser (c.872A&gt;G: rs12470652), of LHR gene (Luteinizing hormone receptor gene) in peripheral blood samples of Iraqi infertile women diagnosed with premature ovarian failure (POF) and normosmic idiopathic hypogonadotropic hypogonadism(niHH, patients with normal sense of smell). Following the hormonal analysis, fifty women diagnosed with premature ovarian failure and fifty women diagnosed with normosmic idiopathic hypogonadotropic hypogonadism were included as patient groups, while fifty healthy fertile women were enrolled as a control group. The blood samples were obtained from patient and control groups at Kamal Al-Samarrai Hospital in Baghdad, Iraq through March to December 2018. The genotyping of the SNP (rs12470652) was carried out by real-time polymerase chain reaction (real-time PCR) of the purified genomic DNA obtained from All-cell-pellet (ACP) of blood samples. The frequency of the LHR (rs12470652), p.Asn291Ser minor allele G, was found to be 32% healthy fertile women, 30 % of those with POF (p = 0.879), and 28% in the niHH patients (p = 0.644) Therefore, no statistically significant differences were found. This research aims to study the relationship between polymorphism in the region of LHR gene position: 872 A &gt; G, (Asn291Ser), (rs12470652), and both premature ovarian failure and normosmic idiopathic hypogonadotropic hypogonadism. Therefore, the potential influence of (rs12470652) p.Asn291Ser polymorphism on both types of female infertility of an Iraqi population was evaluated. In conclusion, no impact was observed since the conducted study on a sample population of Iraqi women showed that the prevalence of LHR (rs12470652) polymorphisms did not significantly differ in the two infertile patients groups (POF and niHH) as compared to the healthy fertile control group.

Normosmic idiopathic hypogonadotropic hypogonadism due to a novel GNRH1 variant in two siblings.

SummaryHypogonadotropic hypogonadism is characterised by insufficient secretion of pituitary gonadotropins resulting in delayed puberty, anovulation and azoospermia. When hypogonadotropic hypogonadism occurs in the absence of structural or functional lesions of the hypothalamic or pituitary gland, the hypogonadism is defined as idiopathic hypogonadotropic hypogonadism (IHH). This is a rare genetic disorder caused by a defect in the secretion of gonadotropin releasing hormone (GNRH) by the hypothalamus or a defect in the action of GNRH on the pituitary gland. Up to 50% of IHH cases have identifiable pathogenic variants in the currently known genes. Pathogenic variants in the GNRHR gene encoding the GNRH receptor are a relatively common cause of normosmic IHH, but reports of pathogenic variants in GNRH1 encoding GNRH are exceedingly rare. We present a case of two siblings born to consanguineous parents who were found to have normosmic idiopathic hypogonadotropic hypogonadism due to homozygosity of a novel loss-of function variant in GNRH1. Case 1 is a male who presented at the age of 17 years with delayed puberty and under-virilised genitalia. Case 2 is a female who presented at the age of 16 years with delayed puberty and primary amenorrhea.Learning points:IHH is a genetically heterogeneous disorder which can be caused by pathogenic variants affecting proteins involved in the pulsatile gonadotropin-releasing hormone release, action, or both.Currently known genetic defects account for up to 50% of all IHH cases. GNRH1 pathogenic variants are a rare cause of normosmic IHH.IHH is associated with a wide spectrum of clinical manifestations.IHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty.Early diagnosis and gonadotrophin therapy can prevent negative physical sequelae and mitigate psychological distress with the restoration of puberty and fertility in affected individuals.

Identification of KISS1R gene mutations in disorders of non-obstructive azoospermia in the northeast population of China.

BackgroundNon‐obstructive azoospermia (NOA), a serious phenotype of male spermatogenesis failure, is a multifactorial disease which is regulated by genetic, epigenetic, and environmental factors. Some gene structural variants have been demonstrated to be related to NOA. Loss‐of‐function mutations of KISS1R cause normosmic idiopathic hypogonadotropic hypogonadism (IHH) which result in azoospermia at the pre‐testicular level. The objective of this research was to investigate genetic variants of KISS1R in NOA patients.MethodsThe entire coding region of 52 spermatogenesis‐associated genes (KISS1R included) was sequenced from 200 NOA patients. Mutation screening was performed to identify genetic variations of these genes by targeted exome sequencing. Sequencing data analysis was carried out by a series of bioinformatics tools. Candidate variants confirmation was performed by Sanger sequencing. Functional analysis of candidate variants was evaluated using SIFT and PolyPhen‐2.ResultsThree heterozygous missense variants in KISS1R were identified in three patients, respectively. No deleterious variations in other candidate genes were found in the three patients. Two of these three variants, p.A211T and p.G186E, had been reported in the ExAC and dbSNP database, respectively, while the other variant p.A301D was novel. These variants were all predicted to be likely pathogenic by in silico analysis.ConclusionOur study revealed three heterozygous missense variants in KISS1R which expanded the mutation spectrum of KISS1R in infertile men with NOA in the northeast of China.

An Isolated Hypogonadotropic Hypogonadism due to a L102P Inactivating Mutation of KISS1R/GPR54 in a Large Family

KISS1R (GPR54) mutations have been reported in several patients with congenital normosmic idiopathic hypogonadotropic hypogonadism (nIHH). We aim to describe in detail nIHH patients with KISS1R (GPR54) mutations belonging to one related extended family and to review the literature. A homozygous mutation (T305C) leading to a leucine substitution with proline (L102P) was found in three affected kindred (2 males and 1 female) from a consanguineous Saudi Arabian family. This residue is localized within the first exoloop of the receptor, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs its function. In the affected female, a combined gonadotropin administration restored regular period and ovulation and she conceived with a healthy baby boy after 4 years of marriage. We showed that a loss-of-function mutation (p.Tyr305C) in the KISS1R gene can cause (L102P) KISS1 receptor dysfunction and familial nIHH, revealing the crucial role of this amino acid in KISS1R function. The observed restoration of periods and later on pregnancy by an exogenous gonadotropin administration further support, in humans, that the KISS1R mutation has no other harmful effects on the patients apart from the gonadotropin secretion impairment.

SAT-287 Hypogonadotropic Hypogonadism in RPL10 Mutation-Associated Syndromic Intellectual Disability

Background: A multitude of inactivating genetic mutations have been implicated in Idiopathic Hypogonadotropic Hypogonadism (IHH), either in Kallmann syndrome or in norm-osmic IHH. Over the last decade, a limited number of studies described variations in ribosomal protein L10 (RPL10) gene as a cause of X-linked syndromic intellectual disability; this was associated with a constellation of features, including: short stature, microcephaly, dysmorphic facies, intellectual disability, epilepsy. RPL10 gene is located on chromosome Xq28 in the region of G6PD and color vision genes. Literature review suggests that RPL10 is implicated in central nervous system (CNS) development and is identified as an X-linked autism-susceptibility gene. Clinical Case: Herein, we present an adolescent male who was found to be hemizygous for a novel missense variant, p.Asn73Ser (c.218A>G) in exon 5 of the RPL10 gene. He is also hemizygous for a novel missense variant p.Glu766Asp (c.2298G>T) in exon 19 of the CUL4B gene. Hemizygous mutations in CUL4B gene have been associated with X-linked intellectual disability with short stature, hypogonadotropic hypogonadism and abnormal gait. Patient has microcephaly, dysmorphic facial features, short stature and global developmental delays with profound intellectual disability. He is nonverbal, non-ambulatory and has bilateral sensorineural hearing loss, near blindness, seizure disorder, dystonia. At 16 years of age he developed neurologic complications: right side focal motor weakness, followed by left side weakness 4 months later. Subsequently, he developed central hypotonia with peripheral hypertonia. He developed primary acquired hypothyroidism with negative thyroid antibodies at age 15 years and also has hypogonadotropic hypogonadism. He became exclusively fed via G-tube due to aspiration pneumonia. Brain MRI showed subependymal heterotopia, thinning of the posterior corpus callosum, signal abnormality of the left hippocampus with mild volume loss of the right hippocampus; normal pituitary and pineal glands. This patient has 2 novel genetic mutations, both affecting central nervous system. Conclusion: This is the first description of IHH occurring in a patient with novel gene mutations of CUL4B and RPL10. While CUL4B gene mutations are known to be involved in CNS dysfunction, including IHH, it remains to be determined if mutations in RPL10 play a role in endocrinopathies of CNS origin.