Idiopathic Hypogonadotropic Hypogonadism Research Articles

Reversibility of congenital hypogonadotropic hypogonadism: lessons from a rare disease.

Reversibility of congenital hypogonadotropic hypogonadism: lessons from a rare disease.

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.

Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement.

There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.

Classes and predictors of reversal in male patients with congenital hypogonadotropic hypogonadism: a cross-sectional study of six international referral centres

Although some male patients with congenital hypogonadotropic hypogonadism (CHH) undergo spontaneous reversal following treatment, predictors of reversal remain elusive. We aimed to assemble the largest cohort of male patients with CHH reversal to date and identify distinct classes of reversal. This multicentre cross-sectional study was conducted in six international CHH referral centres in Brazil, Finland, France, Italy, the UK, and the USA. Adult men with CHH (ie, absent or incomplete spontaneous puberty by age 18 years, low serum testosterone concentrations, and no identifiable cause of hypothalamic-pituitary-gonadal [HPG] axis dysfunction) were eligible for inclusion. CHH reversal was defined as spontaneous recovery of HPG axis function off treatment. Centres provided common data elements on patient phenotype, clinical assessment, and genetics using a structured, harmonised data collection form developed by COST Action BM1105. Latent class mixture modelling (LCMM) was applied to establish whether at least two distinct classes of reversal could be identified and differentially predicted, and results were compared with a cohort of patients without CHH reversal to identify potential predictors of reversal. The primary outcome was the presence of at least two distinct classes of reversal. A total of 87 male patients with CHH reversal and 108 without CHH reversal were included in the analyses. LCMM identified two distinct reversal classes (75 [86%] in class 1 and 12 [14%] in class 2) on the basis of mean testicular volume, micropenis, and serum follicle-stimulating hormone (FSH) concentration. Classification probabilities were robust (0·998 for class 1 and 0·838 for class 2) and modelling uncertainty was low (entropy 0·90). Compared with class 1, patients in class 2 had significantly larger testicular volume (p<0·0001), no micropenis, and higher serum FSH concentrations (p=0·041), consistent with the Pasqualini syndrome (fertile eunuch) subtype of CHH. Patients without CHH reversal were more likely to have anosmia (p=0·016), cryptorchidism (p=0·0012), complete absence of puberty (testicular volume <4 cm³; p=0·0016), and two or more rare genetic variants (ie, oligogenicity; p=0·0001). Among patients who underwent genetic testing, no patients (of 75) with CHH reversal had a rare pathogenic ANOS1 variant compared with ten (11%) of 95 patients without CHH reversal. Individuals with CHH reversal had a significantly higher rate of rare variants in GNRHR than did those without reversal (nine [12%] of 75 vs three [3%] of 95; p=0·025). Applying LCMM to a large cohort of male patients with CHH reversal uncovered two distinct classes of reversal. Genetic investigation combined with careful clinical phenotyping could help surveillance of reversal after withdrawing treatment, representing the first tailored management approach for male patients with this rare endocrine disorder. National Institutes of Health National Center for Advancing Translational Sciences; Ministry of Health, Rome, Italy; Ministry of University, Rome, Italy; National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the Josiah Macy Jr Foundation. For the Italian translation of the abstract see Supplementary Materials section.

"Results of Genetic Studies of Adolescents with Idiopathic Hypogonadotropic Hypogonadism"

"Results of Genetic Studies of Adolescents with Idiopathic Hypogonadotropic Hypogonadism"

"The significance of the GNRH 1 gene polymorphism (rs 6185, rs1812594) in the development of idiopathic hypogonadotropic hypogonadism."

The purpose of the study is to study the significance of the GNRH 1 gene polymorphism (rs 6185, rs1812594) in the development of idiopathic hypogonadotropic hypogonadism in boys and girls.

Heavy Metal Levels in Males With Idiopathic Hypogonadotropic Hypogonadism.

The toxic effects of heavy metals on biological systems are being investigated with increasing interest day by day. Our purpose was to investigate heavy metals such as aluminum (Al), cadmium (Cd), arsenic (As), lead (Pb), and nickel (Ni) in males with idiopathic hypogonadotropic hypogonadism (IHH) and to determine whether there is a relationship between heavy metals and testosterone levels. Twenty-six male patients with IHH aged 18-50 and 22 healthy males aged 21-50 admitted to the Outpatient Department of Endocrinology for follow-up were enrolled.BMIs were calculated by measuring the height and weight of all participants. Al, Cd, As, Pb, and Ni levels were measured and compared between groups. Testosterone levels were measured to investigate whether there was a correlation with heavy metal levels. Al, Cd, As, Pb, and Ni levels were statistically higher in the patient group compared to the control group (p<0.001). A moderately strong significant negative correlation was detected between the patients' testosterone and As levels (p=0.001, r=-0.609, R2=0.371). Decreased As and Cd levels were observed as the patients' ages increased (p=0.013, r=-0.471). Heavy metals might play potential roles in IHH. We hope that investigating heavy metal levels in IHH and adding toxicity-preventive treatments to hormonal therapies will be beneficial in the multifaceted management of the disease in clinical practice.

Clinical manifestations and spermatogenesis outcomes in Chinese patients with congenital hypogonadotropic hypogonadism caused by inherited or de novo FGFR1 mutations.

Fibroblast growth factor receptor 1 (FGFR1) mutations are associated with congenital hypogonadotropic hypogonadism (CHH) through inheritance or spontaneous occurrence. We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital (Beijing, China) using next-generation and Sanger sequencing. We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups. Among 19 patients with FGFR1 mutations, three were recurrent, and 16 were novel variants. Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines, with the prevalent P366L variant. The majority of FGFR1 mutations was inherited (57.9%), with frameshift mutations exclusive to the de novo mutation group. The inherited mutation group had a lower incidence of cryptorchidism, short stature, and skeletal deformities. In the inherited mutation group, luteinizing hormone (LH) levels were 0.5 IU l-1, follicle-stimulating hormone (FSH) levels were 1.0 IU l-1, and testosterone levels were 1.3 nmol l-1. In contrast, the de novo group had LH levels of 0.2 IU l-1, FSH levels of 0.5 IU l-1, and testosterone levels of 0.9 nmol l-1, indicating milder hypothalamus-pituitary-gonadal axis (HPGA) functional deficiency in the inherited group. The inherited mutation group showed a tendency toward higher spermatogenesis rates. In conclusion, this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations, contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations.

High Population Frequency of GNRHR p.Q106R in Malta: An Evaluation of Fertility and Hormone Profiles in Heterozygotes.

The gonadotropin-releasing hormone receptor variant GNRHR p.Q106R (rs104893836) in homozygosity, compound heterozygosity, or single heterozygosity is often reported as the causative variant in idiopathic hypogonadotropic hypogonadism (IHH) patients with GnRH deficiency. Genotyping of a Maltese newborn cord-blood collection yielded a minor allele frequency (MAF) 10 times higher (MAF = 0.029; n = 493) than that of the global population (MAF = 0.003). To determine whether GNRHR p.Q106R in heterozygosity influences profiles of endogenous hormones belonging to the hypothalamic-pituitary axis and the onset of puberty and fertility in adult men (n = 739) and women (n = 239). Analysis of questionnaire data relating to puberty and fertility, genotyping of the GNRHR p.Q106R variant, and hormone profiling of a highly phenotyped Maltese adult cohort from the Maltese Acute Myocardial Infarction Study. Out of 978 adults, 43 GNRHR p.Q106R heterozygotes (26 men and 17 women) were identified. Hormone levels and fertility for all heterozygotes are within normal parameters except for TSH, which was lower in men 50 years or older. Hormone data and baseline fertility characteristics of GNRHR p.Q106R heterozygotes are comparable to those of homozygous wild-type individuals who have no reproductive problems. The heterozygous genotype alone does not impair the levels of investigated gonadotropins and sex steroid hormones or affect fertility. GNRHR p.Q106R heterozygotes who exhibit IHH characteristics must have at least another variant, probably in a different IHH gene, that drives pathogenicity. We also conclude that GNRHR p.Q106R is likely a founder variant due to its overrepresentation and prevalence in the island population of Malta.

Digenic CHD7 and SMCHD1 inheritance Unveils phenotypic variability in a family mainly presenting with hypogonadotropic hypogonadism

ObjectivesCHARGE syndrome is a congenital hereditary condition involving multiple systems. Patients are easily misdiagnosed with idiopathic hypogonadotropic hypogonadism (IHH) due to the overlap of clinical manifestations. An accurate clinical diagnosis remains challenging when the predominant clinical manifestation resembles hypogonadotropic hypogonadism. MethodsThis original research is conducted based on the genetic finding and analysis of clinical cases. Whole-exome sequencing (WES) and in-silico analyse were performed on two sisters to investigate the pathogenesis in this family. Homology modelling was conducted to evaluate structural changes in the variants. ResultsWES and Sanger sequencing revealed two siblings carrying a nonsense mutation (NM_017780.4: c.115C > T) in exon 2 of CHD7 inherited from a mildly affected mother and a missense mutation (NM_015295.3: c.2582T > C) in exon 20 of SMCHD1 inherited from an asymptomatic father. The nonsense mutation in CHD7 was predicted to generate nonsense-mediated decay, whereas the missense mutation in SMCHD1 decreased protein stability. ConclusionsWe identified digenic CHD7 and SMCHD1 mutations in IHH-associated diseases for the first time and verified the synergistic role of oligogenic inheritance. It was also determined that WES is an effective tool for distinguishing diseases with overlapping features and establishing a molecular diagnosis for cases with digenic or oligogenic hereditary disorders, which is beneficial for timely treatment, and family genetic counseling.

Role of Inhibin B, AMH, GnRHa Test and HCG Stimulation Test to Distinguish Isolated Hypogonadotropic Hypogonadism (IHH) from Constitutional Delay in Growth and Puberty (CDGP)

Abstract Background: This study aimed to distinguish isolated hypogonadotropic hypogonadism (IHH) from constitutional delay in growth and puberty (CDGP) by various hormonal tests in both sexes. Methods: Boys with testicular volume (TV) &lt;4 ml (14–18 years) and girls with breast B1 stage (13–18 years) were enrolled in this study. A detailed history, clinical examination and hormonal analysis including basal luteinising hormone (LH), follicle-stimulating hormone (FSH), inhibin B, anti-Mullerian hormone (AMH), testosterone (boys), oestradiol (girls), triptorelin stimulation test and 3-day human chorionic gonadotropin (HCG) stimulation test (boys) were performed. All patients were followed for 1.5 years or till 18 years of age. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-offs with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for various hormones to distinguish IHH from CDGP. Results: Of 34 children (male: 22 and female: 12), CDGP and IHH were diagnosed in 21 and 13 children, respectively. 4 hours post-triptorelin LH had the highest sensitivity (100%) and specificity (100%) for identifying IHH in both sexes. Basal inhibin B had good sensitivity (male: 85.7% and female: 83.8%) and specificity (male: 93.3% and female: 100%) for diagnosing IHH. 24 hours post-triptorelin testosterone (&lt;34.5 ng/dl), day 4 post-HCG testosterone (&lt;99.7 ng/dl) and 24 hours post-triptorelin oestradiol (&lt;31.63 pg/ml) had reasonable sensitivity and specificity for identifying IHH. Basal LH, FSH and AMH were poor discriminators for IHH in both sexes. Conclusion: The best indicator was post-triptorelin 4-hour LH followed by inhibin B, which had a reasonable diagnostic utility to distinguish IHH from CDGP in both boys and girls.

Gonadotropin-Releasing Hormone Receptor (GnRHR) and Hypogonadotropic Hypogonadism

Human sexual and reproductive development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which is primarily controlled by the gonadotropin-releasing hormone (GnRH) acting on its receptor (GnRHR). Dysregulation of the axis leads to conditions such as congenital hypogonadotropic hypogonadism (CHH) and delayed puberty. The pathophysiology of GnRHR makes it a potential target for treatments in several reproductive diseases and in congenital adrenal hyperplasia. GnRHR belongs to the G protein-coupled receptor family and its GnRH ligand, when bound, activates several complex and tissue-specific signaling pathways. In the pituitary gonadotrope cells, it triggers the G protein subunit dissociation and initiates a cascade of events that lead to the production and secretion of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) accompanied with the phospholipase C, inositol phosphate production, and protein kinase C activation. Pharmacologically, GnRHR can be modulated by synthetic analogues. Such analogues include the agonists, antagonists, and the pharmacoperones. The agonists stimulate the gonadotropin release and lead to receptor desensitization with prolonged use while the antagonists directly block the GnRHR and rapidly reduce the sex hormone production. Pharmacoperones include the most recent GnRHR therapeutic approaches that directly correct the misfolded GnRHRs, which are caused by genetic mutations and hold serious promise for CHH treatment. Understanding of the GnRHR’s genomic and protein structure is crucial for the most appropriate assessing of the mutation impact. Such mutations in the GNRHR are linked to normosmic hypogonadotropic hypogonadism and lead to various clinical symptoms, including delayed puberty, infertility, and impaired sexual development. These mutations vary regarding their mode of inheritance and can be found in the homozygous, compound heterozygous, or in the digenic state. GnRHR expression extends beyond the pituitary gland, and is found in reproductive tissues such as ovaries, uterus, and prostate and non-reproductive tissues such as heart, muscles, liver and melanoma cells. This comprehensive review explores GnRHR’s multifaceted role in human reproduction and its clinical implications for reproductive disorders.

Can clinical, biochemical and genetic parameters help distinguish congenital hypogonadotrophic hypogonadism from self-limited delayed puberty?

Can clinical, biochemical and genetic parameters help distinguish congenital hypogonadotrophic hypogonadism from self-limited delayed puberty?

How human genetic context can inform pathogenicity classification: FGFR1 variation in idiopathic hypogonadotropic hypogonadism.

Precision medicine requires precise genetic variant interpretation, yet many disease-associated genes have unresolved variants of unknown significance (VUS). We analyzed variants in a well-studied gene, FGFR1, a common cause of Idiopathic Hypogonadotropic Hypogonadism (IHH) and examined whether regional genetic enrichment of missense variants could improve variant classification. FGFR1 rare sequence variants (RSVs) were examined in a large cohort to (i) define regional genetic enrichment, (ii) determine pathogenicity based on the American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) variant classification framework, and (iii) characterize the phenotype of FGFR1 variant carriers by variant classification. A total of 143 FGFR1 RSVs were identified in 175 IHH probands (n = 95 missense, n = 48 protein-truncating variants). FGFR1 missense RSVs showed regional enrichment across biologically well-defined domains: D1, D2, D3, and TK domains and linker regions (D2-D3, TM-TK). Using these defined regions of enrichment to augment the ACMG/AMP classification reclassifies 37% (20/54) of FGFR1 missense VUS as pathogenic or likely pathogenic (PLP). Non-proband carriers of FGFR1 missense VUS variants that were reclassified as PLP were more likely to express IHH or IHH-associated phenotypes [anosmia or delayed puberty] than non-proband carriers of FGFR1 missense variants that remained as VUS (76.9% vs 34.7%, p = 0.035). Using the largest cohort of FGFR1 variant carriers, we show that integration of regional genetic enrichment as moderate evidence for pathogenicity improves the classification of VUS and that reclassified variants correlated with phenotypic expressivity. The addition of regional genetic enrichment to the ACMG/AMP guidelines may improve clinical variant interpretation.

THU206 Constitutional Delay Of Puberty And Idiopathic Hypogonadotropic Hypogonadism: Differential Contributions Of Common Genetic Variants

Abstract Disclosure: M.F. Lippincott: None. E. Schafer: None. A.A. Hindman: None. R. Brauner: None. A. Delaney: None. K. McElreavey: None. J.E. Hall: None. J.N. Hirschhorn: None. M.R. Palmert: None. S.B. Seminara: None. R.M. Salem: None. Y. Chan: None. Introduction: Disorders of pubertal timing include self-limited constitutional delay of puberty (CDP) and longer lasting idiopathic hypogonadotropic hypogonadism (IHH). Both conditions have strong genetic influences. We sought to determine if common genetic variants that influence pubertal timing contribute to CDP and IHH. Hypothesis: IHH and CDP can sometimes be caused by the accumulation of common genetic variants that delay pubertal onset. Therefore, compared to controls, patients with CDP and IHH have higher polygenic risk scores (PRS) based on genome-wide association studies (GWAS) for pubertal timing. Methods: All research and data-sharing were conducted with participant/guardian consent and institutional ethical approval. We defined CDP as puberty starting between 12 and 18 y in girls and between 13.5 and 18 y in boys and IHH as low sex steroids and non-elevated gonadotropins at ≥18 y, both with no cause identified on standard clinical evaluation. We genotyped CDP cases (n=106) on the Illumina Infinium OmniExpress Exome 8-1v6 platform and retrieved array-matched control data from dbGaP (n=9,222). IHH cases (n=713) and controls from the Schizophrenia Psychiatric GWAS (n=1,868) were genotyped on the Infinium PsychArray. After data harmonization, quality control, and principal components analysis were performed on combined sets, genotype imputation was performed on all unrelated individuals of European ancestry using the Michigan Imputation Server. We downloaded summary statistics for: 1) GWAS meta-analysis for age at menarche (AAM), 2) multi-trait GWAS for male pubertal hallmarks, and 3) a negative control using GWAS for basal cell carcinoma (BCC). We calculated and compared PRS between cases and controls using PRS-CS and PRSice2, with the first 10 ancestral principal components and sex as covariates. We also performed sex-stratified analyses. Results: Both the CDP and the IHH cohorts had significantly higher PRS for male pubertal hallmarks compared to controls, but the difference was smaller for IHH (CDP Cohen’s d=0.59, p=2×10-10; IHH d=0.13, p=0.007). The CDP cohort also had a significantly higher PRS for AAM compared to controls (d=0.83, p=8×10-20), but the IHH cohort did not (d=0.08, p=0.06). Of note, sex-specific PRS provided greater discrimination between CDP cases and controls in stratified analyses of the corresponding sex (AAM in females: d=1.1, p=4×10-11; AAM in males d=0.72, p=8×10-11; male hallmarks in females: d=0.52, p=0.001; male hallmarks in males: d=0.63, p=2×10-8). No significant differences were observed between cases and controls for BCC PRS. Conclusions: Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, with some sex-specificity, but only weakly to IHH. These findings support the hypothesis that the common-variant genetics of CDP and IHH are largely distinct. Presentation: Thursday, June 15, 2023

FRI285 Evidence For ZIC1 As A Novel Gene For Isolated Hypogonadotropic Hypogonadism With Phenotypic Pleiotropic Intersection With Cerebellar Malformation

Abstract Disclosure: J. Cassin: None. D.L. Keefe: None. K.E. Sung: None. C.C. Bojo: None. G. Santiago: None. L. Plummer: None. K.B. Salnikov: None. S.B. Seminara: None. R. Balasubramania: None. P.L. Mellon: None. Isolated Hypogonadotropic Hypogonadism (IHH) is a condition marked by absent pubertal development and low sex steroids in the setting of low/normal gonadotropins. Mutations in known IHH genes only explain &amp;lt;50% of the genetic etiology suggesting significant missing heritability in IHH. To explore this missing IHH heritability, we examined whole exome sequencing data from approximately 1400 IHH probands for rare genetic variants in novel genes that are enriched in IHH patients. We identified four IHH probands with rare, novel heterozygous variants in ZIC1 (p.H134Rfs*21, p.Y287X, p.E299K, p.S413Y), a gene encoding C2H2-type zinc finger protein (rare variant enrichment p &amp;lt;0.0001 for both truncating and missense alleles). Prior literature review show that heterozygous deletions affecting the ZIC1 gene have been linked to Dandy Walker malformation [DWM], a cerebellar malformation, while gain-of-function ZIC1 single nucleotide variants have been linked to coronal craniosynostosis (premature cranial suture fusion). Notably, two IHH subjects with novel ZIC1 variants in our cohort exhibited posterior fossa abnormalities (DWM [p.H134Rfs*21] and ventriculomegaly [E299K]) but none had any cranial suture defects. Given the above genetic enrichment, phenotypic overlap between DWM and IHH, and ZIC1’s known high expression in the hypothalamus, we explored whether ZIC1 regulates the expression of hypothalamic releasing factors. We determined that ZIC1 overexpression increases GNRH1 luciferase expression in the immortalized GnRH cell line, GT1-7. We next explored whether the rare ZIC1 variants identified in the four IHH probands would affect this phenotype. We discovered that three of the four ZIC1 variants significantly reduced GNRH1-luciferase expression. Of those, one truncating mutation, p.H134Rfs*21, resulted in lower ZIC1 protein content in the cell and failure to localize to the nucleus, suggesting a hypomorphic mechanism of action. These findings implicate ZIC1 variants as putatively causal for IHH. Further studies will define the precise ZIC1 transcriptional targets that relate to ZIC1’s pleotropic effects on GnRH transcription, neuronal function, cerebellar development, and cranial suture fusion. Presentation: Friday, June 16, 2023

OR34-04 Defective FGFR1 Signaling Disrupts Glucose Regulation In Humans: Evidence From Patients With Isolated Hypogonadotropic Hypogonadism Harboring FGFR1 Mutations

Abstract Disclosure: M. Stamou: None. C.J. Chiu: None. S. Jadhav: None. K. Salnikov: None. L. Plummer: None. S.B. Seminara: None. R. Balasubramanian: None. Introduction: Recent studies have shown that antibody-mediated activation of FGFR1 receptor improves metabolic health in rodents, nonhuman primates, and humans. Hence, disruption of the FGFR1 receptor may lead to glucose dysregulation. FGFR1 mutations contribute to 12% of the genetic background of subjects with isolated hypogonadotropic hypogonadism (IHH), a rare Mendelian disease caused by GnRH deficiency. In this study, we examined glucose effectiveness and insulin sensitivity in IHH subjects with rare FGFR1 variants and hypothesized that these subjects will display defective glucose metabolism compared healthy non-carrier controls. Methods: Nine subjects with IHH (7 males and 2 females) with heterozygous rare FGFR1 variants were enrolled [7 subjects with protein truncating variants: p.Q680*, p.R622*, p.Q52*, p.I347Nfs*61, p.R576Pfs*77, p.Q309*, c.1553-2A&amp;gt;G and 2 subjects with deleterious missense variants: p.G97S &amp; p.Y701C. Thirty healthy controls (17 males and 13 females) with no FGFR1 variants were enrolled from the Mass General Brigham Biobank. Medical history, physical exam, laboratory evaluation, a bone density scan, and an intravenous glucose tolerance test (IVGTT) were performed. The area under the curve (AUC) for glucose, insulin, and C-peptide response to 50% dextrose (0.3g/kg, t=0min) and an insulin bolus (0.03u/kg, t=20 min) were estimated for each subject. The glucose effectiveness (Sg), insulin sensitivity (SI), acute insulin response to glucose (AIR), and the disposition index (DI= AIRG*SI) were calculated using the Minimal Model Analysis. Statistical comparisons were performed with t-test and non-parametric Wilcoxon rank sum test. A linear regression model was used to adjust the t-test outcomes for potential confounders. Results: Despite similar BMIs (28 vs. 26.5, p=0.29), IHH FGFR1 positive subjects demonstrated higher % fat mass compared to controls (38 vs. 31, p=0.02). IHH patients were supplemented with sex-steroids at the time of the study. Male patients demonstrated similar testosterone levels compared to controls (385 vs. 451 ng/dL, p=0.52). IHH FGFR1 positive subjects demonstrated a higher AUC for C-peptide compared to controls (167 vs. 92, p=0.001), that remained significant after adjusting for age, gender, BMI, and % fat mass. Non-parametric test showed higher AUC for glucose, insulin, and C-peptide (p 0.01, 0.01 &amp; 0.005 respectively) as well as lower SI (p=0.01) and higher AIRg (p=0.037) in the IHH FGFR1 positive group compared to non-carrier controls. Discussion: This is the first study to evaluate glucose metabolism in humans with naturally occurring FGFR1 variants. IHH FGFR1 positive subjects showed higher insulin response to glucose and lower insulin sensitivity during an IVGTT test compared to the healthy non-carrier controls. These findings confirm that FGFR1 signaling is a key regulator of insulin secretion and action in humans. Presentation: Sunday, June 18, 2023

THU201 Atypical Presentation Of Kallmann Syndrome With A Rare Genetic Mutation

Abstract Disclosure: E.L. Montgomery: None. B. Thrasher: None. S. Watson: None. Kallmann Syndrome presents as idiopathic hypogonadotropic hypogonadism with additional findings of hyposmia or anosmia and midline facial defects, including cleft lip/palate. We present a case of Kallmann Syndrome due to a rare genetic mutation with absent Mullerian structures. A 15 year, 6 month old female with history of cleft lip and palate and short stature was referred for primary amenorrhea. Clinical history was notable for limited sense of smell and no signs of puberty, including thelarche or adrenarche. Family History unknown (adopted). Significant physical exam findings include tanner 1 breast, no pubic or axillary hair, normal external female genitalia without clitoromegaly, unestrogenized vaginal introitus. Height 147cm (0.88%ile for age). Lab evaluation consisted of: LH 0.66 mIU/ml (2.4-12.6 mIU/ml), FSH 1.63 mIU/ml (3.5-12.5 mIU/ml), prolactin 11.30 ng/ml (4.79-23.30 ng/ml), BhCG negative, testosterone 8 ng/dl (2-17 ng/dl), free testosterone 1.1 pg/ml (&amp;lt;2.2 pg/ml), estradiol 3.0 pg/ml (9.0-249.0 pg/ml), AMH 2.46 ng/ml (1.05-12.86 ng/ml), thyroid function testing and growth factors normal. Imaging included pelvic ultrasound that showed no uterus or gonads. An MRI was obtained that confirmed these findings and also a blind-ending vaginal canal. While the presentation is suggestive of Kallmann Syndrome, the lack of Mullerian structures on imaging has not previously been described. Further evaluation included karyotype (46, XX) and hypogonadotropic hypogonadism genetic panel that identified a mutation in the FGFR1 gene with c.2172C&amp;gt;G (p.Asn724Lys), heterozygous, variant of uncertain significance. Estrogen replacement therapy was initiated with subsequent expected pubertal progression. Repeat imaging after seven months of treatment demonstrated presence of normal developing uterus and bilateral ovaries. Clinical Lesson/Conclusion: 1.Rare mutation with now 3 reports suggesting it is a true pathologic variant2.Unique presentation with hypoplastic Mullerian structures not detected on imaging.This patient’s particular variant has previously been described in in 2 individuals (mother/son) with features of Kallmann Syndrome (PMID: 16606836) with normal and partial puberty respectively, increasing the suspicion that this variant is pathogenic. Newly described FGFR1 variant associated with Kallmann Syndrome / hypogonadotropic hypogonadism. Kallmann Syndrome is not associated with lack of Mullerian structures, however this patient presented with features of Kallmann Syndrome and imaging that did not demonstrate presence of Mullerian structures. Since initiating estrogen therapy, she has had appropriate development of uterus and ovaries. This case demonstrates that prior to estrogen therapy, patients with Kallmann Syndrome may have underdeveloped Mullerian structures that not recognized on imaging prior to estrogen replacement therapy. Presentation: Thursday, June 15, 2023

Idiopathic hypogonadotropic hypogonadism caused by compound heterozygosity for two novel mutations in the GNRH1 gene: a case report

BackgroundIdiopathic hypogonadotropic hypogonadism (IHH) is a rare congenital or acquired genetic disorder caused by gonadotropin-releasing hormone (GnRH) deficiency. IHH patients are divided into two major groups, hyposmic or anosmic IHH (Kallmann syndrome) and normosmic IHH (nIHH), according to whether their sense of smell is intact. Here we report a case of novel compound heterozygous mutations in the GNRH1 gene in a 15-year-old male with nIHH.Case presentationThe patient presented typical clinical symptoms of delayed testicular development, with testosterone < 3.5 mmol/L and reduced gonadotropin (follicle-stimulating hormone, luteinizing hormone) levels. Two heterozygous variants of the GNRH1 gene were detected, nonsense variant 1: c.85G > T:p.G29* and variant 2: c.1A > G:p.M1V, which disrupted the start codon.ConclusionsTwo GNRH1 mutations responsible for nIHH are identified in this study. Our findings extend the mutational spectrum of GNRH1 by revealing novel causative mutations of nIHH.

FRI439 Spermatogenesis Induction For Hypogonadotrophic Hypogonadism In An Australian Tertiary Hospital Andrology Service

Abstract Disclosure: S. Sarlos: None. M. Herath: None. I. Sim: None. R. Upreti: None. R.I. McLachlan: None. C.A. Allan: None. Infertility affects 8-12% of couples with male factors contributing to 50% and solely responsible in 20-30% of cases. Male infertility due to hypogonadotrophic hypogonadism (HH) is amenable to medical treatment. We report a series of 23 men treated for infertility from HH (congenital n=13, acquired n=10) with a median age of 33 years. Causes included panhypopituitarism (n=11) [empty sella (n=2), adenoma (n=3), craniopharyngioma (n=1), pituitary hypoplasia (n=3), CHARGE syndrome (n=1), cranial radiotherapy (n=1)], Kallmann syndrome (n=1), thalassaemia major (n=1) and idiopathic (n=10). Urinary or recombinant human chorionic gonadotrophin (hCG) as an LH substitute was used based on established protocols. Commencing doses were 1500 IU or 62.5mcg s/cut twice weekly respectively and titrated to achieve normal serum total testosterone. Recombinant FSH was added after 6 months for persisting azoospermia. Wherever possible, men previously treated with long-acting injectable testosterone undecanoate were transitioned to transdermal testosterone for a minimum of 6 months prior to initiation of gonadotrophin therapy. There was wide variability in time to first appearance of sperm (median 16 months, range 4 - 42). In androgen treatment-naive men with acquired HH in adulthood (n=9), sperm was detected at a median 8 months (range 3 - 21 months) and for 4 men, hCG monotherapy was sufficient. For men with congenital causes of HH (n=13), time to first sperm detection was longer (median 17 months, range 12 - 42) and all required addition of FSH. In men previously treated with intramuscular testosterone (n=8), the median time to sperm appearance was 17 months (range 12-24) as compared to 13 months (5-42) in men treated with transdermal testosterone (n=6). To date, 11 of the 16 men actively seeking fertility have had children, with 7 requiring assisted reproduction. Gonadotrophin therapy is an effective fertility treatment for most men with HH. Clinicians can anticipate a longer time to spermatogenesis in men pre-treated with intramuscular androgens and those with congenital HH. Couples often move to assisted reproductive therapy, likely due to considerations such as semen quality, co-existing female factors and/or desire for prompt conception. Presentation: Friday, June 16, 2023