Expanding the Spectrum of Endocrine Abnormalities Associated with SOX11-related Disorders.

CONTEXT: SOX11 variants cause Coffin-Siris Syndrome (CSS), characterized by developmental delay, hypogonadotropic hypogonadism (HH), skeletal and facial defects. OBJECTIVE: To examine the contribution of SOX11 variants to the pathogenesis of Idiopathic Hypogonadotropic Hypogonadism (IHH), a disorder caused by hypothalamic GnRH deficiency. SETTING: The Reproductive Endocrine Unit and the Pediatric Endocrinology Division, Massachusetts General Hospital. PATIENTS OR OTHER PARTICIPANTS: A cohort of 1810 unrelated IHH probands. INTERVENTIONS: Exome sequencing data from the entire cohort were examined for SOX11 rare single nucleotide variants (SNVs) [minor allele frequency in the gnomAD database <0.1%]. Rare SOX11 variant association testing was performed between the IHH and gnomAD population. Phenotyping of individuals harboring pathogenic/likely pathogenic SNVs (determined by the ACMG criteria) was performed. MAIN OUTCOMES/RESULTS: Four pathogenic SOX11 SNVs were identified in 5 IHH probands. The IHH cohort was enriched for SOX11 protein truncating SNVs (frameshift/nonsense) across the entire protein (2 SNVs in 3 IHH cases [p.S303X (de-novo); p.S345Afs*13]; p 0.0004981) and for SOX11 missense SNVs within the SOX11-high-mobility group (HMG) domain (2 SNVs in 2 IHH cases p.G84D[de-novo]; p.P114S; p=0.00313922). The phenotypic spectrum of SOX11 variant carriers revealed additional endocrine defects including anosmic and normosmic forms of IHH, growth-hormone deficiency, pituitary and hypothalamic structural defects, and hypothyroidism. A pathogenic SOX11 SNV was also identified in a patient with functional HH (FHH, p.R100Q). CSS-associated features were present in 4/5 probands. CONCLUSIONS: Deleterious SOX11 variants cause IHH and other pituitary hormone deficiencies, suggesting that the human SOX11-associated disorder may stem from both hypothalamic and pituitary level defects.

Defective FGFR1 Signaling Disrupts Glucose Regulation: Evidence From Humans With FGFR1 Mutations.

Context: Activation of fibroblast growth factor receptor 1 (FGFR1) signaling improves the metabolic health of animals and humans, while inactivation leads to diabetes in mice. Direct human genetic evidence for the role of FGFR1 signaling in human metabolic health has not been fully established. Objective: We hypothesized that individuals with naturally occurring FGFR1 variants ("experiments of nature") will display glucose dysregulation. Methods: Participants with rare FGFR1 variants and noncarrier controls. Using a recall-by-genotype approach, we examined the ß-cell function and insulin sensitivity of 9 individuals with rare FGFR1 deleterious variants compared to 27 noncarrier controls, during a frequently sampled intravenous glucose tolerance test at the Reproductive Endocrine Unit and the Harvard Center for Reproductive Medicine, Massachusetts General Hospital. FGFR1-mutation carriers displayed higher ß-cell function in the face of lower insulin sensitivity compared to controls. Conclusion: These findings suggest that impaired FGFR1 signaling may contribute to an early insulin resistance phase of diabetes pathogenesis and support the candidacy of the FGFR1 signaling pathway as a therapeutic target for improving the human metabolic health.

Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms.

Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.

Reproductive Phenotypes and Genotypes in Men With IHH.

CONTEXT: Isolated hypogonadotropic hypogonadism (IHH) is phenotypically and genetically heterogeneous. OBJECTIVE: This work aimed to determine the correlation between genotypic severity with pubertal and neuroendocrine phenotypes in IHH men. METHODS: A retrospective study was conducted (1980-2020) examining olfaction (Kallmann syndrome [KS] vs normosmic IHH [nHH]), baseline testicular volume (absent vs partial puberty), neuroendocrine profiling (pulsatile vs apulsatile luteinizing hormone [LH] secretion), and genetic variants in 62 IHH-associated genes through exome sequencing (ES). RESULTS: In total, 242 men (KS: n = 131 [54%], nHH: n = 111 [46%]) were included. Men with absent puberty had significantly lower gonadotropin levels (P < .001) and were more likely to have undetectable LH (P < .001). Logistic regression showed partial puberty as a statistically significant predictor of pulsatile LH secretion (R2 = 0.71, P < .001, OR: 10.8; 95% CI, 3.6-38.6). Serum LH of 2.10 IU/L had a 95% true positive rate for predicting LH pulsatility. Genetic analyses in 204 of 242 IHH men with ES data available revealed 36 of 204 (18%) men carried protein-truncating variants (PTVs) in 12 IHH genes. Men with absent puberty and apulsatile LH were enriched for oligogenic PTVs (P < .001), with variants in ANOS1 being the predominant PTV in this genotype-phenotype association. Men with absent puberty were enriched for ANOS1 PTVs compared to partial puberty counterparts (P = .002). PTVs in other IHH genes imparted more variable reproductive phenotypic severity. CONCLUSION: Partial puberty and LH greater than or equal to 2.10 IU/L are proxies for pulsatile LH secretion. ANOS1 PTVs confer severe reproductive phenotypes. Variable phenotypic severity in the face of severe genetic variants in other IHH genes point to significant neuroendocrine plasticity of the HPG axis in IHH men.

Reversible hypogonadotropic hypogonadism in men with the fertile eunuch/Pasqualini syndrome: A single-center natural history study.

Congenital hypogonadotropic hypogonadism (HH) is a heterogeneous genetic disorder characterized by disrupted puberty and infertility. In most cases, HH is abiding yet 10-15% undergo reversal. Men with HH and absent and partial puberty (i.e., testicular volume <4mL and >4mL respectively) have been well-studied, but the rare fertile eunuch (FE) variant remains poorly characterized. This natural history study of 240 men with HH delineates the clinical presentation, neuroendocrine profile, rate of reversal and genetics of the FE variant. We compared three HH groups: FE (n=38), absent puberty (n=139), and partial puberty (n=63). The FE group had no history of micropenis and 2/38 (5%) had cryptorchidism (p<0.0001 vs. other groups). The FE group exhibited higher rates of detectable gonadotropins, higher mean LH/FSH levels, and higher serum inhibin B levels (all p<0.0001). Neuroendocrine profiling showed pulsatile LH secretion in 30/38 (79%) of FE men (p<0.0001) and 16/36 (44%) FE men underwent spontaneous reversal of HH (p<0.001). The FE group was enriched for protein-truncating variants (PTVs) in GNRHR and FGFR1 and 4/30 (13%) exhibited oligogenic PTVs. Findings suggest men with the FE variant exhibit the mildest neuroendocrine defects of HH men and the FE sub-type represents the first identified phenotypic predictor for reversible HH.

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. OBJECTIVE: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients. RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.