OR26-05 Non-Reproductive Features are Widespread and Occur in Phenotypic Clusters in Patients with Isolated Hypogonadotropic Hypogonadism (IHH)

Abstract Disclosure: A. Goel: None. S. Shekhar: None. J. Priest: None. S.B. Seminara: None. L. Plummer: None. W.F. Crowley: None. A. Delaney: None. J.E. Hall: None. Introduction: Isolated hypogonadotropic hypogonadism (IHH) is a syndrome characterized by a deficiency in GnRH secretion. We evaluated non-reproductive phenotypes and genetic architecture in subjects with IHH. Methods: 94 IHH subjects (58 males; mean age (±SD) 24.3 ± 9.3 yrs) were evaluated with a detailed history and physical examination, olfactory, audiology and ophthalmic testing, renal and pelvic/testicular ultrasounds, DXA, skeletal X-rays, 12 hours of every 10-minute blood sampling for LH and hormonal testing. Phenotypic differences were categorized by olfactory status and pulsatile LH secretion. Phenotypic clusters were identified using K-means clustering and stratified by sex. Exome sequencing in 56 IHH genes was used to identify rare sequence variants (RSVs, moderate- to high-impact, minor allele frequency <1%). Pathogenic/likely pathogenic (P/LP) RSVs were defined by ClinVar annotation and/or >80% deleteriousness in in silico prediction models. Results: Hyposomia (including anosmia) and LH pulses were noted in 77 (82%) and 25 (27%) subjects, respectively. Neurologic (27%), psychiatric (23%), and endocrine-metabolic (endo-met, 25%) were the most prevalent non-reproductive anomalies. FGFR1 had the most frequent P/LP RSVs (14%) among 98 IHH RSVs across 37 genes. DXA Z-scores for whole body (r=0.42), AP spine (r=0.49), hip (r=0.32), and femur (r=0.33) correlated with post-infancy sex steroid exposure duration (ster-exp) (all p<0.01). Hyposmic subjects had a greater frequency of bimanual synkinesia (p=0.04), renal anomalies (p=0.04), short metacarpals (p = 0.04), and lower AP spine Z-scores (mean difference: -0.73 ± 0.39 p=0.04). Compared to subjects with apulsatile LH secretion, those with LH pulses had more thoracic spinal anomalies (p=0.02) and higher DXA Z-scores in whole body (p=0.02) and hip (p=0.03) regions without differences in ster-exp. Among three phenotypic clusters in all subjects, cluster 3 (n=20) was the largest, consisting of olfactory, ocular, endo-met and palmoplantar anomalies. Sex-stratified analysis revealed two male clusters, with Cluster 2 (n=23) dominating with a high prevalence of ocular, craniofacial and dental anomalies. Among three female clusters, cluster 3 (n=13) dominated, with ocular, craniofacial, endo-met and palmoplantar anomalies. Conclusion: In those with IHH, neurologic and psychiatric anomalies were common. There were significant differences in non-reproductive phenotypic features based on olfactory and pulsatile LH secretory status, and bone density correlated with post-infancy sex steroid exposure duration. The presence of distinct phenotypic clusters suggests certain features often co-occur in IHH patients, which may facilitate clinical screening. Additional analyses will determine whether genotype-phenotype correlations can inform genetic screening. Presentation: Monday, July 14, 2025