EP1365 - ECE_2455 - Oligogenic hypogonadotropic hypogonadism: divergent clinical trajectories associated with heterozygous variants in WDR11, AIRE and FGFR1

Abstract

Hypogonadotropic hypogonadism (HH) is increasingly recognized as a genetically complex disorder characterized by incomplete penetrance and variable expressivity. Beyond classical monogenic inheritance, growing evidence supports an oligogenic model, whereby heterozygous variants in multiple genes regulating the hypothalamic–pituitary–gonadal (HPG) axis interact with developmental and systemic modifiers to determine clinical outcome. To explore the role of heterozygous variants in HH-associated genes in shaping divergent phenotypes, including early-onset, reversible or persistent HH. We describe three male patients with idiopathic HH who underwent detailed endocrine phenotyping, longitudinal clinical follow-up, neuroimaging, and whole-exome-sequencing. Genetic variants were interpreted according to ACMG-criteria and correlated with pubertal development, comorbidities, treatment response, and long-term gonadal axis function. A 16-year-old male presented with delayed puberty and biochemically-confirmed HH, with normosmia and no structural abnormalities of the pituitary gland on magnetic-resonance-imaging. Whole-exome-sequencing identified heterozygous variants in WDR11 (NM_018117.12:c.371A>T, p.Asn124Ile; variant-of-uncertain-significance) and AIRE (NM_000383.4:c.769C>T,p.Arg257*; pathogenic). Following short-term testosterone priming, spontaneous recovery of gonadotropin and endogenous testosterone secretion was observed, consistent with reversible HH. A 30-year-old male was diagnosed with HH in early adulthood (age 20). Whole-exome-sequencing revealed a heterozygous WDR11 variant (NM_018117.12:c.2246G>A,p.Arg749Gln; variant-of-uncertain-significance). Neuroimaging performed during childhood demonstrated generalized cortical atrophy, widened Sylvian fissures, and an atrophic brainstem, suggesting early neurodevelopmental involvement. Despite normosmia and the absence of structural pituitary abnormalities, pubertal development remained incomplete. The patient is currently maintained on long-term hormone- replacement-therapy. A 48-year-old male presented with long-standing HH and eunuchoid body proportions. His medical history was notable for intermediate-β-thalassemia, diagnosed at the age of 3 years, requiring monthly blood transfusions until the age of 7, when transfusions were discontinued following splenectomy. At the age of 39, he was diagnosed with familial Mediterranean fever, treated with colchicine, and regular monthly transfusions were reinitiated. Whole-exome-sequencing identified a heterozygous FGFR1 variant (NM_001174063.3:c.266A>G,p.Gln89Arg; variant-of-uncertain significance). The patient exhibited persistent gonadotropin deficiency without spontaneous recovery and remains on lifelong hormone-replacement-therapy. Across cases, heterozygous variants were associated with markedly different clinical trajectories, suggesting that genetic background, systemic disease burden, and developmental modifiers collectively influence HPG axis integrity. These observations support an oligogenic and modulatory model of HH, in which heterozygous variants in WDR11, AIRE, and FGFR1 may interact with clinical and developmental factors to determine disease severity and reversibility. This framework has important implications for prognosis, genetic counseling, and individualized therapeutic strategies, emphasizing the need for periodic reassessment of endogenous gonadal function in selected patients.