Characteristics of a nationwide cohort of patients presenting with Isolated Hypogonadotropic Hypogonadism (IHH)

IHH is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present altough information on their frequency are scanty, particularly according to the age of presentation. DESIGN: Observational cohort study carried out between January 2008-June 2016 within a national network of academic or general hospitals Methods: We performed a detailed phenotyping of 503 IHH patients with: 1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; 2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided upon IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n=275), KS (n=184), AO-nIHH (n=36) and AO-doIHH (AO-IHH with defective olfaction, n=8). RESULTS: 90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were found also among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in KS patients. Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH. CONCLUSIONS: KS patients are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.