The Spectrum of Congenital Hypogonadotropic Hypogonadism: A 30‐Year Experience at a Tertiary Paediatric Centre

ABSTRACT Congenital hypogonadotropic hypogonadism (CHH) is a rare group of disorders of gonadotropin deficiency, either isolated or as a part of multiple pituitary hormone deficiencies (MPHD). We aimed to describe the spectrum of presentation, diagnosis, and management practices of CHH spanning 30 years at an Australian tertiary paediatric centre. This is a retrospective cohort study of patients with CHH seen at the Children's Hospital at Westmead between January 1994 and December 2024 ( n = 96, 66% male), categorised by diagnostic subtypes: Kallmann Syndrome (KS), normosmic HH, MPHD and other syndromes (including CHARGE). Results In patients with KS ( n = 31, 87% male), the most common presenting features were micropenis and/or cryptorchidism (45%) or pubertal delay (45%), with two peak ages of presentation: 0.6 [IQR 0.3–0.8] and 14.6 [11.5–15.7] years. Patients with MPHD ( n = 23, 52% male) presented with neonatal hypoglycaemia in 52%. Comorbidities stratified by diagnostic subtypes (KS, MPHD, and other syndromes) included hearing impairment (10%, 4%, 100%), visual impairment (7%, 17%, 77%), cardiac anomalies (3%, 9%, 77%), and intellectual disability (13%, 26%, 46%). Genetic testing was performed in 32% in 1995–2009 vs 66% in 2010–2024. Pathogenic gene variants associated with HH were found in 61% of those tested, including CHD7 ( n = 10), ANOS1 (n = 4), and FGFR1 ( n = 3). Pubertal induction was commenced in males at a mean age of 14.1 ± 1.6 years using testosterone ( n = 27 oral; 14 intramuscular; 1 subcutaneous) or gonadotropins ( n = 5), and in females, at a mean age of 14.6 ± 1.8 years using oestradiol ( n = 21 oral; 8 transdermal) ± progesterone. Conclusions CHH is a heterogeneous group of disorders, with varying prevalence of associated comorbidities according to diagnostic subtypes. Our data highlight the paediatric‐specific modes of presentation of CHH, and in KS, the bimodal distribution of age at presentation in males and the under‐representation and delayed diagnoses in females. Despite advances in genetics in the past three decades, there remain areas for further research in the diagnostics and therapeutics of CHH in the paediatric age group.