A Case of Sifrim-Hitz-Weiss Syndrome Associated with Hypogonadotropic Hypogonadism

Sifrim-Hitz-Weiss syndrome (SIHIWES) is a rare neurodevelopmental disorder caused by heterozygous pathogenic variants in CHD4, with variable phenotypic features, including endocrine involvement. Even though hypogonadotropic hypogonadism has been reported in the literature, its pathophysiology and natural history remain unclear. We describe a 12-year-old boy with SIHIWES carrying the heterozygous CHD4 c.3563C>T p.(Ala1188Val) variant, previously reported in a single individual. He presented with micropenis, prepubertal testicular volumes and absent pubertal progression. Evaluation confirmed hypogonadotropic hypogonadism, pituitary hypoplasia and cerebrovascular abnormalities consistent with a Moyamoya pattern. Testosterone therapy induced pubertal progression, although testicular volume remained prepubertal. Multidisciplinary follow-up revealed possible prior transient ischemic attacks. This case reinforces the phenotypic spectrum of SIHIWES and provides longitudinal endocrine data that contribute to addressing an existing knowledge gap regarding hypogonadotropic hypogonadism in this condition. It also highlights the importance of brain imaging and multidisciplinary evaluation in affected patients.