Genetic landscape of a neonatal hypogonadotropic hypogonadism series: Novel variants and phenotypic spectrum

Abstract To describe clinical presentation and genetic findings in a cohort of infants with congenital hypogonadotropic hypogonadism (CHH) diagnosed before 2 years of age. From a large cohort of patients who underwent next‐generation sequencing (NGS) for CHH between 2019 and 2025, we identified all patients tested at ≤2 years of age. Genetic analysis consisted of a targeted CHH gene panel, followed by a CPHD‐NGS panel. In one remaining patient with neurodevelopmental defects, whole‐exome sequencing was performed. Phenotypic data were collected through the GENHYPOPIT registry. Twelve male infants (1.5% of the total cohort) met the inclusion criteria; one additional patient via familial screening was included, for a total of 13 patients. All had micropenis; four had associated cryptorchidism (bilateral in half of cases). CHH was biologically confirmed during mini‐puberty in 10 infants, at a median age of 6.8 weeks. Seven of these 10 infants received gonadotropin therapy, at an average of 4.1 months. MRI revealed bilateral olfactory bulb agenesis in five cases. A pathogenic or likely pathogenic variant was identified in 7 of 12 patients (58%), involving TACR3 ( n  = 2), ANOS1 , FGFR1 (including two novel variants), SOX10 , GLI2 (through the CPHD panel), and SOX11 (identified by exome sequencing). A genetic cause was identified in 58% of cases, a diagnostic yield higher than reported in pubertal cohorts. Early genetic diagnosis allowed anticipatory monitoring for syndromic manifestations and associated pituitary deficiencies—particularly relevant for FGFR1 and GLI2 variant carriers at risk of CPHD. Our findings support the inclusion of GLI2 and SOX11 in targeted HH gene panels.