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

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.