EP1318 - ECE_1139 - Two siblings with normosmic hypogonadotrophic hypogonadism caused by an FGFR-1 gene variant

Abstract

Mutations in the fibroblast growth factor receptor 1 (FGFR1) gene disrupt gonadotropin-releasing hormone (GnRH) neuron development and are a known cause of congenital hypogonadotropic hypogonadism (CHH), including Kallmann syndrome. FGFR1 plays a crucial role in embryonic cell proliferation, differentiation, and migration, particularly within the forebrain and olfactory system. While FGFR1 mutations classically present with anosmia and midline defects, some individuals exhibit normosmic CHH without syndromic features. Increasing genetic heterogeneity within disorders of sexual development highlights the importance of genetic testing. To describe two adolescent brothers with normosmic hypogonadotropic hypogonadism and delayed puberty, emphasizing the diagnostic value of identifying an FGFR1 variant in the absence of olfactory or structural abnormalities. Both brothers presented with absent pubertal progression. Examination showed Tanner stage I-II genitalia, small testicular volumes, and sub- physiological testosterone levels. Gonadotropins (LH/FSH) were inappropriately low at baseline and after stimulation, while prolactin, thyroid, and adrenal function were normal. MRI of the hypothalamic–pituitary region was unremarkable, and olfactory testing confirmed normal smell. Given the familial presentation, targeted NGS using a CHH gene panel identified a shared pathogenic FGFR1 variant, confirming FGFR1-related normosmic hypogonadotropic hypogonadism. Testosterone replacement therapy (Nebido® 1 g every 12 weeks) successfully induced and maintained pubertal development. Growth hormone therapy was not required. Table 1 Summary of clinical and endocrine findings. Parameter Sibling 1 Sibling 2 Age at presentation (years) 17.0 15.8 Tanner stage (genitalia) I-II I Bone age delay 3 years 3.5 years Testosterone (nmol/L) 2.1 0.6 LH (IU/L) 1.0 0.2 FSH (IU/L) 1.4 1.2 IGF-1 (nmol/L) 16.1 12.3 Pituitary MRI Normal Normal Genetic result Pathogenic FGFR1 variant Same variant Fibroblast Growth Factor Receptor 1 (FGFR1) is a receptor tyrosine kinase essential for embryonic development, hypothalamic–pituitary axis formation, and metabolic regulation. Pathogenic FGFR1 variants include loss-of-function missense, nonsense, frameshift, splice-site mutations, and rare deletions. These mutations are a recognized cause of congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome, and may also be associated with growth hormone abnormalities. FGFR1-related disorders demonstrate marked phenotypic heterogeneity. In addition to endocrine manifestations, affected individuals may exhibit craniofacial anomalies, skeletal abnormalities, hearing loss, and neurodevelopmental features. Identification of FGFR1 mutations supports early and accurate diagnosis, guides pubertal induction and fertility treatment strategies using gonadotropins or pulsatile GnRH, and enabling genetic counselling for autosomal dominant inheritance with incomplete penetrance.