SAT-160 Functional study of a novel variant of FGFR1 detected in an adult patient with Kallmann syndrome on the gonadal steroidogenesis

Abstract Disclosure: F. Otsuka: None. Y. Soejima: None. N. Iwata: None. K. Yamamoto: None. A. Suyama: None. Y. Nakano: None. Kallmann syndrome (KS) is a congenital developmental disorder characterized by hypogonadotropic hypogonadism and anosmia, which results from incomplete embryonic migration of gonadotropin-releasing hormone (GnRH)-synthesizing neurons and olfactory neurons. KS is often accompanied by cryptorchidism, testicular atrophy, micropenis, orofacial clefts and/or tooth agenesis, renal anomalies, bimanual synkinesis, and hearing loss. KS exhibits different inheritance patterns and genetic heterogeneity including X-linked recessive, ANOS1; autosomal recessive, PROK2 and PROKR2; and autosomal dominant, FGFR1, FGF8, and CHD7. Fibroblast growth factor receptor 1 (FGFR1) was the first gene to be identified as an autosomal dominant form of KS, and more than 140 FGFR1 variants have so far been reported. FGFR1, also known as KAL2, is a tyrosine kinase receptor for FGF and it regulates cell proliferation, differentiation and migration. FGFR1 gene is expressed mainly in Rathke’s pouch and the ventral diencephalon during the embryonic period. It has been reported that variants of FGFR1 cause KS and variants have been detected in 10% of KS cases. We here report an adult case of KS with a novel variant of FGFR1. A middle-aged male was refereed for a compression fracture of a lumbar vertebra. It was shown that he had severe osteoporosis, anosmia, gynecomastia, and a past history of operations for cryptorchidism. Endocrine workup by pituitary and gonadal stimulation tests revealed the presence of both primary and central hypogonadism. Genetic testing revealed a novel variant of FGFR1 (c.2197_2199dup, p.Met733dup). To identify the pathogenicity of the novel variant and the clinical significance for the gonads, we investigated the effects of the FGFR1 variant on downstream signaling of FGFR1 and gonadal steroidogenesis by using human steroidogenic granulosa KGN cells. It was revealed that transfection of the variant gene significantly impaired FGFR1 signaling, detected by downregulation of SPRY2, compared with that in the case of forced expression of wild-type FGFR1, and that the forced expression of the variant gene apparently altered the expression levels of key steroidogenic factors including StAR and aromatase in the gonad. Collectively, the results suggested that the novel variant of FGFR1 detected in a patient with KS was linked to impairment of FGFR1 signaling as well as alteration of gonadal steroidogenesis, leading to the pathogenesis of latent primary hypogonadism. Presentation: Saturday, July 12, 2025