Abstract
Some mutations in FGFR1 affect the sense of smell while others do not, resulting in Kallmann syndrome (KS) and normosmic isolated hypogonadotropic hypogonadism (nIHH), respectively. The underlying mechanism is still unclear. FGFR1 variants are found in less than 10% of patients with KS and nIHH, and among them, only some have undergone functional analysis. Thus, the correlation between the phenotype and genotype cannot be clearly verified. This study reports a case of nIHH and explores the potential mechanism of the FGFR1 gene in the pathogenesis of nIHH. A preschooler with cryptorchidism, micropenis, strabismus, and hypopsia is described. As he had a normal sense of smell, he was diagnosed with nIHH. A de novo mutation in FGFR1 (c.2008G>A) was detected in the patient along with a novel variant in CEP290 (c.964G>A) inherited from his mother. We present compelling in vitro evidence that this FGFR1 mutation-induced posttranslational modification defect, including defective glycosylation and impaired trans-autophosphorylation, along with the final reduction in expression, could lead to impairment of the receptor and abnormal signaling and eventually result in developmental abnormalities and inhibition of GnRH neuron release. The identification of an additional variant suggests that CEP290 might play a potential role in GnRH development.