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.

中文翻译：

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成纤维细胞生长因子受体1的翻译后修饰缺陷是正常分离性促性腺激素性性腺功能减退的原因

FGFR1中的某些突变影响嗅觉，而其他突变则不影响嗅觉，分别导致Kallmann综合征（KS）和正常的孤立性性腺功能减退性腺功能减退（nIHH）。潜在的机制仍不清楚。在不到10％的KS和nIHH患者中发现了FGFR1变体，其中只有一些经过了功能分析。因此，表型和基因型之间的相关性不能清楚地验证。这项研究报告一例nIHH，并探讨了FGFR1基因在nIHH发病中的潜在机制。描述了一种患有隐睾症，微型阴茎，斜视和低视的学龄前儿童。由于他的嗅觉正常，因此被诊断出患有nIHH。FGFR1的从头突变（c.2008G> A）在患者中检测与以一种新颖的变体沿着CEP290从母亲继承（c.964G> A）。我们提供了令人信服的体外证据，表明该FGFR1突变诱导的翻译后修饰缺陷（包括缺陷的糖基化和反式自磷酸化受损）以及最终的表达降低，可能导致受体损伤和异常信号传导，最终导致发育异常和抑制GnRH神经元释放。对其他变体的鉴定表明，CEP290可能在GnRH的发育中发挥潜在作用。