Endocrine Abstracts

Context: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is a rare endocrine disease in which patients have isolated gonadotropin releasing hormone (GnRH) deficiency in the context of otherwise normal structure and function of anterior pituitary and hypothalamus with normal olfactory ability.

Objective: To explore the underlying pathogenic defect in patients with delayed puberty.

Patients: We investigated genetic defects in a consanguineous family of Pakistan patients with nIHH. The proband is a male who presented with delayed puberty at the age of 22 years. His younger sister, who was 18 years old at the time of presentation experienced primary amenorrhea. Both of them have a normal sense of smell.

Methods: High-throughput exome sequencing with the NHS Genomic Medicine R148 Hypogonadotropic Hypogonadism gene panel (14 genes) was undertaken. The identified predicted pathogenic variant in KISS1R was confirmed by Sanger sequencing.

Results: Hormonal profiles confirmed isolated GnRH deficiency in the proband with undetectable LH and testosterone, and inhibin B 26.7 pg/ml, as well as in his younger sister. A homozygous variant in KISSR1 was identified, namely a nonsense stopgain (c.827G>A; p.(Trp276Ter)) in both siblings. The variant is not present in the gnomAD database.

Conclusion: We describe a novel homozygous nonsense variant in KISS1R resulting in nIHH in one kindred exhibiting delayed or absent pubertal onset.

Keywords: hypogonadism, normosmic, delayed puberty.