Endocrine Abstracts

JOINT622

Background: Nuclear receptor subfamily 5 group A member 1 gene (NR5A1) plays a crucial role in adrenal and gonadal development. NR5A1 mutations are associated with a wide phenotypic spectrum of differences of sex development (DSD). While, heterozygous inheritance is the prevalent pattern, NR5A1 dosage significantly influences its biological function.

Case description: We report the first two Kuwaiti families with identifiable NR5A1 mutations. Case1: A 13-years-10-month-old individual, raised as a female, and presented with delayed puberty. Clinical examination revealed Tanner stage 1 breast development, Tanner stage 4 pubic hair, posterior labioscrotal fusion, a 4.5 cm phallus and bilateral palpable inguinal testes (External genital Score was 6.5). Laboratory tests indicated hypergonadotropic hypogonadism, low anti-Mullerian hormone (AMH) and high testosterone levels. MRI pelvis confirmed bilateral small testes at external inguinal rings with no mullerian structures. Karyotype was 46, XY (SRY+). Whole exome sequencing (WES) and Sanger sequencing revealed a novel heterozygote in-frame deletion (c.1070_1075del; p. Gln357_Leu358del). The father, carrying the same mutation, had severe oligospermia and required assisted reproductive techniques (ART) for conception. Case 2: A 1-month-old 46, XY infant presented with penoscrotal hypospadias and bilateral undescended testes. Post-human chorionic gonadotropin (hCG) testing indicated an adequate testosterone response. WES and Sanger sequencing revealed a novel heterozygous missense (c.1105G > T; p.Val369Phe) variant in the NR5A1 gene. Although, parents were not genetically tested, the father also had severe oligospermia and required ART. Both cases have normal adrenal functions by ACTH stimulation test and a normal spleen on ultrasound.

Conclusion: Trio sequencing (patient and parents) is crucial to establish inheritance patterns. The broad phenotypic spectrum of NR5A1 gene mutations within and across families may be related to the epigenetic modifiers or coinheritance of pathogenic variants in different testis/ovarian-determining genes. These findings expand the mutational spectrum of NR5A1 and highlight the importance of genetic screening in DSD and infertility cases.

References: 1. Luppino G, Wasniewska M, Coco R, et al. Role of NR5A1 Gene Mutations in Disorders of Sex Development: Molecular and Clinical Features. Curr Issues Mol Biol. 2024 May 9;46(5):4519-4532.

2. Lillepea K, Juchnewitsch AG, Kasak L, et al. Toward clinical exomes in diagnostics and management of male infertility. Am J Hum Genet. 2024 May 2;111(5):877-895.