Endocrine Abstracts

JOINT2789

Background: Androgen Insensitivity Syndrome(AIS) is an X-linked disorder and the most common cause of disorders/differences of sexual development(DSDs) in individuals with a 46, XY karyotype. AIS is classified into complete(CAIS), partial(PAIS), and mild(MAIS) forms based on clinical and genetic findings. Phenotypic expression varies from normal female external genitalia in complete CAIS, to normal male genitalia with infertility or gynecomastia in MAIS. The phenotype may be variable in PAIS including incomplete virilization. This study aimed to evaluate the clinical and genetic characteristics of AIS.

Materials and Methods: The data about the medical history, and clinical examination were recorded from the patient files. Chromosomal analysis was performed in all. Next-generation sequencing(NGS) was performed using the SOPHIA™ Clinical Exome Solution(CES) v3 and Illumina NovaSeq platform, covering 6,300 genes.A custom gene panel targeting 24 genes associated with XY DSD was analyzed using the Sophia DDM platform. The study included 15 patients from 9 families with hemizygous variants in the AR gene (NM:000044.6).

Results: Among 15 patients, seven presented with a female external genital phenotype, six showed incomplete virilization, and two siblings had unique presentations(one with undescended testes, the other with oligoasthenospermia). The consanguinity ratio was 27%. Based on molecular genetic analysis,7 patients were classified as PAIS, 6 as CAIS, and 2 as MAIS. Four patients with CAIS presented with primary amenorrhea, and two were diagnosed after testicular tissue was observed during hernia surgery. All were assigned as female, and five of them underwent gonadectomy in the pubertal period. Frameshift variants[c.1625_1629dup, p.(Arg544Leufs20)(n = 2, novel); c.1890del, p.(Lys631Serfs2)(n = 2)] and nonsense variants [c.1921C>T, p.(Gln641*)(n = 1, novel); c.1605C>G, p.(Tyr535*)(n = 1)]were identified in the CAIS group. In PAIS, four presented in the neonatal period with incomplete virilization, while three presented with pubertal virilization. Neonatal cases were assigned male gender, while pubertal cases transitioned from female to male. All patients with PAIS had microphallus, undescended testes, and four had hypospadias, and all underwent orchiopexy. Missense variants [c.2134C>G, p.(Gln712Glu)(n = 4), c.1794C>A, p.(Ser598Arg)(n = 1,novel), c.1789G>A, p.(Ala597Thr) (n = 1)] were identified. One of the patients with peviously reported c.2072A>G, p.(Asp691Gly) variant was presented with complete female phenotype. Two siblings had the MAIS phenotype and one of them presented with undescended testes, while the other had oligoasthenospermia. Both patients were reared as male gender.A missense variant [c.1174C>T, p.(Pro392Ser) (n = 2)] was detected. Elevated Anti-mullerian hormone concentrations were detected in pubertal patients except the patients with oligoasthenospermia only.

Conclusion: The combined evaluation of genetic and clinical characteristics is critical for diagnosing and managing AIS and underscores the importance of individualized patient care. Our study identified 9 variants, including 3 novel ones, contributing to the understanding of phenotypic variability of the AIS.

Keywords: Androgen insensitivity syndrome,AR gene, Disorders/differences of sexual development.