Complete androgen insensitivity syndrome in two siblings with a pathogenic androgen receptor gene variant: a case series

Complete androgen insensitivity syndrome (CAIS) is a rare X-linked disorder caused by pathogenic variants in the androgen receptor (AR) gene, resulting in complete resistance to androgen action in individuals with a 46,XY karyotype. Familial cases of CAIS provide important insights into genotype–phenotype correlation and multidisciplinary management in disorders of sex development (DSD). We report two Vietnamese siblings with genetically confirmed CAIS who presented with primary amenorrhea and are currently undergoing multidisciplinary counseling regarding long-term gonadal management and gender-related ethical considerations. Two Vietnamese siblings aged 15 and 14 years, both reared as females, presented to our hospital with primary amenorrhea. Both patients had a female phenotype with Tanner stage 4–5 breast development but complete absence of pubic and axillary hair. Hormonal evaluation demonstrated testosterone concentrations within the adult male range (707–934 ng/dL), elevated luteinizing hormone levels, and persistent anti-Müllerian hormone secretion (> 23 ng/mL). Imaging studies revealed absence of the uterus and intra-abdominal testes in both patients. Cytogenetic analysis demonstrated a 46,XY karyotype. Next-generation sequencing identified a nonsense variant, c.175C>T (p.Gln59Ter), in exon 1 of the AR gene in both siblings. A multidisciplinary counseling process involving endocrinology, genetics, urology, psychology, and ethics specialists is currently underway to discuss long-term gonadal management based on shared decision-making with the patients and their family. CAIS is a complex disorder requiring coordinated multidisciplinary management. Identification of the p.Gln59Ter AR variant established a definitive molecular diagnosis and guided genetic counseling. Long-term management strategies should balance biological safety, psychological well-being, and respect for gender identity through a neutral and patient-centered counseling process before major interventions are undertaken.