Molecular pathogenesis, diagnosis and management challenges in complete androgen insensitivity syndrome

Chunqing Wang¹Qinjie Tian^2*

• ¹Beijing Tiantan Hospital, Capital Medical University, Beijing, China
• ²Peking Union Medical College Hospital (CAMS), Beijing, Beijing Municipality, China

Complete androgen insensitivity syndrome (CAIS) is a rare X-linked recessive disorder caused by androgen receptor (AR) gene mutation and present with female phenotypes with male chromosomal karyotype. Primitive bipotent gonads in CAIS differentiate into testes producing androgens and antimüllerian hormone (AMH). However, androgens can not stimulate embryonic wolffian ducts into male internal reproductive organs owing to AR defect and hormone resistance while AMH induces regression of müllerian ducts with absence of uterus, fallopian tubes, and upper third of vagina. So with male sex chromosome and testes, individuals with CAIS present with typical female phenotype, primary amenorrhea (PA) and infertility, spontaneous thelarche during puberty, absent or sparse axillary/pubic hair, and increased risk of gonadal tumors in cryptorchidism. Though theoretically CAIS can be screened prenatally through discrepancy between chromosomal karyotype and fetal external genitalia, suspected in bilateral inguinal "hernia" cases with female genital phenotype, and considered in cases with elevated testosterone (T) levels but no signs of virilization, lack of typical symptoms brings great challenges to diagnosis and management. Endocrinological hormone assay is helpful for identification of CAIS which reveals normal or elevated T levels, elevated luteinizing hormone for impairment of negative feedback of T and normal follicle stimulating hormone which is regulated by both sex hormones and inhibin. Diagnosis of CAIS after puberty is similar to diagnostic workfllow of PA with additional tests and should be differentiated with PA-related etiologies and other kinds of DSD, such as Swyer syndrome, Mayer-Rokitanskey-Küster-Haüser syndrome, Leydig cell hypoplasia, and several steroidogenic enzymatic deficiencies. Clinical manifestations, hormonal profiles, chromosomal karyotype, and pelvic imaging can provide comprehensive information for diagnosis. AR gene test or binding capacity can be performed for definitive diagnosis. Management of CAIS includes gonadectomy, hormone supplementation, and psychological support and education. Although with the development of molecular biology and awareness of the clinical entity more cases were reported, diagnostic and management challenges exist due to its rarity, untypical clinical manifestations, increased risk of gonadal malignancy, inflluence on physiology and psychology, disease-related and treatment-related stress. This review provides a comprehensive overview of the molecular pathogenesis, pathophysiology, diagnostic evaluation, differential diagnosis, and management of CAIS.