Clinical Pearls & Morning Reports
Published September 19, 2018
Although the risk of the development of seminoma is lower with the androgen insensitivity syndrome than with other disorders of sexual development, the risk increases over time. Read the latest NEJM Case Records of the Massachusetts General Hospital here.
Q: Describe some of the processes involved in sexual differentiation.
A: Gonadal differentiation depends on the presence or absence of a Y chromosome and specifically on expression of the SRY gene, which maps to the short arm of the Y chromosome (Yp). Expression of SRY mediates the development of the undifferentiated gonad into a testis. Then, fetal testosterone secretion occurs, leading to the development of the wolffian ducts and ultimately to a typical male genital phenotype. In addition, secretion of antimüllerian hormone by the Sertoli cells of the fetal testis induces regression of the müllerian ducts. In the absence of a Y chromosome (and SRY expression) and in the presence of two intact X chromosomes, female gonadal and phenotypic differentiation occurs, with ovarian development, normal typical female genital phenotype, and reproductive function of typical onset and duration.
Q: At what age is complete androgen insensitivity syndrome typically diagnosed?
A: Complete androgen insensitivity syndrome is most often diagnosed during childhood, when a testis is found at the time of an inguinal hernia repair, or at puberty, when a patient presents with primary amenorrhea. Approximately 50% of patients with complete androgen insensitivity syndrome have an inguinal hernia, and 1 to 2% of female patients with an inguinal hernia have complete androgen insensitivity syndrome. Any female patient who undergoes an inguinal hernia repair during childhood would usually also undergo routine vaginoscopy to confirm the presence of a cervix or undergo diagnostic laparoscopy by way of the hernia sac to rule out the presence of intraabdominal testes.
A: Patients with this syndrome have an XY genotype and mutations in the androgen receptor gene, which is located on chromosome Xq1.1–1.2. Patients with complete androgen insensitivity syndrome have testes and secrete high levels of androgens (particularly testosterone). However, because of the absence of a functional androgen receptor, there is no response to the hormones in peripheral tissues, either in utero or after puberty. As a result, the wolffian ducts do not develop. In parallel, the müllerian ducts regress owing to the secretion of antimüllerian hormone by Sertoli cells. Thus, patients with complete androgen insensitivity syndrome have female-appearing external genitalia but no uterus, cervix, or upper vagina, and they have cryptorchidism, with either intraabdominal testes or testes at various stages of descent in the inguinal canal. In addition, they undergo puberty and breast development as a result of the peripheral conversion of androgens to estrogens by aromatase, but they have virtually no axillary or pubic hair.
A: In general, gonadal tumors that are associated with complete androgen insensitivity syndrome are germ-cell tumors (usually gonadoblastoma, dysgerminoma, or seminoma). However, Sertoli-cell adenomas and tumors of the Sertoli and Leydig cells are also common. In an adult with newly diagnosed complete androgen insensitivity syndrome, surgical removal of the gonads would be recommended. In contrast, among pediatric patients with complete androgen insensitivity syndrome, the optimal timing of orchiectomy can be challenging and an individualized approach is important. The gonads produce estradiol, which contributes to the development of a female phenotype; therefore, many prefer to leave the gonads in situ until puberty is complete. Patients for whom gonadectomy would not be delayed include those with palpable testes and those with an inguinal hernia.