Complete androgen insensitivity syndrome

(aka testicular feminization) can result from a variety of inactivating mutations in the AR gene. The AR gene is located on the X chromosome (Xq12) , and therefore follows an X linked recessive pattern of inheritance.

One in three phenotypic sisters of an affected individual will have an XY Karyotype.

Approach to diagnosis –

Complete AIS should be suspected in girls with inguinal hernias or labial masses with primary amenorrhoea.  Most patients present with normal breast development , absent or scant pubic and axillary hair, a short or blind vagina , absent cervix and uterus , serum testosterone in the normal male range and a 46XY karyotype.

The AR receptor defect results in insensitivity to androgen, so androgen induced wolffian duct development cannot take place normally. The presence or absence of wolffian duct derivatives (epididymis , vasa deferentia ) varies with the type of mutation.

The normal testes produce normal amounts of AMH , which effectively inhibits mullerian duct development. Therefore, uterus and fallopian tubes are completely absent. The testes may be found in the abdomen, but more commonly are located in the inguinal canals or in labia majora , probably because AMH normally mediates their descent.

The external genitalia are clearly female . Breast development is female and enhanced due to action of estrogen unopposed by the action of androgens.

Serum testosterone concentrations are normal or moderately increased , LH levels are increased due to resistance to the negative feedback effects of androgens at the hypothalamic-pituitary level. Estrogen production is also increased by approximately 70% over that in normal men. Serum FSH is in the normal range.

Management

Clinical management includes appropriate hormone therapy , creation of a functional vagina(progressive vaginal dilatation, vaginoplasty) , gonadectomy to prevent tumorigenesis in cryptorchid testes, and psychological support.

In patients of complete AIS , gonadectomy is best delayed until after puberty is complete (approx age 16-18) because pubertal development generally proceeds more smoothly in response to endogenous hormone production and because the overall risk for tumor development is quite low (5-10%), particularly before puberty.

Ruling out Differential diagnoses –

• Mullerian agenesis (MRKH syndrome) – They have normal amounts of pubic and axillary hair, normal female levels of testosterone concentration , and a 46XX karyotype.
• Males with defect in testosterone biosynthesis –

They may have female phenotype ,but breast development doesn’t occur.

• Complete gonadal dysgenesis (Swyer syndrome)-Despite the presence of 46XY karyotype , phenotype is female because streak gonads produce neither AMH nor androgen. Consequently the vagina , cervix , uterus , fallopian tubes develop normally and the internal and external genitalia do not masculinize. Patient generally presents with delayed sexual maturation , primary amenorrhea, normal pubic hair , and normal female internal and external genital anatomy.
• Incomplete androgen insensitivity syndrome –

The spectrum of clinical presentation can vary from phenotypic females with mild virilization to undervirilized males who may be fertile or infertile.Phenotypic females resemble those with complete AIS but have normal axillary and pubic hair , external genitalia exhibiting partial fusion of the labioscrotal folds,with or without clitoromegaly , and they both virilize and feminize at puberty. They have no mullerian structures , underdeveloped male genitalia,and testis similar to those with complete AIS. Breast development , overall body habits and gender identity are distinctly female.