Androgen Insensitivity Syndrome

Introduction

• Description: Patients with androgen insensitivity have a normal male karyotype but a genetic alteration that results in somatic cells that cannot recognize or respond to testosterone. This results in a normal female phenotype, absent uterus, and scant (or absent) body hair. The syndrome was known at one time as “testicular feminization.”

• Prevalence: Uncommon; 10% of patients with primary amenorrhea (third most common cause). May be as high as 1/20,000 phenotypic females.

• Predominant Age: Generally discovered in middle to late teens.

• Genetics: Absence of an X-chromosome gene (eight exon androgen receptor gene located on chromosome Xq11-12) that encodes for cytoplasmic or nuclear testosterone receptor protein, X-linked recessive. Over 1000 mutations have been identified in individuals with androgen insensitivity syndrome. Most mutations have been localized in the hormone-binding domain of the gene.

Etiology and Pathogenesis

• Causes: Testosterone and gonadotropin levels are essentially normal (there may be a slight increase in luteinizing hormone, but the testosterone is biologically ineffective because of the body’s inability to use it. Consequently, masculinization does not occur, and the normal production of Müllerian-inhibiting factor results in the regression of the upper genital tract and a blind vaginal pouch.

• Risk Factors: None known.

Signs and Symptoms

There is a spectrum of androgen receptor dysfunction (partial androgen insensitivity) that results in a spectrum of traits and impacts ranging from hypomasculinized males (hypospadias, sparce body hair, undescended testes, and subfertility) to the complete syndrome described here.

• Amenorrhea

• Tall stature

• Normal breast development with immature nipples and hypopigmented areolae

• Short or absent blind vaginal pouch

• Scant or no pubic or axillary hair

• Gonads (testes) may be palpable in the inguinal canal or labioscrotal folds

• Inguinal hernia (50%, as many as 1%–2% of girls with inguinal hernias may have complete androgen insensitivity syndrome)

Diagnostic Approach