Androgen insensitivity syndrome

Definition

• Androgen insensitivity syndrome is a difference of sex development in individuals with a 46,XY karyotype caused by impaired androgen receptor function; the complete form (CAIS) results in a typical female phenotype with functioning testes.

Classification

• Complete (CAIS), partial (PAIS) with varying degrees of undervirilisation and mild (MAIS) forms with male genitalia, infertility and/or gynaecomastia are distinguished.

Occurrence & epidemiology

Epidemiology

• The complete form affects about 2 to 5 in 100,000 female newborns; the partial form is thought to be at least as common.

Aetiopathogenesis

Aetiology and pathogenesis

• The cause is inactivating mutations in the androgen receptor gene on the X chromosome (Xq11-12) with X-linked recessive inheritance; about 30% of cases result from new mutations.
• The testes secrete anti-Müllerian hormone, causing regression of the uterus, cervix and upper vagina; breast development at puberty results from aromatisation of androgens to oestrogens in the absence of androgen action.

Clinical features

• Typical is primary amenorrhoea with normal breast development, absent or sparse pubic and axillary hair and a blind-ending vagina without a uterus.
• In childhood, the testes are often found in connection with a unilateral or bilateral inguinal hernia; there is also a risk of gonadal germ cell tumours, which is low before puberty.

Diagnosis

• Hormonally, LH is raised with normal to raised testosterone and usually normal FSH; after puberty, oestradiol is normal or slightly raised relative to the male reference range.
• The diagnosis integrates clinical findings, hormone tests, a 46,XY karyotype and sequencing of the AR gene.

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Further reading (selection)

1. MedlinePlus Genetics: Androgen insensitivity syndrome (U.S. National Library of Medicine)
2. Androgen insensitivity syndrome: a review (Arch Endocrinol Metab 2018, PubMed Central)
3. Complete Androgen Insensitivity Syndrome: From Bench to Bed (Int J Mol Sci 2021, PubMed Central)

Cross-references