Complete androgen insensitivity syndrome

Overview

Complete Androgen Insensitivity Syndrome (CAIS) is a rare genetic condition in which a person who is genetically male (46,XY karyotype) is resistant to androgens, the male sex hormones. As a result, individuals with CAIS develop a typical female external appearance despite having internal undescended testes and no uterus or ovaries. The condition is usually discovered during adolescence due to absent menstruation (primary amenorrhea). CAIS is part of a spectrum of androgen insensitivity syndromes, with complete, partial, and mild forms depending on the degree of androgen resistance.

Causes

CAIS is caused by mutations in the androgen receptor (AR) gene, located on the X chromosome (Xq11-q12). This gene provides instructions for making the androgen receptor, which allows the body to respond to androgens like testosterone and dihydrotestosterone (DHT). In CAIS, mutations lead to a nonfunctional or absent receptor, rendering tissues completely insensitive to these hormones. As the AR gene is on the X chromosome, the condition is inherited in an X-linked recessive manner. Most individuals with CAIS are raised as girls and typically identify as female.

Symptoms

Symptoms of CAIS may not be apparent at birth due to the typically female external genitalia, but signs become more noticeable during puberty. Common features include:

• Normal female external genitalia: Despite having XY chromosomes

• Absence of menstruation (primary amenorrhea): Due to lack of uterus and upper vagina

• Well-developed breasts: Estrogen is produced by conversion of androgens

• Sparse or absent pubic and underarm hair: Due to androgen insensitivity

• Short or blind-ending vagina: Vaginal depth may be reduced

• Undescended testes: Often located in the abdomen, inguinal canal, or labia

Most individuals with CAIS are raised as female and typically have a female gender identity. Infertility is universal due to the absence of functional ovaries and uterus.

Diagnosis

Diagnosis of CAIS may occur at birth, during childhood, or in adolescence when puberty does not progress as expected. Diagnostic steps include:

• Karyotype testing: Reveals a 46,XY male chromosome pattern

• Hormone analysis: Elevated levels of testosterone and luteinizing hormone (LH) consistent with male-range production

• Pelvic ultrasound or MRI: Shows absence of uterus and ovaries; may identify undescended testes

• Genetic testing: Confirms mutations in the AR gene

• Physical exam: Assessing external genitalia, breast development, and hair distribution

Treatment

Management of CAIS involves medical, psychological, and surgical care tailored to the individual's needs and preferences. Treatment strategies include:

• Gonadectomy (removal of testes): Recommended after puberty to prevent the small risk of testicular cancer; delayed removal allows for natural estrogen-driven breast development

• Hormone replacement therapy (HRT): Estrogen replacement is needed after gonadectomy to maintain bone health and secondary sexual characteristics

• Psychological support and counseling: For patients and families to address identity, fertility, and emotional well-being

• Vaginal dilation or surgery: If vaginal depth is insufficient for comfortable intercourse and the individual desires it

• Regular monitoring: For bone density, hormone levels, and general health

• Genetic counseling: For the patient and family members to understand inheritance patterns and carrier status

Prognosis

With appropriate management, individuals with Complete Androgen Insensitivity Syndrome can lead healthy, fulfilling lives. Life expectancy is normal, and with estrogen replacement, bone health and other physiological functions are well maintained. Early diagnosis, supportive care, and respect for the individual’s gender identity and autonomy are crucial in promoting mental and emotional well-being. Although fertility is not possible, many individuals with CAIS develop strong social and personal identities and adapt well with family and professional support.