Partial androgen insensitivity syndrome

Synonyms

9

Overview

Partial androgen insensitivity syndrome (PAIS) is a disorder of sex development that affects the growing reproductive and genital organs of a fetus. Androgen insensitivity refers to the inability of the body of an individual with a 46, XY karyotype (usually leading to normal male development) to properly respond to male sex hormones (androgens). In PAIS, the body partially responds to these hormones.

The extent of androgen insensitivity in 46 XY individuals is quite variable, even in a single family. Partial androgen insensitivity typically results in "ambiguous genitalia." The clitoris is large or, alternatively, the penis is small and hypospadic (these are two ways of labeling the same anatomical structure). Partial androgen insensitivity may be quite common, and has been suggested as the cause of infertility in many men whose genitals are of typically male appearance.

PAIS is one of three types of androgen insensitivity syndrome, which is divided into three categories that are differentiated by the degree of genital masculinization: complete androgen insensitivity syndrome (CAIS) is indicated when the external genitalia is that of a normal female, mild androgen insensitivity syndrome (MAIS) is indicated when the external genitalia is that of a normal male, and partial androgen insensitivity syndrome (PAIS) is indicated when the external genitalia is partially, but not fully masculinized.

Symptoms

Signs and symptoms of PAIS can vary greatly:

  • Range of differences in genital appearance
  • Unusually small penis
  • Bifid scrotum
  • Female external genitalia with an abnormally large clitoris
  • Partial fusion of the labia and gynecomastia (excessive development of male breasts)
  • Infertility, which is related to hardening of the tubules in the testis (seminiferous tubular sclerosis), and either very little or no sperm in the semen
  • Abnormal penis in which the urethra opens on the underside (hypospadias)
  • Impaired production of male hormones due to dysfunction of gonads (hypogonadism)
  • One or both testes may fail to descend normally
  • Decrease in the functioning of the cells in the testis that produce androgens (leydic cell hyperplasia) may lead to impotence later in life
  • Facial and chest hair may be sparse or missing and the voice may have a high pitch
  • Sparse beard
  • Small prostate
  • Development of female pelvis
  • Female fat distribution 

Causes

Partial androgen insensitivity syndrome (PAIS) is inherited as an X-linked recessive genetic disorder and is caused by mutations in the AR gene. The gene involved is located on the long arm of the X chromosome (Xq11-q12).

The affected gene codes for, or stimulates the production of, a protein known as the androgen receptor. It is this protein that affects the developing fetus and signals the fetus to respond to the presence of the male hormones. When the AR gene is defective the development of the genitalia of either sex is interfered with.

Diagnosis

Unfortunately, the number of differentials to consider for PAIS is particularly large. Prompt diagnosis is particularly urgent when a child is born with ambiguous genitalia, as some causes are associated with potentially life-threatening adrenal crises. Determination of testosterone, testosterone precursors and dihydrotestosterone (DHT) at baseline and / or after human chorionic gonadotropin (hCG) stimulation can be used to exclude such defects in androgen biosynthesis.

Approximately one half of all 46,XY individuals born with ambiguous genitalia will not receive a definitive diagnosis. Androgen receptor (AR) gene mutations cannot be found in 27% to 72% of individuals with PAIS. As a result, genetic analysis can be used to confirm a diagnosis of PAIS, but it cannot be used to rule out PAIS. Evidence of abnormal androgen binding in a genital skin fibroblast study has long been the gold standard for the diagnosis of PAIS, even when an AR mutation is not present. However, some cases of PAIS, including AR-mutant-positive cases, will show normal androgen binding. A family history consistent with X-linked inheritance is more commonly found in AR-mutant-positive cases than AR-mutant-negative cases.

The use of dynamic endocrine tests is particularly helpful in isolating a diagnosis of PAIS. One such test is the human chorionic gonadotropin (hCG) stimulation test. If the gonads are testes, there will be an increase in the level of serum testosterone in response to the hCG, regardless of testicular descent. The magnitude of the testosterone increase can help differentiate between androgen resistance and gonadal dysgenesis, as does evidence of a uterus on ultrasound examination. Testicular function can also be assessed by measuring serum anti-Müllerian hormone levels, which in turn can further differentiate PAIS from gonadal dysgenesis and bilateral anorchia.

Another useful dynamic test involves measuring the response to exogenous steroids; individuals with AIS show a decreased response in serum sex hormone binding globulin (SHBG) after a short term administration of anabolic steroids.[51][52] Two studies [51][52] indicate that measuring the response in SHBG after the administration of stanozolol could help to differentiate individuals with PAIS from those with other causes of ambiguous genitalia, although the response in individuals with predominantly male phenotypes overlaps somewhat with the response in normal males.

Treatment

The use of drugs that replace testosterone at an early age may restore fertility in males with partian androgen insensitivity syndrome. Surgery may be undertaken to correct the condition in which the penis is drained through an opening on its underside (hypospadia). Corrective surgery may also be done on enlarged breasts in males. Patients with more severe defects may be raised as females and have corrective surgery performed before puberty. These patients may use estrogen therapy at puberty. Psychological counseling is recommended to help young males and teenagers through the problems associated with the disorder and the issues of gender determination.

Genetic counseling may be of benefit for patients and their families. The treatment is symptomatic and supportive.

Resources

  • NIH