Androgen insensitivity syndrome overview

# Overview
Androgen insensitivity syndrome is due to hormone resistance which may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. AIS is an X linked disorder. The development of Androgen insensitivity syndrome is a result of genetic mutations of the androgen receptor (AR) gene located on the chromosome Xq11-12. Associated conditions include primary amenorrhea, infertility and dyspareunia. Androgen receptor (AR) gene defects inhibit the normal development of both internal and external genital structures in 46XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia. Androgen insensitivity syndrome (AIS) represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes such as complete, partial and mild AIS. A multidisciplinary approach is recommended for clinical management from infancy through to adulthood. Hormone replacement therapy is needed following gonadectomy. Patients who have decided to retain their gonads are considered to be at risk for developing germ cell tumors and for these the sensitive circulating tumor markers may become available soon. Surgical approach to the Androgen insensitivity syndrome involves vaginal dilation or gonadectomy or determination of sex which depend on various factors such as the type of AIS, age, sex and preventive measures to be taken in adolescence and adulthood.

# Historical Perspective
In 1953, the first medical report on AIS was published by J. M. Morris, an american gynecologist. In 1989, the exact location of the human Androgen receptor (AR) gene on Xq11-12 locus was determined and the proof that it is caused by mutations in this gene.

# Classification
Androgen insensitivity syndrome (AIS) represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes such as complete, partial and mild AIS.

# Pathophysiology
It is thought that Androgen insensitivity syndrome is caused due to hormone resistance which may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. AIS is an X linked disorder. The development of Androgen insensitivity syndrome is a result of genetic mutations of the androgen receptor (AR) gene located on the chromosome Xq11-12. Associated conditions include primary amenorrhea, infertility and dyspareunia.

# Causes
Androgen insensitivity syndrome is caused due to mutations in the X-linked androgen receptor gene. Androgen receptor (AR) gene defects inhibit the normal development of both internal and external genital structures in 46XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia.

# Differentiating Androgen insensitivity syndrome from Other Diseases
Androgen insensitivity syndrome must be differentiated from other conditions based on the genotype, phenotype and developmental characteristics.

# Epidemiology and Demographics
CAIS has a prevalence of 2 per 100,000 to 5 per 100,000. The incidence of complete AIS is about in 5 in 100,000. There is no racial predilection for androgen insensitivity syndrome.

# Risk Factors
The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood. Benign tumors of nongerminomatous germ cell tumor include Sertoli cell adenoma and hamartomas.

# Screening
The diagnosis of AIS is mostly made post-natally. Studies have shown that the AIS may be identified prenatally by imaging techniques and comparative study such as preimplantation genetic screening, noninvasive prenatal screening and ultrasonography.

# Natural History, Complications, and Prognosis
If left untreated, androgen insensitivity syndrome may lead to cancers of the male breast, larynx, liver, testes and bladder. Common complications of androgen insensitivity syndrome include Infertility, psychological and social issues, osteoporosis, and cancers. Prognosis is good after orchidectomy at the proper time. For incomplete AIS patients, it depends on the presence and severity of ambiguous genitalia.

# Diagnosis

## History and Symptoms
The diagnosis of AIS is determined in a 46,XY individual by the undermasculinization of the external genitalia, impaired spermatogenesis and absent or rudimentary mullerian structures. Cases of CAIS are diagnosed during abdominal surgery, delayed menarche and infertility.

## Physical Examination
Androgen insensitivity syndrome (AIS) is typically characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in individuals with a 46,XY karyotype.

## Laboratory Findings
Laboratory findings which suggest the presence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased luteinizing hormone (LH) production by the pituitary gland AND/OR by the identification of a hemizygous pathogenic variant.

## Electrocardiogram
There are no ECG findings observed in androgen insensitivity syndrome.

## X-ray
There are no X-ray findings associated with androgen insensitivity syndrome.

## Ultrasound
Pelvic ultrasound helps in determining the presence or absence of uterus and gonads.

## CT scan
Findings of seminoma are observed by FDG PET/CT in androgen insensitivity syndrome. Incidental detection of sertoli-Leydig cell tumor by FDG PET/CT imaging.

## MRI
MRI may be helpful in the diagnosis of Androgen insensitivity syndrome. MRI may be helpful in localizing the testes, diagnosing malignancy in cryptorchid testes and describing mullerian duct anomalies.

## Other Imaging Findings
There are no other imaging findings associated with androgen insensitivity syndrome.

## Other Diagnostic Studies
There are no other diagnostic studies associated with androgen insensitivity syndrome.

# Treatment

## Medical Therapy
A multidisciplinary approach is recommended for clinical management from infancy through to adulthood. Hormone replacement therapy is needed following gonadectomy. Patients who choose to retain the gonads are at risk of developing germ cell tumors for which sensitive circulating tumor markers may soon become available.

## Surgery
Surgical approach to the Androgen insensitivity syndrome involves vaginal dilation or gonadectomy or determination of sex which depend on various factors such as the type of AIS, age, sex and preventive measures to be taken in adolescence and adulthood.

## Prevention
Currently there are no established methods to prevent androgen insensitivity syndrome (AIS). However, various treatment options may help manage the symptoms of AIS. Genetic counseling is advisable for parents as well as the affected individuals. The use of preimplantation genetic screening, noninvasive prenatal screening and ultrasonography and laparoscopic surgery may help identify, prevent or rectify accordingly. Women with CAIS have decreased bone mineral density, regardless of timing of gonadectomy.