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==Historical Perspective== | ==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== | ==Classification== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]
Overview
Androgen insensitivity syndrome (AIS) is an undervirilization syndrome in individuals with 46, XY karyotype. The undervirilization can be complete feminization or incomplete virilization with some grades of ambiguity. AIS is caused by mutations in the androgen receptor, resulting in resistance to the physiologic activities of androgens. Differing degrees of resistance to androgen, AIS lead to three phenotypes: a complete form with female-appearing external genitalia, a partial form with a wide range of virilization, and a mild form with only minor undervirilization. AIS presents different challenges depending on whether resistance is complete or partial. Challenges include sex assignment, which impacts other medical decisions such as gonadectomy, hormonal replacement, and other surgical interventions. This review describes medical, psychosocial, and ethical concerns for each stage of development in complete and partial AIS, from the neonatal period to adulthood. These aspects of care should be addressed within an ethical framework by a multidisciplinary team, with the patients and families being the stakeholders in the decision-making process.
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
Androgen insensitivity syndrome results from mutations of the gene encoding the androgen receptor. AIS involves variable degree of undervirilization and/or infertility in genetically male person. Family history of other affected individuals related to each other in a pattern consistent with X-linked inheritance. Androgen insensitivity syndrome is associated with conditions such as 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 46,XY 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 should be differentiated from other more common forms of male undervirilization, including Leydig cell hypoplasia, several uncommon defects of testosterone synthesis, and 5 alpha reductase deficiency which can produce similar genital anatomy.
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. AIS is typically characterized by evidence of feminization (i.e., under masculinization). 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 müllerian 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
Evidence 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.
Imaging Findings
There are no X-ray and MRI findings associated with androgen insensitivity syndrome. 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. Radiology findings in the “predominantly male” phenotype including impaired development of the prostate and of the wolffian duct derivatives demonstrated by ultrasonography or genitourography.
Other Diagnostic Studies
There are 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.