Androgen Insensitivity Syndrome, Partial

Androgen Insensitivity Syndrome, Partial

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Androgen Insensitivity Syndrome, Partial is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Gilbert-Dreyfus Syndrome
  • Incomplete Testicular Feminization
  • Lubs Syndrome
  • Rosewater Syndrome
  • Type I Familial Incomplete Male Pseudohermaphroditism
  • Reifenstein Syndrome

Disorder Subdivisions

  • None

General Discussion

Androgen insensitivity refers to an inability of the body to respond properly to male sex hormones (androgens) produced during pregnancy. This occurs because of a change (mutation) in a gene involved in the production of the protein inside cells that receives the androgen hormone and instructs the cell in how to use it.



Partial androgen insensitivity syndrome (pais) is part of a spectrum of syndromes that also includes androgen insensitivity syndrome (AIS) and mild androgen insensitivity syndrome (mais). In each case, the development of the reproductive and genital organs of the fetus is affected, as a result of the gene mutation.



During the first 10 weeks of pregnancy, the external anatomy of male and female embryos appears to be identical. The presence or absence of the male sex hormone testosterone determines whether male or female genitalia develop. In partial androgen insensitivity syndrome, the development of the external genitals will be intermediate between male and female (ambiguous genitalia).



Each of these forms of AIS is also a hereditary form of male pseudohermaphroditism, in which the baby is born with testes and possesses both male and female characteristics. The disorder is inherited as an X-linked, recessive trait.

Symptoms

The symptoms of partial androgen insensitivity syndrome can vary greatly. In the least severe cases, the only symptom that presents itself may be 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.



In more severe cases, an abnormal penis in which the urethra opens on the underside (hypospadias), impaired production of male hormones due to dysfunction of gonads (hypogonadism), and excessive development of the male breasts (gynecomastia) may also occur. One or both testes may fail to descend normally, and a 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.

Causes

Partial androgen insensitivity syndrome (PAIS) is inherited as an X-linked recessive genetic disorder. 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.



Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.



Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome Xq11-q12" refers to the region on the long arm of the X chromosome between bands 11 and 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.



X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is "turned off". A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.



Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.



All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.



Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Affected Populations

PAIS is a very rare genetic disorder. This disorder only occurs in males but females are the carriers of the genetic defect. There have been many reports of multiple males in a family inheriting the syndrome.

Standard Therapies

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.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.



For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996:1290-92



Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:4130-32.



REVIEW ARTICLES

Mazen I, Lumbroso S, Abdel Ghaffar S, et al. Mutation of the androgen receptor (R840S) in an Egyptian patient with partial androgen insensitivity syndrome: review of the literature on the clinical expression of different R840 substitutions. J Endocrinol Invest. 2004;27:57-60.



Sultan C, Lumbroso S, Paris F, et al. Disorder of androgen action. Semin Reprod Med. 2002;20:217-28.



Brinkmann AO. Molecular basis of androgen insensitivity. Mol Cell Endocrinol. 2001;179:105-09.



Sultan C, Paris F, Terouanne B, et al. Disorders linked to insufficient androgen action in male children. Hum Reprod Update. 2001;7:314-22.



JOURNAL ARTICLES

Lower KM, Kumar R, Woollatt E, et al. Partial Androgen Insensitivity Syndrome and t(X;5): Are There Upstream Regulatory Elements of the Androgen Receptor Gene? Horm Res. 2004;62:208-14.



Dessouky NM. Gender assignment for children with intersex problems: An Egyptian perspective. Saudi Med J. 2003;24 (5Suppl):S51-52.



Migeon CJ, Wisniewski AB, Gearhart JP, et al. Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcomes. Pediatrics. 2002;110:e31.



Foresta C, Betella A, Ferlin A, et al. Response to local dihydrotestosterone treatment ina patient with partial androgen insensitivity syndrome due to a novel mutation in the androgen receptor gene. Am J Med Genet. 2002;107:259-60.



Lundberg Giwercman Y, Nikoshkov A, Lindsten K, et al. Response to treatment in patients with partial androgen insensitivity syndrome due to mutations in the DNA-binding domain of the androgen receptor. Horm Res. 2000;53:83-88.



FROM THE INTERNET

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Androgen Receptor; AR. Entry Number; 313700: Last Edit Date; 12/14/2004.



Medical Encyclopedia: Reifenstein syndrome. Update Date: 1/30/2003. 3pp.

www.nlm.nih.gov/medlineplus/ency/article/001169.htm



Medical Encyclopedia: Testicular feminization. Update Date: 10/6/2003. 3pp.

www.nlm.nih.gov/medlineplus/ency/article/001180.htm



Wilson BE. Androgen Insensitivity Syndrome. emedicine. Last Updated: July 11, 2003. 14pp.

www.emedicine.com/ped/topic2222.htm



Wilson BE. 5-Alpha-Reductase Deficiency. emedicine. Last Updated:may 26,2004. 14pp.

www.emedicine.com/ped/topic1980.htm



Gottlieb B, Beitel LK, Trifiro MA. Androgen Insensitivity Syndrome. GENEReviews. Last Update: 8 April 2004. 16pp.

www.geneclinics.org/profiles/androgen/details.html



What is AIS. AIS Support Group. Last updated 12 Sept 2004. 8pp.

www.medhelp.org/www/ais/21_OVERVIEW.HTM



Partial AIS. AIS Support Group. Last updated 17 Feb 2003. 6pp.

www.medhelp.org/www/ais/23_PAIS.HTM



What is the Androgen Insensitivity Syndrome? Intersex Society of North America. Posted Thu, Jan 01 2004.

www.isna.orgdrupal/node/view/187



Capelanes AR, Jeanty P. Partial androgen insensitivity syndrome. The Fetus Net. nd. 3pp.

www.thefetus.net/page.php?id=262

Resources

AIS/DSD Support Group for Women and Families

P.O. Box 2148

Duncan, OK 73534-2148

USA

Email: aissgusa@hotmail.com

Internet: http://www.aissg.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Accord Alliance

531 Route 22 East #244

Whitehouse Station, NJ 08889

USA

Tel: (908)349-0534

Fax: (801)349-0534

Email: janet.green@accordalliance.org

Internet: http://www.accordalliance.org



For a Complete Report

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