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46,XX testicular disorder of sex development

Reviewed November 2008

What is 46,XX testicular disorder of sex development?

46,XX testicular disorder of sex development is a condition in which individuals with two X chromosomes in each cell, the pattern normally found in females, have a male appearance. People with this disorder have male external genitalia. They generally have small testes and may also have abnormalities such as undescended testes (cryptorchidism) or the urethra opening on the underside of the penis (hypospadias). A small number of affected people have external genitalia that do not look clearly male or clearly female (ambiguous genitalia). Affected children are typically raised as males and have a male gender identity.

At puberty, most affected individuals require treatment with the male sex hormone testosterone to induce development of male secondary sex characteristics such as facial hair and deepening of the voice (masculinization). Hormone treatment can also help prevent breast enlargement (gynecomastia). Adults with this disorder are usually shorter than average for males and are unable to have children (infertile).

How common is 46,XX testicular disorder of sex development?

Approximately 1 in 20,000 individuals with a male appearance have 46,XX testicular disorder.

What are the genetic changes related to 46,XX testicular disorder of sex development?

People normally have 46 chromosomes in each cell. Two of the 46 chromosomes, known as X and Y, are called sex chromosomes because they help determine whether a person will develop male or female sex characteristics. Females typically have two X chromosomes (46,XX), and males usually have one X chromosome and one Y chromosome (46,XY).

The SRY gene, normally located on the Y chromosome, provides instructions for making the sex-determining region Y protein. The sex-determining region Y protein causes a fetus to develop as a male.

In about 80 percent of individuals with 46,XX testicular disorder of sex development, the condition results from an abnormal exchange of genetic material between chromosomes (translocation). This exchange occurs as a random event during the formation of sperm cells in the affected person's father. The translocation causes the SRY gene to be misplaced, almost always onto an X chromosome. If a fetus is conceived from a sperm cell with an X chromosome bearing the SRY gene, it will develop as a male despite not having a Y chromosome. This form of the condition is called SRY-positive 46,XX testicular disorder of sex development.

About 20 percent of people with 46,XX testicular disorder of sex development do not have the SRY gene. This form of the condition is called SRY-negative 46,XX testicular disorder of sex development. The cause of the disorder in these individuals is unknown. They are more likely to have ambiguous genitalia than are people with the SRY-positive form.

Related Chromosome(s)

Changes involving these chromosomes are associated with 46,XX testicular disorder of sex development.

  • X chromosome
  • Y chromosome

Related Gene(s)

Changes in this gene are associated with 46,XX testicular disorder of sex development.

  • SRY

Can 46,XX testicular disorder of sex development be inherited?

SRY-positive 46,XX testicular disorder of sex development is almost never inherited. This condition results from the translocation of a Y chromosome segment containing the SRY gene during the formation of sperm (spermatogenesis). Affected people typically have no history of the disorder in their family and cannot pass on the disorder because they are infertile.

In rare cases, the SRY gene may be misplaced onto a chromosome other than the X chromosome. This translocation may be carried by an unaffected father and passed on to a child with two X chromosomes, resulting in 46,XX testicular disorder of sex development. In another very rare situation, a man may carry the SRY gene on both the X and Y chromosome; a child who inherits his X chromosome will develop male sex characteristics despite having no Y chromosome.

The inheritance pattern of SRY-negative 46,XX testicular disorder of sex development is unknown. A few families with unaffected parents have had more than one child with the condition, suggesting the possibility of autosomal recessive inheritance. Autosomal recessive means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of 46,XX testicular disorder of sex development?

These resources address the diagnosis or management of 46,XX testicular disorder of sex development and may include treatment providers.

  • Gene Review: 46,XX Testicular Disorder of Sex Development (http://www.ncbi.nlm.nih.gov/books/NBK1416)
  • Genetic Testing Registry: 46,XX sex reversal, type 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2748895)
  • Genetic Testing Registry: 46,XX testicular disorder of sex development (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2936420)
  • MedlinePlus Encyclopedia: Ambiguous Genitalia (http://www.nlm.nih.gov/medlineplus/ency/article/003269.htm)
  • MedlinePlus Encyclopedia: Intersex (http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm)

You might also find information on the diagnosis or management of 46,XX testicular disorder of sex development in Educational resources (http://www.ghr.nlm.nih.gov/condition/46xx-testicular-disorder-of-sex-development/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/46xx-testicular-disorder-of-sex-development/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about 46,XX testicular disorder of sex development?

You may find the following resources about 46,XX testicular disorder of sex development helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for 46,XX testicular disorder of sex development?

  • 46,XX sex reversal
  • XX male syndrome
  • XX sex reversal

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about 46,XX testicular disorder of sex development?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding 46,XX testicular disorder of sex development?

autosomal ; autosomal recessive ; cell ; chromosome ; cryptorchidism ; fetus ; gene ; genitalia ; gynecomastia ; hermaphrodite ; His ; hormone ; hormone treatment ; hypospadias ; infertile ; inheritance ; inheritance pattern ; inherited ; protein ; puberty ; recessive ; sex chromosomes ; sex hormone ; sperm ; spermatogenesis ; syndrome ; testes ; testosterone ; translocation

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Abbas N, McElreavey K, Leconiat M, Vilain E, Jaubert F, Berger R, Nihoul-Fekete C, Rappaport R, Fellous M. Familial case of 46,XX male and 46,XX true hermaphrodite associated with a paternal-derived SRY-bearing X chromosome. C R Acad Sci III. 1993;316(4):375-83. (http://www.ncbi.nlm.nih.gov/pubmed/8402263?dopt=Abstract)
  • Ergun-Longmire B, Vinci G, Alonso L, Matthew S, Tansil S, Lin-Su K, McElreavey K, New MI. Clinical, hormonal and cytogenetic evaluation of 46,XX males and review of the literature. J Pediatr Endocrinol Metab. 2005 Aug;18(8):739-48. (http://www.ncbi.nlm.nih.gov/pubmed/16200839?dopt=Abstract)
  • Grigorescu-Sido A, Heinrich U, Grigorescu-Sido P, Jauch A, Hager HD, Vogt PH, Duncea I, Bettendorf M. Three new 46,XX male patients: a clinical, cytogenetic and molecular analysis. J Pediatr Endocrinol Metab. 2005 Feb;18(2):197-203. (http://www.ncbi.nlm.nih.gov/pubmed/15751609?dopt=Abstract)
  • Kolon TF, Ferrer FA, McKenna PH. Clinical and molecular analysis of XX sex reversed patients. J Urol. 1998 Sep;160(3 Pt 2):1169-72; discussion 1178. (http://www.ncbi.nlm.nih.gov/pubmed/9719302?dopt=Abstract)
  • Queralt R, Madrigal I, Vallecillos MA, Morales C, Ballescá JL, Oliva R, Soler A, Sánchez A, Margarit E. Atypical XX male with the SRY gene located at the long arm of chromosome 1 and a 1qter microdeletion. Am J Med Genet A. 2008 May 15;146A(10):1335-40. doi: 10.1002/ajmg.a.32284. (http://www.ncbi.nlm.nih.gov/pubmed/18412126?dopt=Abstract)
  • Rajender S, Rajani V, Gupta NJ, Chakravarty B, Singh L, Thangaraj K. SRY-negative 46,XX male with normal genitals, complete masculinization and infertility. Mol Hum Reprod. 2006 May;12(5):341-6. Epub 2006 Mar 23. (http://www.ncbi.nlm.nih.gov/pubmed/16556678?dopt=Abstract)
  • Rizvi AA. 46, XX man with SRY gene translocation: cytogenetic characteristics, clinical features and management. Am J Med Sci. 2008 Apr;335(4):307-9. doi: 10.1097/MAJ.0b013e31811ec1b4. (http://www.ncbi.nlm.nih.gov/pubmed/18414071?dopt=Abstract)
  • Vorona E, Zitzmann M, Gromoll J, Schüring AN, Nieschlag E. Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab. 2007 Sep;92(9):3458-65. Epub 2007 Jun 19. (http://www.ncbi.nlm.nih.gov/pubmed/17579198?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: November 2008
Published: December 16, 2014