46,XX Testicular Disorder

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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/46xx-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.

genetic conditions

1. Introduction

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).

2. Frequency

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

3. Causes

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 often unknown, although changes affecting other genes have been identified. Individuals with SRY-negative 46,XX testicular disorder of sex development are more likely to have ambiguous genitalia than are people with the SRY-positive form.

4. Inheritance

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.

5. Other Names for This Condition

46,XX sex reversal
XX male syndrome
XX sex reversal

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,XXtrue hermaphrodite associated with a paternal-derived SRY-bearing X chromosome. CR Acad Sci III. 1993;316(4):375-83.
Ergun-Longmire B, Vinci G, Alonso L, Matthew S, Tansil S, Lin-Su K, McElreaveyK, New MI. Clinical, hormonal and cytogenetic evaluation of 46,XX males andreview of the literature. J Pediatr Endocrinol Metab. 2005 Aug;18(8):739-48.
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, cytogeneticand molecular analysis. J Pediatr Endocrinol Metab. 2005 Feb;18(2):197-203.
Kolon TF, Ferrer FA, McKenna PH. Clinical and molecular analysis of XX sexreversed patients. J Urol. 1998 Sep;160(3 Pt 2):1169-72; discussion 1178.
Kremen J, Chan YM, Swartz JM. Recent findings on the genetics of disorders of sex development. Curr Opin Urol. 2017 Jan;27(1):1-6. Review.
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 May15;146A(10):1335-40. doi: 10.1002/ajmg.a.32284.
Rajender S, Rajani V, Gupta NJ, Chakravarty B, Singh L, Thangaraj K.SRY-negative 46,XX male with normal genitals, complete masculinization andinfertility. Mol Hum Reprod. 2006 May;12(5):341-6.
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.
Vorona E, Zitzmann M, Gromoll J, Schüring AN, Nieschlag E. Clinical,endocrinological, and epigenetic features of the 46,XX male syndrome, comparedwith 47,XXY Klinefelter patients. J Clin Endocrinol Metab. 2007Sep;92(9):3458-65.

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Peter Tang

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Table of Contents

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1. Introduction

2. Frequency

3. Causes

4. Inheritance

5. Other Names for This Condition

References

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1. Introduction

2. Frequency

3. Causes

3.1. The genes and chromosomes associated with 46,XX testicular disorder of sex development

4. Inheritance

5. Other Names for This Condition

References