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46,XX testicular difference of sex development is a condition in which individuals with two X chromosomes in each cell, the pattern typically found in females, have a male appearance. People with this condition havemale external genitalia
. They generally have small testes and may also have other features 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.
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 condition are usually shorter than average for males and are unable to have children (infertile).
Approximately 1 in 20,000 individuals with a male appearance have 46,XX testicular difference of sex development.
People normally have 46 chromosomes in each cell. Two of the 46 chromosomes, known as X and Y, are calledsex chromosomes
because they help determine whether a person will develop male-typical or female-typical sex characteristics. Females usually have two X chromosomes (46,XX), and males usually have oneX chromosome and oneY chromosome(46,XY).
TheSRY 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 difference 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 ofsperm cells
in the affected person's father. The translocation causes theSRY gene to be misplaced, almost always onto an X chromosome. If a fetus is conceived from a sperm cell with an X chromosome bearing theSRY gene, it will develop as a male despite not having a Y chromosome. This form of the condition is calledSRY-positive 46,XX testicular difference of sex development.
About 20 percent of people with 46,XX testicular difference of sex development do not have theSRY gene. This form of the condition is calledSRY-negative 46,XX testicular difference of sex development. The cause of the condition in these individuals is often unknown, although changes affecting other genes involved in the development of sex characteristics have been identified in a small number of people with the condition. Individuals withSRY-negative 46,XX testicular difference of sex development are more likely to have genitalia that do not clearly look male or female than are people with theSRY-positive form.
Additional Information from NCBI Gene:
SRY-positive 46,XX testicular difference of sex development is almost never inherited. This condition results from thetranslocation of a Y chromosome segment containing theSRY gene during the formation ofsperm (spermatogenesis). Affected people typically have no history of the condition in their family and cannot pass on the condition because they are infertile.
In rare cases, theSRY 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 difference of sex development. In another very rare situation, a male may carry theSRY 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 ofSRY-negative 46,XX testicular difference of sex development is variable. In affected people with a known genetic cause, the condition often follows anautosomal dominant
pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the condition. In some cases, the genetic variant (also known as a mutation) is inherited from an unaffected parent. Usually, the variant is inherited from an unaffected father. Sometimes, the variant is inherited from an unaffected mother. When some people with the variant do not develop features of the condition, it is said to have reduced (or incomplete) penetrance.
Other cases ofSRY-negative 46,XX testicular difference of sex development result fromnew (de novo) variants
in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the condition in their family.
The inheritance pattern ofSRY-negative 46,XX testicular difference of sex development without an identified genetic cause is unknown. A few families with unaffected parents have had more than one child with the condition, suggesting the possibility ofautosomal recessive
inheritance. Autosomal recessive means both copies of a gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.
The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.
