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 have male 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. Affected children are typically raised as males and develop 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 condition are usually shorter than average for males and are unable to have children (infertile).

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-typical or female-typical sex characteristics. Females usually 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 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 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 difference of sex development.

About 20 percent of people with 46,XX testicular difference of sex development do not have the SRY gene. This form of the condition is called SRY-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 with SRY-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 the SRY-positive form.

Normal Function

The SRY gene provides instructions for making a protein called the sex-determining region Y protein. This protein is involved in male-typical sex development, which usually follows a certain pattern based on an individual's chromosomes. People usually 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. Girls and women typically have two X chromosomes (46,XX karyotype), while boys and men typically have one X chromosome and one Y chromosome (46,XY karyotype).

The SRY gene is found on the Y chromosome. The sex-determining region Y protein produced from this gene acts as a transcription factor, which means it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. This protein starts processes that cause a fetus to develop male gonads (testes) and prevent the development of female reproductive structures (uterus and fallopian tubes).

Health Conditions Related to Genetic Changes

Swyer syndrome

Variants (also called mutations) in the SRY gene have been identified in approximately 15 percent of individuals with Swyer syndrome, also known as 46,XY complete gonadal dysgenesis or 46,XY pure gonadal dysgenesis. Swyer syndrome is a condition that affects sex development. Individual with this condition have a male-typical chromosome pattern (46,XY karyotype), but they develop female-typical sex characteristics.

SRY gene variants that cause Swyer syndrome prevent production of the sex-determining region Y protein or result in the production of a nonfunctioning protein. Without functional sex-determining region Y protein, a fetus will not develop testes but will develop a uterus and fallopian tubes, despite having an X and a Y chromosome.

46,XX testicular difference of sex development

Changes affecting the SRY gene have been found to cause 46,XX testicular difference of sex development. Individuals with this condition have a female-typical chromosome pattern (46,XX karyotype) but develop male sex characteristics, including testes, though they may be small and undescended.

In most individuals with 46,XX testicular difference of sex development, the condition results from an abnormal exchange of genetic material (translocation) between the Y chromosome and another chromosome, most often the X chromosome. This exchange occurs as a random event during the formation of sperm cells in the affected person's father. In this condition, the SRY gene (which is on the Y chromosome) is misplaced, almost always onto an X chromosome. A fetus with an X chromosome that carries the SRY gene will develop male sex characteristics despite not having a Y chromosome.

Other disorders

SRY gene variants that impair the function of the sex-determining region Y protein have been identified in a small number of people with 46,XY difference of sex development, or partial gonadal dysgenesis. The effects of these variants on the function of the sex-determining region Y protein is likely less severe than those of variants that cause Swyer syndrome (described above). Individuals with 46,XY difference of sex development have a male-typical chromosome pattern (46,XY karyotype), but they have external genitalia that do not look clearly male or clearly female or other abnormalities of the genitals and reproductive organs.

Translocations that misplace the SRY gene onto an X chromosome cause about 10 percent of cases of a condition called ovotesticular difference of sex development. Individuals with this condition have a female-typical chromosome pattern (46,XX karyotype) and tissue from both female and male reproductive organs (ovarian and testicular tissue).

Other Names for This Gene

• essential protein for sex determination in human males
• sex determining region protein
• sex-determining region on Y
• SRY_HUMAN
• TDF
• TDY
• testis-determining factor

Genomic Location

SRY-positive 46,XX testicular difference 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 condition in their family and cannot pass on the condition 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 difference of sex development. In another very rare situation, a male 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 difference of sex development is variable. In affected people with a known genetic cause, the condition often follows an autosomal 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 of SRY-negative 46,XX testicular difference of sex development result from new (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 of SRY-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 of autosomal 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.

Approximately 1 in 20,000 individuals with a male appearance have 46,XX testicular difference of sex development.