46,XX testicular disorder of sex development

Alternate names

46,XX testicular DSD; 46,XX gonadal dysgenesis; XX male syndrome; 46, XX gonadal sex reversal; XX sex reversal

Definition

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.

Epidemiology

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

Cause

• 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. T
• he 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.

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.

Signs and symptoms

• 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).

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Ambiguous genitalia(Ambiguous external genitalia)
• Decreased testicular size(Small testes)
• Male hypogonadism(Decreased function of male gonad)
• Polycystic ovaries

5%-29% of people have these symptoms

• Ovotestis

Diagnosis

Diagnosis of nonsyndromic 46,XX testicular DSD is based on the combination of clinical findings, endocrine testing, and cytogenetic testing.

• Endocrine studies usually show hypergonadotropic hypogonadism secondary to testicular failure.
• Cytogenetic studies at the 550-band level demonstrate a 46,XX karyotype.
• SRY, the gene that encodes the sex-determining region Y protein, is the principal gene known to be associated with 46,XX testicular DSD.
• Approximately 80% of individuals with nonsyndromic 46,XX testicular DSD are SRY positive as shown by use of FISH or chromosomal microarray (CMA).
• Rearrangements in or around SOX9 and SOX3 detected by CMA, or rarely karyotype, have recently been reported in a few cases; at least one more as-yet-unknown gene at another locus is implicated.

Treatment

Testosterone-replacement therapy

• Management of individuals with 46,XX testicular DSD with testosterone deficiency is similar to that for other causes of testosterone deficiency. Physicians should check for the most current preparations and dosage recommendations before initiating testosterone replacement therapy.
• After age 14 years, low-dose testosterone therapy can be initiated.
• Testosterone enanthate is given IM every three to four weeks, starting at 100 mg and increasing by 50 mg every six months to 200-400 mg. Initial high doses of testosterone should be avoided to prevent priapism. The treatment should plateau, in adulthood, at the best possible dosage, typically between 50 and 400 mg every two to four weeks.
• Injection of testosterone enanthate is the preferred method of replacement therapy because of low cost and easy, at-home regulation of dosage; however, side effects include pain associated with injection and large variations of serum testosterone concentration between injections, resulting in a higher risk of mood swings.
• Alternative delivery systems that result in a more stable dosing include transdermal patches (scrotal and non-scrotal) and transdermal gels. Testosterone-containing gels, however, are associated with the risk of interpersonal transfer, which can be reduced by the use of newer hydroalcoholic gels .

Gynecomastia Regression of gynecomastia may occur with testosterone replacement therapy. If it does not, and if it causes psychological distress to the individual, reduction mammoplasty can be offered.

Osteopenia Depending on the degree of osteopenia, treatment may include: calcium, exercise, vitamin D, biphosphonates, or calcitonin. Referral to an internist, pediatrician, or endocrinologist is recommended.

Psychological support Sensitivity is necessary when conveying information to individuals with 46,XX testicular DSD about the genetic cause and associated sterility of the disorder. This information must be presented in a manner that helps minimize psychological distress. Providers are encouraged to anticipate the need for further psychological assistance.

NIH genetic and rare disease info

• NIH info on 46,XX testicular disorder of sex development

46,XX testicular disorder of sex development is a rare disease.

46,XX testicular disorder of sex development Resources
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