XX Male Syndrome

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XX male syndrome

Definition

XX male syndrome occurs when the affected individual appears as a normal male, but has female chromosomes. Two types of XX male syndrome can occur: those with detectable SRY gene and those without detectable SRY (sex determining region Y) . SRY is the main genetic switch for determining that a developing embryo will become male.

Description

XX male syndrome is a condition in which the sex chromosomes of an individual do not agree with the physical sex of the affected person. Normally, there are 46 chromosomes, or 23 pairs of chromosomes, in each cell. The first 22 pairs are the same in men and women. The last pair, the sex chromosomes, is two X chromosomes in females (XX) and an X and a Y chromosome in males (XY).

In XX male syndrome, the person has female chromosomes but male physical features. The majority of persons with XX male syndrome have the Y chromosome gene SRY attached to one of their X chromosomes. The rest of the individuals with XX male syndrome do not have SRY detectable in their cells. Hence, other genes on other chromosomes in the pathway for determining sex must be responsible for their male physical features.

Genetic profile

In XX male syndrome caused by the gene SRY, a translocation between the X chromosome and Y chromosome causes the condition. A translocation occurs when part of one chromosome breaks off and switches places with part of another chromosome. In XX male syndrome, the tip of the Y chromosome that includes SRY is translocated to the X chromosome. As a result, an embryo with XX chromosomes with a translocated SRY gene will develop the physical characteristics of a male. Typically, a piece of the Y chromosome in the pseudoautosomal region exchanges with the tip of the X chromosome. In XX male syndrome, this crossover includes the SRY portion of the Y.

In individuals with XX male syndrome who do not have an SRY gene detectable in their cells, the cause of the condition is not known. Scientists believe that one or more genes that are involved in the development of the sex of an embryo are mutated or altered and cause physical male characteristics in a chromosomally female person. These genes could be located on the X chromosome or on one of the 22 pairs of autosomes that males and females have in common. No genes have been found to explain the female to male sex reversal in people affected with XX male syndrome who are SRY negative. Approximately 20% of XX males do not have a known cause and are SRY negative. It is thought that SRY is a switch point, and the protein that is made by SRY regulates the activity of one or more genes (likely on an autosomal chromosome) that contribute to sex development. Also there have been some studies that demonstrate autosomal recessive and autosomal dominant inheritance for the XX male.

Disorders associated with multiple X or Y chromosome inheritance

DisorderChromosome affectedKarotypeIncidenceSymptoms
Turner syndromeX45, X (monosomy)1 in 2,000Growth retardation Infertility Cardiovascular malformations Learning disabilities
Klinefelter syndromeX47, XXY (trisomy)1 in 500–800Taller than average Poor upper body strenght; clumsiness Mild interntional tremo (20–50%) Breast enlargement (33%) Decreased testosterone production Infertility Dyslexia (50%)
Triple XX47, XXX (trisomy)1 in 1,000Mild delays in motor, linguistic and emotional development Learning disabilities Slightly taller than average
XYY syndromeY47, XYY1 in 1,000Taller than average Lack of coordination Acne Some infertility Learning disabilities (50%) Behavior problems, especially impulse control
XX male syndromeY46, X, t(X,Y) (translocation of the SRY gene [90%] or other gene responsible for male sex determination)1 in 20,000–25,000Usually normal male physical features but may have ambiguous genitalia, hypospadias or undescended testes Infertility Shorter than average

Demographics

XX male syndrome occurs in approximately one in 20,000 to one in 25,000 individuals. The vast majority, about 90%, has SRY detectable in their cells. The remaining 10% are SRY negative, although some research indicates that up to 20% can be SRY negative. XX male syndrome can occur in any ethnic background and usually occurs as a sporadic event, not inherited from the person's mother of father. However, some exceptions of more than one affected family member have been reported.

Signs and symptoms

SRY positive XX male syndrome

Males with SRY positive XX male syndrome look like and identify as males. They have normal male physical features including normal male body, genitals, and testicles. All males with XX male syndrome are infertile (cannot have biological children) because they lack the other genes on the Y chromosome involved sperm production. Men with XX male syndrome are usually shorter than an average male, again because they do not have certain genes on the Y chromosome involved in height. A similar syndrome that effects males with two X chromosomes is Klinefelter syndrome. Those individuals with 46XX present with a condition similar to Klinefelter, such as small testes and abnormally long legs.

SRY negative XX male syndrome

People with SRY negative XX male syndrome are more likely to be born with physical features that suggest a condition. Many have hypospadias, where the opening of the penis is not at the tip, but further down on the shaft. They may also have undescended testicles, where the testicles remain in the body and do not drop into the scrotal sac. Occasionally, an SRY negative affected male has some female structures such as the uterus and fallopian tubes. Men with SRY negative XX male syndrome can also have gynecomastia, or breast development during puberty, and puberty can be delayed. As with SRY positive XX male syndrome, these men are infertile and shorter than average because they lack other Y specific genes. The physical features can vary within a family, but most affected people are raised as males.

A small portion of people with SRY negative XX male syndrome are true hermaphrodites. This means they have both testicular and ovarian tissue in their gonads. They are usually born with ambiguous genitalia, where the genitals of the baby have both male and female characteristics. Individuals with XX male syndrome and true hermaphrodites can occur in the same family, suggesting there is a common genetic cause to both. Research indicates that 15% of 46XX true hermaphrodites have the SRY gene.

Diagnosis

For people with XX male syndrome who have ambiguous genitalia, hypospadias, and/or undescended testicles, the diagnosis is suspected at birth. For males with XX male syndrome and normal male features, the diagnosis can be suspected during puberty when breast development occurs. Many men do not know they have XX male syndrome until they try to have their own children, are unable to do so, and therefore are evaluated for infertility.

When the condition is suspected in a male, chromosome studies can be done on a small sample of tissue such as blood or skin. The results show normal sex chromosomes, or XX chromosomes. Further genetic testing is available and needed to determine if the SRY gene is present.

Some affected individuals have had SRY found in testicular tissue, but not in their blood cells. This is called mosaicism. Most males only have their blood cells tested for SRY and not their testicular tissue. Hence, some men who think they have SRY negative XX male syndrome may actually be mosaic and have SRY in their gonads.

XX male syndrome can be detected before a baby is born. This occurs when a mother-to-be has prenatal testing done that shows female chromosomes but on ultra-sound male genitals are found. Often the mother has had prenatal testing for a reason other than XX male syndrome, such as for an increased risk of having a baby with Down syndrome due to her age. Genetic testing for the presence of the SRY gene can be done by an amniocentesis . An amniocentesis is a procedure in which a needle is inserted through the mother's abdomen into the sac of fluid surrounding the baby. Some of the fluid is removed and used to test for the presence of the SRY gene. Amniocentesis slightly increases the risk of miscarriage.

Treatment and management

For those with XX male syndrome with normal male genitals and testicles, no treatment is necessary. Affected males with hypospadias or undescended testicles may require one or more surgeries to correct the condition. If gynecomastia is severe enough, breast reduction surgery is possible. The rare person with true hermaphrodism usually requires surgery to remove the gonads, as they can become cancerous.

Parents who learn their child has been diagnosed with XX male syndrome are encouraged to gain both emotional and educational support. Issues such as explaining the condition to their child when they are grown is a topic that can be worked through with the help of both medical professionals, and those whose own children live with the condition.

Prognosis

The prognosis for males with XX male syndrome is excellent. Surgery can usually correct any physical problems. Men with XX male syndrome have normal intelligence and a normal life span. However, all affected men will be infertile.

Resources

BOOKS

Wilson, J.D., and J.E. Griffin. "Disorders of Sexual Differentiation." In Harrison's Online. Ed. Eugene Braunwald, et al. New York: McGraw-Hill, 2001.

PERIODICALS

Abramsky, L., et al. "What Parents Are Told After Prenatal Diagnosis of a Sex Chromosome Abnormality: Interview and Questionnaire Study." British Medical Journal 322 (2001): 463-466.

Biesecker, B. "Prenatal Diagnoses of Sex Chromosome Conditions: Parents Need More Than Just Accurate Information." British Medical Journal 322 (2001): 441-2.

Zenteno, Juan, et al. "Two SRY-negative XX Male Brothers Without Genital Ambiguity." Human Genetics 100 (1997): 606-610.

ORGANIZATIONS

Intersex Society of North America. PO Box 301, Petaluma, CA 94953-0301. <http://www.isna.org>.

RESOLVE, The National Infertility Association. 1310 Broadway, Somerville, MA 02144-1779. (617) 623-0744. [email protected]

Carin Lea Beltz, MS, CGC