XX male syndrome, also known as de la Chapelle syndrome, is a rare congenital intersex condition in which an individual with a 46,XX karyotype (otherwise associated with females) has phenotypically male characteristics that can vary among cases. Synonyms include 46,XX testicular difference of sex development (46,XX DSD), 46,XX sex reversal, nonsyndromic 46,XX testicular DSD, and XX sex reversal.
In 90 percent of these individuals, the syndrome is caused by the Y chromosome's SRY gene, which triggers male reproductive development, being atypically included in the crossing over of genetic information that takes place between the pseudoautosomal regions of the X and Y chromosomes during meiosis in the father. When the X with the SRY gene combines with a normal X from the mother during fertilization, the result is an XX male. Less common are SRY-negative XX males, which can be caused by a mutation in an autosomal or X chromosomal gene. The masculinization of XX males is variable.
This syndrome is diagnosed through various detection methods and occurs in approximately 1:20,000 newborn males, making it much less common than Klinefelter syndrome. Treatment is medically unnecessary, although some individuals choose to undergo treatments to make them appear more male or female. The alternative name for XX male syndrome refers to Finnish scientist Albert de la Chapelle, who studied the condition and its etiology.
Signs and symptoms
The appearance of XX males can fall into one of three categories: 1) males that have normal internal and external genitalia, 2) males with external ambiguities, and 3) males that have both internal and external genital ambiguities. External genital ambiguities can include hypospadias, micropenis, and clitoromegaly. Typically, the appearance of XX males differs from that of an XY male in that they are smaller in height and weight. Most XX males have small testes, and have an increase in maldescended testicles compared to XY males. All are believed to be sterile; however, there is a possibility some could be fertile. Some XX male individuals have decreased amounts of body hair and decreased libido. Individuals with this condition sometimes have feminine characteristics, with varying degrees of gynecomastia but with no intra-abdominal Müllerian tissue. According to research at the University of Oklahoma health science centers, despite XX males exhibiting feminine characteristics, their behaviours are usually representative of masculinity in their culture.
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 are likely to have a male gender identity.
Masculinization
The degree to which individuals with XX male syndrome develop the male phenotype is variable, even among SRY-positive individuals. A completely male phenotype usually develops in the presence of the SRY gene but, in some cases, the presence of the SRY gene can result in internal and/or external genitalia ambiguities. Normal XX females undergo X inactivation during which one copy of the X chromosome is silenced. It is thought that X inactivation in XX males may account for the genital ambiguities and incomplete masculinization seen in SRY-positive XX males. The X chromosome with the SRY gene is preferentially chosen to be the active X chromosome 90% of the time, which explains complete male phenotype being observed often in SRY-positive XX males. In the remaining 10%, X inactivation spreads to include a portion of the SRY gene, resulting in incomplete masculinization.
Masculinization of SRY-negative XX males is dependent upon which genes have mutations and at what point in development these mutations occur.
Genetics
Males typically have one X chromosome and one Y chromosome in each diploid cell of their bodies. Females typically have two X chromosomes. XX males that are SRY-positive have two X chromosomes, with one of them containing genetic material (the SRY gene) from the Y chromosome; this gene causes them to develop a male phenotype despite having chromosomes more typical of females. Some XX males, however, do not have the SRY gene (SRY-negative) and the male phenotype may be caused by another gene on one of the autosomes.