Abstract

XX male syndrome is a rare congenital condition where an individual with a female genotype has phenotypically male characteristics that can vary between cases. In 90% of these individuals the syndrome is caused by unequal crossing over between X and Y chromosomes during meiosis in the father, and results in the X chromosome containing the SRY gene, as opposed to the Y chromosome where it is normally found. 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 less common than Klinefelter syndrome. Treatment is medically unnecessary, although some individuals choose to undergo treatments to make them appear more male or female. It is also called de la Chapelle syndrome, for Albert de la Chapelle, who characterized it in 1972.

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 (true hermaphrodites). External genital ambiguities can include hypospadias, micropenis, and clitoromegaly. On average, 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, are sterile, and have an increase in maldescended testicles compared to XY males. 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.

Signs and symptoms | 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 is why a complete male phenotype is often seen 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 from the Y chromosome, making them phenotypically male but genetically female.

Genetics | SRY-positive

The SRY gene plays an important role in sex determination by initiating testicular development. In most XX males the SRY gene is present. The tip of the Y chromosome contains the SRY gene and, during recombination, a translocation occurs in which the SRY gene on the Y chromosome is moved to become part of an X chromosome. The presence of the translocated SRY gene leads to an XX embryo developing male characteristics.

Genetics | SRY-negative

In rare cases, an XX male does not have the SRY gene. The exact cause of this condition is unknown but it has been proposed that mutations in the SOX9 gene may contribute to this syndrome since SOX9 plays a role in testes differentiation during development. Another proposed cause is mutations to the DAX1 gene which encodes a nuclear hormone receptor. DAX1 represses masculinizing genes, therefore, if there is a loss of function of DAX1 then testes can develop in an XX individual. Mutations in SF1 and WNT4 genes are also being studied in connection with SRY-negative XX male syndrome.

Diagnosis

In cases where the individual is being evaluated for ambiguous genitalia, such as a small phallus, hypospadias, or labioscrotal folds, exploratory surgery may be used to determine if male and/or female internal genitalia is present.

A standard karyotype can be completed to cytogenetically determine that an individual with a partial or complete male phenotype has a XX genotype.

FISH analysis determines the presence or absence of the SRY gene.

Localization of the SRY gene can by determined using fluorescent "in situ" hybridization.

Indicators include two testes which have not descended the inguinal canal, although this is seen in a minority of XX males, and the absence of Müllerian tissue.

Treatment

XX males are sterile due to low or no sperm content and there is currently no treatment to address this infertility. Genital ambiguities, while not necessary to treat for medical reasons, can be treated through the use of hormonal therapy, surgery, or both. Since XX male syndrome is variable in its presentation, the specifics of treatment varies widely as well. In some cases gonadal surgery can be performed to remove partial or whole female genitalia. This may be followed by plastic and reconstructive surgery to make the individual appear more externally male. Conversely, the individual may wish to become more feminine and feminizing genitoplasty can be performed to make the ambiguous genitalia appear more female. Hormonal therapy may also aid in making an individual appear more male or female.