XX Male syndrome

XX male syndrome, also referred to as de la Chapelle syndrome or 46,XX testicular disorder of sex development (46,XX DSD), is a rare condition where an individual with a 46,XX karyotype develops a male phenotype.

In 90% of these cases, the syndrome results from the Y chromosome's SRY gene, which initiates male reproductive development, being unusually incorporated during the crossing over of genetic material that occurs between the pseudoautosomal regions of the X and Y chromosomes during meiosis in the father. When the X chromosome carrying the SRY gene merges with a normal X from the mother during fertilization, it leads to testicular differentiation of the gonads. Less frequently, SRY-negative individuals, who generally have a typical female karyotype, may experience this condition due to a mutation in an autosomal or X chromosomal gene.

The degree of masculinization in affected individuals varies, and they are infertile. This syndrome is identified in about 1 in 20,000 newborn boys, making it much rarer than Klinefelter syndrome. Medical treatment varies, though it is often unnecessary. The clinical term "de la Chapelle syndrome" honors Finnish scientist Albert de la Chapelle, who first described it.

Signs and symptoms

Although variability exists, most individuals diagnosed with de la Chapelle Syndrome exhibit a typical male phenotype, with male-typical external genitalia, making early diagnosis rare. Genital ambiguity is more frequent in those lacking the SRY gene or other Y chromosome-derived genes, though reported rates vary. Such ambiguities may include hypospadias, micropenis, and cryptorchidism.

In most SRY-positive men, significant signs are few before puberty, although small testes are almost universally observed; post-puberty, gynecomastia often develops. XX males tend to be shorter on average than XY males.

Based on limited evidence, most have typical body and pubic hair, penis size, libido, and erectile function. All reported cases show sterility, with azoospermia (absence of sperm in the ejaculate). Due to its subtle presentation, many are diagnosed late when seeking infertility treatment in adulthood; it's probable that many cases remain undiagnosed.

Masculinization

The extent to which individuals with XX male syndrome develop a male phenotype varies, even among SRY-positive individuals.

Masculinization in SRY-positive XX males is believed to depend on which X chromosome is inactivated. Typical XX females undergo X inactivation, where one X chromosome is silenced. It is thought that X inactivation in XX males may explain the genital ambiguities and incomplete masculinization seen in SRY-positive XX males. The X chromosome with the SRY gene is preferentially active 90% of the time, explaining the complete male phenotype often observed in SRY-positive cases. In the remaining 10%, the X chromosome with the SRY gene is inactivated, leading to incomplete masculinization.

Masculinization in SRY-negative individuals depends on which genes have mutations and when these mutations occur during development.

Genetics

Males typically possess one X and one Y chromosome in each diploid cell, while females usually have two X chromosomes. SRY-positive XX males have two X chromosomes, with one carrying genetic material (the SRY gene) from the Y chromosome, causing them to develop a male phenotype despite having chromosomes more typical of females. Some 46,XX individuals lack the SRY gene (SRY-negative); the reason for their male phenotype is not well understood and remains under research.

SRY-positive

The SRY gene, typically found on the Y chromosome, is crucial in sex determination by initiating testicular development. In about 80% of XX males, the SRY gene is present on one of the X chromosomes.

The condition arises from an abnormal genetic material exchange between chromosomes (translocation). This exchange happens randomly during sperm cell formation in the affected person's father. The Y chromosome's tip contains the SRY gene, and during recombination, a translocation occurs where the SRY gene becomes part of the X chromosome. If a fetus is conceived from a sperm cell with an X chromosome carrying the SRY gene, it develops as a male despite lacking the full Y chromosome. This form is known as SRY-positive 46,XX testicular disorder of sex development.

SRY-negative

About 20% of those with 46 XX testicular disorder of sex development lack the SRY gene. This form is termed SRY-negative 46,XX testicular disorder of sex development. The disorder's cause in these individuals is often unknown, though changes affecting other genes have been identified. SRY-negative individuals are more likely to have ambiguous genitalia than those with the SRY-positive form.

The exact cause remains unknown, but three theories exist: first, undetected gonadal mosaicism for SRY; second, de-repression of male development due to mutations in non-Y chromosome genes; third, altered expression of other genes downstream of SRY, leading to masculinization. For instance, mutations in the SOX9 gene may contribute, as SOX9 is involved in testes differentiation. Another proposed cause is mutations to the DAX1 gene, which may suppress masculinization; if there is a loss of function of DAX1, testes can develop in an XX individual. Mutations in SF1 and WNT4 genes have also been studied as potential causes.

Diagnosis

No consensus exists on diagnostic criteria; diagnosis typically involves evaluating physical development alongside karyotyping and the presence of the SRY gene or related genes, such as SOX9. Hormone level tests and azoospermia assessments may also be conducted.

Most individuals with de la Chapelle Syndrome have a typical male phenotype at birth, so diagnosis usually occurs at puberty onset, if traits like gynecomastia are investigated, or later, when infertility is explored. Diagnosis at birth is more common in SRY-negative individuals, who are more likely to have ambiguous genitalia.

When evaluating ambiguous genitalia, such as a small phallus, hypospadias, or labioscrotal folds, exploratory surgery may determine the presence of male and/or female internal genitalia. Indicators include two testes that haven't descended the inguinal canal, though this is seen in a minority of XX males, and the absence of Müllerian tissue. External indicators include decreased body weight, gynecomastia, and small testes.

A standard karyotype can be performed to cytogenetically confirm that an individual with a partial or complete male phenotype has an XX genotype. The presence and location of the SRY gene can be determined using fluorescence in situ hybridization (FISH).

Treatment

Treatment generally focuses on affirming the gender presentation of affected men, varies significantly based on the individual's phenotype, and may include counseling. In some XX males, testosterone therapy may enhance virilization. While most XX males have typical male external genital development, cases of genital ambiguity may be addressed with hormonal therapy, surgery, or both. Gonadal surgery may be performed to remove partial or whole female genitalia, followed by plastic and reconstructive surgery to create a more externally male appearance. Conversely, the individual may prefer a more feminine appearance, and feminizing genitoplasty can make the ambiguous genitalia appear more female.

There is no treatment for infertility in XX males – supportive management and options like sperm donation or adoption are advised.

Epidemiology

It is estimated that 1 in every 20,000 to 30,000 males has a 46,XX karyotype, making it much rarer than other related syndromes, such as Klinefelter syndrome.