The XX male syndrome, also known as 46,XX testicular disorder of sex development (DSD), is a rare genetic condition where an individual with the typical female chromosomal pattern (46,XX karyotype) develops a male physical appearance (phenotype). Normally, XX chromosomes result in female development, but this condition is an exception. It is considered a DSD because it involves an incongruence between chromosomal sex and gonadal or genital development. It is estimated to affect approximately one in 20,000 newborn boys.
The Genetic Basis of XX Maleness
The most common cause of the XX male syndrome is a genetic accident involving the transfer of material from the Y chromosome. In typical male development, the Sex-determining Region Y (SRY) gene initiates the cascade leading to the formation of testes. This gene acts as the master switch for male sex development. In 80 to 90 percent of XX males, the condition results from an abnormal exchange of genetic material between the sex chromosomes.
This exchange, known as translocation, occurs randomly during the formation of sperm cells in the father. A small segment of the Y chromosome, including the SRY gene, is incorrectly transferred onto one of the X chromosomes. If a sperm carrying this SRY-positive X chromosome fertilizes an egg, the resulting embryo has a 46,XX karyotype, but one X chromosome possesses the SRY gene. This misplaced SRY gene is sufficient to trigger the male developmental pathway, leading to the formation of testes.
A smaller group, about 10 to 20 percent of cases, have the SRY-negative XX male syndrome. Scientists hypothesize that a mutation in another gene acts downstream of SRY in the sex determination pathway. This mutation may cause a gene normally repressed in females to become inappropriately activated, mimicking the effect of the SRY gene and leading to male development.
Physical Characteristics and Development
Individuals with the XX male syndrome develop a male physical appearance, but the degree of masculinization varies. They typically have small testes (testicular hypoplasia), which often leads to diagnosis later in life. The testes usually produce androgens, but not enough to support complete male characteristics or reproductive function. Since the SRY gene initiates male development, internal female reproductive organs, such as the uterus and fallopian tubes, are typically absent in the SRY-positive form.
The expression of male secondary sex characteristics is often incomplete, particularly after puberty. Diagnosis frequently occurs when individuals seek medical attention for breast development (gynecomastia), which results from a sex hormone imbalance. Other common features include reduced facial and body hair compared to typical males. While most SRY-positive individuals have male external genitalia, some may present with ambiguous features, such as the urethra opening on the underside of the penis (hypospadias).
The most significant reproductive implication is primary infertility. All reported cases of XX male syndrome result in azoospermia, the complete absence of sperm in the ejaculate. The testes cannot support spermatogenesis due to the lack of a full complement of Y-chromosome genes necessary for complete testicular function. Consequently, individuals with this condition are unable to conceive children naturally.
Diagnosis and Clinical Management
The diagnostic process begins with a physical examination and medical history, often prompted by delayed puberty, gynecomastia, or infertility investigation. Definitive diagnosis relies on karyotyping, a cytogenetic study that analyzes the chromosomes in a patient’s cells. Karyotyping confirms the 46,XX chromosomal pattern, the hallmark of this condition.
Specific genetic testing is then performed to determine the presence of the SRY gene. Techniques such as Polymerase Chain Reaction (PCR) or Fluorescence In Situ Hybridization (FISH) detect the location and presence of the SRY gene or other Y-chromosome sequences. Endocrine testing measures hormone levels, typically revealing hypergonadotropic hypogonadism: low testosterone and elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This profile indicates primary testicular failure.
Clinical management focuses on addressing hormonal deficiencies and providing supportive care. Testosterone replacement therapy is the standard treatment, administered to promote male secondary sex characteristics, preserve bone density, and address symptoms like low libido or fatigue. Due to universal infertility, testicular sperm extraction is not a viable option. Patients are offered counseling and psychological support to navigate the diagnosis and implications of sterility. Fertility options include adoption or in vitro fertilization with a sperm donor.