XX male Syndrome

Overview

XX Male Syndrome, also known as de la Chapelle Syndrome, is a rare genetic condition where an individual has a typical male phenotype (external male characteristics) but possesses two X chromosomes instead of the usual XY configuration. Despite having no Y chromosome, individuals with XX Male Syndrome often develop as males due to the presence of the SRY gene, which triggers male sex development. This condition affects approximately 1 in 20,000 to 25,000 newborn males.

Causes

XX Male Syndrome is primarily caused by the abnormal presence of the SRY (Sex-determining Region Y) gene on one of the X chromosomes. This usually occurs due to an error during paternal meiosis when the SRY gene, normally found on the Y chromosome, is translocated to the X chromosome. As a result, although the individual has two X chromosomes, the presence of SRY leads to the development of testes and male physical traits.

There are two main types:

• SRY-positive XX males: Carry the SRY gene and typically appear male with normal external genitalia.

• SRY-negative XX males: Do not carry the SRY gene and usually present with ambiguous genitalia or varying degrees of undervirilization.

Symptoms

Symptoms can vary depending on whether the individual is SRY-positive or SRY-negative. Common features include:

• Normal male external genitalia (in most SRY-positive cases)

• Small testes and reduced testicular function

• Gynecomastia (breast tissue development in adolescence)

• Infertility due to azoospermia (absence of sperm in semen)

• Shorter stature than average males

• Possible hypospadias or undescended testes in SRY-negative individuals

• Delayed puberty or low testosterone levels

In some cases, genital ambiguity or sexual development disorders may be noted at birth, especially in SRY-negative individuals.

Diagnosis

Diagnosis of XX Male Syndrome typically involves a combination of clinical evaluation, hormonal testing, and genetic analysis:

• Physical examination: To assess genitalia, secondary sexual characteristics, and testicular size

• Hormonal tests: May show elevated gonadotropins (FSH, LH) and low testosterone

• Karyotyping: Reveals a 46,XX chromosomal pattern

• SRY gene analysis: Determines whether the SRY gene is present or absent

• Semen analysis: Usually shows azoospermia, confirming infertility

Genetic counseling is often recommended to help individuals and families understand the condition.

Treatment

There is no cure for XX Male Syndrome, but management focuses on addressing specific symptoms and improving quality of life. Treatment options include:

• Hormone therapy: Testosterone replacement therapy may be given to support puberty and maintain male secondary sexual characteristics

• Surgical correction: If ambiguous genitalia are present, surgery may be considered to improve function and appearance

• Psychological support: Counseling can help address identity, emotional, and social concerns, especially during adolescence

• Fertility counseling: Most individuals are infertile, but options like sperm donation or adoption can be discussed

Prognosis

The long-term outlook for individuals with XX Male Syndrome is generally good, especially in SRY-positive individuals with typical male appearance. With proper hormonal and psychological support, most can lead normal lives. However, infertility and the psychosocial impact of a genetic diagnosis may present challenges. Early diagnosis, multidisciplinary care, and ongoing support are crucial for optimal outcomes.