46,XX testicular difference of sex development

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

46,XX testicular difference of sex development is a condition in which individuals with two X chromosomes in each cell, the pattern typically found in females, have a male appearance. People with this condition have male external genitalia. They generally have small testes and may also have other features 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.

At puberty, most affected individuals require treatment with the male sex hormone testosterone to induce development of male secondary sex characteristics such as facial hair and deepening of the voice (masculinization). Hormone treatment can also help prevent breast enlargement (gynecomastia). Adults with this condition are usually shorter than average for males and are unable to have children (infertile).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

People normally have 46 chromosomes in each cell. Two of the 46 chromosomes, known as X and Y, are called sex chromosomes because they help determine whether a person will develop male-typical or female-typical sex characteristics. Females usually have two X chromosomes (46,XX), and males usually have one X chromosome and one Y chromosome (46,XY).

The SRY gene, normally located on the Y chromosome, provides instructions for making the sex-determining region Y protein. The sex-determining region Y protein causes a fetus to develop as a male.

In about 80 percent of individuals with 46,XX testicular difference of sex development, the condition results from an abnormal exchange of genetic material between chromosomes (translocation). This exchange occurs as a random event during the formation of sperm cells in the affected person's father. The translocation causes the SRY gene to be misplaced, almost always onto an X chromosome. If a fetus is conceived from a sperm cell with an X chromosome bearing the SRY gene, it will develop as a male despite not having a Y chromosome. This form of the condition is called SRY-positive 46,XX testicular difference of sex development.

About 20 percent of people with 46,XX testicular difference of sex development do not have the SRY gene. This form of the condition is called SRY-negative 46,XX testicular difference of sex development. The cause of the condition in these individuals is often unknown, although changes affecting other genes involved in the development of sex characteristics have been identified in a small number of people with the condition. Individuals with SRY-negative 46,XX testicular difference of sex development are more likely to have genitalia that do not clearly look male or female than are people with the SRY-positive form.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

SRY-positive 46,XX testicular difference of sex development is almost never inherited. This condition results from the translocation of a Y chromosome segment containing the SRY gene during the formation of sperm (spermatogenesis). Affected people typically have no history of the condition in their family and cannot pass on the condition because they are infertile.

In rare cases, the SRY gene may be misplaced onto a chromosome other than the X chromosome. This translocation may be carried by an unaffected father and passed on to a child with two X chromosomes, resulting in 46,XX testicular difference of sex development. In another very rare situation, a male may carry the SRY gene on both the X and Y chromosome; a child who inherits his X chromosome will develop male sex characteristics despite having no Y chromosome.

The inheritance pattern of SRY-negative 46,XX testicular difference of sex development is variable. In affected people with a known genetic cause, the condition often follows an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the condition. In some cases, the genetic variant (also known as a mutation) is inherited from an unaffected parent. Usually, the variant is inherited from an unaffected father. Sometimes, the variant is inherited from an unaffected mother. When some people with the variant do not develop features of the condition, it is said to have reduced (or incomplete) penetrance.

Other cases of SRY-negative 46,XX testicular difference of sex development result from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the condition in their family.

The inheritance pattern of SRY-negative 46,XX testicular difference of sex development without an identified genetic cause is unknown. A few families with unaffected parents have had more than one child with the condition, suggesting the possibility of autosomal recessive inheritance. Autosomal recessive means both copies of a gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Approximately 1 in 20,000 individuals with a male appearance have 46,XX testicular difference of sex development.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Ambiguous genitalia · Very frequent (99-80%)

A genital phenotype that is not clearly assignable to a single gender. Ambiguous genitalia can be evaluated using the Prader scale: Prader 0: Normal female external genitalia. Prader 1: Female external genitalia with clitoromegaly. Prader 2: Clitoromegaly with partial labial fusion forming a funnel-shaped urogenital sinus. Prader 3: Increased phallic enlargement. Complete labioscrotal fusion forming a urogenital sinus with a single opening. Prader 4: Complete scrotal fusion with urogenital opening at the base or on the shaft of the phallus. Prader 5: Normal male external genitalia. The diagnosis of ambiguous genitalia is made for Prader 1-4.

Decreased testicular size · Very frequent (99-80%)

Reduced volume of the testicle (the male gonad).

Male hypogonadism · Very frequent (99-80%)

Decreased functionality of the male gonad, i.e., of the testis, with reduced spermatogenesis or testosterone synthesis.

Polycystic ovaries · Very frequent (99-80%)

Which doctor should you see?

The suggested department for discussing 46,XX testicular difference of sex development is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.