XY gonadal dysgenesis

Overview

XY gonadal dysgenesis is a rare disorder of sex development (DSD) where individuals with a typically male (46,XY) karyotype fail to develop functional testes. As a result, the gonads are non-functional “streak gonads” and do not produce the hormones necessary for typical male sexual development. Affected individuals may appear female or have ambiguous genitalia at birth, and the condition is often discovered during evaluation for delayed puberty or amenorrhea. XY gonadal dysgenesis is also referred to as Swyer syndrome when the external genitalia are typically female.

Causes

XY gonadal dysgenesis can be caused by mutations or deletions in genes critical for testis development, including:

• SRY: The sex-determining region on the Y chromosome, responsible for initiating male development. Mutations or deletions here are a common cause.

• NR5A1, DHH, MAP3K1, SOX9, and others: These genes regulate downstream pathways involved in gonadal differentiation.

The condition may be inherited or occur sporadically. In many cases, the cause remains unknown even after genetic testing.

Symptoms

Symptoms and physical findings vary depending on the degree of gonadal and genital development but may include:

• Typical female external genitalia: Most individuals with complete gonadal dysgenesis have a female phenotype at birth

• Streak gonads: Non-functional fibrous tissue instead of ovaries or testes

• Primary amenorrhea: Absence of menstruation due to lack of functional ovaries

• Delayed or absent puberty: Due to insufficient sex hormone production

• Tall stature: May occur due to lack of estrogen-mediated closure of growth plates

• Risk of gonadal tumors: Particularly gonadoblastoma or dysgerminoma in the streak gonads

Partial forms of XY gonadal dysgenesis may result in ambiguous genitalia or mixed male and female traits at birth.

Diagnosis

Diagnosis is often made in adolescence when puberty fails to occur, or earlier if genital ambiguity is noted at birth. Diagnostic steps include:

• Karyotype analysis: Reveals a 46,XY chromosomal pattern

• Hormonal studies: Show low levels of testosterone and estrogen with high gonadotropins (FSH, LH)

• Pelvic ultrasound or MRI: To evaluate internal reproductive structures

• Genetic testing: To identify mutations in genes involved in sex differentiation (e.g., SRY, SOX9)

• Gonadal biopsy: May be performed to assess tumor risk or confirm streak gonads

Treatment

Treatment focuses on hormone replacement and reducing cancer risk. Standard interventions include:

• Gonadectomy (surgical removal of gonads): Due to the high risk of malignant transformation in streak gonads

• Hormone replacement therapy (HRT): Estrogen and progesterone for puberty induction and maintenance of secondary female sexual characteristics

• Psychological support and counseling: To assist with gender identity, fertility, and emotional well-being

• Fertility counseling: Individuals are infertile, but options like assisted reproduction or adoption can be discussed

A multidisciplinary team - endocrinologist, gynecologist, geneticist, and psychologist - is essential for comprehensive care.

Prognosis

With early diagnosis and proper management, individuals with XY gonadal dysgenesis can lead healthy, fulfilling lives. Hormone therapy allows for the development of normal secondary sexual characteristics and maintenance of bone health. Lifelong follow-up is necessary to manage hormone levels and monitor for long-term health risks. With appropriate counseling and support, psychosocial outcomes are generally positive.