What are the implications of mixed gonadal dysgenesis with 88% Y (Y chromosome) and 12% X (X chromosome) mosaicism?

From the Guidelines

Mixed gonadal dysgenesis with a 88% Y and 12% X chromosomal mosaic pattern is a high-risk condition for gonadoblastoma, and prophylactic gonadectomy is recommended, typically before puberty, to prevent the development of this tumor. Management of this condition requires a multidisciplinary approach involving pediatric endocrinologists, urologists, geneticists, and mental health professionals. The high percentage of Y chromosome material (88%) increases the risk of gonadoblastoma, as seen in WT1-related syndromes, such as Denys-Drash Syndrome (DDS) and Frasier Syndrome (FS), where the risk of gonadoblastoma is estimated to be greater than 40% 1.

Key considerations in the management of mixed gonadal dysgenesis include:

• Hormone replacement therapy, with estrogen or testosterone, depending on the gender of rearing and the individual's gender identity
• Surgical reconstruction of external genitalia, which may be considered based on the degree of ambiguity, though many experts now recommend deferring irreversible procedures until the individual can participate in decision-making
• Psychological support, which is essential throughout development
• Regular follow-up with endocrinology, to monitor hormone therapy and overall health

The condition results from mitotic errors during early embryonic development, leading to chromosomal mosaicism that affects gonadal differentiation and subsequent sexual development. Karyotype testing, as recommended for males with primary infertility and azoospermia or sperm concentration <5 million sperm/mL, when accompanied by elevated FSH, testicular atrophy, or a diagnosis of impaired sperm production, can help identify chromosomal abnormalities, such as Y-chromosome microdeletions, which are found in 5% of males with sperm concentrations 0 to 1 million 1.

In the context of mixed gonadal dysgenesis, the risk of gonadoblastoma and other tumors, such as Wilms tumor, must be carefully considered, and management should be guided by the most recent and highest quality evidence, including guidelines for the management of disorders of sex development and tumor screening recommendations for individuals with WT1-related syndromes 1.

From the Research

Mixed Gonadal Dysgenesis

• Mixed gonadal dysgenesis (MGD) is a disorder of sex development caused by mosaicism of the Y chromosome, represented by 45,X/46,XY 2.
• The condition presents with a range of phenotypes, including short stature, virilization, and delayed puberty 3.
• MGD is associated with a high risk of malignancy, particularly gonadoblastoma, and prophylactic gonadectomy is often recommended 2, 4.

Clinical Characteristics

• Patients with MGD may exhibit a range of clinical features, including:
  • Short stature 3
  • Virilization 3
  • Delayed puberty 3
  • Autoimmune thyroid disease 3
  • Ambiguous external genitalia 5
  • Internal genitalia abnormalities, such as a hypoplastic vagina and uterus 5

Management

• Management of MGD is multi-disciplinary and may include:
  • Gonadectomy 2, 4
  • Hormone replacement therapy 2, 3
  • Genital reconstruction surgeries 3
  • Close surveillance for malignancy 4, 6
• Growth hormone therapy may be considered for patients with short stature, but gonadectomy or biopsy of underlying dysgenetic gonads is essential prior to therapy 6.

Chromosomal Aberrations

• MGD is characterized by 45,X/46,XY mosaicism, with a predominance of 45,X cells in both peripheral lymphocytes and gonads 4.
• The presence of a Y chromosome increases the risk of malignant transformation 4.
• Chromosomal aberrations are present in 2-7% of adult pairs with fertility disorders and in 0.6% of newborns 4.