Clinical Features of Gonadal Dysgenesis
Gonadal dysgenesis presents with a wide clinical spectrum ranging from phenotypically normal females with Turner-like features to individuals with ambiguous genitalia to undervirilized or normal-appearing males, depending on the karyotype and degree of gonadal dysfunction. 1, 2
Phenotypic Presentation by Karyotype
45,X/46,XY Gonadal Dysgenesis (Mixed Gonadal Dysgenesis)
External Genitalia and Sexual Development:
- Significant phenotypic heterogeneity ranging from typical female external genitalia to ambiguous genitalia to normal-appearing males 1, 3
- Virilization is the most common presenting manifestation (80% of cases) 4
- Undervirilization in males with hypospadias, micropenis, or cryptorchidism 1
- Asymmetric gonadal development: typically one streak gonad and one dysgenetic testis at varying levels of descent 3
Internal Reproductive Structures:
- Persistent Müllerian structures are typical, including hemi-uterus 3
- Variable presence of fallopian tubes and uterine structures 3
Growth and Stature:
Pubertal Development:
WT1-Related Gonadal Dysgenesis Syndromes
Denys-Drash Syndrome (DDS):
- Ambiguous genitalia/gonadal dysgenesis specifically in 46,XY individuals 5
- Nephrotic syndrome due to mesangial sclerosis 5
- Greater than 90% risk of Wilms tumor 5
- Caused by missense mutations in exon 8 or 9 of WT1 5
Frasier Syndrome (FS):
- Ambiguous genitalia/gonadal dysgenesis in 46,XY individuals with dysgenetic gonads 5
- Focal segmental glomerulosclerosis (FSGS) rather than mesangial sclerosis 5
- Greater than 40% risk of gonadoblastoma 5
- Caused by mutations in the WT1 intron 9 donor splice site 5
WAGR Syndrome:
- Genitourinary abnormalities as part of the constellation with Wilms tumor, aniridia, and intellectual disability 5
- Approximately 50% risk of Wilms tumor 5
- Significant risk of nephropathy 5
Critical Malignancy Risk Features
Gonadoblastoma Risk:
- In 46,XY individuals with gonadal dysgenesis (FS or DDS), the risk of gonadoblastoma exceeds 40% 5
- Although most gonadoblastomas develop in adolescents or young adults, occurrences in infants have been described 5
- Risk is directly related to the presence of gonadal dysgenesis in the context of Y-chromosome material 5, 2, 6
- Risk is low when the phenotypic sex matches the karyotype 5
General Malignancy Considerations:
- Presence of Y chromosome or Y-chromosome material renders patients at increased risk for gonadal malignancy 2, 6
- Y-specific sequences may not be cytogenetically evident but can be detected by molecular techniques 6
Associated Systemic Features
Endocrine Abnormalities:
- Hypoparathyroidism with hypocalcemia in WT1-related syndromes 5
- Autoimmune thyroid disease (40% in 45,X/46,XY cases) 4
Renal Manifestations:
Cardiac Abnormalities:
- Congenital cardiac defects, particularly conotruncal malformations in 22q11.2 deletion syndrome 7
Key Clinical Pitfalls
Delayed Diagnosis:
- Delayed presentation is less common now but poses significant clinical challenges when it occurs 4
- Early counseling and gender assignment by a panel of specialists is crucial 4
Misdiagnosis Risk:
- 45,X/46,XY subjects may present clinically like Turner syndrome, potentially delaying appropriate evaluation for gonadal malignancy risk 4
- Mixed gonadal dysgenesis is often confused with other conditions due to significant phenotypic heterogeneity 3
Evaluation Requirements:
- Evaluation for gonadal dysgenesis is indicated in all patients with 46,XY karyotype, and if present, gonadectomy is generally recommended 5
- Initial evaluation should include hormonal assessment and imaging 5
- Molecular testing for Y-sequences is essential even when not cytogenetically evident to guide prophylactic gonadectomy decisions 6