How to investigate gonad issues in a patient with Turner syndrome and 45,X/46,XY mosaicism?

Investigation of Gonadal Issues in Turner Syndrome with 45,X/46,XY Mosaicism

Immediate Gonadectomy Indication

In any patient with Turner syndrome and Y chromosome material (including 45,X/46,XY mosaicism), bilateral gonadectomy is indicated due to the >40% risk of gonadoblastoma, regardless of gonadal location or phenotype. 1

The presence of Y chromosomal material in Turner syndrome creates an exceptionally high malignancy risk that supersedes other considerations. This risk exceeds 40% for gonadoblastoma development and can progress to invasive germ cell tumors. 1, 2, 3

Pre-Surgical Diagnostic Workup

Hormonal Assessment

Perform comprehensive endocrine evaluation to determine gonadal function and guide surgical planning:

• Müllerian inhibiting substance (MIS/AMH): Indicates presence of functional Sertoli cells and testicular tissue 4
• Testosterone (baseline and post-hCG stimulation): Assesses Leydig cell function 4
• FSH and LH: Elevated levels suggest gonadal failure or absence 4
• Inhibin B: Marker of Sertoli cell function; undetectable with absent testicular tissue 4

If MIS and inhibin B are undetectable with elevated FSH/LH, this suggests anorchia or complete gonadal dysgenesis. 4 However, in 45,X/46,XY mosaicism, variable gonadal tissue is typically present requiring surgical exploration regardless of hormone levels. 3

Imaging Studies

Do NOT perform ultrasound for gonadal localization, as it has only 45% sensitivity and 78% specificity for nonpalpable testes and cannot reliably confirm gonadal absence. 4

Instead, proceed directly to:

• Pelvic MRI: Superior soft-tissue contrast for identifying gonadal tissue, müllerian structures, and anatomic variants without radiation exposure 4
• Physical examination by experienced provider: Determines if gonads are palpable (occurs in >70% of cases) versus nonpalpable 4

Karyotype Confirmation in Multiple Tissues

The distribution of 45,X versus 46,XY cells varies dramatically between tissue types:

• Peripheral blood lymphocytes: May show up to 90% Y-containing cells 5
• Gonadal tissue: Typically shows 11-31% Y-containing cells 5
• Skin fibroblasts: May show as low as 4% Y-containing cells 5

This tissue-specific mosaicism means peripheral blood karyotype alone underestimates gonadal Y chromosome exposure. 5 Gonadal tissue karyotyping at the time of surgery provides definitive assessment. 5, 3

Surgical Exploration and Gonadectomy

Timing

Perform gonadectomy promptly after diagnosis, ideally before puberty, given the >40% gonadoblastoma risk. 1 The median age for gonadectomy in published series is 9.5 months. 3

Surgical Approach

• Diagnostic laparoscopy: Gold standard for identifying and removing nonpalpable gonads 4
• Open exploration: Alternative when laparoscopy unavailable or anatomy complex 4
• Bilateral procedure: Remove both gonads regardless of appearance, as both carry malignancy risk 3

Expected Gonadal Histology

In 45,X/46,XY mosaicism with genital anomalies, gonadal histology is highly variable: 3

• Palpable gonads: 28% histologically normal testes, 11% streak gonads, 6% dysgenetic gonads with mixed testicular/ovarian stroma 3
• Intra-abdominal gonads: Predominantly dysgenetic testes or streak gonads, with 7% showing pre-malignant changes 3
• Mixed gonadal dysgenesis: Combination of testicular tissue and ovarian stroma is common 5, 2

Pathology Evaluation

Submit all gonadal tissue for:

• Histopathologic examination: Identify gonadoblastoma, dysgerminoma, or other germ cell tumors 2
• Immunohistochemistry: OCT3/4, PLAP, and c-KIT for germ cell neoplasia 1
• Karyotype analysis: Confirm Y chromosome presence in gonadal tissue 5

Associated Syndrome Screening

Screen for conditions associated with gonadal dysgenesis and Y chromosome abnormalities:

• Renal ultrasound: Evaluate for structural abnormalities (WAGR syndrome has 50% Wilms tumor risk) 1
• Cardiac evaluation: Already mandated by Turner syndrome diagnosis, but particularly important given 48% prevalence of associated anomalies in 45,X/46,XY patients 3
• Ophthalmologic examination: Screen for aniridia (WAGR syndrome) 1
• Serum calcium and PTH: Evaluate for hypoparathyroidism in WT1-related syndromes 1

Post-Gonadectomy Management

Hormone Replacement Therapy

Initiate age-appropriate sex hormone replacement after gonadectomy:

• Estrogen therapy: Begin at typical pubertal age (11-12 years) with gradual dose escalation 3
• Progesterone: Add after 2 years of estrogen or breakthrough bleeding 3

Surveillance for Residual/Recurrent Disease

• Tumor markers: AFP and β-hCG every 3-6 months for 2 years post-gonadectomy if germ cell tumor identified 1
• Pelvic MRI: At 6 months and 1 year post-operatively to ensure complete gonadal removal 4

Fertility Counseling

Spontaneous fertility is extremely rare but documented in 45,X/46,XY mosaicism. 6 After gonadectomy, fertility requires assisted reproductive technology with donor oocytes. 6 Pre-conception cardiac evaluation is mandatory given Turner syndrome-associated aortic dissection risk. 7, 8

Critical Pitfalls to Avoid

• Never delay gonadectomy for pubertal development or fertility preservation in 45,X/46,XY mosaicism—the >40% gonadoblastoma risk is unacceptable. 1
• Never rely on peripheral blood karyotype alone to determine Y chromosome tissue distribution, as gonadal mosaicism differs substantially. 5
• Never use ultrasound as the definitive imaging modality for gonadal localization due to poor sensitivity. 4
• Never assume bilateral streak gonads based on phenotype—28% of palpable gonads in 45,X/46,XY patients are histologically normal testes requiring removal. 3