What is ordered for genetic testing of leiomyoma (uterine fibroids)?

Genetic Testing for Leiomyoma (Uterine Fibroids)

Order fumarate hydratase (FH) gene testing when patients present with multiple uterine leiomyomas requiring surgery before age 30-40, particularly when there are cutaneous leiomyomas, a family history of early-onset fibroids, or renal cell carcinoma. 1

Clinical Indications for FH Gene Testing

Primary Testing Criteria

Genetic counseling referral and FH gene testing should be considered for:

• Multiple cutaneous leiomyomas (histopathologically confirmed) 1
• Severe uterine leiomyomas requiring surgery before age 40, especially with characteristic histological findings 1
• Type 2 papillary, collecting duct, or tubulopapillary renal cell carcinoma before age 40 1
• First-degree relative with any of the above features 1

Additional High-Risk Scenarios

• Young women (under age 30) with multiple uterine leiomyomas (more than seven tumors shows statistically significant correlation with FH mutations) 2
• Highly symptomatic fibroids at young ages (24-36 years) requiring myomectomy 3
• Strong family history with multiple closely related women affected by early-onset uterine leiomyomas 4

Testing Methodology

Molecular Genetic Testing Approach

Both sequencing and deletion/duplication analysis must be performed to identify all mutation types:

• FH gene sequencing to detect missense, frameshift, nonsense, indels, and splice-site mutations 1
• Multiplex ligation-dependent probe amplification (MLPA) or similar deletion/duplication testing to detect whole gene deletions 1

Important: Testing should begin with an affected individual when possible to identify the familial mutation before pursuing predictive testing in at-risk relatives 1

Limitations of Alternative Testing Methods

Immunohistochemistry (IHC) for FH protein is unreliable and should not exclude genetic testing:

• FH IHC shows variable results across different leiomyomas in the same patient (retained staining in some tumors, loss in others) 3
• Retained FH staining does not exclude HLRCC—2 of 6 proven HLRCC patients showed retained FH staining in all sections 3
• 2-succinocysteine (2SC) positivity combined with FH absence correlates with mutations in only some cases 2

Histomorphologic features are only partially sensitive:

• Characteristic "FH-deficient morphology" (enlarged nucleoli with clear halos, fibrillary cytoplasm, eosinophilic globules, staghorn vessels) may be absent, focal, or subtle even in confirmed HLRCC cases 3, 2
• These features should prompt testing but their absence does not exclude the diagnosis 3

Clinical Context and Rationale

Why Testing Matters for Morbidity and Mortality

Early identification enables life-saving renal cancer surveillance:

• HLRCC-associated renal cell carcinomas are highly aggressive and can develop as early as childhood 5
• Annual renal MRI surveillance starting at age 8 years is recommended for mutation carriers 1
• Early detection of renal tumors is curative with surgery when found in earliest form 1

Syndrome Characteristics

Women with HLRCC develop:

• Symptomatic uterine leiomyomas in nearly all cases, typically requiring surgery at young ages (20s-30s) 3, 5
• Multiple cutaneous leiomyomas causing significant pain 5
• 15-20% lifetime risk of aggressive renal cell carcinoma 1

Common Pitfalls to Avoid

• Do not rely on immunohistochemistry alone—molecular genetic testing is the only reliable diagnostic tool 2
• Do not exclude HLRCC based on absence of cutaneous leiomyomas or renal tumors—uterine manifestations often precede other features 3, 6
• Do not dismiss young patients with "just fibroids"—consider testing when multiple tumors or early surgery is required 2, 4
• Test more than one affected family member when possible to account for phenocopies 4

Practical Screening Protocol

For gynecologists encountering young women with symptomatic fibroids:

1. Document number of leiomyomas (≥7 tumors increases suspicion) 2
2. Assess age at presentation (surgery before age 30-40 is high-risk) 1, 2
3. Obtain family history of early-onset fibroids, cutaneous leiomyomas, or renal cancer 4
4. Refer for genetic counseling when criteria are met, even if histology appears benign 3
5. Order FH gene sequencing plus deletion/duplication analysis 1