What genetic testing is recommended for a 22-year-old patient with a family history of leiomyoma (uterine fibroids), specifically with a mother who tested positive for leiomyoma?

Genetic Testing for a 22-Year-Old with Maternal History of Leiomyoma

Order FH (fumarate hydratase) gene testing with both sequencing and deletion/duplication analysis for this patient, as she meets criteria for hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome evaluation based on her first-degree relative with leiomyomas. 1

Testing Approach

Recommended Genetic Test

• Order comprehensive FH gene testing that includes both sequencing and deletion/duplication analysis (such as multiplex ligation-dependent probe amplification/MLPA) to detect all mutation types including missense, frameshift, nonsense, indels, splice-site mutations, and whole gene deletions 1

• The American College of Medical Genetics and Genomics recommends genetic counseling referral and FH gene testing for individuals with a first-degree relative who has cutaneous leiomyomas or characteristic features of HLRCC 2

Clinical Context for Testing

• The mother's leiomyoma diagnosis warrants clarification: If the mother had multiple uterine leiomyomas requiring surgery before age 30-40, particularly with early onset or severity, this significantly strengthens the indication for FH testing 1

• If the mother has cutaneous leiomyomas (skin lesions that are histopathologically confirmed smooth muscle tumors), this is a strong indication for FH testing in both the mother and patient 2

• The presence of multiple uterine leiomyomas (more than 7) in young women under age 30 shows statistically significant correlation with FH gene mutations 3

Why This Testing Matters

Cancer Risk Implications

• Women with HLRCC have a 15-20% lifetime risk of highly aggressive renal cell carcinoma that can develop as early as childhood, making early identification critical for mortality reduction 1

• HLRCC-associated renal cell carcinomas are typically high stage at presentation, aggressive, and have poor clinical outcomes, but early detection through surveillance is curative with surgery 1, 4

Surveillance Benefits if Positive

• If FH mutation is identified, the patient should begin annual renal MRI surveillance starting immediately (guidelines recommend starting at age 8, so at age 22 she should already be under surveillance) 2, 1

• Annual skin examinations should be performed to assess for cutaneous leiomyomas and evaluate for changes suggestive of leiomyosarcoma 2

• Annual gynecologic examinations with ultrasound as needed should begin at age 20 or earlier if symptomatic 2

Testing Strategy

Optimal Approach

• Ideally, test the affected mother first to identify the specific familial mutation, which then allows for targeted testing in the patient and other at-risk family members 2, 1

• If the mother tests positive for an FH mutation, the patient has a 50% chance of inheriting it due to autosomal dominant inheritance with incomplete penetrance 2

• If the mother is unavailable for testing or declines, proceed with comprehensive FH testing in the patient given her family history 1

Important Caveats

Phenotype Variability

• Not all FH mutation carriers develop all features of HLRCC: Some families may have predominantly uterine leiomyomas without cutaneous lesions or renal cancer, but the renal cancer risk remains present 5, 6

• The syndrome shows incomplete penetrance, meaning not everyone with an FH mutation will develop clinical manifestations, but surveillance is still warranted 2

Testing Limitations

• Immunohistochemistry for 2-succinocysteine (2SC) and FH on leiomyoma tissue can support the diagnosis but is not sufficiently sensitive or specific to replace genetic testing, as missense mutations may show retained FH staining 4, 3

• Morphologic features of HLRCC-associated leiomyomas (eosinophilic cytoplasmic inclusions, prominent nucleoli with perinucleolar halos) are helpful but not present in every case 4, 3