What are the management and preventive measures for individuals with a Fumarate Hydratase (FH) gene variant?

Management and Preventive Measures for Individuals with Fumarate Hydratase (FH) Gene Variant

Individuals with pathogenic FH gene variants require comprehensive surveillance starting at age 8-10 years, with annual renal MRI as the cornerstone of management to detect aggressive renal cell carcinoma early. 1

Understanding HLRCC Syndrome

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome is an autosomal dominant condition caused by pathogenic variants in the FH gene. It is characterized by:

• Multiple cutaneous leiomyomas (benign skin tumors)
• Early-onset uterine leiomyomas (fibroids)
• Aggressive type 2 papillary renal cell carcinoma (RCC)

The FH gene encodes fumarate hydratase, an enzyme in the Krebs cycle. Pathogenic variants lead to abnormal accumulation of fumarate, activating hypoxia-inducible factor (HIF) and promoting tumor development 1.

Genetic Testing and Counseling

• Predictive genetic testing should be offered to at-risk family members starting at age 8 years 1
• If a familial mutation is unknown, diagnostic testing should include:
  • Full sequencing of the FH gene
  • Deletion/duplication testing (e.g., multiplex ligation-dependent probe amplification) 1
• Reproductive counseling should be offered to carriers of heterozygous FH mutations 1

Cancer Risk Assessment

• Lifetime risk of renal cell carcinoma is approximately 15% 2
• Age-related penetrance: 1% by age 15,2% by age 20, and 21% by age 70 1
• RCC in HLRCC is particularly aggressive, with cases reported in individuals as young as 18 years 3
• No clear genotype-phenotype correlations have been established; all carriers should be considered at risk 1

Surveillance Recommendations

Renal Cancer Surveillance

• Annual renal MRI starting at age 8-10 years 1
  • MRI protocol should include:
    • Diffusion-weighted imaging
    • Chemical shift (in and out of phase) sequences
    • Consider gadolinium-based contrast only for characterization of detected lesions 1

Skin Surveillance

• Annual full skin examinations from the time of diagnosis 1
• Dermatology referral as needed for:
  • Assessment of cutaneous leiomyomas
  • Evaluation of changes suggestive of leiomyosarcoma (rare) 1

Gynecologic Surveillance (for females)

• Annual gynecologic examination starting at age 20 (or earlier if symptomatic) 1
• Ultrasound as needed to assess:
  • Uterine fibroids
  • Significant growth that could suggest leiomyosarcoma 1

Management of Detected Lesions

Renal Tumors

• Prompt surgical intervention with wide-margin excision
• Consider retroperitoneal lymph node dissection 2
• Systemic treatment for metastatic disease should ideally be part of clinical trials 2

Cutaneous and Uterine Leiomyomas

• Treatment warranted only for symptomatic lesions 1
• Educate patients about concerning features:
  • Rapid increase in growth rate
  • Changes in appearance of cutaneous lesions 1

Diagnostic Considerations

Immunohistochemistry can aid in diagnosis:

• Positive staining for 2-succinocysteine (2SC) is highly sensitive for HLRCC-associated tumors 1, 4
• Loss of FH staining is specific but less sensitive 4

Special Considerations

• Homozygous FH mutations cause a separate autosomal recessive condition (FH deficiency) characterized by severe metabolic and neurologic impairment with short lifespan 1
• Multiple cutaneous leiomyomas should raise suspicion for HLRCC, with 85% showing FH mutations versus only 9% in single leiomyomas 4
• Women with FH-deficient uterine leiomyomas have an 18.8% chance of harboring germline FH mutations 5

Pitfalls to Avoid

• Delaying surveillance until adulthood (cases reported in teenagers)
• Using ultrasound alone for renal surveillance (lower sensitivity than MRI)
• Failing to refer for genetic counseling after diagnosis of atypical uterine leiomyomas (only 34% receive documented genetic testing) 5
• Overlooking the need for prompt surgical intervention when renal tumors are detected

By implementing these comprehensive surveillance and management strategies, the morbidity and mortality associated with HLRCC can be significantly reduced through early detection and intervention.