Genes are the blueprints within our cells, guiding body development and operation. Mutations, changes in these instructions, can alter gene function and lead to various health conditions.
The FH Gene’s Normal Function
The FH gene (Fumarate Hydratase) is located on chromosome 1q43. It provides instructions for creating the enzyme fumarate hydratase.
The Krebs cycle, or citric acid cycle, is a central mitochondrial process generating energy. Fumarate hydratase catalyzes fumarate to malate conversion, crucial for the cycle’s operation and efficient ATP production, the cell’s primary energy currency. Proper FH gene function ensures efficient energy production, vital for cellular health.
Conditions Caused by FH Gene Mutations
Mutations in the FH gene are associated with Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC). This inherited disorder causes benign skin and uterine tumors, and a heightened risk for a specific kidney cancer.
Individuals with HLRCC often develop cutaneous leiomyomas: benign, firm skin bumps, typically on the torso and limbs. These lesions can be painful, especially with cold exposure or pressure.
In individuals assigned female at birth, uterine leiomyomas (fibroids) are common. These non-cancerous uterine growths can be numerous and large, causing heavy menstrual bleeding, pelvic pain, and pressure. HLRCC-associated fibroids develop earlier and grow more rapidly than typical fibroids.
The most serious concern is the increased risk of aggressive renal cell carcinoma. This kidney cancer often presents as a solitary tumor but can be multifocal or bilateral, appearing in multiple locations or both kidneys. The kidney tumors linked to HLRCC are often characterized by papillary type 2 histology and can be aggressive, with a tendency to metastasize early.
While HLRCC typically arises from a mutation in one FH gene copy, a rare and more severe condition, Fumarate Hydratase Deficiency (FHD), occurs if an individual inherits mutations in both copies. FHD is a metabolic disorder primarily affecting infants, characterized by severe neurological impairment, developmental delays, and fumarate buildup.
Inheritance and Identification
HLRCC has an autosomal dominant inheritance pattern: only one mutated FH gene copy from either parent is needed. Each child of an affected parent has a 50% chance of inheriting the mutation, explaining its appearance across generations.
Genetic testing is the primary method for identifying an FH gene mutation, typically analyzing blood or saliva samples for specific gene sequence changes. Testing is recommended for individuals with characteristic HLRCC symptoms: multiple cutaneous leiomyomas, early-onset or numerous uterine fibroids, or renal cell carcinoma suggestive of HLRCC.
Genetic testing may also be offered to family members of an affected individual, even without symptoms. This “cascade testing” allows early identification of at-risk relatives. Clinical assessment (medical history and physical examination) helps identify HLRCC signs. Imaging studies, like MRI scans of the abdomen and pelvis, are crucial for detecting and monitoring kidney tumors and uterine fibroids.
Living with an FH Gene Mutation
Living with an FH gene mutation requires proactive medical management, primarily regular surveillance to detect potential complications early. The most significant surveillance involves routine kidney imaging for renal cell carcinoma. MRI scans are typically recommended annually, or as determined by a healthcare provider, to monitor for aggressive kidney tumors requiring timely intervention.
Management of cutaneous and uterine leiomyomas often involves symptomatic treatment. For skin lesions, pain management or surgical removal can be considered for bothersome lesions. Uterine fibroids may require medical management for symptoms like heavy bleeding, or surgical removal (e.g., myomectomy or hysterectomy), depending on their size, number, and patient preferences.
Genetic counseling is an important aspect of care for individuals with an FH gene mutation and their families. Counselors provide detailed information on inheritance, risks, and family planning, helping individuals make informed decisions about genetic testing. Treatment for HLRCC-associated renal cell carcinoma is tailored to the individual and cancer stage, often involving surgical tumor removal. For advanced or metastatic disease, targeted therapies and other systemic treatments may control tumor growth and improve outcomes.