What is the workup for a mutation of the Succinate Dehydrogenase Subunit A (SDHA) gene?

From the Guidelines

The workup for SDHA gene mutations should include annual biochemical screening and whole-body MRI every other year, with the interval potentially increasing to every third year if normal, as recommended for first-degree relatives of affected individuals. According to the guidelines for genetic testing and surveillance in hereditary pheochromocytoma and paraganglioma 1, biochemical screening should include methoxycatecholamines (normetanephrine and metanephrine) in plasma or urine. Key points to consider in the workup and surveillance of SDHA gene mutations include:

• Genetic testing using next-generation sequencing panels that include the SDHA gene
• Biochemical screening for plasma or 24-hour urinary metanephrines and catecholamines
• Imaging studies with whole-body MRI, focusing on the head, neck, thorax, abdomen, and pelvis
• Regular surveillance for patients with confirmed SDHA mutations, typically including annual biochemical screening and imaging every 1-2 years starting from age 10-15
• Cascade genetic testing for family members The SDHA gene mutation is associated with autosomal dominant inheritance and can lead to the development of paragangliomas, pheochromocytomas, gastrointestinal stromal tumors (GISTs), pituitary adenomas, and renal cell carcinomas, as a result of dysfunction in the succinate dehydrogenase complex 1.

From the Research

SDHA Gene Mutation Workup

• The SDHA gene mutation is associated with an increased risk of developing pheochromocytoma and paraganglioma, which are rare neuroendocrine tumors that can cause potentially life-threatening complications 2.
• A study of 10 patients with SDHA-related metastatic pheochromocytoma and paraganglioma found that these tumors can occur early and at extra-adrenal locations, behave aggressively, and have a tendency to develop metastatic disease within a short period of time 2.
• Biochemical tests, such as those for noradrenergic and/or dopaminergic phenotype, can be useful in diagnosing and monitoring the disease 2.
• Imaging tests, such as 68Ga-DOTATATE PET/CT, 18F-FDG PET/CT, and 123I-MIBG scintigraphy, can be used to detect and monitor the disease, with 68Ga-DOTATATE PET/CT being recommended for evaluation and follow-up of patients with SDHA-related metastatic pheochromocytoma and paraganglioma 2.

Screening and Follow-up

• An international consensus algorithm has been established for the initial screening and follow-up of asymptomatic SDHx mutation carriers, including clinical, biochemical, and imaging screening at diagnosis and during surveillance for both adults and children 3.
• The algorithm recommends genetic counseling for first-degree relatives of patients with a pathogenic SDHx mutation, and suggests that optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed upon 3.
• A study of SDHA PGV carriers suggests that lifetime penetrance for SDHA-associated tumors is low, particularly when identified outside the context of a family history, and recommends careful surveillance of affected patients and a search for effective therapies 4.

Clinical Characterization

• Clinical management guidelines for patients with germline mutations in the SDHA gene are lacking, and effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis 5.
• A study of the clinical spectra and age-related penetrance of individuals with mutations in the SDHA gene found that SDHA disease can occur as early as 8 years of age, and that extra-adrenal tumors occur in 79% of SDHA mutation carriers, particularly with head and neck paraganglioma 5.
• The study also found that penetrance in SDHA carriers was 39% at 40 years of age, and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001) 5.

Counseling and Management

• Counseling patients with SDHx mutations poses challenges due to the inability to accurately predict the appearance, nature, and location of tumors, as well as their tendency to recur or metastasize 6.
• A study of SDHA PGV carriers recommends an intensive protocol for surveillance, considering low penetrance for tumor development, surveillance burden, and patient anxiety 4.
• An expert SDHA working group has outlined recommendations for testing and management of SDHA PGV carriers in clinical practice, including genetic testing and regular, systematic whole-body investigation 4.