How Genetics Influence Pheochromocytoma Development

Pheochromocytoma is a rare tumor of the adrenal glands made of chromaffin cells that has been estimated to affect only eight in one million people. While the condition is known for causing surges in blood pressure, sweating, and rapid heart rate, the role of inherited mutations in its development has brought new insights into how this enigmatic tumor forms. 

Recent advances in genetic research have revealed that as many as 35% of these tumors are linked to inherited genetic mutations. Understanding the genetic factors behind pheochromocytoma not only helps unravel the tumor's biology but also opens doors for earlier diagnosis, personalized treatment, and potential preventative strategies for those at risk.

[signup]

Genetic Mutations Associated with Pheochromocytoma

Genetic mutations are changes or alterations in the DNA sequence that can affect the normal function of genes. These mutations can occur spontaneously or be inherited from a parent. When mutations occur in certain genes, they can disrupt normal cellular processes, such as the regulation of cell growth, division, and death, leading to tumor development.

Approximately 20 gene mutations have been identified as having a contributing role in pheochromocytoma development, including RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, MDH2, IDH1, PHD1/PHD2, HIF2A/EPAS1/2, TMEM127, MAX, HRAS, MAML3, and CSDE1.

RET Proto-Oncogene

Proto-oncogenes are genes that regulate cell growth, division, and differentiation. If a proto-oncogene is mutated in a way that causes it to be "turned on" (activated) when it isn't supposed to be, it is called an oncogene. Oncogenes promote tumor growth through uncontrolled cell growth and division. (17) 

The RET proto-oncogene on chromosome 10 encodes a protein that functions as a tyrosine kinase receptor. This receptor is involved in signaling pathways that regulate cell proliferation and differentiation. Mutations in RET can cause its receptor to become permanently activated, leading to continuous stimulation of these growth signals.

RET proto-oncogenes are strongly associated with multiple endocrine neoplasia type 2 (MEN2), a hereditary cancer syndrome. Up to 70% of patients with MEN2 will develop pheochromocytomas, along with other types of endocrine tumors.  

Von Hippel-Lindau (VHL) Gene Mutation

The VHL gene is a tumor suppressor gene that encodes a protein called VHL protein. This protein is part of the VCB-CUL2 complex, which tags proteins to be broken down when the body no longer needs them. When VHL is mutated, this degradation process can fail, leading to the accumulation of proteins that promote uncontrolled cell growth (17). 

Over 370 inherited mutations in the VHL gene have been linked to von Hippel-Lindau syndrome, an inherited disorder characterized by the formation of tumors and cysts in multiple organs. Pheochromocytomas occur in 25-30% of patients with VHL syndrome. 

Neurofibromatosis Type 1 (NF1) Gene

NF1 is another tumor suppressor gene that encodes a protein called neurofibromin. Neurofibromin helps control the activity of a signaling pathway called the RAS pathway, which is responsible for regulating cell division. Neurofibromin prevents cells from proliferating uncontrollably by turning off RAS signaling when appropriate.

Mutations in the NF1 gene cause loss of function in neurofibromin and are linked to neurofibromatosis type 1 (NF1). Pheochromocytomas occur in about 1-5% of individuals with NF1.

Succinate Dehydrogenase (SDH) Mutations

SDH is an enzyme complex in the mitochondria that plays a dual role in cellular metabolism. It functions as part of both the citric acid cycle (Krebs cycle) and the electron transport chain (ETC), where it helps convert succinate to fumarate and simultaneously participates in energy production by transferring electrons. (22) 

Mutations in the genes encoding SDH subunits – particularly SDHB, SDHC, and SDHD – have been associated with tumor formation, including pheochromocytoma. It is theorized that these mutations impair mitochondrial function and cause pseudohypoxia, in which cells behave as if they are oxygen-deprived. In this state, signaling pathways that promote cell growth and survival, such as the hypoxia-inducible factor (HIF) pathway, are activated abnormally. (22) 

SDHB mutations, in particular, are associated with aggressive pheochromocytomas with a higher risk of malignancy (4).  

Hereditary Syndromes Linked to Pheochromocytoma

Up to 35% of people who have pheochromocytoma have a genetic condition that is linked to it. If you have one of the following conditions, you have an increased risk of getting pheochromocytoma:

Multiple Endocrine Neoplasia Type 2 (MEN2)

MEN2 is a hereditary cancer syndrome caused by mutations in the RET proto-oncogene, characterized by the development of tumors in endocrine glands. MEN2 is subdivided into two main types: 

MEN2A is the more common form, and individuals with this type typically develop medullary thyroid carcinoma (MTC), pheochromocytomas, and parathyroid hyperplasia (leading to hyperparathyroidism). MEN2A accounts for about 95% of MEN2 cases. (7)  

MEN2B, a rarer and more aggressive form, is also associated with MTC and pheochromocytomas but lacks parathyroid involvement. Patients with MEN2B also develop noncancerous tumors on the lips, tongue, and digestive tract and have a "marfanoid" body habitus (tall stature, long limbs, and hyper-flexibility). (7) 

Von Hippel-Lindau Syndrome

VHL syndrome is rare, affecting one in 36,000 people, and is characterized by the growth of different types of cysts and tumors in multiple organ systems. VHL syndrome follows an autosomal dominant inheritance pattern, meaning that an affected individual has a 50% chance of passing the mutation to their offspring. (28)

Research shows that 97% of people with the VHL mutation will develop tumors by age 65. In addition to pheochromocytomas, people with VHL syndrome can develop the following cancers, tumors, and cysts (28): 

• Clear cell renal carcinoma: a type of kidney cancer
• Pancreatic neuroendocrine tumors
• Broad ligament (near the fallopian tubes) and epididymal (near the testicles) cystadenomas
• Hemangioblastomas: benign tumors that grow in the blood vessels in the brain, spinal cord, and retina
• Endolymphatic sac tumors: tumors that develop in the inner ear
• Kidney and pancreatic cysts (fluid-filled growths)

Neurofibromatosis Type 1

NF1 is a genetic disorder caused by mutations in the NF1 gene that lead to noncancerous tumors (neurofibromas) on the nerves in the brain, spinal cord, and skin.

Given the increased incidence of pheochromocytoma in individuals with NF1, research suggests the need for routine screening for pheochromocytoma in this population every 1-2 years, especially in people with high blood pressure, palpitations, headache, or excessive sweating.

Hereditary Paraganglioma-Pheochromocytoma Syndromes (HPPS)

HPPS is a group of inherited disorders characterized by the development of paragangliomas and pheochromocytomas. Paragangliomas are chromaffin cell-derived tumors that grow outside of the adrenal glands. 

In addition to pheochromocytomas and paragangliomas, individuals with HPPS may develop other types of tumors, such as gastrointestinal stromal tumors (GISTs) and clear cell renal carcinoma (6). 

HPPS is closely linked to mutations in the SDH genes, particularly SDHB, SDHD, SDHC, SDHA, and SDHAF2 (23). 

Genetic Testing for Pheochromocytoma

Doctors recommend consulting a genetic counselor for genetic testing for the following populations:

• People with a personal or family history of hereditary medical conditions linked to pheochromocytoma
• People with tumors in both adrenal glands
• People with more than one tumor in one adrenal gland
• People exhibiting signs or symptoms of pheochromocytoma
• People who have been diagnosed with pheochromocytoma before age 40

A genetic counselor is a trained healthcare professional specializing in assessing the risk of genetic disorders and providing information and support to individuals and families regarding genetic conditions. They help patients understand genetic testing options, interpret test results, and make informed decisions about their health and family planning. 

Genetic tests are available to detect mutations in the genes most commonly associated with pheochromocytoma, including:

• RET proto-oncogene
• VHL tumor suppressor gene
• NF1 tumor suppressor gene
• SDH subunit genes (SDHA, SDHB, SDHC, and SDHD)
• Genes responsible for modifying the SDHA subunit (SDHAF2 and SDH5)
• TMEM127 tumor suppressor gene

Comprehensive genetic panels can evaluate multiple genes simultaneously, providing a broader assessment of hereditary syndromes associated with pheochromocytoma. 

Genetic testing is a proactive means of identifying at-risk individuals so that associated tumors can be frequently monitored, detected early, and managed appropriately. 

Management of Pheochromocytoma With Genetic Predispositions

Genetic testing is recommended for all individuals with a personal or family history of pheochromocytoma. To facilitate early disease detection, annual screening is recommended for those with identified genetic mutations. Testing for pheochromocytoma includes plasma-free metanephrines, 24-hour urine catecholamines, and adrenal imaging studies (such as MRI or CT scans). (10) 

The primary treatment for pheochromocytoma is surgical removal of the tumor, which has a 90% treatment success rate. Other treatment options include radiation therapy, chemotherapy, ablation therapy, or embolization therapy. Prior to treatment of the tumor, patients usually require pharmacological management to control hypertension and other symptoms caused by excessive hormone production. Ultimately, treatment choice will be determined based on tumor characteristics and patient symptoms. (20, 30) 

In addition to conventional medical management, integrative and holistic approaches can support the overall health of individuals at risk for pheochromocytoma and help manage symptoms. Strategies could include:

• Heart-Healthy Diet: Emphasizing a diet rich in fruits, vegetables, whole grains, lean proteins, and healthy fats can support cardiovascular health. Foods high in potassium and magnesium can help regulate blood pressure.
• Regular Exercise: Engaging in physical activity, such as walking, cycling, or swimming, can help manage weight and blood pressure, reduce stress, and improve overall cardiovascular fitness.
• Stress Management: Techniques such as mindfulness, yoga, meditation, and deep-breathing exercises can help reduce stress and anxiety, which may help mitigate symptoms related to catecholamine surges.
• Nutritional Support for Adrenal Health: Incorporating adaptogenic herbs (like ashwagandha or rhodiola) may help support adrenal function, though they should be used cautiously and in consultation with a healthcare provider.

[signup]

Key Takeaways

• Pheochromocytoma is closely associated with various genetic mutations and hereditary disorders, including those linked to the RET proto-oncogene, VHL gene, NF1 gene, and SDH mutations. 
• These genetic factors significantly contribute to the risk of developing pheochromocytoma, underscoring the importance of genetic counseling and testing for individuals with a family history or clinical signs suggestive of hereditary syndromes. 
• Incorporating genetic testing into clinical practice is a proactive measure for early detection of pheochromocytoma in at-risk patients. By doing so, healthcare providers can facilitate early tumor detection, successful management of pheochromocytoma and related conditions, and empower patients to make informed decisions regarding their health and family planning.