pheochromocytoma/paraganglioma syndrome 4

Pheochromocytoma/paraganglioma syndrome 4 is an autosomal dominant tumor predisposition disorder primarily associated with pathogenic variants in the SDHB gene. This condition increases the risk for developing paragangliomas in the head and neck region, extra-adrenal and adrenal pheochromocytomas, and may also predispose individuals to renal cell carcinoma and gastrointestinal stromal tumors. Although precise prevalence estimates are not available, the syndrome is recognized as a rare disorder that requires careful clinical and genetic evaluation. It can present at various ages and its presentation, including tumor type and number, can vary widely between individuals.

The clinical features of pheochromocytoma/paraganglioma syndrome 4 center around the development of tumors in various locations. Characteristic manifestations include paragangliomas of the head and neck and extra-adrenal pheochromocytomas, occurring in approximately 30 to 79% of affected individuals. In addition, adrenal pheochromocytomas, gastrointestinal stromal tumors, and even neuroblastomas are reported, with frequencies ranging from 5 to 29%. Individuals may initially become symptomatic when tumors are discovered incidentally on imaging studies or during evaluation of symptoms such as high blood pressure, palpitations, or unexplained episodes of sweating. Not all individuals experience all features, and severity varies considerably, meaning that some affected individuals may have only one type of tumor while others might develop multiple neoplasms over time.

Pathogenic variants in the SDHB gene are the underlying cause of pheochromocytoma/paraganglioma syndrome 4. The SDHB gene encodes a component of the mitochondrial complex II, which plays a critical role in cellular energy production. Disruption of this protein’s normal function can promote tumor development by affecting cellular metabolism and growth regulation. The condition is inherited in an autosomal dominant manner, which means that a single mutated copy of the gene is sufficient to predispose an individual to tumor development. As with many inherited conditions, not everyone who carries the pathogenic variant will necessarily develop tumors, and the severity and specific types of tumors can differ even within the same family. Genetic counseling is recommended for affected individuals and their families to discuss testing and family planning options.

Currently, management of pheochromocytoma/paraganglioma syndrome 4 focuses on supportive care and symptom management, as there are no FDA-approved treatments specifically for this condition. Treatment strategies are individualized and typically involve a multidisciplinary team that may include endocrinologists, oncologists, and surgeons. Regular surveillance is an essential part of long-term care, with periodic evaluations to monitor tumor growth and detect potential complications at an early stage. In addition to interventions addressing active symptoms, patients should discuss potential investigational therapies with their healthcare team, and genetic counseling is recommended to guide family planning and further management decisions.

The course of pheochromocytoma/paraganglioma syndrome 4 is highly variable, with outcomes depending on factors such as tumor type, extent of disease, and the individual’s access to specialized care. With current standards of care and regular surveillance, many individuals continue to live into adulthood and benefit from timely interventions when new tumors or complications arise. Outcomes described in medical literature continue to evolve as standards of care improve, and while some individuals experience a more indolent course, others may be challenged by more aggressive tumor development. Families often find it helpful to connect with specialists and genetic counselors to understand the potential risks and management strategies, as well as to join patient registries that foster research and support.

Clinical trials are currently underway exploring new treatment approaches for pheochromocytoma/paraganglioma syndrome 4. Although only one active trial has been noted at this time, ongoing research is essential to expand our understanding of the condition and to develop more targeted therapeutic options in the future. Individuals interested in learning more about these investigational therapies are encouraged to search ClinicalTrials.gov or discuss available options with their care team.