Paragangliomas (PGLs) are rare and seldom malignant tumors affecting the paraganglia, which is a group of neuroendocrine cells found in many locations across the human body. These tumors can occur in several anatomic locations, and predominant involvement is in the head, neck, and thorax regions. These are actively growing structures that are vascularised and very relevant because they are premalignant conditions. There is a significant focus on understanding the role of genetics in the development of hereditary paragangliomas, and some of the genes that probably contribute to the development of these diseases have been identified. In this regard, germline mutations in the succinate dehydrogenase (SDH) genes have been identified to yield a profound understanding of the molecular basis of PGLs. The improvement of molecular biology techniques has not only improved diagnostics but has also enriched our knowledge of the disease’s pathophysiology. In this blog, we present a review of the principal molecular accomplishments made in the identification of hereditary paragangliomas, as well as the impact of these specific mutations.
Genetic Foundations of Hereditary Paragangliomas
The succinate dehydrogenase complex is affected by genetic changes that are linked to hereditary paragangliomas. This complex is a part of both the Krebs cycle and the electron transport chain. The SDH complex consists of four subunits: the four known subtypes of SDHA, SDHB, SDHC, and SDHD, which are recognized to be encoded by individual genes. Loss of function of any of these proteins causes failure in the proper working of the SDH complex and an abnormal cell process that may lead to tumorigenesis.
SDHB Mutations: Of all the SDH genes, the cut that stands out most significantly is the SDHB. SDHB mutations cause PGLs at various body sites and are likely to cause cancer. Mutations in the SDHB gene can affect susceptibility for paragangliomas such as pheochromocytomas, which occur in the abdomen and are derived from the adrenal gland. These tumors can secrete more than normal amounts of catecholamines and thus present with symptoms such as hypertension, palpitations, and headache. The malignancy of SDHB-related tumors suggests that early genetic identification is of paramount importance for patient care.
SDHC Mutations: Mutations in the SDHC gene also occur, though in a smaller number of people with hereditary paragangliomas. These mutations are more often linked with tumors at the top of the head and in the neck region. Although mutations in the SDHB gene are less likely to cause malignancy, SDHC gene mutations still pose risks and require close monitoring. The fact that SDHC mutations are rare can occasionally complicate a diagnosis; however, in recent years, the advent of mutational analysis has facilitated quicker detection of SDHC mutations and thus improved the surveillance strategy.
SDHD Mutations: SDHD is associated most commonly with paragangliomas localized in the head and neck area, like SDHC. However, SDHD is mutually special because of its parent-of-origin effect, where paternal transmission of the mutation is more potent in causing tumor formation than maternal one. This is a clear example of showing that hereditary paragangliomas are not as straightforward as was initially thought, and proper assessment of inheritance is crucial in genetic diagnosis.