Pheochromocytoma: The Expanding Genetic Differential Diagnosis

Abstract

Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system; pheochromocytomas are tumors of the adrenal medulla, and paragangliomas are extra-adrenal tumors arising from either the sympathetic nervous system or parasympathetic ganglia. It has previously been estimated that approximately 10%-15% of pheochromocytomas are due to hereditary causes. However, our increased understanding of the three hereditary syndromes (neurofibromatosis 1, multiple endocrine neoplasia type 2, and von Hippel-Lindau syndrome) in which pheochromocytoma is found and the recent discovery that mutations in genes in the succinate dehydrogenase family (SDHB and SDHD) predispose to pheochromocytoma have necessitated a re-evaluation of the genetic basis of pheochromocytoma. These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%. In all patients with pheochromocytoma, including those with known hereditary syndrome or a positive family history, the frequency of germline mutations in these four genes together approaches 30%. Given the frequency of germline mutations, consideration should be given to genetic counseling for all patients with pheochromocytoma and is particularly important for individuals with a positive family history, multifocal disease, or a diagnosis before age 50. Identification of patients with hereditary pheochromocytoma is important because it can guide medical management in mutation-positive patients and their families. This review provides an overview of the known genetic syndromes that are commonly associated with pheochromocytoma, examines recent data on the association of germline mutations in the succinate dehydrogenase gene family with pheochromocytoma, and suggests guidelines for the genetic evaluation of pheochromocytoma patients.

The clinical genetics of phaeochromocytoma and paraganglioma

“…In addition, bilateral phaeochromocytomas are mostly found with these same mutations (11,12,14,21,26,42,45,53). On the other hand, SDH mutations cause intra-adrenal tumours less commonly; 25% of SDHB-related tumours are phaeochromocytomas while the frequency of intraadrenal tumours in SDHD, SDHA and SDHC are even lower (4,7,36,37,41,53). Most of the extra-adrenal tumours are due to mutations in SDH genes (4,7,36,37,40,53).…”

“…On the other hand, SDH mutations cause intra-adrenal tumours less commonly; 25% of SDHB-related tumours are phaeochromocytomas while the frequency of intraadrenal tumours in SDHD, SDHA and SDHC are even lower (4,7,36,37,41,53). Most of the extra-adrenal tumours are due to mutations in SDH genes (4,7,36,37,40,53). Apart from which, extra-adrenal tumours were also found in rare EGLN1 mutation (47).…”

“…Of the SDH mutations, SDHD-related tumours are commonly seen in the head and neck region and are usually multiple. Head and neck tumour are also seen in SDHB and SDHC mutations; however, they are much less common (7,31,53). An even rarer cause for head-and-neck paraganglioma is the SDHAF2 mutation, which should be considered if SDHD, SDHB, and SDHC testing is negative (36).…”

“…Due to high rate of an underlying genetic defects, head and neck paraganglioma negative for all SDH mutations can be tested for VHL and TMEM127 (although the possibility is very rare). Sympathetic paragangliomas, which are large, solitary tumours located in abdomen, thorax and pelvis, are often due to SDHB mutations, while SDHC and SDHA can rarely be causal (7,31,36,38,40,41,53).…”

“…The presence of malignant features can suggest certain genetic defects; phaeochromocytomas and especially extra-adrenal paragangliomas of malignant nature are associated mostly with SDHB mutations (in 30% patients) (4,(36)(37)(38)40). Malignant phaeochromocytomas can also be not infrequently seen with several mutations including MAX (25%) and NF1 (12%) mutations (7,14,21,45,53). Malignant tumours are rare (< 5%) in RET, VHL, SDHD, SDHC, SDHAF2 and TMEM127 mutations.…”