Modern Management of Adrenal Tumours: Focus on SDHB Mutation – Related Pheochromocytoma

Abstract

Pheochromocytoma (PHEO) and paraganglioma (PGL) are tumours that originate from neural crest cells. PHEOs arise from adrenal medulla. Although the majority of the tumours are sporadic, these can also be developed as an element of hereditary syndromes in a percentage of 30%-40% of patients. It was described a number higher than 20 genes that are involved in PHEO and PGL. The most frequent germinal mutations which predispose for PHEO are found in von Hippel-Lindau (tumour suppressor gene), RET proto-oncogene in multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1 (NF-1), Mycassociated factor X (MAX), TMEM 127, whereas the A,B,C,D subunits of the mitochondrial succinate dehydrogenase complex (SDHA, SDHB, SDHC, SDHD), succinate dehydrogenase assembly factor 2 (SDHAF2) and hypoxiainducible factor 2α (HIF2A/EPAS1) are more susceptible to PGL. In this narrative review of literature we focus on SHDB mutations underling PHEO among adrenal tumours. The genetic mutations of the SDH complex are the most implicated in patients with PGL, predominantly the SDHD gene, followed by SDHB and SDHAF1 genes. It is well known that SDHB mutations penetrance is incomplete and influenced by age. On the other hand, the SDHD mutations lead to PGL only from paternal transmission. At first, it was thought that SDHB and SDHD germline mutations penetrance was very high, approximately 70%-80% by the age of 50 years old, with a higher overall penetrance in SDHD. Once genetic testing has gotten a broader number of applications, the penetrance has fallen, especially for SDHB, reaching a level below 50% during a lifetime. Germline mutations in SDHB gene are responsible for about 10% of PHEOs/PGLs. At this time, these are associated with the most aggressive behaviour with increased metastasis incidence and lethality. Taking into consideration the high prevalence of genetic mutation and the unfavourable behaviour that some of them could have, all individuals with PHEO/PGL should test for a hereditary aetiology, especially young patient with positive family history, multifocal PGL or bilateral PHEO. Even a small percent of patients with non-familial PGL bears occult germline mutations in SDHx.