Prior to the turn of this century, it was widely accepted that a phaeochromocytoma followed a rule of ‘tens’: (i) 10% were bilateral; (ii) 10% were malignant; (iii) 10% were extra- adrenal (now termed paraganglioma (PGL) arising from sympathetic ganglia anywhere from the thorax to pelvis); and finally and (iv) 10% were hereditary.
Familial occurrence of phaeochromocytoma (PC) was first recognized by Chase et al. in 1937 and almost 50 years later the co- occurrence of PC and its extra- adrenal counterpart PGL in the same kindred was reported. Those tumours that were familial were associated with hereditary syndromes such as neurofibromatosis type 1, caused by germline mutations in the neurofibromin 1 gene (NF1), multiple endocrine neoplasia type 2 (MEN2) caused by germline mutations in the RET proto- oncogene and Von Hippel– Lindau syndrome (VHL), caused by germline mutations in the VHL tumour suppressor gene. Each of these syndromes predispose to the development of bilateral phaeochromocytoma but extra- adrenal tumours are rarely encountered and typically each of these syndromes are associated with other characteristic phenotypic features.
Between the years 2000 and 2010, nine further phaeochromocytoma predisposition genes were identified and this era of discovery completely dispelled the contention that only 10% were hereditary. This era of discovery was triggered by the seminal finding that some families affected by a head and neck paragangliomas (HNPGL) such as a chemodectoma or glomus jugulare tumour, carried a mutation in the succinate dehydrogenase subunit D gene (SDHD). Between 2000 and 2011, all four of the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC and SDHD) were implicated in the development of familial PPG, as well as the SDHAF2 gene which encodes its namesake protein responsible for the flavination of the SDHA protein.
In 2010, an integrated genomics approach led to the finding that a gene encoding a transmembrane protein (TMEM127) localized to chromosome 2, was implicated in familial PPGL. This trans membrane protein normally functions as a modulator of the mTOR pathway and notably patients with mutations in the TMEM127 gene were found to present at an older age compared to patients with other syndromic causes of PPGL. Subsequently, whole- exome sequencing identified recurrent mutations in the MAX (MYC as sociated factor X) gene in three unrelated patients with hereditary PPGL. Though all of these genes are inherited in an autosomal dominant manner, SDHD, SDHAF2, and MAX are associated with predisposition to PPGL, almost always only after paternal transmission of a mutation.
Finally, mutations in another citric acid cycle enzyme encoding gene fumarate hydratase (FH) were implicated in hereditary phaeochromocytoma, in addition to its previously accepted role in hereditary leiomyomatosis and renal cell cancer.
Importantly, PPGLs are now considered to be the most heritable of all tumours with 40% of patients having a genetic predisposition in one of 11 major susceptibility genes routinely screened for in clinical practice (SDHA, SDHB, SDHC, SDHD, SDHAF2, NF1, RET, TMEM127, MAX, FH, VHL). Although several additional predisposition genes have been reported in the past five years (e.g. malate dehydrogenase 2 (MDH2) gene, SLC25A11 gene, which encodes the mitochondrial 2- oxoglutarate/ malate carrier and EPAS1, which encodes the hypoxia inducible factor- 2 alpha (HIF- 2alpha)), these are a rare cause of PPGL and not commonly analysed in first- line genetic testing.
