Pheochromocytoma and paraganglioma syndromes: genetics and management update

Abstract

Pheochromocytomas (pheos) and paragangliomas (pgls) are rare tumours of the autonomic nervous system, originating from paraganglia, which are dispersed neuroendocrine organs characterized by catecholamine and peptide-producing cells derived from the neural crest. Medical textbooks have traditionally suggested that 10% of pheos are heritable. However, the frequency of heritable pheo has been underestimated. Three syndromic conditions-Von Hippel-Lindau (vhl), multiple endocrine neoplasia type 2 (men2), and neurofibromatosis type 1 (nf1)-and three genes-subunits of the succinate dehydrogenase (SDH) complex: SDHB, SDHC, and SDHD-are established causes of hereditary pheo-pgl. In the last few years, four new genes (SDHA, SDHAF2, MAX, and TMEM127) have been found to be associated with predisposition to these tumours. The present review, illustrated by three case reports, gives an update of the genetic basis of pheo-pgl and of the parent-of-origin effect implicated in the transmission of SDHD and SDHAF2. We discuss the referral criteria that should guide the decision to offer genetic testing to affected patients. We also specify the genes that are most likely implicated-based on particular features such as malignancy, bilateralism, or childhood-onset-to help geneticists efficiently order appropriate genetic tests. Finally, we review the screening recommendations for carriers of a pheo-pgl predisposition mutation.

Keywords: Pheochromocytoma; genetics; management; paraganglioma; parent-of-origin effect; predisposition; screening; testing.

FIGURE 1

Pedigree of patient 3. Squares = men; circles = women; filled symbols = tumour-affected individuals (diagnoses indicated); diagonal line = deceased person; arrow = proband; number(y) = age or age at diagnosis in years; Dx = diagnosed at; R = right; L = left.

FIGURE 2

Transmission of the SDHD gene and the parent-of-origin effect. The inactivation of both SDHD genes can be explained by a germline mutation (transmitted by a parent—usually the father, but in rare instances, the mother) in one allele and by a somatic mutation or loss (present only in the tumour) of the other allele. Loss of the maternal 11p15 region is also a somatic event.

FIGURE 3

Referral and testing protocol (based on Fishbein and Nathanson, Jimerez et al., Gimenez–Roqueplo et al., Jafri and Maher, and Erlic et al.15). The numbering system in the boxes refers to the likelihood of identifying mutations, with 1 being most likely. Criteria in the middle should trigger a referral to oncogenetics. Pheo = pheochromocytoma; Pgl = paraganglioma; ihc = immunohistochemistry.