Succinate dehydrogenase (SDH) deficiency, Carney triad and the epigenome

• Published in: Molecular and cellular endocrinology Vol. 469; pp. 107 - 111
• Main Authors: Settas, Nikolaos, Faucz, Fabio R., Stratakis, Constantine A.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 05.07.2018
• Subjects: Carney triad; Carney-Stratakis syndrome; Gastrointestinal stromal tumor (GIST); Methylation; Paraganglioma; Paraganglioma; Carney triad; Carney-Stratakis syndrome; Methylation; Gastrointestinal stromal tumor (GIST)
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2017.07.018

In this report, we review the relationship between succinate dehydrogenase (SDH) deficiency and the epigenome, especially with regards to two clinical conditions. Carney triad (CT) is a very rare disease with synchronous or metachronous occurrence of at least three different tumor entities; gastric gastrointestinal stromal tumor (GIST), paraganglioma (PGL), and pulmonary chondroma. This condition affects mostly females and it is never inherited. Another disease that shares two of the tumor components of CT, namely GIST and PGL is the Carney-Stratakis syndrome (CSS) or dyad. CSS affects both genders during childhood and adolescence. We review herein the main clinical features and molecular mechanisms behind those two syndromes that share quite a bit of similarities, but one is non-hereditary (CT) whereas the other shows an autosomal-dominant, with incomplete penetrance, inheritance pattern (CSS). Both CT and CSS are caused by the deficiency of the succinate dehydrogenase (SDH) enzyme. The key difference between the two syndromes is the molecular mechanism that causes the SDH deficiency. Most cases of CT show down-regulation of SDH through site-specific hyper-methylation of the SDHC gene, whereas CSS cases carry inactivating germline mutations within one of the genes coding for the SDH subunits A, B, C, or D (SDHA, SDHB, SDHC, and SDHD). There is only partial overlap between the two conditions (there are a few patients with CT that have SDH subunit mutations) but both lead to increased methylation of the entire genome in the tumors associated with them. Other tumors (outside CT and CSS) that have SDH deficiency are associated with increased methylation of the entire genome, but only in CT there is site-specific methylation of the SDHC gene. These findings have implications for diagnostics and the treatment of patients with these, often metastatic tumors.