Carney Triad, Carney-Stratakis Syndrome, 3PAS and Other Tumors Due to SDH Deficiency.

Georgia Pitsava,Nikolaos Settas,Fabio R Faucz,Constantine A Stratakis

doi:10.3389/fendo.2021.680609

Abstract

Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and SDHD. All SDH-deficient tumors are caused by or secondary to loss of SDH activity. As many as half of the familial cases of paragangliomas (PGLs) and pheochromocytomas (PHEOs) are due to mutations of the SDHx subunits. Gastrointestinal stromal tumors (GISTs) associated with SDH deficiency are negative for KIT/PDGFRA mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. SDH-deficient GISTs may be part of distinct clinical syndromes, Carney-Stratakis syndrome (CSS) or dyad and Carney triad (CT). CSS is also known as the dyad of GIST and PGL; it affects both genders equally and is inherited in an autosomal dominant manner with incomplete penetrance. CT is a very rare disease; PGL, GIST and pulmonary chondromas constitute CT which shows female predilection and may be a mosaic disorder. Even though there is some overlap between CT and CSS, as both are due to SDH deficiency, CSS is caused by inactivating germline mutations in genes encoding for the SDH subunits, while CT is mostly caused by a specific pattern of methylation of the SDHC gene and may be due to germline mosaicism of the responsible genetic defect.

Highlights

Succinate dehydrogenase (SDH - known as mitochondrial complex II or succinate-ubiquinone oxydoreductase) is the only enzyme that is concurrently both a functional member of both the Krebs cycle and the electron transport chain (ETC), where it provides electrons for oxidative phosphorylation [1]. It is comprised of four mitochondrial subunit proteins: SDHA, SDHB, SDHC, SDHD encoded by nuclear genes, mapped to 5p15.22, 1p36.13, 1q23.3 and 11q23.1, respectively (Figure 1)
SDHA is a flavoprotein and SDHB is an iron-sulfur protein; together they make up the main catalytic component of the complex
They translocate to the nucleus, they dimerize with HIFb and create a complex that activates genes that induce angiogenesis, cell proliferation and glycolysis [12, 13]

Summary

INTRODUCTION

Succinate dehydrogenase (SDH - known as mitochondrial complex II or succinate-ubiquinone oxydoreductase) is the only enzyme that is concurrently both a functional member of both the Krebs cycle (or citric acid or tricarboxylic acid cycle) and the electron transport chain (ETC), where it provides electrons for oxidative phosphorylation [1]. It is comprised of four mitochondrial subunit proteins: SDHA, SDHB, SDHC, SDHD encoded by nuclear genes, mapped to 5p15.22, 1p36.13, 1q23.3 and 11q23.1, respectively (Figure 1). This loss of SDHB can be detected rapidly by immunohistochemistry (IHC) and loss of immunohistochemical staining for SDHB is used as the hallmark of SDH-deficient tumors [6,7,8,9]

HOW DO SDHX MUTATIONS LEAD TO TUMORIGENESIS?

Carney triad Hypermethylation of SDHC promoter Unknown Very rare No

Genetic Counseling and Genetic Testing

AUTHOR CONTRIBUTIONS

Findings

SUMMARY