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

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.

Treatment of Gastrointestinal Stromal Tumors (GISTs): A Focus on Younger Patients

“…In histological examination, these tumors are characterized by a multinodular growth pattern with epithelioid cells, which are multifocal. Additionally, it was found that SDH-deficient GISTs overexpress insulin-like growth factor receptors (IGF1R) [ 18 ]. Testing for germline mutations in SDH should be considered in young adults with GISTs wild type for KIT/PDGFRA mutations.…”

“…Carney’s triad is usually caused by a specific pattern of methylation of the SDHC gene and may be due to germline mosaicism of the responsible genetic defect. Carney-Stratakis syndrome is instead caused by inactivating germline mutations in genes encoding for the SDH subunits [ 18 ].…”

SDH-deficient gastrointestinal stromal tumours

“…The summary of the main characteristics of SDH-deficient GIST is presented in table I and II. Over 80% of pediatric GIST has inactivating mutations in SDH subunits [23,24].…”

“…Succinate dehydrogenase (SDH, also known as mitochondrial complex II or succinate-ubiquinone oxydoreductase) is a highly conserved heterotetrameric enzyme complex (composed of four protein subunits -SDHA, SDHB, SDHC, and SDHD, encoded by nuclear genes, mapped to 5p15.22, 1p36.13, 1q23.3 and 11q23.1, respectively), which acts at the interphase of the tricarboxylic acid cycle and electron transport chain. SDH 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 [24].…”

Clinical and morphological characteristics of patients of gastrointestinal stromal tumor with deficiency of succinate dehydrogenase

“…Примерно у 50% пациентов с дефицитом SDH имеет место гиперметилирование промотора SDHC, у 30% -мутации генов SDHA и у 20% -мутации SDHB, SDHC, SDHD. Мутации и эпигенетические изменения приводят к потере экспрессии одной из субъединиц комплекса и к накоплению в клетке сукцината, который ингибирует семейство 5-метилцитозингидроксилаз TET, которые превращают 5-метидцитозин в 5-гидроксиметилцитозин (деметилируют цитозин), что в дальнейшем приводят к изменению метилирования ДНК [8]. Инактивация SDH вызывает активацию сигнальных путей, что приводит к усилению ангиогенеза и клеточной пролиферации [9].…”