A genetic predisposition for paragangliomas and adrenal or extra-adrenal phaeochromocytomas was recognized years ago. Beside the well-known syndromes associated with an increased risk of adrenal phaeochromocytoma, Von Hippel Lindau disease, multiple endocrine neoplasia type 2 and neurofibromatosis type 1, the study of inherited predisposition to head and neck paragangliomas led to the discovery of the novel 'paraganglioma-phaeochromocytoma syndrome' caused by germline mutations in three genes encoding subunits of the succinate dehydrogenase (SDH) enzyme (SDHB, SDHC and SDHD) thus opening an unexpected connection between mitochondrial tumour suppressor genes and neural crest-derived cancers. Germline mutations in SDH genes are responsible for 6% and 9% of sporadic paragangliomas and phaeochromocytomas, respectively, 29% of paediatric cases, 38% of malignant tumours and more than 80% of familial aggregations of paraganglioma and phaeochromocytoma. The disease is characterized by autosomal dominant inheritance with a peculiar parent-of-origin effect for SDHD mutations. Life-time tumour risk seems higher than 70% with variable clinical manifestantions depending on the mutated gene. In this review we summarize the most recent knowledge about the role of SDH deficiency in tumorigenesis, the spectrum and prevalence of SDH mutations derived from several series of cases, the related clinical manifestantions including rare phenotypes, such as the association of paragangliomas with gastrointestinal stromal tumours and kidney cancers, and the biological hypotheses attempting to explain genotype to phenotype correlation.

中文翻译：

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肿瘤发生和遗传性内分泌肿瘤中的 SDH 突变：嗜铬细胞瘤-副神经节瘤综合征的教训。

多年前就发现了副神经节瘤和肾上腺或肾上腺外嗜铬细胞瘤的遗传易感性。除了与肾上腺嗜铬细胞瘤、Von Hippel Lindau 病、2 型多发性内分泌瘤和 1 型神经纤维瘤病风险增加相关的众所周知的综合征外，对头颈部副神经节瘤的遗传易感性的研究还发现了新型“副神经节瘤”。由编码琥珀酸脱氢酶 (SDH) 酶亚基（SDHB、SDHC 和 SDHD）的三个基因的种系突变引起的嗜铬细胞瘤综合征，从而在线粒体肿瘤抑制基因和神经嵴衍生的癌症之间开辟了意想不到的联系。SDH 基因的种系突变分别导致 6% 和 9% 的散发性副神经节瘤和嗜铬细胞瘤，以及 29% 的儿科病例，38%的恶性肿瘤和80%以上的家族性聚集性副神经节瘤和嗜铬细胞瘤。该疾病的特征是常染色体显性遗传，对 SDHD 突变具有特殊的亲本效应。终生肿瘤风险似乎高于 70%，临床表现因突变基因而异。在这篇综述中，我们总结了关于 SDH 缺乏在肿瘤发生中的作用的最新知识，来自几个系列病例的 SDH 突变的谱和流行率，相关的临床表现，包括罕见的表型，例如副神经节瘤与胃肠道间质瘤的关联和肾癌，以及试图解释基因型与表型相关性的生物学假设。