Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumours (GISTs) and pulmonary chondromas (PCH). A number of other lesions have been described in the condition including pheochromocytomas, oesophageal leiomyomas and adrenocortical adenomas; CT is a novel form of multiple endocrine neoplasia (MEN), a genetic condition with a female predilection. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD have been found in familial and sporadic PGLs, and gain-of-function mutations of the oncogenes c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) cause sporadic and familial GISTs. We recently reported an international series of patients with CT, 34 females and three males (median age of presentation 21 years) who did not carry SDHA, SDHB, SDHC, SDHD, KIT or PDGFRA gene mutations. Comparative genomic hybridization revealed a number of DNA copy number changes. The most frequent and greatest contiguous change was a deletion within the 1pcen13-q21 region, which harbours the SDHC gene. Another frequent change was loss of 1p. Although GISTs showed more frequent losses of 1p than PGLs, the pattern of chromosomal changes was similar in the two tumours despite their different tissue origin and histology; the findings were consistent with a common genetic aetiology of these two tumours in CT. In a separate condition, in which the association (or dyad) of GISTs with PGLs is inherited in an autosomal dominant manner (Carney-Stratakis syndrome, CSS), germline mutations of the SDHB, SDHC and SDHD genes (but not KIT or PDFGRA) were found; GISTs in this condition were caused by SDH deficiency. We conclude that CT is a novel MEN syndrome whose genetic defect remains elusive. CSS is caused by SDH defects, suggesting that sarcomas (GISTs) can be caused by defective mitochondrial oxidation, consistent with recent data implicating this enzyme in a variety of endocrine and other tumours. The above have clinical implications (i) for patients with GISTs that are cKIT- and PDGFRA-mutation negative: these tumours are usually resistant to treatment with currently available tyrosine kinase inhibitors and may be part of a syndrome such as CT or CSS; and (ii) for patients with an inherited PGL syndrome, family history should be explored to identify any other tumours in the family, and in particular other endocrine lesions and GISTs.

中文翻译：

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副神经节瘤、胃间质瘤和肺软骨瘤三联征（卡尼三联征），以及副神经节瘤和胃间质肉瘤（卡尼-斯特拉塔基斯综合征）二联征：分子遗传学和临床意义。


卡尼三联征 (CT) 描述了副神经节瘤 (PGL) 与胃肠道间质瘤 (GIST) 和肺软骨瘤 (PCH) 的关联。该病症还描述了许多其他病变，包括嗜铬细胞瘤、食管平滑肌瘤和肾上腺皮质腺瘤； CT 是多发性内分泌肿瘤 (MEN) 的一种新型形式，是一种女性好发的遗传性疾病。在家族性和散发性 PGL 中发现了线粒体复合物 II 琥珀酸脱氢酶 (SDH) 酶亚基 SDHB、SDHC 和 SDHD 的失活突变，以及癌基因 c-kit (KIT) 和血小板衍生生长因子的功能获得性突变受体 A (PDGFRA) 会导致散发性和家族性 GIST。我们最近报道了一系列国际 CT 患者，其中 34 名女性和 3 名男性（中位就诊年龄 21 岁）不携带 SDHA、SDHB、SDHC、SDHD、KIT 或 PDGFRA 基因突变。比较基因组杂交揭示了许多 DNA 拷贝数变化。最常见和最大的连续变化是 1pcen13-q21 区域内的缺失，该区域包含 SDHC 基因。另一个频繁的变化是 1p 的丢失。尽管 GIST 比 PGL 表现出更频繁的 1p 丢失，但这两种肿瘤的染色体变化模式相似，尽管它们的组织起源和组织学不同。这些结果与 CT 中这两种肿瘤的共同遗传病因学一致。在另一种情况下，GIST 与 PGL 的关联（或二元体）以常染色体显性方式遗传（卡尼-斯特拉塔基斯综合征，CSS），SDHB、SDHC 和 SDHD 基因的种系突变（但不是 KIT 或 PDFGRA）被发现；这种情况下的 GIST 是由 SDH 缺乏引起的。 我们得出的结论是，CT 是一种新型 MEN 综合征，其遗传缺陷仍然难以捉摸。 CSS 是由 SDH 缺陷引起的，这表明肉瘤 (GIST) 可能是由线粒体氧化缺陷引起的，这与最近的数据一致，表明这种酶与多种内分泌肿瘤和其他肿瘤有关。上述内容具有临床意义：(i) 对于 cKIT 和 PDGFRA 突变阴性的 GIST 患者：这些肿瘤通常对目前可用的酪氨酸激酶抑制剂治疗有抵抗力，并且可能是 CT 或 CSS 等综合征的一部分； (ii) 对于患有遗传性 PGL 综合征的患者，应探查家族史，以确定家族中是否有任何其他肿瘤，特别是其他内分泌病变和胃肠道间质瘤。