Bertherat Jérôme, Horvath Anélia, Groussin Lionel, Grabar Sophie, Boikos Sosipatros, Cazabat Laure, Libe Rosella, René-Corail Fernande, Stergiopoulos Sotirios, Bourdeau Isabelle, Bei Thalia, Clauser Eric, Calender Alain, Kirschner Lawrence S, Bertagna Xavier, Carney J Aidan, Stratakis Constantine A
Institut National de la Santé et de la Recherche Médicale Unit 567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, Endocrinology, Metabolism and Cancer Department, Paris 75014, France.
J Clin Endocrinol Metab. 2009 Jun;94(6):2085-91. doi: 10.1210/jc.2008-2333. Epub 2009 Mar 17.
The "complex of myxomas, spotty skin pigmentation, and endocrine overactivity," or "Carney complex" (CNC), is caused by inactivating mutations of the regulatory subunit type 1A of the cAMP-dependent protein kinase (PRKAR1A) gene and as yet unknown defect(s) in other gene(s). Delineation of a genotype-phenotype correlation for CNC patients is essential for understanding PRKAR1A function and providing counseling and preventive care.
A transatlantic consortium studied the molecular genotype and clinical phenotype of 353 patients (221 females and 132 males, age 34 +/- 19 yr) who carried a germline PRKAR1A mutation or were diagnosed with CNC and/or primary pigmented nodular adrenocortical disease.
A total of 258 patients (73%) carried 80 different PRKAR1A mutations; 114 (62%) of the index cases had a PRKAR1A mutation. Most PRKAR1A mutations (82%) led to lack of detectable mutant protein (nonexpressed mutations) because of nonsense mRNA mediated decay. Patients with a PRKAR1A mutation were more likely to have pigmented skin lesions, myxomas, and thyroid and gonadal tumors; they also presented earlier with these tumors. Primary pigmented nodular adrenocortical disease occurred earlier, was more frequent in females, and was the only manifestation of CNC with a gender predilection. Mutations located in exons were more often associated with acromegaly, myxomas, lentigines, and schwannomas, whereas the frequent c.491-492delTG mutation was commonly associated with lentigines, cardiac myxomas, and thyroid tumors. Overall, nonexpressed PRKAR1A mutations were associated with less severe disease.
CNC is genetically and clinically heterogeneous. Certain tumors are more frequent, with specific mutations providing some genotype-phenotype correlation for PRKAR1A mutations.
“黏液瘤、皮肤斑点状色素沉着和内分泌功能亢进综合征”，即“卡尼综合征”（CNC），由环磷酸腺苷依赖性蛋白激酶（PRKAR1A）基因的1A调节亚基失活突变以及其他基因中尚不明确的缺陷引起。明确CNC患者的基因型-表型相关性对于理解PRKAR1A功能以及提供咨询和预防保健至关重要。
一个跨大西洋的研究团队研究了353例患者（221例女性和132例男性，年龄34±19岁）的分子基因型和临床表型，这些患者携带种系PRKAR1A突变或被诊断为CNC和/或原发性色素沉着性结节性肾上腺皮质疾病。
共有258例患者（73%）携带80种不同的PRKAR1A突变；114例（62%）索引病例存在PRKAR1A突变。大多数PRKAR1A突变（82%）由于无义mRNA介导的降解导致无法检测到突变蛋白（无表达突变）。携带PRKAR1A突变的患者更易出现皮肤色素沉着病变、黏液瘤以及甲状腺和性腺肿瘤；他们出现这些肿瘤的时间也更早。原发性色素沉着性结节性肾上腺皮质疾病发病更早，在女性中更常见，是CNC唯一具有性别倾向的表现。位于外显子的突变更常与肢端肥大症、黏液瘤、雀斑样痣和神经鞘瘤相关，而常见的c.491-492delTG突变通常与雀斑样痣、心脏黏液瘤和甲状腺肿瘤相关。总体而言，无表达的PRKAR1A突变与病情较轻相关。
CNC在遗传和临床方面具有异质性。某些肿瘤更为常见，特定突变可为PRKAR1A突变提供一些基因型-表型相关性。
