Serviço de Endocrinologia e Nutriço, Ponta Delgada, São Miguel 9500, Azores, Portugal.
J Clin Endocrinol Metab. 2012 Feb;97(2):351-9. doi: 10.1210/jc.2011-2244. Epub 2011 Nov 23.
Most tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, we describe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-α (RIα) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC.
We studied the genotype-phenotype correlation in CNC.
We reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center.
Twenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations.
Cushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did not have PPNAD. A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism. Unlike in other RIα defects, loss of heterozygosity was not observed in AC. The S147G mutation was compared to other expressed PRKAR1A mutations; it led to decreased cAMP and catalytic subunit binding by RIα and increased protein kinase A activity in vitro.
In a large family with CNC, one amino acid substitution caused a spectrum of adrenal disease that ranged from lack of manifestations to cancer. PPNAD and AC were the only manifestations of CNC in these patients, in addition to lentigines. These data have implications for counseling patients with CNC and are significant in documenting the first case of AC in the context of PPNAD.
大多数卡尼综合征(CNC)中的肿瘤为良性,包括 CNC 中的主要内分泌肿瘤——原发性色素性结节性肾上腺皮质病(PPNAD)。该综合征中从未观察到肾上腺皮质癌(AC)。在此,我们描述了一个大型亚速尔群岛家族,其 CNC 是由编码 cAMP 依赖性蛋白激酶 A Ⅰ型-α(RIα)调节亚单位的 PRKAR1A 基因突变引起的,该家族中的索引患者表现为 AC。
我们研究了 CNC 的基因型-表型相关性。
我们在三级转诊中心报告了一系列病例,并对 PRKAR1A 突变进行了体外检测。
对一个家族的 22 名成员进行了库欣综合征和其他 CNC 成分的调查;对他们的 DNA 进行了 PRKAR1A 突变测序。
4 名患者发生了 PPNAD 引起的库欣综合征,包括先证者,她表现为 AC,另外 3 名患者有库欣综合征和/或 PPNAD。6 名额外的患者有色素沉着斑,但没有 PPNAD。在先证者、另外 3 名有 PPNAD 的患者、先证者的双胞胎女儿(有色素沉着斑,但无高皮质醇血症证据)以及另外 5 名家族成员(包括 1 名无色素沉着斑和无高皮质醇血症证据的成员)中发现了 PRKAR1A 的碱基替换(c.439A>G/p.S147G)。与其他 RIα 缺陷不同,AC 中未观察到杂合性丢失。S147G 突变与其他表达的 PRKAR1A 突变进行了比较;它导致 RIα 与 cAMP 和催化亚基的结合减少,并在体外增加蛋白激酶 A 的活性。
在一个大型 CNC 家族中,一个氨基酸取代导致了从无表现到癌症的一系列肾上腺疾病。在这些患者中,除了色素沉着斑外,PPNAD 和 AC 是 CNC 的唯一表现。这些数据对 CNC 患者的咨询具有启示意义,并首次在 PPNAD 背景下记录了 AC 病例。