Krull I, M-Woelfle M, Bärlocher K, Koehler K, Huebner A, Brändle M
Division of Endocrinology and Diabetes, Department of Internal Medicine, Cantonal Hospital St. Gallen, Switzerland.
Exp Clin Endocrinol Diabetes. 2010 Aug;118(8):530-6. doi: 10.1055/s-0030-1247516. Epub 2010 Mar 3.
Triple A syndrome, also known as Allgrove syndrome, is a rare autosomal recessive disorder characterized by three cardinal symptoms: adrenal insufficiency due to ACTH insensitivity, achalasia and alacrima. Various progressive neurological abnormalities and skin changes have been described in association with the syndrome. The disease is caused by mutation in the AAAS gene on chromosome 12q13. AAAS encodes a protein named ALADIN which is part of the nuclear pore complex (NPC). The mislocalization of mutated ALADIN proteins in the cytoplasm and/or the nucleus results in an impaired protein function. Phenotypes of previously reported patients with triple A syndrome varied within and between affected families so that no genotype-phenotype could be established.
Genetic analysis was performed in two unrelated patients, their parents and one sister. AAAS coding sequences including exon-intron boundaries were amplified and sequenced using an ABI 3100 sequencing machine.
We present two unrelated Swiss patients with triple A syndrome demonstrating similar phenotypic characteristics. Both showed a progression of the disease presenting with adrenal insufficiency and alacrima in early childhood. At the age between 30-40 years they developed symptomatic achalasia. The pattern and severity of progressive neurological and autonomic dysfunction was comparable. In both patients molecular genetic analysis revealed an identical novel homozygous mutation (c.618delC, p.Ser207fs) in the AAAS gene.
Recent genotype/phenotype studies showed a marked inter- and intrafamiliar variability in triple A syndrome. Here we present a rather tight genotype/phenotype correlation in two unrelated patients carrying the identical novel p.Ser207fs mutation in the AAAS gene.
三 A 综合征，也称为阿尔格罗夫综合征，是一种罕见的常染色体隐性疾病，其特征为三个主要症状：促肾上腺皮质激素不敏感导致的肾上腺功能不全、贲门失弛缓症和无泪症。已描述了与该综合征相关的各种进行性神经异常和皮肤变化。该疾病由 12q13 染色体上的 AAAS 基因突变引起。AAAS 编码一种名为 ALADIN 的蛋白质，它是核孔复合体（NPC）的一部分。突变的 ALADIN 蛋白在细胞质和/或细胞核中的定位错误导致蛋白质功能受损。先前报道的三 A 综合征患者的表型在受影响的家族内部和之间存在差异，因此无法建立基因型 - 表型关系。
对两名无关患者、他们的父母和一名姐妹进行了基因分析。使用 ABI 3100 测序仪扩增并测序包括外显子 - 内含子边界的 AAAS 编码序列。
我们展示了两名患有三 A 综合征的无关瑞士患者，他们表现出相似的表型特征。两人均在幼儿期出现疾病进展，表现为肾上腺功能不全和无泪症。在 30 至 40 岁之间，他们出现了有症状的贲门失弛缓症。进行性神经和自主神经功能障碍的模式和严重程度相当。在两名患者中，分子遗传学分析均揭示了 AAAS 基因中相同的新型纯合突变（c.618delC，p.Ser207fs）。
最近的基因型/表型研究表明，三 A 综合征在家族间和家族内存在显著变异性。在此，我们展示了两名携带 AAAS 基因相同新型 p.Ser207fs 突变的无关患者中相当紧密的基因型/表型相关性。
