Triple-A Syndrome (TAS) is a rare autosomal recessive disorder characterized by three cardinal symptoms: alacrimia, achalasia and adrenal insufficiency due to ACTH insensitivity. 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. Mutations in AAAS were identified in more than 90% of individuals and families with TAS. The protein encoded by AAAS was termed ALADIN and is part of the WD repeat family of proteins, that have been found to be involved in many different functions such as protein-protein interaction, RNA processing, cytoskeleton assembly, control of cell division, signal transduction and apoptosis. Immunohistochemical analysis showed that mutated or truncated ALADIN localizes to the cytoplasm rather than to the nuclear pore complex. The exact function of ALADIN and the mechanisms that lead to the ACTH-resistant adrenal phenotype remains largely unknown. Nonetheless, recent studies provided some insights on the role of ALADIN as a member of the Nuclear Pore Complex not only implicated in the import of proteins involved in DNA repair and oxidative stress homeostasis but also in the strengthening of the mitotic spindle assembly. Early identification of the syndrome is challenging, given the rarity of the condition and high phenotypic heterogeneity even among members of the same family. In this review, we aim to summarize the current knowledge of clinical and molecular profile of patients with TAS and recommendations for the diagnosis, management, and follow-up of patients.

Triple-A综合征（TAS）是一种罕见的常染色体隐性遗传疾病，其特征在于三种主要症状：由于ACTH不敏感而导致的软性无足，失弛缓症和肾上腺功能不全。已经描述了与该综合征相关的各种进行性神经学异常和皮肤变化。该疾病是由12q13号染色体上的AAAS基因突变引起的。在超过90％的TAS个人和家庭中发现了AAAS突变。由AAAS编码的蛋白质被称为ALADIN，是WD重复蛋白质家族的一部分，发现该蛋白质具有许多不同的功能，例如蛋白质-蛋白质相互作用，RNA处理，细胞骨架装配，细胞分裂控制，信号转导和凋亡。免疫组织化学分析表明，突变或截短的ALADIN定位于细胞质而不是核孔复合体。ALADIN的确切功能和导致ACTH耐药的肾上腺表型的机制仍然未知。尽管如此，最近的研究提供了一些关于ALADIN作为核孔复合体成员的作用的见解，不仅涉及与DNA修复和氧化应激稳态有关的蛋白质的进口，而且还涉及有丝分裂纺锤体组装的增强。考虑到这种病的罕见性和表型异质性很高，即使在同一个家庭中，也很难对这种综合征进行早期识别。在这篇综述中，我们旨在总结TAS患者的临床和分子概况方面的最新知识以及诊断建议，