Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
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DOI：
10.1172/jci.insight.88782
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发表时间：
2016-08-18
期刊：
影响因子：
8
通讯作者：
Lionakis, Michail S.
中科院分区：
文献类型：
--
作者：
Ferre, Elise M. N.;Rose, Stacey R.;Lionakis, Michail S.
自身免疫性多内分泌病-念珠菌病-外胚层营养不良（APECED）是一种罕见的原发性免疫缺陷疾病，通常由AIRE纯合突变引起。典型表现为慢性皮肤粘膜念珠菌病和自身免疫，主要针对内分泌组织；甲状旁腺功能减退和肾上腺功能不全是最常见的。出现这些典型的三联征中的任何两种表现都可以确定诊断。尽管在非内分泌自身免疫表现不常见的欧洲被广泛认可，但在西半球患者中APECED的定义较少。我们招募了35名连续的美国APECED患者（其中33名来自美国）进行前瞻性观察性自然史研究，并系统地检查了他们的遗传、临床、自身抗体和免疫学特征。多数患者为复合杂合子；最常见的AIRE突变为c.967_979del13。除了一名患者外，所有患者都有抗ifn -omega自身抗体，包括5名没有双等位基因AIRE突变的患者中的4名。荨麻疹疹、肝炎、胃炎、肠道功能障碍、肺炎和干燥样综合征，这些在欧洲APECED队列中不常见的疾病，影响了40%-80%的美国病例。典型诊断性双染色体的发展平均延迟7.38年。80%的患者在诊断前平均有3种非三联征表现。只有20%的患者出现了典型三联症的前两种表现。早期表现为荨麻疹疹、肠道功能障碍和牙釉质发育不全。患者外周血CD4(+) T细胞和CD21（低）CD38（低）B淋巴细胞扩增。总之，与欧洲患者相比，美国APECED患者表现出多样化的综合征，在生命早期就开始出现器官特异性非内分泌表现。将这些新表现纳入美国诊断标准将使诊断时间缩短约4年，并有可能预防危及生命的内分泌并发症。
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13. All but one patient had anti-IFN-omega autoantibodies, including 4 of 5 patients without biallelic AIRE mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjogren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4(+) T cells and CD21(lo)CD38(lo) B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.