1型自身免疫性多内分泌综合征的纵向随访
A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1.
作者信息
Bruserud Øyvind, Oftedal Bergithe E, Landegren Nils, Erichsen Martina M, Bratland Eirik, Lima Kari, Jørgensen Anders P, Myhre Anne G, Svartberg Johan, Fougner Kristian J, Bakke Åsne, Nedrebø Bjørn G, Mella Bjarne, Breivik Lars, Viken Marte K, Knappskog Per M, Marthinussen Mihaela C, Løvås Kristian, Kämpe Olle, Wolff Anette B, Husebye Eystein S
机构信息
Department of Clinical Science (Ø.B., B.E.O., E.B., B.G.N., L.B., P.M.K., K.Lo., A.B.W., E.S.H.), University of Bergen, 5021 Bergen, Norway; Department of Medicine (Solna) (N.L., O.K.), Karolinska Institutet, 171 76 Stockholm, Sweden; Science for Life Laboratory (N.L.), Department of Medical Sciences, University of Uppsala, 751 05 Uppsala, Sweden; Department of Medicine (M.M.E., K.Lo., E.S.H.), Haukeland University Hospital, 5021 Bergen, Norway; Department of Medicine (K.Li.,), Akershus University Hospital, 1474 Nordbyhagen, Norway; Department of Endocrinology (K.Li., A.P.J.), Oslo University Hospital, 0372 Oslo, Norway; Department of Pediatrics (A.G.M.), Oslo University Hospital, 0424 Oslo, Norway; Division of Internal Medicine (J.S.), University Hospital of North Norway, 9019 Tromsø, Norway; Institute of Clinical Medicine (J.S.), University of Tromsø, The Artic University of Norway, 9019 Tromsø, Norway; Department of Endocrinology (K.J.F.), St. Olavs Hospital, 7006 Trondheim, Norway; Department of Medicine (Å.B.), Stavanger University Hospital, 4011 Stavanger, Norway; Department of Medicine (B.G.N.), Haugesund Hospital, 5504 Haugesund, Norway; Department of Medicine (B.M.), Østfold Hospital, 1603 Fredrikstad, Norway; Department of Immunology (M.K.V.), Oslo University Hospital, 0372 Oslo, Norway; University of Oslo (M.K.V.), 0372 Oslo, Norway; Center for Medical Genetics and Molecular Medicine (P.M.K.), Haukeland University Hospital, 5021 Bergen, Norway; Department of Clinical Dentistry (M.C.M.), Faculty of Medicine and Dentistry, University of Bergen, 5021 Bergen, Norway; and Oral Health Centre of Expertise in Western Norway (M.C.M.), 5021 Bergen, Norway.
出版信息
J Clin Endocrinol Metab. 2016 Aug;101(8):2975-83. doi: 10.1210/jc.2016-1821. Epub 2016 Jun 2.
CONTEXT
Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse.
OBJECTIVE
To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016).
PATIENTS
All known Norwegian patients with APS1.
RESULTS
Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes.
CONCLUSIONS
Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.
背景
自身免疫性多内分泌腺综合征1型（APS1）是一种儿童期发病的单基因疾病，由以下三个主要成分中的两个存在来定义：甲状旁腺功能减退、原发性肾上腺皮质功能不全和慢性黏膜皮肤念珠菌病（CMC）。关于APS1纵向随访的信息很少。
目的
描述APS1的表型，并在长期随访（1996 - 2016年）期间将临床特征与自身抗体谱和自身免疫调节因子（AIRE）突变相关联。
患者
所有已知的挪威APS1患者。
结果
确定了来自34个家庭的52名患者。大多数患者在儿童期出现主要疾病成分之一。釉质发育不全、甲状旁腺功能减退和CMC是最常见的成分。随着年龄增长，大多数患者出现三到五种疾病表现，尽管有些患者在成年期被诊断为较轻的表型。15名患者在随访期间死亡（死亡中位年龄为34岁），或者是很可能未被诊断出APS1的已故兄弟姐妹。除3名患者外，所有患者都有干扰素ω自身抗体，并且都有器官特异性自身抗体。最常见的AIRE突变是c.967_979del13，15名患者为纯合子。轻度表型与剪接突变c.879 + 1G>A相关。原发性肾上腺皮质功能不全和1型糖尿病与保护性人类白细胞抗原基因型相关。
结论
多种可能的自身免疫表现，特别是甲状旁腺功能减退、CMC和釉质发育不全，即使在成年人中也应促使使用自身抗体分析（如干扰素ω）和AIRE测序进行进一步的诊断检查以揭示APS1。治疗复杂，死亡率高。应在专业中心进行结构化随访。
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