Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
J Med Genet. 2012 Jan;49(1):47-57. doi: 10.1136/jmedgenet-2011-100382.
Aneurysms-osteoarthritis syndrome (AOS) is a new autosomal dominant syndromic form of thoracic aortic aneurysms and dissections characterised by the presence of arterial aneurysms and tortuosity, mild craniofacial, skeletal and cutaneous anomalies, and early-onset osteoarthritis. AOS is caused by mutations in the SMAD3 gene.
A cohort of 393 patients with aneurysms without mutation in FBN1, TGFBR1 and TGFBR2 was screened for mutations in SMAD3. The patients originated from The Netherlands, Belgium, Switzerland and USA. The clinical phenotype in a total of 45 patients from eight different AOS families with eight different SMAD3 mutations is described. In all patients with a SMAD3 mutation, clinical records were reviewed and extensive genetic, cardiovascular and orthopaedic examinations were performed.
Five novel SMAD3 mutations (one nonsense, two missense and two frame-shift mutations) were identified in five new AOS families. A follow-up description of the three families with a SMAD3 mutation previously described by the authors was included. In the majority of patients, early-onset joint abnormalities, including osteoarthritis and osteochondritis dissecans, were the initial symptom for which medical advice was sought. Cardiovascular abnormalities were present in almost 90% of patients, and involved mainly aortic aneurysms and dissections. Aneurysms and tortuosity were found in the aorta and other arteries throughout the body, including intracranial arteries. Of the patients who first presented with joint abnormalities, 20% died suddenly from aortic dissection. The presence of mild craniofacial abnormalities including hypertelorism and abnormal uvula may aid the recognition of this syndrome.
The authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up.
动脉瘤-骨关节炎综合征（AOS）是一种新的常染色体显性遗传性胸主动脉瘤和夹层综合征，其特征为存在动脉瘤和扭曲、轻度颅面、骨骼和皮肤异常以及早发性骨关节炎。AOS 是由 SMAD3 基因突变引起的。
对 393 例无 FBN1、TGFBR1 和 TGFBR2 突变的动脉瘤患者进行 SMAD3 基因突变筛查。这些患者来自荷兰、比利时、瑞士和美国。描述了来自 8 个不同 AOS 家系的 45 例患者的总共 8 种不同的 SMAD3 突变的临床表型。对所有携带 SMAD3 突变的患者，均进行了临床记录回顾和广泛的遗传、心血管和骨科检查。
在 5 个新的 AOS 家系中发现了 5 种新的 SMAD3 突变（1 种无义突变、2 种错义突变和 2 种移码突变）。作者对之前描述过的 3 个携带 SMAD3 突变的家系进行了随访描述。在大多数患者中，早发性关节异常，包括骨关节炎和剥脱性骨软骨炎，是其最初寻求医疗建议的症状。近 90%的患者存在心血管异常，主要涉及主动脉瘤和夹层。在全身的主动脉和其他动脉，包括颅内动脉，都发现了动脉瘤和扭曲。在最初表现为关节异常的患者中，有 20%因主动脉夹层突然死亡。轻度颅面异常，包括眼距过宽和异常悬雍垂的存在，可能有助于识别这种综合征。
作者进一步深入了解了携带 SMAD3 突变的 AOS 的表型，并提出了临床评估建议。
