Briggs Tracy A, Rice Gillian I, Adib Navid, Ades Lesley, Barete Stephane, Baskar Kannan, Baudouin Veronique, Cebeci Ayse N, Clapuyt Philippe, Coman David, De Somer Lien, Finezilber Yael, Frydman Moshe, Guven Ayla, Heritier Sébastien, Karall Daniela, Kulkarni Muralidhar L, Lebon Pierre, Levitt David, Le Merrer Martine, Linglart Agnes, Livingston John H, Navarro Vincent, Okenfuss Ericka, Puel Anne, Revencu Nicole, Scholl-Bürgi Sabine, Vivarelli Marina, Wouters Carine, Bader-Meunier Brigitte, Crow Yanick J
Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
J Clin Immunol. 2016 Apr;36(3):220-34. doi: 10.1007/s10875-016-0252-y. Epub 2016 Mar 8.
Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases.
We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations.
We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.
Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.
脊椎骨骺发育异常是一种由ACP5双等位基因突变引起的罕见免疫性骨发育异常疾病。我们旨在对一组经分子确诊的病例中的该疾病的骨骼、神经和免疫表现进行调查。
我们汇总了来自18个家系的总共26例患者的临床、遗传和血清学数据，所有患者均有ACP5双等位基因突变。
我们观察到骨骼、神经和免疫表型存在变异性，有时甚至在受影响的兄弟姐妹之间也很明显。26例患者中共有22例表现出自身免疫性疾病，最常见的是自身免疫性血小板减少症和系统性红斑狼疮。4例患者被认为未表现出临床自身免疫性疾病，尽管其中2例自身抗体呈阳性。在大多数接受检测的患者中，我们检测到干扰素刺激基因（ISGs）的表达上调，这与自身免疫表型以及缺陷蛋白抗酒石酸酸性磷酸酶（TRAP）可能的免疫调节功能一致。两名突变阳性患者未表现出ISGs上调，其中一名患者患有严重的自身免疫性疾病，通过免疫抑制治疗得到控制。
我们的数据扩展了脊椎骨骺发育异常的已知表型。我们认为，脊椎骨骺发育异常和伴有免疫失调的脊椎骨骺发育异常在《医学遗传学在线数据库》（OMIM）中的区分不再合适，因为我们提供的分子证据表明这些表型代表了同一种疾病的连续谱。此外，一名患有严重自身免疫性疾病的患者在接受免疫调节治疗后未出现干扰素特征，这可能表明对脊椎骨骺发育异常的免疫表现具有重要的治疗反应。
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