Balasubramanian Meena, Parker Michael J, Dalton Ann, Giunta Cecilia, Lindert Uschi, Peres Luiz C, Wagner Bart E, Arundel Paul, Offiah Amaka, Bishop Nicholas J
Sheffield Clinical Genetics Service Sheffield Diagnostic Genetics Service Department of Histopathology, Sheffield Children's NHS Foundation Trust Electron Microscopy Unit, Department of Histopathology, Royal Hallamshire Hospital Academic Unit of Child Health, University of Sheffield, Sheffield, UK Division of Metabolism, Connective Tissue Unit and Children's Research Centre, University Children's Hospital, Zurich, Switzerland.
Clin Dysmorphol. 2013 Jul;22(3):93-101. doi: 10.1097/MCD.0b013e32836032f0.
Type V osteogenesis imperfecta (OI) presents with moderate-to-severe skeletal deformity and is characterized by hyperplastic callus formation at fracture sites and calcification of the interosseous membranes of the forearm and lower leg. The facial dysmorphism is not well characterized and has not been described in previous reports. Inheritance is autosomal dominant, although the genetic aetiology remained unknown until very recently. The aims of this study were to establish the genetic aetiology in patients with type V OI and further characterize patients with this condition, and to ascertain whether they have a similar clinical phenotype and facial dysmorphism. Three families (one mother-daughter pair and two singletons) were identified with the above features and further investigations (molecular genetic analysis and skin biopsy including electron microscopy, histology and collagen species analysis) were performed. Accurate phenotyping of patients with type V OI was performed. PCR amplification was performed using the Sheffield Diagnostic Genetics Service pyrosequencing assay for the interferon-induced transmembrane protein-5 (IFITM5) gene. All the patients had been confirmed to have a heterozygous variant, c.[-14C>T];[=], in the 5'-UTR of the IFITM5 gene, which is located in the transcribed region of this gene. This recurrent mutation, in IFITM5, also known as bone-restricted interferon-induced transmembrane protein-like protein or BRIL, encodes a protein with a function in bone formation and plays an important role in osteoblast formation. All four patients in this study appear to have similar clinical features and facial dysmorphism, including a short, up-turned nose, a small mouth, a prominent chin and greyish-blue sclerae. Skin biopsy in one patient showed clumping of elastic fibres and normal biochemical analysis of collagen. We have been able to characterize patients with type V OI further and confirm the genetic aetiology in this distinct form of OI. Accurate phenotyping (including describing the common facial features) before investigations is important to enable the useful interpretation of genetic results and/or target-specific gene testing.
V型成骨不全症（OI）表现为中度至重度骨骼畸形，其特征是骨折部位形成增生性骨痂以及前臂和小腿的骨间膜钙化。面部畸形特征尚不明确，既往报道中也未提及。其遗传方式为常染色体显性遗传，不过直到最近其遗传病因仍不清楚。本研究的目的是确定V型OI患者的遗传病因，进一步描述该疾病患者的特征，并确定他们是否具有相似的临床表型和面部畸形。我们识别出了三个具有上述特征的家系（一对母女和两个散发病例），并进行了进一步检查（分子遗传学分析以及包括电子显微镜检查、组织学检查和胶原种类分析在内的皮肤活检）。对V型OI患者进行了准确的表型分析。使用谢菲尔德诊断遗传学服务公司的焦磷酸测序法对干扰素诱导跨膜蛋白5（IFITM5）基因进行PCR扩增。所有患者均被证实IFITM5基因5'-UTR区域存在杂合变异c.[-14C>T];[=]，该区域位于该基因的转录区。IFITM5基因中的这种复发性突变，也称为骨限制性干扰素诱导跨膜样蛋白或BRIL，编码一种在骨形成中起作用的蛋白质，对成骨细胞形成起着重要作用。本研究中的所有四名患者似乎都具有相似的临床特征和面部畸形，包括短而上翘的鼻子、小嘴、突出的下巴和灰蓝色巩膜。对一名患者进行的皮肤活检显示弹性纤维聚集，胶原生化分析正常。我们能够进一步描述V型OI患者的特征，并证实这种特殊类型OI的遗传病因。在进行检查之前进行准确的表型分析（包括描述常见的面部特征）对于有效解读遗传结果和/或进行靶向特定基因检测很重要。
