BACKGROUND Osteogenesis imperfecta (OI) covers a spectrum of bone fragility disorders. OI is classified into five types; however, the genetic causes of OI might hide in pathogenic variants of 20 different genes. Often clinical OI types mimic each other. This sometimes makes it impossible to identify the OI type clinically, which can be a risk for patients. Up to 90% of OI types I-IV are caused by pathogenic variants in the COL1A1/2 genes. OI type V is caused by the c.-14C > T pathogenic variant in the 5'UTR of the IFITM5 gene and is characterized by hyperplastic callus formation and the ossification of interosseous membranes. RESULTS In the current study, we performed IFITM5 5'UTR region mutational analysis using Sanger sequencing on 90 patients who were negative for COL1A1/2 pathogenic variants. We also investigated the phenotypes of five patients with genetically confirmed OI type V. The proportion of OI type V patients in our cohort of all OI patients was 1.48%. In one family, there was a history of OI in at least three generations. Phenotype severity differed from mild to extremely severe among patients, but all patients harbored the same typical pathogenic variant. One patient had no visible symptoms of OI type V and was suspected to have had OI type IV previously. We also identified a case of extremely severe hyperplastic callus in a 15-year-old male, who has hearing loss and brittleness of teeth. CONCLUSIONS OI type V is underlined with some unique clinical features; however, not all patients develop them. The phenotype spectrum might be even broader than previously suspected, including typical OI features: teeth brittleness, bluish sclera, hearing loss, long bones deformities, and joint laxity. We suggest that all patients negative for COL1A1/2 pathogenic variants be tested for the presence of an IFITM5 pathogenic variant, even if they are not expressing typical OI type V symptoms. Further studies on the pathological nature and hyperplastic callus formation mechanisms of OI type V are necessary.

中文翻译：

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IFITM5致病变异在乌克兰和越南患者中导致具有不同表型严重性的成骨不全V型。

背景技术成骨不全症（OI）涵盖了一系列骨脆性疾病。OI分为五种类型：但是，OI的遗传原因可能隐藏在20种不同基因的致病变异中。临床OI类型常常相互模仿。有时这使得不可能在临床上识别OI类型，这可能会给患者带来风险。高达90％的OI I-IV类型是由COL1A1 / 2基因中的致病性变异引起的。V型OI是由IFITM5基因5'UTR中的c.-14C> T致病变异引起的，其特征在于增生性愈伤组织的形成和骨间膜的骨化。结果在本研究中，我们对90例COL1A1 / 2致病变异阴性的患者进行了Sanger测序，从而对IFITM5 5'UTR区进行了突变分析。我们还调查了五名经遗传学证实为V型OI的患者的表型。在我们所有患者中，V OI型V患者的比例为1.48％。在一个家庭中，至少有三代人有OI的病史。表型严重程度在患者中从轻度到极度不等，但是所有患者均具有相同的典型致病变异。一名患者没有可见的V型OI症状，并且怀疑以前患有IV型OI。我们还发现了一名15岁的男性，患有严重的增生性愈伤组织，该患者患有听力损失和牙齿脆性。结论V型OI具有某些独特的临床特征。然而，并非所有的患者都会发展它们。该表型谱可能比以前怀疑的还要宽，包括典型的OI特征：牙齿脆性，巩膜偏蓝，听力下降，骨骼长畸形和关节松弛。我们建议对所有COL1A1 / 2致病变异阴性的患者进行测试，以检查是否存在IFITM5致病变异，即使他们没有表达典型的OI V型症状。有必要进一步研究V型OI的病理性质和增生性愈伤组织形成机制。