瓷娃娃，钢筋铁骨 (2)：成骨不全综合征(OI)：临床诊断、命名和严重程度评估：2014年

瓷娃娃，钢筋铁骨 (2)：成骨不全综合征(OI)：临床诊断、命名和严重程度评估：2014年

作者：F S Van Dijk 1 , D O Sillence

作者单位: Department of Clinical Genetics, Center for Connective Tissue Disorders, VU University Medical Center, Amsterdam, The Netherlands.

译者：陶可（北京大学人民医院骨关节科）

合作：任宁涛（解放军总医院第四医学中心骨科）

摘要

最近，Sillence等于1979年提出的成骨不全症(OI)的遗传异质性已通过分子遗传学研究得到证实。目前，已经确定了17种成骨不全症(OI)和密切相关疾病的遗传原因，预计还会有更多。与过去十年发表的关于导致成骨不全症(OI)的遗传原因和生化过程的大多数评论不同，这篇评论侧重于成骨不全症(OI)的临床分类，并详细阐述了2010年新提出的成骨不全症(OI)分类，回归到描述性和数字分组：五个成骨不全症(OI)综合征组。本综述中引入的新成骨不全症(OI)命名法和产前和产后严重程度评估，强调了表型分析对于诊断、分类和评估成骨不全症(OI)严重程度的重要性。这将使患者及其家人深入了解疾病的可能病程，并使医生能够评估治疗效果。结合对特定分子遗传原因的了解，仔细的临床描述是开发和评估包括成骨不全症(OI)在内的遗传性疾病患者治疗的起点。

关键词：分类；I型胶原蛋白；骨折；异质性；成骨不全症

成骨不全症(OI)典型患者因骨纤维合成代谢不足、骨质疏松、骨矿化障碍等易发生脆性骨折，治疗应采取髓内钉固定为主

成骨不全症(OI)典型患儿的蓝色巩膜外观

图1. I型胶原生物合成概述。I型胶原由两条a1链和一条a2链组成。翻译后，pro-a1链和pro-a2链在粗面内质网(rER)中加工。这些链必须对齐才能开始将I型（原）胶原蛋白，折叠成三股螺旋。下一步是对齐三个链，以便开始折叠成三螺旋结构。在此折叠过程中，会发生特定蛋白质的翻译后修饰。编码参与翻译后修饰的蛋白质的基因以及据报道其中的突变会导致成骨不全症(OI)，如图所示。在I型前胶原转运到高尔基复合体并胞吐进入细胞外基质后，C和N前肽的裂解导致I型胶原的形成。随后，I型胶原分子的交联导致原纤维的形成。多个I型胶原原纤维形成胶原纤维，是骨骼的重要成分。

表3 成骨不全症(OI)的产前和产后严重程度分级量表

轻度成骨不全症(OI)【轻度成骨不全症(OI)患者最常患有1型或4型成骨不全症(OI)】

怀孕20周时的超声检查结果

无子宫内长骨骨折或弓形

产后

罕见先天性骨折

正常或接近正常的生长速度和身高

直的长骨，即没有固有的长骨畸形

除了急性骨折的时候，完全可以走动

轻度椎体粉碎性骨折

腰椎骨矿物质密度Z值通常 ＞ 1.5（1.5 至 ±1.5）

年化骨折率小于或等于1

没有慢性骨痛或通过简单镇痛药控制的轻微疼痛

正常上学，即不会因疼痛、嗜睡或疲劳而缺课。

中度成骨不全症(OI)

怀孕20周时的超声检查结果

很少有胎儿长骨骨折或弓背（但在最后三个月可能会增加）

产后（未被双膦酸盐治疗改变）

偶见先天性骨折

生长速度和身高下降

腿部和大腿前弓形

与复发性骨折固定相关的长骨弯曲

椎骨挤压性骨折

腰椎骨矿物质密度Z评分通常 ＞ 2.5 至 ＜ 1.5）但范围很广

年化青春期前骨折率大于1（平均值为3，范围很广）

每年因疼痛缺勤超5天。

严重的成骨不全症(OI)

怀孕20周时的超声检查结果

长骨缩短

长骨骨折和/或弓形，伴有一些生长发育不足

肋骨细长，肋骨骨折不存在或不连续（中间病例，介于严重和极严重之间，肋骨骨折很少，但长骨皱折）

矿化减少

产后（未被双膦酸盐治疗改变）

线性增长明显受损

依赖轮椅

长骨和脊柱进行性畸形（与骨折无关）

多发椎体粉碎性骨折

腰椎骨矿物质密度Z评分通常 ＜ 3.0（范围宽

年龄比较，因为测量值取决于尺寸/身高）

每年超过3次骨折的年化青春期前骨折率（取决于年龄）

慢性骨痛，除非用双膦酸盐治疗

因骨折和疲劳或疼痛为特征的学校出勤率下降。

极度严重的成骨不全症(OI)

怀孕20周时的超声检查结果

长骨缩短

骨折和/或长骨弯曲伴有严重的生长发育不足导致

皱巴巴的（类似手风琴的）长骨

由于多处骨折或肋骨较薄，肋骨连续增厚

（以前分别描述为成骨不全症(OI)类型2-A和2-B）

矿化减少

产后

大腿固定外展和外旋，大多数关节活动受限

严重慢性疼痛的临床指标（脸色苍白、出汗、呜咽或做鬼脸）

被动运动

颅骨骨化减少，长骨和肋骨多处骨折，胸阔小。

缩短的紧实股骨具有类似手风琴的外观

所有椎骨发育不全/压碎

呼吸窘迫导致围产儿死亡

围产期致死过程。

成骨不全综合征(OI)的严重程度分级

在所有成骨不全症(OI)类型中发现COL1A1/2突变后的几年里，临床实践中经常使用四种成骨不全症(OI)类型来反映其严重程度：轻型（OI 1型）、致死性（OI 2型）、严重畸形（OI 3型）和中等程度畸形(OI 4型)。尽管INCDS同意将Sillence分类保留为“对成骨不全症(OI)严重程度进行分类的原型和普遍接受的方法”[Warman等2011年]，但有人提出需要国际商定的受影响个体严重程度分级标准，并且采纳，也反映了成骨不全症(OI)患者治疗的改进可能性（手术、药物和保守治疗）。这里提出的严重程度分级量表依赖于临床、历史数据、骨折频率、骨密度测定和活动水平（表3）。利塞膦酸盐在成骨不全症中的POISE（小儿成骨不全症的安全性和有效性研究）采用了这种严重程度分级，该研究确定了来自11个国家的22名研究人员确定的231名儿童[Munns和Sillence，2013 年；Bishop等2013]。作者在此修改了POISE研究的分级，增加了产前临床和超声检查结果的一般指南。该量表将需要通过专业中心与足够患者的合作进一步验证，并使用设施进行全面评估，以进一步确认和阐明其临床实用性。

注：利塞膦酸钠属于第三代双膦酸盐，是一种骨吸收抑制剂，用于治疗各类骨质疏松。 利塞膦酸钠是与羟基磷灰石有非常强的亲和力，能够沉积于骨骼及关节骨质中，它不仅能够抑制破骨细胞活性，也能促进破骨细胞出现凋亡，减缓骨丢失和骨吸收速度。

成骨不全症(OI)的临床表现和特征

成骨不全症(OI)的一般临床表现和特征

主要特征：易骨折和骨质疏松

虽然终生容易骨折是最重要的临床特征，但1型成骨不全症(OI)家庭的经验表明，可能有10%的受影响个体在童年时期没有发生过长骨骨折[Sillence，1980年]。然而，用于测量骨密度的更新技术，例如骨骼的双能X线吸收测定法(DXA) [Lu et al., 1994]和/或最近的外周定量计算机断层扫描(pQCT) [Gatti et al., 2003]; Folkestad等2012]的前臂和下肢，经常显示在那些通过正式遗传分析患有成骨不全症(OI)的个体中，至少一个骨骼区域的骨密度显着降低（表3）。

净骨脆性是原发性骨脆性和骨质疏松症导致的继发性骨脆性共同作用的最终结果。大多数成骨不全症(OI)患者会出现骨质疏松症。成骨不全症(OI)患者骨转换血清和尿液标志物升高的发现与骨组织形态学的发现一起考虑，最好用骨形成增加和骨吸收增加的组合来解释[Rauch和Glorieux，2004]。净效应是小的进行性骨质流失，因为骨吸收通常大于骨形成，固定也对骨形成产生负面影响。

许多成骨不全症(OI)儿童在经主治医师仔细评估后开始使用旨在降低破骨细胞活性的双膦酸盐治疗。在这方面，静脉注射双膦酸盐的周期性治疗已成为治疗中度至重度成骨不全症(OI)儿童的金标准。最近一项针对成骨不全症(OI)儿童口服利塞膦酸盐的随机、双盲、安慰剂对照试验（包括大部分受轻度至中度影响的儿童）表明骨折风险显着降低，从而扩大了该疗法的治疗益处成骨不全症(OI)儿童[Bishop等2013]。

一般相关的功能

一些受累个体（而非其他个体）的相关特征包括明显的巩膜发蓝、年轻成人发作的听力损失、牙本质发育不全(DI)、关节活动过度、身材矮小和进行性骨骼畸形。据报道，成人成骨不全症(OI)患者会出现心脏瓣膜功能障碍和主动脉根部扩张等心血管并发症，更常见于3型成骨不全症(OI)患者[Radunovic 等，2011]。

下面更详细地描述了几个相关的特征。

蓝巩膜

几篇主要评论和至少一部专着[Smars, 1961; Sillence 等，1979; Sillence 等; 1993]得出结论，在患有“蓝色巩膜”的患者中，巩膜的颜色与Wedgewood蓝色的色调相似，并且非常独特，以至于巩膜看起来像是涂了漆。当存在“蓝色硬化”时，它们终生保持明显的蓝色。

Berfenstam和Smårs在一项基于人群的研究中[1956]表明，两组成骨不全症(OI)患者（具有蓝灰色巩膜的患者和具有正常巩膜的患者）在表型症状和肌肉骨骼并发症模式方面存在统计学显着差异。对1979年维多利亚人口研究中95名1型和4型成骨不全症(OI)患者队列的数据进行了重新分析，以证实该发现[Sillence等，1993]。人们还注意到一种误解，即1型成骨不全症(OI)中的蓝灰色巩膜是由于巩膜变薄所致。Eichholtz和Muller[1972]曾报道1型成骨不全症(OI)的巩膜总厚度正常，巩膜胶原纤维之间的电子致密颗粒物质增加。有人提出，在1型成骨不全症(OI)的发病机制中，听力障碍、容易瘀伤和可能明显的关节过度活动最好用结缔组织成分的继发性失调来解释。有进一步的证据表明，导致成骨不全症(OI) 1型表型的过早终止/无意义/剪接突变的高流行率与基质组成的改变有关[Byers和Cole，2002]。

牙本质发育不全症(DI)

牙本质发育不全症会导致牙齿明显变黄和明显透明，这些牙齿通常会过早磨损或折断。有些牙齿可能有特别灰的色调。受影响牙齿的放射学研究表明，它们的牙根短，冠-根连接处收缩[Bailleul-Forestier 等，2008]。

脊柱侧弯和基底压痕等继发性畸形

脊柱侧弯和基底压痕等骨骼畸形被认为是继发性畸形，而不是原发性畸形。尽管长骨无畸形已被作为诊断标准提出，但畸形的存在似乎至少在一定程度上受到护理质量的显着影响。在发展中国家，畸形可能是次优护理的证据，反映出缺乏处理骨折的初级保健服务，而不是骨变形内在过程的证据。

具有蓝色巩膜的非变形成骨不全症(OI)—成骨不全症(OI)类型1

1型成骨不全症(OI)的特征是骨脆性增加，这通常与低骨量、明显的蓝灰色巩膜以及在青春期和青年期开始的传导性听力损失的易感性有关。长骨或脊柱的畸形并不常见，发生脊柱侧凸的地方通常是特发性脊柱侧凸。1型成骨不全症(OI)是欧洲衍生社区中最常见的成骨不全症(OI)类型，出生率约为1:25,000活产，人口频率相似[Steiner et al., 2013]。骨折频率和通常轻微的长骨和脊柱畸形意味着它通常被认为是轻度严重的，但偶尔它是中度严重的，特别是当存在牙本质发育不全症(DI)时[Paterson等, 1983]。

在一些具有这种特征的家庭中观察到牙本质发育不全症(DI)，而在其他家庭中则没有。Paterson及其同事表明，患有1型成骨不全症(OI)和牙本质发育不全症(DI)的患者比没有牙本质发育不全症(DI)的患者更容易在出生时发生骨折（25%对6%）。此外，1型成骨不全症(OI)和牙本质发育不全症(DI)患者的骨折频率更高，身材矮小更严重，骨骼畸形更多。两个亚组都有相似的关节过度活动、瘀伤、耳聋和关节脱位的频率[Paterson et al., 1983]。

到40岁时，超过50%的1型成骨不全症(OI)患者可检测到由传导性和感音神经性损失引起的听力损伤[Kuurila 等，2002；Swinnen等，2011]。眩晕是许多成骨不全症(OI)患者的麻烦症状，包括1型成骨不全症(OI) [Kuurila等，2003]。

许多研究报告了具有常染色体显性遗传和可变表达的家族。蓝巩膜的外显率接近100%，但临床骨折的发生率仅为90-95% [Smars, 1961; Sillence 等人，1979]。

一般变异性成骨不全症(OI)—成骨不全症(OI)类型4

这些患者有反复骨折、骨质疏松症和不同程度的长骨和脊柱畸形，但巩膜正常。巩膜在出生时可能呈蓝色，但在儿童时期蓝色调会逐渐消失。听力障碍并不常见。由于后颅窝底抬高的基底压痕导致的后颅窝压迫综合征的患病率增加。患有牙本质发育不全症(DI)的4型成骨不全症(OI)患者发生基底压痕的相对风险高5倍 [Sillence, 1994]。约30%的4型成骨不全症(OI)患者在筛查时有基底印象，但其中只有16%有症状[Sillence, 1994]。具有正常巩膜的常见成骨不全症(OI)偶尔表现为常染色体隐性遗传[van Dijk et al., 2010]和X连锁遗传[van Dijk et al., 2013]，但它通常作为常染色体显性遗传病遗传（表1)。家庭内部的严重程度差异很大。很多家庭中有许多人患有轻度成骨不全症(OI)，但同一家庭中有少数人患有中度严重的成骨不全症(OI) [Holcomb，1931；Seedorf，1949]。

逐渐变形的成骨不全症(OI)–成骨不全症(OI)类型3

3型成骨不全症(OI)患者通常有新生儿或婴儿表现，骨骼脆弱和多处骨折导致骨骼进行性畸形。他们通常在足月或接近足月出生，出生体重正常，出生身长通常正常，但由于出生时下肢畸形可能会缩短。虽然巩膜在出生时可能是蓝色的，但对许多患有这种综合征的患者的观察表明，随着年龄的增长，巩膜的蓝色逐渐变淡[Sillence等，1986年]。持续存在的蓝色巩膜通常表示1型非变形成骨不全症(OI) 1型胶原基因的无意义突变或移码突变，而患有各种常染色体隐性遗传疾病的患者通常会出现灰白色巩膜[Byers和Pyott，2012]。所有患者的纵向生长都较差，身高远低于年龄和性别的第三个百分位。进行性脊柱侧凸在儿童时期发展并发展到青春期。患有此综合征的儿童尚未报告听力受损，但成人听力损失更为常见。牙本质发育不全症(DI)是一个可变特征。

出生时，放射学研究显示全身性骨质减少和多发性骨折。随着长骨干的频繁过度损伤与修复，弓形和成角畸形存在不同程度。在几周到几个月内，在一些婴儿中，长骨干的发育不足会导致“宽骨”外观。从几岁开始，干骺端的密度和不规则性增加。这些被指定为“爆米花”外观的干骺端变化可能只会在青春期后完全消退。肋骨变薄，骨质疏松，并随着扁平椎的增加而逐渐拥挤。头骨显示出多个Wormian骨骼，尽管这些骨骼可能要到几周到几个月大时才会明显[Sillence等, 1979; Sillence等, 1986; Spranger等, 2003; van Dijk等, 2011]。

过去，大约三分之二的患者在20岁时死亡。死亡通常由骨骼胸壁畸形的并发症引起，包括脊柱侧凸、肺动脉高压和心肺功能衰竭。使用目前的治疗选择，特别是循环静脉内帕米膦酸盐的双膦酸盐治疗[Glorieux et al., 1998]在婴儿期开始，可以预期今天大多数3型成骨不全症(OI)患者将存活到成年生活。几项研究表明，管理严重成骨不全症(OI)儿童的专业中心在婴儿3岁时开始循环静脉注射帕米膦酸盐，从而大大降低骨折频率和接近正常生长速度[Plotkin等，2000 年；DiMeglio等，2004；Munns等，2005年；Astrom等，2007]。最近的一份出版物证实，治疗似乎具有良好的耐受性，并且与骨密度增加、骨折频率降低和椎体形状改善有关[Alcausin 等，2013]。

围产期致死性成骨不全症(OI)综合征——2型成骨不全症(OI)

这组胎儿和儿童的骨骼、关节和骨骼外特征极为严重。围产期致死率是一个结果，而不是一个诊断特征。在妊娠18-20周检测到的胎儿长骨短而皱缩，长骨弯曲或成角畸形，面部和颅骨骨化明显不足。在妊娠早期，可能很少有肋骨骨折，但在子宫内每个月都会出现肋骨骨折，导致连续的串珠状外观和皱缩（手风琴状）的长骨，这是极端严重的一端的特征，以成骨不全症(OI) 2型（成骨不全症(OI)类型2-A）为代表[Sillence等, 1984]。根据我们的经验，循环静脉注射帕米膦酸治疗并不适用，因为骨形成如此受损，关节受限如此严重，几乎没有任何正常童年生活经历的机会。使用简单的镇痛剂或皮下吗啡来缓解疼痛特别有价值，可以改善舒适度和呼吸。在2型成骨不全症(OI)的骨骼外特征中，神经病理学发现如脑迁移缺陷和/或白质改变已在有限数量的病例中得到报道[Emery et al., 1999]。有些婴儿的表型不太严重，肋骨骨折较少（成骨不全症(OI) 2-B型）[Sillence等，1984]，因此它们可能与成骨不全症(OI) 3型重叠[Spranger，1984]。这些婴儿很少能存活下来，即使是成年，也可以通过循环静脉注射帕米膦酸盐治疗“获救”。

在发达国家，许多或大多数2型成骨不全症(OI)儿童目前在产前诊断（通过超声和DNA分析），通常导致妊娠终止。平均出生身长和体重小于第50个百分位数[Sillence等，1984]。大腿外展并外旋。由于多处肋骨骨折引起的疼痛以及受影响最严重的每根肋骨骨折愈伤组织半连续串珠的异常生物力学特性，因此妊娠期胸部较小，呼吸运动可能受到抑制。一些临床特征表明，患有2型成骨不全症(OI)的新生儿会持续疼痛。由于多处骨折，他们可能会出汗过多、脸色苍白、被触摸时表现出焦虑并且四肢很少活动。五分之一死产，90%死于4周龄[Sillence et al., 1984]。

骨间膜钙化的成骨不全症(OI)——成骨不全症(OI)类型5

具有中度至重度骨脆性的5型成骨不全症(OI)最初由Battle和Shattock [1908]定义为前臂和下肢骨间膜进行性钙化的一种成骨不全症(OI)。独立地，它是通过增加增生性愈伤组织的倾向来识别的。Bauze等详细描述了该综合征[1975]，他观察到10%的中度至重度成骨不全症(OI)且巩膜正常的患者患有5型成骨不全症(OI) [Bauze等，1975]。在一项针对4型中重度成骨不全症(OI)的组织形态学研究中，检测到26例中有7例(25%)具有骨组织形态学异常，这是5型成骨不全症(OI)的特征 [Glorieux等，2000]。在临床研究中，它约占在医院就诊的成骨不全症(OI)患者的5%。

从生命早期就可以观察到前臂骨间膜的钙化，这会导致旋前和旋后受限，并最终导致桡骨头脱位。巩膜是白色的，不存在DI和Wormian骨头。那些受影响的人往往具有较高的血清碱性磷酸酶值，并且在骨折或整形外科手术后发生增生性愈伤组织的风险增加。特征性骨组织形态学进一步支持了一种独特的发病机制，该组织形态学显示粗网状层状结构，可将5型成骨不全症(OI)与4型成骨不全症(OI)区分开来[Glorieux等，2000]。

增生性骨痂是5型成骨不全症(OI)患者罕见的医疗急症。其特征是骨折部位有肿块骨痂并伴有肿胀和疼痛，可能与应力性骨折一样轻微。及时使用消炎痛，一种抗炎COX-1和COX-2前列腺素抑制剂，已被推荐用于避免愈伤组织的进展，尽管尚未报告随机临床试验[Glorieux et al., 2000; Cho 和 Moffat，2014]。

成骨不全症(OI)的分子遗传学

目前，已鉴定出1,000多个杂合COL1A1/2突变（https://oi.gene.le.ac.uk，2013年4月1日访问）[Dalgleish, 1997, 1998]。突变类型和位置影响表型，因此在一定程度上存在基因型-表型关系。

常染色体显性成骨不全症(OI)（OI类型1-5）

在大多数来自欧洲血统的受影响个体中，1-4型成骨不全症(OI)是由COL1A1/2基因的杂合突变引起的，该基因分别编码I型胶原蛋白的alpha1和alpha2链（图1）。表3.3描述了I型胶原的生物合成。由于父母之一的杂合显性突变的性腺嵌合体，可能会发生没有受累父母的兄弟姐妹[Byers and Cole, 2002]。

1型成骨不全症(OI)患者和有时4型成骨不全症(OI)患者的1型原胶原合成减少约50%（定量或单倍体不足效应），通常是由于一个COL1A1等位基因的杂合突变（无意义、移码和剪接位点改变）导致mRNA不稳定性和单倍体不足。其他原因是整个COL1A1等位基因缺失或甘氨酸被COL1A1或COL1A2等位基因中三螺旋结构域氨基末端附近的小氨基酸（半胱氨酸、丙氨酸和丝氨酸）取代[van Dijk等，2012]。 管单个细胞的胶原蛋白合成减少了50%，但这些患者的新骨形成高于平均水平，这是稳态机制的结果，增加了骨形成单位的数量。这种新骨形成的增加与骨转换的增加有关，因此净效应是每年的骨质流失量很小，如果因骨折或疼痛不能活动，骨质流失会加剧[Rauch和Glorieux，2004]。

北美和欧洲的大多数2-4型成骨不全症(OI)病例是显性遗传的，并且大多数病例是由于导致甘氨酸替代的杂合COL1A1/2突变所致。一般而言，羧基末端附近的甘氨酸取代似乎导致最严重的表型。不太常见的突变包括剪接位点改变、插入/删除/复制突变，这些突变导致框内序列改变和羧基末端原肽编码域的变异[van Dijk等，2012]杂合突变破坏了类型的三螺旋组装I型胶原蛋白多肽，导致负责I型（原）胶原蛋白翻译后修饰的酶过度加工，从而产生异常I型胶原蛋白。这种翻译后过度修饰可通过SDS-聚丙烯酰胺凝胶电泳证明。突变和正常I型胶原蛋白链的交织导致异常I型胶原蛋白的产生，该蛋白迅速降解（显性负效应）。

最近，两份独立文献阐明了5型成骨不全症(OI)的遗传原因[Cho et al., 2012; Semler et al., 2012] 并由IFITM5 (c.-14C＞T)的5‘UTR（非翻译区）中的杂合C＞T转换组成。IFITM5编码干扰素诱导的跨膜蛋白5，该蛋白的表达已显示在小鼠和大鼠早期矿化阶段的成骨细胞形成过程中达到峰值[Hanagata等，2011]。

常染色体隐性成骨不全症(OI)（OI类型2-4）

过去已经在南部非洲的黑人人群中发现了一种相对较高频率的严重的常染色体隐性3型成骨不全症(OI) [Wallis等，1993]（表3）。如今，还已知1.5%的西非人和0.4%的非裔美国人携带LEPRE1的创始人突变[Cabral et al., 2012]。在过去的6年中，已经在2-4型成骨不全症(OI)中发现了参与I型胶原生物合成和翻译后修饰的基因的隐性突变。最近对这些进行了深入审查[Byers and Pyott, 2012]。隐性突变涉及编码参与I型胶原蛋白生物合成的蛋白质的基因，可细分为(i)负责alpha1链中一个特定残基(P986)的3-脯氨酰羟基化的酶复合物[van Dijk 等，2012]并且可能用于启动链对齐和螺旋折叠[Pyott等，2011]（CRTAP、LEPRE1、PPIB）；(ii)胶原蛋白三螺旋(SERPINH1, FKBP10)的质量控制检查；(iii) I型折叠（前）胶原蛋白链的后期加工，即三螺旋端肽中赖氨酸残基的羟基化对于I型胶原蛋白在骨骼中的交联很重要[van Dijk et al., 2012] (PLOD2, FKBP10)和裂解C前肽(BMP1) [Martínez-Glez等，2012]（图1）。

此外，在编码Osterix的SP7（一种成骨细胞特异性转录因子）、可能参与骨形成和重建的SERPINF1 [van Dijk等，2012]和编码三聚体细胞内阳离子通道的TMEM38B [Shaheen等, 2012; Volodarsky等, 2013]。

最近描述的WNT1突变，编码参与成骨细胞分化和增殖的信号肽[Fahiminiya等，2013； Keupp 等，2013；Laine等，2013]以及与FRIZZLED及其配体LRP5的相互作用，其中后者的突变已知会导致患有严重综合征性成骨不全症(OI)的患者，预测对来自内婚人群的严重成骨不全症(OI)患者的进一步研究将揭示突变机制在WNT-β连环蛋白信号通路的后续步骤中。最近，在一个具有严重进行性畸形成骨不全症(OI)表型的家族中发现了CREB3L1的纯合缺失。CREB3L1编码内质网应激传感器OASIS，该传感器已在小鼠模型中显示可与Col1a1启动子中的成骨细胞特异性UPRE（未折叠蛋白反应元件）调节区结合。这一发现扩大了成骨不全症(OI)的遗传异质性，并说明了ER应激在成骨不全症(OI)病理生理学中的作用[Symoens et al., 2013]。

在隐性基因中发现的致病性突变（Dalgleish，R：成骨不全变异数据库（https://oi.gene.le.ac.uk，2013年4月1日访问），主要是纯合子或复合杂合子功能丧失突变，导致在两个无效等位基因中，正常蛋白质的产生严重减少或没有。

X连锁成骨不全症(OI)

骨质疏松症和骨折的X连锁遗传仅在D. Sillence的论文（Pedigree 41，附录）[Sillence，1980] 中有过一次报道。最近，发现编码plastin-3的PLS3中的功能丧失突变是一种形式的X连锁骨质疏松症伴骨折的原因[van Dijk等，2013]。在半合子男性中，PLS3的致病性突变与通常在儿童时期发生的中轴和四肢骨骼的骨质疏松症和骨质疏松性骨折有关。杂合子女性成员的临床表现是多变的，范围从正常的骨矿物质密度和没有骨折到早发性骨质疏松症。受影响的男性没有成骨不全症(OI)的骨骼外特征，但表型在许多其他类型的成骨不全症(OI)患者中无法区分，它可能最适合常见变量成骨不全症(OI)（OI类型4）组，其中不到50%的患者具有头骨中的Wormian骨和巩膜等特征，颜色正常，儿童期呈蓝色，成人后逐渐褪色。

结论

从医学遗传学家的角度来看，核心原则是个体的表型分析（畸形学）以及这些家族在遗传模式和表型变异性方面的研究。1979年的成骨不全症(OI)分类是畸形学的重要性和可能性的典型例子，因为它根据临床/放射学特征和遗传，结合成骨不全症(OI)具有遗传异质性的假设，对四种成骨不全症(OI)综合征进行了描述，许多人证实了这一点多年后通过分子遗传学研究。

目前，据推测，下一代测序等分子技术将减少对表型分析的需求。然而，本文描述的新成骨不全症(OI)命名法和严重程度分级量表强调了表型分析对于诊断、分类和评估成骨不全症(OI)严重程度的重要性。这将使患者及其家人深入了解疾病的可能病程，并使医生能够评估治疗效果。结合对特定分子遗传原因的了解，仔细的临床描述是开发和评估包括成骨不全症(OI)在内的遗传性疾病患者治疗的起点。后者是我们在未来十年面临的最大挑战。

SEVERITY GRADING IN OSTEOGENESIS IMPERFECTA SYNDROMES

In the years following the discovery of COL1A1/2 mutations in all OI types, the four OI types were often used in clinical practice to reflect severity with mild (OI type 1), lethal (OI type 2), severely deforming (OI type 3), and moderately deforming (OI type 4). Although the INCDS agreed to retain the Sillence classification as “the prototypic and universally accepted way to classify the degree of severity in OI” [Warman et al., 2011], the need for internationally agreed criteria for grading severity between affected individuals was proposed and adopted, reflecting also the improved treatment possibilities (surgical, pharmacological and conservative) for patients with OI. The severity grading scale proposed here relies on clinical, historical data, fracture frequency, bone densitometry, and level of mobility (Table (Table3).3). This severity grading was adopted for the POISE (Pediatric Osteogenesis Imperfecta Safety and Efficacy study) of Risedronate in osteogenesis imperfecta in 231 children ascertained from 22 investigators drawn from 11 countries [Munns and Sillence, 2013; Bishop et al., 2013]. The grading for the POISE study is modified here by the authors with addition of a general guideline to prenatal clinical and ultrasonographic findings. The scale will require further validation by collaboration between Centres of Expertise with sufficient patients and access to facilities for comprehensive assessment in order to further confirm and clarify its clinical utility.

CLINICAL PRESENTATIONS AND FEATURES OF OSTEOGENESIS IMPERFECTA

Clinical Presentations and Features of OI in General

Primary feature: liability to fractures and osteoporosis

While liability to fractures throughout life is the single most important clinical feature, experience with families with OI type 1 indicate that perhaps 10% of affected individuals have not had a long bone fracture during childhood [Sillence, 1980]. However, newer techniques for measuring bone density, such as dual energy X-ray absorptiometry (DXA) of the skeleton [Lu et al., 1994] and/or more recently peripheral quantative computerized tomography (pQCT) [Gatti et al., 2003; Folkestad et al., 2012] of forearm and leg, frequently reveal significantly reduced bone density in a least one area of the skeleton in those individuals who by formal genetic analysis have OI (Table 3).

Net bone fragility is the final result of contributions from primary bone fragility and the secondary fragility resulting from osteoporosis. Osteoporosis develops in the majority of patients with OI. The finding of elevated serum and urine markers of bone turnover in patients with OI considered along with the findings of bone histomorphometry, is best explained by a combination of increased bone formation and increased bone resorption [Rauch and Glorieux, 2004]. The net effect is a small progressive bone loss since bone resorption is often greater than bone formation, with immobilization also exerting a negative effect on bone formation.

Bisphosphonate treatment aimed at reduction of osteoclast activity, is initiated in many children with OI after careful assessment by the treating physician. In that regard cyclical treatment with intravenous bisphosphonates has become the gold standard for treatment of children with moderate to severe OI. A very recent randomized, double-blind, placebo-controlled trial of oral Risedronate in children with OI, including a large proportion of more mild to moderately affected children, demonstrated a significant reduction in fracture risk, thus extending the therapeutic benefits of this therapy in children with OI [Bishop et al., 2013].

Associated features in general

Associated features in some affected individuals, but not others, include distinct blueness of the sclerae, young adult onset hearing loss, dentinogenesis imperfect (DI), joint hypermobility, short stature, and progressive skeletal deformity. Cardiovascular complications such as valvular dysfunction and aortic root dilatation have been reported in adult OI patients, more often in patients with OI type 3 [Radunovic et al., 2011]. Several associated features are more elaborately described below.

Blue Sclerae

Several major reviews and at least one monograph [Smars, 1961; Sillence et al., 1979; Sillence et al., 1993] concluded that in patients with “blue sclerae” the color of the sclerae is similar to Wedgewood blue in hue and is so very distinctive that the sclerae appear painted. When “blue sclerotics” are present, they remain distinctly blue throughout life.

Berfenstam and Smårs in a population based study [1956] showed that there were statistically significant differences in patterns of phenotypic symptoms and musculoskeletal complications between two groups of patients with OI, those with blue-grey sclerae and those with normal sclerae. Data from a cohort of 95 patients with OI type 1 and OI type 4 in the 1979 Victorian population study were reanalysed to confirm that finding [Sillence et al., 1993]. Attention was also drawn to the misconception that the blue-gray sclerae in OI type 1 are due to the thinning of the sclerae. Eichholtz and Muller [1972] had reported that overall thickness of the sclerae in OI type 1 was normal and there was increased electron dense granular material between scleral collagen fibers. It was proposed that in the pathogenesis of OI type 1, the hearing impairment, easy bruising and possibly the marked joint hypermobility would be best explained by secondary dysregulation of connective tissue composition. There is further evidence that the high prevalence of premature termination/nonsense/splicing mutations which cause the OI type 1 phenotype are associated with alterations in matrix composition [Byers and Cole, 2002].

Dentinogenesis imperfecta

Dentinogenesis imperfecta produces a distinctive yellowing and apparent transparency of the teeth, which are often worn prematurely or broken. Some teeth may have a particularly greyish hue. Radiologic studies of affected teeth show that they have short roots with constricted corono-radicular junctions [Bailleul-Forestier et al., 2008].

Secondary deformations

Skeletal deformities such as scoliosis and basilar impression are regarded as secondary deformations rather than primary malformations. Although the absence of deformity of long bones has been advanced as a diagnostic criterion, the presence of deformity seems at least partly significantly influenced by quality of care. In developing countries, deformity may be evidence of sub-optimal care reflecting lack of primary care services for managing fractures, rather than evidence of an intrinsic process of bone deformation.

Non-Deforming OI With Blue Sclerae—OI Type 1

OI type 1 is characterized by increased bone fragility, which is usually associated with low bone mass, distinctly blue-gray sclerae, and susceptibility to conductive hearing loss commencing in adolescence and young adult life. Deformity of long bones or spine is uncommon and where scoliosis develops it is commonly an idiopathic scoliosis. OI type 1 is the most common variety of OI in European derived communities and has a birth prevalence in the order of 1:25,000 live births and a similar population frequency [Steiner et al., 2013]. Fracture frequency and usually mild long bone and spine deformity mean that it is generally perceived to be of mild severity but occasionally it is moderately severe, particularly when DI is present [Paterson et al., 1983].

DI is observed in some families with this trait and not others. Paterson and colleagues showed that patients with OI type 1 and DI are more likely to have fractures at birth (25% vs. 6%) than those without DI. Furthermore, patients with OI type 1 and DI have a higher fracture frequency, more severe short stature, and more skeletal deformity. Both subgroups have a similar frequency of joint hypermobility, bruising, deafness, and joint dislocations [Paterson et al., 1983].

Hearing impairment resulting from both conductive and sensorineural loss is detectable in over 50% of patients with OI type 1 by 40 years of age [Kuurila et al., 2002; Swinnen et al., 2011]. Vertigo is a troublesome symptom in many people with OI including OI type 1 [Kuurila et al., 2003].

Families with autosomal dominant inheritance and variable expressivity have been reported in many studies. Penetrance for blue sclerae is close to 100% but frequency of clinical fractures is only 90–95% [Smars, 1961; Sillence et al., 1979].

Common Variable OI—OI Type 4

These patients have recurrent fractures, osteoporosis and variable degrees of deformity of long bones and spine but normal sclerae. The sclerae may be bluish at birth but the blue tinge fades during childhood. Hearing impairment is not often encountered. Posterior fossa compression syndromes due to basilar impression with elevation of the floor of the posterior cranial fossa are increased in prevalence. Patients with OI type 4 who have DI have a five times higher relative risk for basilar impression [Sillence, 1994]. Some 30% of patients with OI type 4 have basilar impression on screening but only 16% of these are symptomatic [Sillence, 1994]. Common variable osteogenesis imperfecta with normal sclerae shows occasionally autosomal recessive [van Dijk et al., 2010] and X-linked inheritance [van Dijk et al., 2013] but it is usually inherited as an autosomal dominant disorder (Table 1). Severity is highly variable within families. It is not uncommon to find families where there are many affected with mild OI but a few individuals in the same family with moderately severe OI [Holcomb, 1931; Seedorf, 1949].

Progressively Deforming OI–OI Type 3

Individuals with OI type 3 usually have newborn or infant presentation with bone fragility and multiple fractures leading to progressive deformity of the skeleton. They are generally born at or near term and have normal birth weight and often normal birth length, although this may be reduced because of deformities of the lower limbs at birth. Although the sclerae may be blue at birth, observation of many patients with this syndrome documents that the sclerae become progressively less blue with age [Sillence et al., 1986]. Persisting blue sclerae are usually an indication of nonsense or frameshift mutations in type 1 collagen genes characteristic of non-deforming OI type 1 whereas patients with the various autosomal recessive disorders will usually have grey-white sclerae [Byers and Pyott, 2012]. All patients have poor longitudinal growth and fall well below the third centile in height for age and sex. Progressive kyphoscoliosis develops during childhood and progresses into adolescence. Hearing impairment has not been reported in children with this syndrome but hearing loss is more frequent in adults. DI is a variable feature.

At birth, radiographic studies show generalized osteopenia and multiple fractures. Bowing and angulation deformities exist to a variable degree with frequent over-modeling of the shafts of the long bones. Within weeks to months, in some infants, under-modeling of the shafts of long bones results in a “broad-bone” appearance. From several years of age, metaphyses develop increasing density and irregularity. These metaphyseal changes designated a “pop-corn” appearance may evolve only to resolve completely after puberty. The ribs are thin, osteopenic, and progressively crowded as platyspondyly increases. The skull shows multiple Wormian bones, although these may not be evident until several weeks to months of age [Sillence et al., 1979; Sillence et al., 1986; Spranger et al., 2003; van Dijk et al., 2011].

In the past, approximately two-thirds of the patients died by the end of the second decade. Death usually resulted from the complications of skeletal chest wall deformity including kyphoscoliosis, pulmonary hypertension, and cardio-respiratory failure. With the present therapeutic options, specifically bisphosphonate treatment with cyclic intravenous Pamidronate [Glorieux et al., 1998] commenced in infancy, it can be expected that today the majority of patients with OI type 3 will survive into adult life. Several studies demonstrate that centers of expertise that manage children with severe OI, achieve very reduced fracture frequency and near normal growth velocity in infants commenced on cyclic intravenous pamidronate by 3 years of age [Plotkin et al., 2000; DiMeglio et al., 2004; Munns et al., 2005; Astrom et al., 2007]. A recent publication confirmed that treatment appears to be well tolerated and associated with an increase in bone density, reduced fracture frequency and improved vertebral shape [Alcausin et al., 2013].

Perinatally Lethal OI Syndromes—OI Type 2

The skeletal, joint, and extraskeletal features of this group of fetuses and children are extremely severe. Perinatal lethality is an outcome rather than a diagnostic feature. Fetuses detected at 18–20 weeks gestation have short crumpled long bones, bowing or angulation deformities of long bones and marked deficiency of ossification of facial and skull bones. At this early gestation, there may be few rib fractures but with each month in utero there is progressive fracturing of ribs resulting in the continuously beaded appearance combined with crumpled (accordion-like) long bones that is characteristic of the extremely severe end of the spectrum represented by OI type 2 (OI type 2-A) [Sillence et al., 1984]. In our experience, treatment with cyclic intravenous pamidronate is not indicated as bone formation is so impaired and joint restriction so severe there is virtually no chance of any normal childhood life experience. Pain relief with simple analgesics or subcutaneous morphine is particularly valuable, improving comfort and breathing. Among the extraskeletal features in OI type 2, neuropathological findings such as brain migrational defects and/or white matter changes have been reported in a limited number of cases [Emery et al., 1999]. Some babies have a phenotype which is a little less severe with fewer rib fractures (OI type 2-B) [Sillence et al., 1984] and as such they can show overlap with OI type 3 [Spranger, 1984]. Rarely these babies survive, even to adult life and can be “rescued” with treatment with cyclic intravenous pamidronate.

In developed countries, many or most children with OI type 2 are at present diagnosed prenatally (by ultrasound and DNA analysis), often resulting in termination of pregnancy. Mean birth length and weight are less than the fiftieth centile [Sillence et al., 1984]. The thighs are held abducted and in external rotation. The chest is small for gestation and respiratory excursion may be depressed because of the pain from multiple rib fractures and the abnormal biomechanical properties of semicontinuous beading from fracture callus along each rib in the most severely affected. Several clinical features suggest that newborns with OI type 2 are in constant pain. They may have excessive perspiration, pallor, show anxiety at being touched and move their limbs very little because of multiple fractures. One-fifth are stillborn and 90% die by 4 weeks of age [Sillence et al., 1984].

OI With Calcification in Interosseous Membranes—OI Type 5

OI type 5 with moderate to severe bone fragility was originally defined by Battle and Shattock [1908] as a type of OI with progressive calcification of the inter-osseous membranes in the forearms and legs. Independently it was identified by increased propensity to develop hyperplastic callus. The syndrome was delineated in some detail by Bauze et al. [1975], who observed that 10% of patients with moderate to severe OI and normal sclerae, had OI type 5 [Bauze et al., 1975]. In a histomorphometric study of moderately severe OI type 4, 7 of 26 cases (25%) were detected with abnormal bone histomorphometry which is characteristic of OI type 5 [Glorieux et al., 2000]. In clinical studies it accounts for approximately 5% of individuals with OI seen in a hospital setting.

Calcification of the inter-osseous membrane in the forearms is observed from early in life, which leads to restriction of pronation and supination, and eventual dislocation of the radial heads. The sclerae are white and DI and Wormian bones are not present. Those affected tend to have higher serum alkaline phosphatase values and have an increased risk of developing hyperplastic callus following a fracture or orthopaedic surgery. A distinct pathogenesis is further supported by characteristic bone histomorphometry which shows coarse mesh-like lamellation which distinguishes OI type 5 from OI type 4 [Glorieux et al., 2000].

Hyperplastic callus is a rare medical emergency occurring in patients with OI type 5. This is characterized by massive callus with swelling and pain at the site of a fracture, which may be as minor as a stress fracture. Prompt use of indomethacin, an anti-inflammatory COX-1 and COX-2 prostaglandin inhibitor has been recommended to avert progress although of the callus although a randomized clinical trial has not been reported [Glorieux et al., 2000; Cho and Moffat, 2014].

MOLECULAR GENETICS OF OI

Currently, more than 1,000 heterozygous COL1A1/2 mutations have been identified (https://oi.gene.le.ac.uk, accessed April 1 2013) [Dalgleish, 1997, 1998]. Mutation type and position influence the phenotype and as such genotype–phenotype relations exist to some extent.

Autosomal Dominant OI (OI Types 1-5)

In the majority of affected individuals from European descent, OI types 1–4 result from heterozygous mutations in the COL1A1/2 genes encoding respectively the alpha1 and alpha2 chains of collagen type I (Fig. 1). The biosynthesis of collagen type I has been depicted in Table​Table3.3. Sibling recurrence without an affected parent may occur due to gonadal mosaicism for heterozygous dominant mutations in one of the parents [Byers and Cole, 2002].

Patients with OI type 1 and sometimes OI type 4 have an approximately 50% reduction (quantitative or haploinsufficiency effect) in the synthesis of type 1 procollagen often due to heterozygous mutations in one COL1A1 allele (nonsense, frameshift, and splice site alterations) leading to mRNA instability and haploinsufficiency. Other causes are deletions of the whole COL1A1 allele or substitutions for glycine by small amino acids (cysteine, alanine, and serine) near the amino-terminal ends of the triple helical domains in either one COL1A1 or COL1A2 allele [van Dijk et al., 2012]. Notwithstanding the 50% reduction in collagen synthesis from individual cells, these patients have above average new bone formation, the result of homeostatic mechanisms, which increase the number of bone forming units. This increased new bone formation is linked to increased bone turnover so that the net effect is a small annual bone loss, which is exaggerated if there is immobilization because of fractures or pain [Rauch and Glorieux, 2004].

The majority of cases of OI type 2–4 in North America and Europe are dominantly inherited and most cases are due to heterozygous COL1A1/2 mutations that result in substitutions for glycine. In general, glycine substitutions near the carboxyl-terminal end appear to result in the severest phenotype. Less common mutations include splice site alterations, insertion/deletion/duplication events that lead to in-frame sequence alterations and variants in the carboxyl-terminalpropeptide coding-domains [van Dijk et al., 2012] The heterozygous mutations disrupt triple helical assembly of type I collagen polypeptides, resulting in overprocessing by the enzymes responsible for post-translational modification of (pro) collagen type I and consequently production of abnormal collagen type I. This post-translational over-modification is demonstrable by SDS–polyacrylamide gel electrophoresis. The intertwining of mutated and normal collagen type I chains result in production of abnormal collagen type I protein, which is rapidly degraded (dominant-negative effect).

Recently, the genetic cause of OI type 5 has been elucidated in two independent publications [Cho et al., 2012; Semler et al., 2012] and consists of a heterozygous C＞T transition in the 5′UTR (untranslated region) of IFITM5 (c.-14C＞T). IFITM5 encodes Interferon induced transmembrane protein 5, the expression of this protein has been shown to peak during osteoblast formation in the early mineralization stage in mice and rats [Hanagata et al., 2011].

Autosomal Recessive OI (OI types 2-4)

A severe, autosomal recessive form of OI type 3 with a comparatively high frequency had already been recognized in the past in the black populations of southern Africa [Wallis et al., 1993] (Table​(Table3).3). Nowadays, it is also known that a founder mutation in LEPRE1 is carried by 1.5% of West Africans and 0.4% of African Americans [Cabral et al., 2012]. Recessive mutations in genes involved in collagen type I biosynthesis and post-translational modification have been identified in OI types 2–4 in the last 6 years. These were recently reviewed in depth [Byers and Pyott, 2012]. The recessive mutations concern genes encoding proteins involved in collagen type I biosynthesis, can be subdivided into (i) an enzymatic complex responsible for 3-prolyl hydroxylation of one specific residue (P986) in the alpha1 chain [van Dijk et al., 2012] and probably for initiating chain alignment and helical folding [Pyott et al., 2011] (CRTAP, LEPRE1, PPIB); (ii) quality control check of the collagen triple helix (SERPINH1, FKBP10); (iii) late processing of folded (pro)collagen type I chains i.e. hydroxylation of lysine residues in triple helical telopeptides important for collagen type I cross-linking in bone [van Dijk et al., 2012] (PLOD2, FKBP10) and cleavage of the C-propeptide (BMP1) [Martínez-Glez et al., 2012] (Fig. 1).

Furthermore, recessive mutations have been reported in SP7 encoding Osterix, an osteoblast specific transcription factor, in SERPINF1 possibly involved in bone formation and remodeling [van Dijk et al., 2012] and in TMEM38B encoding a trimeric intracellular cation channel [Shaheen et al., 2012; Volodarsky et al., 2013].

The recent delineation of mutations in WNT1, encoding a signaling peptide involved in osteoblast differentiation and proliferation [Fahiminiya et al., 2013; Keupp et al., 2013; Laine et al., 2013] and the interaction with FRIZZLED and its coligand LRP5, in which mutations in the latter are known to result in patients with severe syndromic OI, predict that further study of patients with severe OI from endogamous populations will uncover mutational mechanisms in the subsequent steps of the WNT-Beta Catenin signaling pathway. Most recently, a homozygous deletion of CREB3L1 was identified in a family with a severe progressively deforming OI phenotype. CREB3L1 encodes the ER-stress transducer OASIS that has been shown in a murine model to bind to the osteoblast-specific UPRE (unfolded protein response element) regulatory region in the Col1a1 promotor. This finding expands the genetic heterogeneity in OI and illustrates the role of ER-stress in the pathophysiology of OI [Symoens et al., 2013].

Pathogenic mutations found in recessive genes (Dalgleish, R: Osteogenesis Imperfecta Variant Database (https://oi.gene.le.ac.uk, accessed April 1 2013), are mostly homozygous or compound heterozygous loss-of-function mutations that result in two null alleles with severely decreased or no production of normal protein.

X-linked OI

X-linked inheritance of osteoporosis and fractures had been reported only once in the thesis of D. Sillence (Pedigree 41, Appendix) [Sillence, 1980]. Recently, loss-of-function mutations in PLS3 encoding plastin-3 were discovered as a cause of one form of X-linked osteoporosis with fractures [van Dijk et al., 2013]. In hemizygous men, pathogenic mutations in PLS3 were associated with osteoporosis and osteoporotic fractures of the axial and appendicular skeleton usually developing in childhood. The clinical picture in heterozygous female members was variable and ranged from normal bone mineral density and an absence of fractures to early-onset osteoporosis. No extraskeletal features of OI were present in affected men, but the phenotype is indistinguishable in many patients with other types of OI, it would probably fit best in the common variable OI (OI type 4) group, of whom less than 50% of patients have features such as Wormian bones in the skull and the sclerae are normal in hue, bluish in childhood and fading to normal adult hue.

CONCLUSION

From a medical geneticist point of view, the core principle is phenotyping of individuals (dysmorphology) and the study of these families with regard to inheritance pattern and phenotypic variability. The OI classification from 1979 is a classic example of the importance and possibilities of dysmorphology since it led to the delineation of four OI syndromes based on clinical/radiological features and inheritance, in combination with the assumption that OI was genetically heterogeneous, which was confirmed many years later by molecular genetic studies.

At present time, it has been postulated that molecular techniques such as Next-Generation Sequencing will decrease the need for phenotyping. However, the new OI nomenclature and the Severity Grading Scale described in this paper, emphasize the importance of phenotyping in order to diagnose, classify and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. The latter is the biggest challenge we face in the upcoming decade(s).

Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment

Abstract

Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Keywords: classification; collagen type I; fractures; heterogeneity; osteogenesis imperfecta.

FIG. 1. Overview of collagen type I biosynthesis. Collagen type I consists of two a1-chains and one a2-chain. After translation, pro-a1-chains and pro-a2 chains are processed in the rough Endoplasmic reticulum (rER). These chains have to align in order to start the folding process of (pro)collagen type I into a triple helix. The next step is alignment of the three chains in order to commence folding into a triple helical structure. During this folding process, post-translational modification by specific proteins takes place. The genes encoding proteins involved in post-translational modification and in which mutations have been reported to cause OI, are depicted in this figure. After transport of procollagen type I to the Golgi complex and following exocytosis into the extracellular matrix, cleavage of the C-and N-propeptides results in formation of collagen type I. Subsequently, cross-linking of collagen type I molecules leads to formation of fibrils. Multiple collagen type I fibrils form into collagen fibers, important constituents of bone.

TABLE III. Pre-and Postnatal Severity Grading Scale of Osteogenesis Imperfecta

Mild OI (Patients with mild OI most often have OI type 1 or 4)

Ultrasound findings at 20 weeks of pregnancy

No intra-uterine long bone fractures or bowing

Postnatal

Rarely congenital fractures

Normal or near normal growth velocity and height

Straight long bones i.e. no intrinsic long bone deformity

Fully ambulant other than at times of acute fracture

Minimal vertebral crush fractures

Lumbar spine bone mineral density Z-score usually ＞

1.5 (1.5 to þ1.5)Annualized fracture rate of less than or equal to 1.

Absence of chronic bone pain or minimal pain controlled by simple analgesics.

Regular school attendance, i.e., does not miss school due to pain, lethargy, or fatigue.

Moderate OI

Ultrasound findings at 20 weeks of pregnancy

Rarely fetal long bone fractures or bowing (but may increase in the last trimester)

Postnatal (Not modified by bisphosphonate therapy)

Occasionally congenital fractures

Decreased growth velocity and height

Anterior bowing of legs and thighs

Bowing of long bones related to immobilization for recurrent fractures

Vertebral crush fractures

Lumbar spine bone mineral density Z-score usually ＞

2.5 to ＜1.5) but a wide rangeAnnualized prepubertal fracture rate greater than 1 (average 3 with a wide range)

Absent from school due to pain more than 5 days per year.

Severe OI

Ultrasound findings at 20 weeks of pregnancy

Shortening of long bones

Fractures and/or bowing of long bones with some under-modeling

Slender ribs with absent or discontinuous rib fractures (cases intermediate

between severe and extremely severe have few rib fractures but crumpled long bones)

Decreased mineralization

Postnatal (not modified by bisphosphonate therapy)

Marked impairment of linear growth

Wheel-chair dependent

Progressive deformity of long bones and spine (unrelated to fractures)

Multiple vertebral crush fractures

Lumbar spine bone mineral density Z-score usually ＜

3.0 (wide range withage comparison as measurement is size/height dependent)

Annualized prepubertal fracture rate greater than 3 fractures per annum (age dependent)

Chronic bone pain unless treated with bisphosphonates

School attendance characterized by absences for fracture care and fatigue or pain

Extremely Severe OI

Ultrasound findings at 20 weeks of pregnancy

Shortening of long bones

Fractures and/or bowing of long bones with severe under-modeling leading to

crumpled (concertina-like) long bones

Thick continuously beaded ribs due to multiple sites of fracture or thin ribs

(previously described as OI type 2-A and 2-B, respectively)

Decreased mineralization

Postnatal

Thighs held in fixed abduction and external rotation with limitation of movement of most joints

Clinical indicators of severe chronic pain (pallor, sweatiness, whimpering or grimacing on

passive movement)

Decreased ossification of skull, multiple fractures of long bones and ribs. Small thorax.

Shortened compacted femurs with a concertina-like appearance

All vertebrae hypoplastic/crushed

Respiratory distress leading to perinatal death

Perinatally lethal course

文献出处：F S Van Dijk 1 , D O Sillence. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment Review, Am J Med Genet A. 2014 Jun;164A(6):1470-81. doi: 10.1002/ajmg.a.36545.