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瓷娃娃，鋼筋鐵骨 (2)：成骨不全綜合征(OI)：臨床診斷、命名和嚴(yán)重程度評(píng)估：2014年瓷娃娃，鋼筋鐵骨(2)：成骨不全綜合征(OI)：臨床診斷、命名和嚴(yán)重程度評(píng)估：2014年作者：FSVanDijk1,DOSillence作者單位:DepartmentofClinicalGenetics,CenterforConnectiveTissueDisorders,VUUniversityMedicalCenter,Amsterdam,TheNetherlands.譯者：陶可（北京大學(xué)人民醫(yī)院骨關(guān)節(jié)科）合作：任寧濤（解放軍總醫(yī)院第四醫(yī)學(xué)中心骨科）摘要最近，Sillence等于1979年提出的成骨不全癥(OI)的遺傳異質(zhì)性已通過(guò)分子遺傳學(xué)研究得到證實(shí)。目前，已經(jīng)確定了17種成骨不全癥(OI)和密切相關(guān)疾病的遺傳原因，預(yù)計(jì)還會(huì)有更多。與過(guò)去十年發(fā)表的關(guān)于導(dǎo)致成骨不全癥(OI)的遺傳原因和生化過(guò)程的大多數(shù)評(píng)論不同，這篇評(píng)論側(cè)重于成骨不全癥(OI)的臨床分類(lèi)，并詳細(xì)闡述了2010年新提出的成骨不全癥(OI)分類(lèi)，回歸到描述性和數(shù)字分組：五個(gè)成骨不全癥(OI)綜合征組。本綜述中引入的新成骨不全癥(OI)命名法和產(chǎn)前和產(chǎn)后嚴(yán)重程度評(píng)估，強(qiáng)調(diào)了表型分析對(duì)于診斷、分類(lèi)和評(píng)估成骨不全癥(OI)嚴(yán)重程度的重要性。這將使患者及其家人深入了解疾病的可能病程，并使醫(yī)生能夠評(píng)估治療效果。結(jié)合對(duì)特定分子遺傳原因的了解，仔細(xì)的臨床描述是開(kāi)發(fā)和評(píng)估包括成骨不全癥(OI)在內(nèi)的遺傳性疾病患者治療的起點(diǎn)。關(guān)鍵詞：分類(lèi)；I型膠原蛋白；骨折；異質(zhì)性；成骨不全癥圖1.I型膠原生物合成概述。I型膠原由兩條a1鏈和一條a2鏈組成。翻譯后，pro-a1鏈和pro-a2鏈在粗面內(nèi)質(zhì)網(wǎng)(rER)中加工。這些鏈必須對(duì)齊才能開(kāi)始將I型（原）膠原蛋白，折疊成三股螺旋。下一步是對(duì)齊三個(gè)鏈，以便開(kāi)始折疊成三螺旋結(jié)構(gòu)。在此折疊過(guò)程中，會(huì)發(fā)生特定蛋白質(zhì)的翻譯后修飾。編碼參與翻譯后修飾的蛋白質(zhì)的基因以及據(jù)報(bào)道其中的突變會(huì)導(dǎo)致成骨不全癥(OI)，如圖所示。在I型前膠原轉(zhuǎn)運(yùn)到高爾基復(fù)合體并胞吐進(jìn)入細(xì)胞外基質(zhì)后，C和N前肽的裂解導(dǎo)致I型膠原的形成。隨后，I型膠原分子的交聯(lián)導(dǎo)致原纖維的形成。多個(gè)I型膠原原纖維形成膠原纖維，是骨骼的重要成分。表3成骨不全癥(OI)的產(chǎn)前和產(chǎn)后嚴(yán)重程度分級(jí)量表輕度成骨不全癥(OI)【輕度成骨不全癥(OI)患者最?；加?型或4型成骨不全癥(OI)】懷孕20周時(shí)的超聲檢查結(jié)果無(wú)子宮內(nèi)長(zhǎng)骨骨折或弓形產(chǎn)后罕見(jiàn)先天性骨折正?；蚪咏５纳L(zhǎng)速度和身高直的長(zhǎng)骨，即沒(méi)有固有的長(zhǎng)骨畸形除了急性骨折的時(shí)候，完全可以走動(dòng)輕度椎體粉碎性骨折腰椎骨礦物質(zhì)密度Z值通常＞1.5（1.5至±1.5）年化骨折率小于或等于1沒(méi)有慢性骨痛或通過(guò)簡(jiǎn)單鎮(zhèn)痛藥控制的輕微疼痛正常上學(xué)，即不會(huì)因疼痛、嗜睡或疲勞而缺課。中度成骨不全癥(OI)懷孕20周時(shí)的超聲檢查結(jié)果很少有胎兒長(zhǎng)骨骨折或弓背（但在最后三個(gè)月可能會(huì)增加）產(chǎn)后（未被雙膦酸鹽治療改變）偶見(jiàn)先天性骨折生長(zhǎng)速度和身高下降腿部和大腿前弓形與復(fù)發(fā)性骨折固定相關(guān)的長(zhǎng)骨彎曲椎骨擠壓性骨折腰椎骨礦物質(zhì)密度Z評(píng)分通常＞2.5至＜1.5）但范圍很廣年化青春期前骨折率大于1（平均值為3，范圍很廣）每年因疼痛缺勤超5天。嚴(yán)重的成骨不全癥(OI)懷孕20周時(shí)的超聲檢查結(jié)果長(zhǎng)骨縮短長(zhǎng)骨骨折和/或弓形，伴有一些生長(zhǎng)發(fā)育不足肋骨細(xì)長(zhǎng)，肋骨骨折不存在或不連續(xù)（中間病例，介于嚴(yán)重和極嚴(yán)重之間，肋骨骨折很少，但長(zhǎng)骨皺折）礦化減少產(chǎn)后（未被雙膦酸鹽治療改變）線性增長(zhǎng)明顯受損依賴(lài)輪椅長(zhǎng)骨和脊柱進(jìn)行性畸形（與骨折無(wú)關(guān)）多發(fā)椎體粉碎性骨折腰椎骨礦物質(zhì)密度Z評(píng)分通常＜3.0（范圍寬年齡比較，因?yàn)闇y(cè)量值取決于尺寸/身高）每年超過(guò)3次骨折的年化青春期前骨折率（取決于年齡）慢性骨痛，除非用雙膦酸鹽治療因骨折和疲勞或疼痛為特征的學(xué)校出勤率下降。極度嚴(yán)重的成骨不全癥(OI)懷孕20周時(shí)的超聲檢查結(jié)果長(zhǎng)骨縮短骨折和/或長(zhǎng)骨彎曲伴有嚴(yán)重的生長(zhǎng)發(fā)育不足導(dǎo)致皺巴巴的（類(lèi)似手風(fēng)琴的）長(zhǎng)骨由于多處骨折或肋骨較薄，肋骨連續(xù)增厚（以前分別描述為成骨不全癥(OI)類(lèi)型2-A和2-B）礦化減少產(chǎn)后大腿固定外展和外旋，大多數(shù)關(guān)節(jié)活動(dòng)受限嚴(yán)重慢性疼痛的臨床指標(biāo)（臉色蒼白、出汗、嗚咽或做鬼臉）被動(dòng)運(yùn)動(dòng)顱骨骨化減少，長(zhǎng)骨和肋骨多處骨折，胸闊小?？s短的緊實(shí)股骨具有類(lèi)似手風(fēng)琴的外觀所有椎骨發(fā)育不全/壓碎呼吸窘迫導(dǎo)致圍產(chǎn)兒死亡圍產(chǎn)期致死過(guò)程。成骨不全綜合征(OI)的嚴(yán)重程度分級(jí)在所有成骨不全癥(OI)類(lèi)型中發(fā)現(xiàn)COL1A1/2突變后的幾年里，臨床實(shí)踐中經(jīng)常使用四種成骨不全癥(OI)類(lèi)型來(lái)反映其嚴(yán)重程度：輕型（OI1型）、致死性（OI2型）、嚴(yán)重畸形（OI3型）和中等程度畸形(OI4型)。盡管INCDS同意將Sillence分類(lèi)保留為“對(duì)成骨不全癥(OI)嚴(yán)重程度進(jìn)行分類(lèi)的原型和普遍接受的方法”[Warman等2011年]，但有人提出需要國(guó)際商定的受影響個(gè)體嚴(yán)重程度分級(jí)標(biāo)準(zhǔn)，并且采納，也反映了成骨不全癥(OI)患者治療的改進(jìn)可能性（手術(shù)、藥物和保守治療）。這里提出的嚴(yán)重程度分級(jí)量表依賴(lài)于臨床、歷史數(shù)據(jù)、骨折頻率、骨密度測(cè)定和活動(dòng)水平（表3）。利塞膦酸鹽在成骨不全癥中的POISE（小兒成骨不全癥的安全性和有效性研究）采用了這種嚴(yán)重程度分級(jí)，該研究確定了來(lái)自11個(gè)國(guó)家的22名研究人員確定的231名兒童[Munns和Sillence，2013年；Bishop等2013]。作者在此修改了POISE研究的分級(jí)，增加了產(chǎn)前臨床和超聲檢查結(jié)果的一般指南。該量表將需要通過(guò)專(zhuān)業(yè)中心與足夠患者的合作進(jìn)一步驗(yàn)證，并使用設(shè)施進(jìn)行全面評(píng)估，以進(jìn)一步確認(rèn)和闡明其臨床實(shí)用性。注：利塞膦酸鈉屬于第三代雙膦酸鹽，是一種骨吸收抑制劑，用于治療各類(lèi)骨質(zhì)疏松。利塞膦酸鈉是與羥基磷灰石有非常強(qiáng)的親和力，能夠沉積于骨骼及關(guān)節(jié)骨質(zhì)中，它不僅能夠抑制破骨細(xì)胞活性，也能促進(jìn)破骨細(xì)胞出現(xiàn)凋亡，減緩骨丟失和骨吸收速度。成骨不全癥(OI)的臨床表現(xiàn)和特征成骨不全癥(OI)的一般臨床表現(xiàn)和特征主要特征：易骨折和骨質(zhì)疏松雖然終生容易骨折是最重要的臨床特征，但1型成骨不全癥(OI)家庭的經(jīng)驗(yàn)表明，可能有10%的受影響個(gè)體在童年時(shí)期沒(méi)有發(fā)生過(guò)長(zhǎng)骨骨折[Sillence，1980年]。然而，用于測(cè)量骨密度的更新技術(shù)，例如骨骼的雙能X線吸收測(cè)定法(DXA)[Luetal.,1994]和/或最近的外周定量計(jì)算機(jī)斷層掃描(pQCT)[Gattietal.,2003];Folkestad等2012]的前臂和下肢，經(jīng)常顯示在那些通過(guò)正式遺傳分析患有成骨不全癥(OI)的個(gè)體中，至少一個(gè)骨骼區(qū)域的骨密度顯著降低（表3）。凈骨脆性是原發(fā)性骨脆性和骨質(zhì)疏松癥導(dǎo)致的繼發(fā)性骨脆性共同作用的最終結(jié)果。大多數(shù)成骨不全癥(OI)患者會(huì)出現(xiàn)骨質(zhì)疏松癥。成骨不全癥(OI)患者骨轉(zhuǎn)換血清和尿液標(biāo)志物升高的發(fā)現(xiàn)與骨組織形態(tài)學(xué)的發(fā)現(xiàn)一起考慮，最好用骨形成增加和骨吸收增加的組合來(lái)解釋[Rauch和Glorieux，2004]。凈效應(yīng)是小的進(jìn)行性骨質(zhì)流失，因?yàn)楣俏胀ǔ４笥诠切纬?，固定也?duì)骨形成產(chǎn)生負(fù)面影響。許多成骨不全癥(OI)兒童在經(jīng)主治醫(yī)師仔細(xì)評(píng)估后開(kāi)始使用旨在降低破骨細(xì)胞活性的雙膦酸鹽治療。在這方面，靜脈注射雙膦酸鹽的周期性治療已成為治療中度至重度成骨不全癥(OI)兒童的金標(biāo)準(zhǔn)。最近一項(xiàng)針對(duì)成骨不全癥(OI)兒童口服利塞膦酸鹽的隨機(jī)、雙盲、安慰劑對(duì)照試驗(yàn)（包括大部分受輕度至中度影響的兒童）表明骨折風(fēng)險(xiǎn)顯著降低，從而擴(kuò)大了該療法的治療益處成骨不全癥(OI)兒童[Bishop等2013]。一般相關(guān)的功能一些受累個(gè)體（而非其他個(gè)體）的相關(guān)特征包括明顯的鞏膜發(fā)藍(lán)、年輕成人發(fā)作的聽(tīng)力損失、牙本質(zhì)發(fā)育不全(DI)、關(guān)節(jié)活動(dòng)過(guò)度、身材矮小和進(jìn)行性骨骼畸形。據(jù)報(bào)道，成人成骨不全癥(OI)患者會(huì)出現(xiàn)心臟瓣膜功能障礙和主動(dòng)脈根部擴(kuò)張等心血管并發(fā)癥，更常見(jiàn)于3型成骨不全癥(OI)患者[Radunovic等，2011]。下面更詳細(xì)地描述了幾個(gè)相關(guān)的特征。藍(lán)鞏膜幾篇主要評(píng)論和至少一部專(zhuān)著[Smars,1961;Sillence等，1979;Sillence等;1993]得出結(jié)論，在患有“藍(lán)色鞏膜”的患者中，鞏膜的顏色與Wedgewood藍(lán)色的色調(diào)相似，并且非常獨(dú)特，以至于鞏膜看起來(lái)像是涂了漆。當(dāng)存在“藍(lán)色硬化”時(shí)，它們終生保持明顯的藍(lán)色。Berfenstam和Sm?rs在一項(xiàng)基于人群的研究中[1956]表明，兩組成骨不全癥(OI)患者（具有藍(lán)灰色鞏膜的患者和具有正常鞏膜的患者）在表型癥狀和肌肉骨骼并發(fā)癥模式方面存在統(tǒng)計(jì)學(xué)顯著差異。對(duì)1979年維多利亞人口研究中95名1型和4型成骨不全癥(OI)患者隊(duì)列的數(shù)據(jù)進(jìn)行了重新分析，以證實(shí)該發(fā)現(xiàn)[Sillence等，1993]。人們還注意到一種誤解，即1型成骨不全癥(OI)中的藍(lán)灰色鞏膜是由于鞏膜變薄所致。Eichholtz和Muller[1972]曾報(bào)道1型成骨不全癥(OI)的鞏膜總厚度正常，鞏膜膠原纖維之間的電子致密顆粒物質(zhì)增加。有人提出，在1型成骨不全癥(OI)的發(fā)病機(jī)制中，聽(tīng)力障礙、容易瘀傷和可能明顯的關(guān)節(jié)過(guò)度活動(dòng)最好用結(jié)締組織成分的繼發(fā)性失調(diào)來(lái)解釋。有進(jìn)一步的證據(jù)表明，導(dǎo)致成骨不全癥(OI)1型表型的過(guò)早終止/無(wú)意義/剪接突變的高流行率與基質(zhì)組成的改變有關(guān)[Byers和Cole，2002]。牙本質(zhì)發(fā)育不全癥(DI)牙本質(zhì)發(fā)育不全癥會(huì)導(dǎo)致牙齒明顯變黃和明顯透明，這些牙齒通常會(huì)過(guò)早磨損或折斷。有些牙齒可能有特別灰的色調(diào)。受影響牙齒的放射學(xué)研究表明，它們的牙根短，冠-根連接處收縮[Bailleul-Forestier等，2008]。脊柱側(cè)彎和基底壓痕等繼發(fā)性畸形脊柱側(cè)彎和基底壓痕等骨骼畸形被認(rèn)為是繼發(fā)性畸形，而不是原發(fā)性畸形。盡管長(zhǎng)骨無(wú)畸形已被作為診斷標(biāo)準(zhǔn)提出，但畸形的存在似乎至少在一定程度上受到護(hù)理質(zhì)量的顯著影響。在發(fā)展中國(guó)家，畸形可能是次優(yōu)護(hù)理的證據(jù)，反映出缺乏處理骨折的初級(jí)保健服務(wù)，而不是骨變形內(nèi)在過(guò)程的證據(jù)。具有藍(lán)色鞏膜的非變形成骨不全癥(OI)—成骨不全癥(OI)類(lèi)型11型成骨不全癥(OI)的特征是骨脆性增加，這通常與低骨量、明顯的藍(lán)灰色鞏膜以及在青春期和青年期開(kāi)始的傳導(dǎo)性聽(tīng)力損失的易感性有關(guān)。長(zhǎng)骨或脊柱的畸形并不常見(jiàn)，發(fā)生脊柱側(cè)凸的地方通常是特發(fā)性脊柱側(cè)凸。1型成骨不全癥(OI)是歐洲衍生社區(qū)中最常見(jiàn)的成骨不全癥(OI)類(lèi)型，出生率約為1:25,000活產(chǎn)，人口頻率相似[Steineretal.,2013]。骨折頻率和通常輕微的長(zhǎng)骨和脊柱畸形意味著它通常被認(rèn)為是輕度嚴(yán)重的，但偶爾它是中度嚴(yán)重的，特別是當(dāng)存在牙本質(zhì)發(fā)育不全癥(DI)時(shí)[Paterson等,1983]。在一些具有這種特征的家庭中觀察到牙本質(zhì)發(fā)育不全癥(DI)，而在其他家庭中則沒(méi)有。Paterson及其同事表明，患有1型成骨不全癥(OI)和牙本質(zhì)發(fā)育不全癥(DI)的患者比沒(méi)有牙本質(zhì)發(fā)育不全癥(DI)的患者更容易在出生時(shí)發(fā)生骨折（25%對(duì)6%）。此外，1型成骨不全癥(OI)和牙本質(zhì)發(fā)育不全癥(DI)患者的骨折頻率更高，身材矮小更嚴(yán)重，骨骼畸形更多。兩個(gè)亞組都有相似的關(guān)節(jié)過(guò)度活動(dòng)、瘀傷、耳聾和關(guān)節(jié)脫位的頻率[Patersonetal.,1983]。到40歲時(shí)，超過(guò)50%的1型成骨不全癥(OI)患者可檢測(cè)到由傳導(dǎo)性和感音神經(jīng)性損失引起的聽(tīng)力損傷[Kuurila等，2002；Swinnen等，2011]。眩暈是許多成骨不全癥(OI)患者的麻煩癥狀，包括1型成骨不全癥(OI)[Kuurila等，2003]。許多研究報(bào)告了具有常染色體顯性遺傳和可變表達(dá)的家族。藍(lán)鞏膜的外顯率接近100%，但臨床骨折的發(fā)生率僅為90-95%[Smars,1961;Sillence等人，1979]。一般變異性成骨不全癥(OI)—成骨不全癥(OI)類(lèi)型4這些患者有反復(fù)骨折、骨質(zhì)疏松癥和不同程度的長(zhǎng)骨和脊柱畸形，但鞏膜正常。鞏膜在出生時(shí)可能呈藍(lán)色，但在兒童時(shí)期藍(lán)色調(diào)會(huì)逐漸消失。聽(tīng)力障礙并不常見(jiàn)。由于后顱窩底抬高的基底壓痕導(dǎo)致的后顱窩壓迫綜合征的患病率增加?；加醒辣举|(zhì)發(fā)育不全癥(DI)的4型成骨不全癥(OI)患者發(fā)生基底壓痕的相對(duì)風(fēng)險(xiǎn)高5倍[Sillence,1994]。約30%的4型成骨不全癥(OI)患者在篩查時(shí)有基底印象，但其中只有16%有癥狀[Sillence,1994]。具有正常鞏膜的常見(jiàn)成骨不全癥(OI)偶爾表現(xiàn)為常染色體隱性遺傳[vanDijketal.,2010]和X連鎖遺傳[vanDijketal.,2013]，但它通常作為常染色體顯性遺傳病遺傳（表1)。家庭內(nèi)部的嚴(yán)重程度差異很大。很多家庭中有許多人患有輕度成骨不全癥(OI)，但同一家庭中有少數(shù)人患有中度嚴(yán)重的成骨不全癥(OI)[Holcomb，1931；Seedorf，1949]。逐漸變形的成骨不全癥(OI)–成骨不全癥(OI)類(lèi)型33型成骨不全癥(OI)患者通常有新生兒或嬰兒表現(xiàn)，骨骼脆弱和多處骨折導(dǎo)致骨骼進(jìn)行性畸形。他們通常在足月或接近足月出生，出生體重正常，出生身長(zhǎng)通常正常，但由于出生時(shí)下肢畸形可能會(huì)縮短。雖然鞏膜在出生時(shí)可能是藍(lán)色的，但對(duì)許多患有這種綜合征的患者的觀察表明，隨著年齡的增長(zhǎng)，鞏膜的藍(lán)色逐漸變淡[Sillence等，1986年]。持續(xù)存在的藍(lán)色鞏膜通常表示1型非變形成骨不全癥(OI)1型膠原基因的無(wú)意義突變或移碼突變，而患有各種常染色體隱性遺傳疾病的患者通常會(huì)出現(xiàn)灰白色鞏膜[Byers和Pyott，2012]。所有患者的縱向生長(zhǎng)都較差，身高遠(yuǎn)低于年齡和性別的第三個(gè)百分位。進(jìn)行性脊柱側(cè)凸在兒童時(shí)期發(fā)展并發(fā)展到青春期。患有此綜合征的兒童尚未報(bào)告聽(tīng)力受損，但成人聽(tīng)力損失更為常見(jiàn)。牙本質(zhì)發(fā)育不全癥(DI)是一個(gè)可變特征。出生時(shí)，放射學(xué)研究顯示全身性骨質(zhì)減少和多發(fā)性骨折。隨著長(zhǎng)骨干的頻繁過(guò)度損傷與修復(fù)，弓形和成角畸形存在不同程度。在幾周到幾個(gè)月內(nèi)，在一些嬰兒中，長(zhǎng)骨干的發(fā)育不足會(huì)導(dǎo)致“寬骨”外觀。從幾歲開(kāi)始，干骺端的密度和不規(guī)則性增加。這些被指定為“爆米花”外觀的干骺端變化可能只會(huì)在青春期后完全消退。肋骨變薄，骨質(zhì)疏松，并隨著扁平椎的增加而逐漸擁擠。頭骨顯示出多個(gè)Wormian骨骼，盡管這些骨骼可能要到幾周到幾個(gè)月大時(shí)才會(huì)明顯[Sillence等,1979;Sillence等,1986;Spranger等,2003;vanDijk等,2011]。過(guò)去，大約三分之二的患者在20歲時(shí)死亡。死亡通常由骨骼胸壁畸形的并發(fā)癥引起，包括脊柱側(cè)凸、肺動(dòng)脈高壓和心肺功能衰竭。使用目前的治療選擇，特別是循環(huán)靜脈內(nèi)帕米膦酸鹽的雙膦酸鹽治療[Glorieuxetal.,1998]在嬰兒期開(kāi)始，可以預(yù)期今天大多數(shù)3型成骨不全癥(OI)患者將存活到成年生活。幾項(xiàng)研究表明，管理嚴(yán)重成骨不全癥(OI)兒童的專(zhuān)業(yè)中心在嬰兒3歲時(shí)開(kāi)始循環(huán)靜脈注射帕米膦酸鹽，從而大大降低骨折頻率和接近正常生長(zhǎng)速度[Plotkin等，2000年；DiMeglio等，2004；Munns等，2005年；Astrom等，2007]。最近的一份出版物證實(shí)，治療似乎具有良好的耐受性，并且與骨密度增加、骨折頻率降低和椎體形狀改善有關(guān)[Alcausin等，2013]。圍產(chǎn)期致死性成骨不全癥(OI)綜合征——2型成骨不全癥(OI)這組胎兒和兒童的骨骼、關(guān)節(jié)和骨骼外特征極為嚴(yán)重。圍產(chǎn)期致死率是一個(gè)結(jié)果，而不是一個(gè)診斷特征。在妊娠18-20周檢測(cè)到的胎兒長(zhǎng)骨短而皺縮，長(zhǎng)骨彎曲或成角畸形，面部和顱骨骨化明顯不足。在妊娠早期，可能很少有肋骨骨折，但在子宮內(nèi)每個(gè)月都會(huì)出現(xiàn)肋骨骨折，導(dǎo)致連續(xù)的串珠狀外觀和皺縮（手風(fēng)琴狀）的長(zhǎng)骨，這是極端嚴(yán)重的一端的特征，以成骨不全癥(OI)2型（成骨不全癥(OI)類(lèi)型2-A）為代表[Sillence等,1984]。根據(jù)我們的經(jīng)驗(yàn)，循環(huán)靜脈注射帕米膦酸治療并不適用，因?yàn)楣切纬扇绱耸軗p，關(guān)節(jié)受限如此嚴(yán)重，幾乎沒(méi)有任何正常童年生活經(jīng)歷的機(jī)會(huì)。使用簡(jiǎn)單的鎮(zhèn)痛劑或皮下嗎啡來(lái)緩解疼痛特別有價(jià)值，可以改善舒適度和呼吸。在2型成骨不全癥(OI)的骨骼外特征中，神經(jīng)病理學(xué)發(fā)現(xiàn)如腦遷移缺陷和/或白質(zhì)改變已在有限數(shù)量的病例中得到報(bào)道[Emeryetal.,1999]。有些嬰兒的表型不太嚴(yán)重，肋骨骨折較少（成骨不全癥(OI)2-B型）[Sillence等，1984]，因此它們可能與成骨不全癥(OI)3型重疊[Spranger，1984]。這些嬰兒很少能存活下來(lái)，即使是成年，也可以通過(guò)循環(huán)靜脈注射帕米膦酸鹽治療“獲救”。在發(fā)達(dá)國(guó)家，許多或大多數(shù)2型成骨不全癥(OI)兒童目前在產(chǎn)前診斷（通過(guò)超聲和DNA分析），通常導(dǎo)致妊娠終止。平均出生身長(zhǎng)和體重小于第50個(gè)百分位數(shù)[Sillence等，1984]。大腿外展并外旋。由于多處肋骨骨折引起的疼痛以及受影響最嚴(yán)重的每根肋骨骨折愈傷組織半連續(xù)串珠的異常生物力學(xué)特性，因此妊娠期胸部較小，呼吸運(yùn)動(dòng)可能受到抑制。一些臨床特征表明，患有2型成骨不全癥(OI)的新生兒會(huì)持續(xù)疼痛。由于多處骨折，他們可能會(huì)出汗過(guò)多、臉色蒼白、被觸摸時(shí)表現(xiàn)出焦慮并且四肢很少活動(dòng)。五分之一死產(chǎn)，90%死于4周齡[Sillenceetal.,1984]。骨間膜鈣化的成骨不全癥(OI)——成骨不全癥(OI)類(lèi)型5具有中度至重度骨脆性的5型成骨不全癥(OI)最初由Battle和Shattock[1908]定義為前臂和下肢骨間膜進(jìn)行性鈣化的一種成骨不全癥(OI)。獨(dú)立地，它是通過(guò)增加增生性愈傷組織的傾向來(lái)識(shí)別的。Bauze等詳細(xì)描述了該綜合征[1975]，他觀察到10%的中度至重度成骨不全癥(OI)且鞏膜正常的患者患有5型成骨不全癥(OI)[Bauze等，1975]。在一項(xiàng)針對(duì)4型中重度成骨不全癥(OI)的組織形態(tài)學(xué)研究中，檢測(cè)到26例中有7例(25%)具有骨組織形態(tài)學(xué)異常，這是5型成骨不全癥(OI)的特征[Glorieux等，2000]。在臨床研究中，它約占在醫(yī)院就診的成骨不全癥(OI)患者的5%。從生命早期就可以觀察到前臂骨間膜的鈣化，這會(huì)導(dǎo)致旋前和旋后受限，并最終導(dǎo)致橈骨頭脫位。鞏膜是白色的，不存在DI和Wormian骨頭。那些受影響的人往往具有較高的血清堿性磷酸酶值，并且在骨折或整形外科手術(shù)后發(fā)生增生性愈傷組織的風(fēng)險(xiǎn)增加。特征性骨組織形態(tài)學(xué)進(jìn)一步支持了一種獨(dú)特的發(fā)病機(jī)制，該組織形態(tài)學(xué)顯示粗網(wǎng)狀層狀結(jié)構(gòu)，可將5型成骨不全癥(OI)與4型成骨不全癥(OI)區(qū)分開(kāi)來(lái)[Glorieux等，2000]。增生性骨痂是5型成骨不全癥(OI)患者罕見(jiàn)的醫(yī)療急癥。其特征是骨折部位有腫塊骨痂并伴有腫脹和疼痛，可能與應(yīng)力性骨折一樣輕微。及時(shí)使用消炎痛，一種抗炎COX-1和COX-2前列腺素抑制劑，已被推薦用于避免愈傷組織的進(jìn)展，盡管尚未報(bào)告隨機(jī)臨床試驗(yàn)[Glorieuxetal.,2000;Cho和Moffat，2014]。成骨不全癥(OI)的分子遺傳學(xué)目前，已鑒定出1,000多個(gè)雜合COL1A1/2突變（https://oi.gene.le.ac.uk，2013年4月1日訪問(wèn)）[Dalgleish,1997,1998]。突變類(lèi)型和位置影響表型，因此在一定程度上存在基因型-表型關(guān)系。常染色體顯性成骨不全癥(OI)（OI類(lèi)型1-5）在大多數(shù)來(lái)自歐洲血統(tǒng)的受影響個(gè)體中，1-4型成骨不全癥(OI)是由COL1A1/2基因的雜合突變引起的，該基因分別編碼I型膠原蛋白的alpha1和alpha2鏈（圖1）。表3.3描述了I型膠原的生物合成。由于父母之一的雜合顯性突變的性腺嵌合體，可能會(huì)發(fā)生沒(méi)有受累父母的兄弟姐妹[ByersandCole,2002]。1型成骨不全癥(OI)患者和有時(shí)4型成骨不全癥(OI)患者的1型原膠原合成減少約50%（定量或單倍體不足效應(yīng)），通常是由于一個(gè)COL1A1等位基因的雜合突變（無(wú)意義、移碼和剪接位點(diǎn)改變）導(dǎo)致mRNA不穩(wěn)定性和單倍體不足。其他原因是整個(gè)COL1A1等位基因缺失或甘氨酸被COL1A1或COL1A2等位基因中三螺旋結(jié)構(gòu)域氨基末端附近的小氨基酸（半胱氨酸、丙氨酸和絲氨酸）取代[vanDijk等，2012]。管單個(gè)細(xì)胞的膠原蛋白合成減少了50%，但這些患者的新骨形成高于平均水平，這是穩(wěn)態(tài)機(jī)制的結(jié)果，增加了骨形成單位的數(shù)量。這種新骨形成的增加與骨轉(zhuǎn)換的增加有關(guān)，因此凈效應(yīng)是每年的骨質(zhì)流失量很小，如果因骨折或疼痛不能活動(dòng)，骨質(zhì)流失會(huì)加劇[Rauch和Glorieux，2004]。北美和歐洲的大多數(shù)2-4型成骨不全癥(OI)病例是顯性遺傳的，并且大多數(shù)病例是由于導(dǎo)致甘氨酸替代的雜合COL1A1/2突變所致。一般而言，羧基末端附近的甘氨酸取代似乎導(dǎo)致最嚴(yán)重的表型。不太常見(jiàn)的突變包括剪接位點(diǎn)改變、插入/刪除/復(fù)制突變，這些突變導(dǎo)致框內(nèi)序列改變和羧基末端原肽編碼域的變異[vanDijk等，2012]雜合突變破壞了類(lèi)型的三螺旋組裝I型膠原蛋白多肽，導(dǎo)致負(fù)責(zé)I型（原）膠原蛋白翻譯后修飾的酶過(guò)度加工，從而產(chǎn)生異常I型膠原蛋白。這種翻譯后過(guò)度修飾可通過(guò)SDS-聚丙烯酰胺凝膠電泳證明。突變和正常I型膠原蛋白鏈的交織導(dǎo)致異常I型膠原蛋白的產(chǎn)生，該蛋白迅速降解（顯性負(fù)效應(yīng)）。最近，兩份獨(dú)立文獻(xiàn)闡明了5型成骨不全癥(OI)的遺傳原因[Choetal.,2012;Semleretal.,2012]并由IFITM5(c.-14C＞T)的5‘UTR（非翻譯區(qū)）中的雜合C＞T轉(zhuǎn)換組成。IFITM5編碼干擾素誘導(dǎo)的跨膜蛋白5，該蛋白的表達(dá)已顯示在小鼠和大鼠早期礦化階段的成骨細(xì)胞形成過(guò)程中達(dá)到峰值[Hanagata等，2011]。常染色體隱性成骨不全癥(OI)（OI類(lèi)型2-4）過(guò)去已經(jīng)在南部非洲的黑人人群中發(fā)現(xiàn)了一種相對(duì)較高頻率的嚴(yán)重的常染色體隱性3型成骨不全癥(OI)[Wallis等，1993]（表3）。如今，還已知1.5%的西非人和0.4%的非裔美國(guó)人攜帶LEPRE1的創(chuàng)始人突變[Cabraletal.,2012]。在過(guò)去的6年中，已經(jīng)在2-4型成骨不全癥(OI)中發(fā)現(xiàn)了參與I型膠原生物合成和翻譯后修飾的基因的隱性突變。最近對(duì)這些進(jìn)行了深入審查[ByersandPyott,2012]。隱性突變涉及編碼參與I型膠原蛋白生物合成的蛋白質(zhì)的基因，可細(xì)分為(i)負(fù)責(zé)alpha1鏈中一個(gè)特定殘基(P986)的3-脯氨酰羥基化的酶復(fù)合物[vanDijk等，2012]并且可能用于啟動(dòng)鏈對(duì)齊和螺旋折疊[Pyott等，2011]（CRTAP、LEPRE1、PPIB）；(ii)膠原蛋白三螺旋(SERPINH1,FKBP10)的質(zhì)量控制檢查；(iii)I型折疊（前）膠原蛋白鏈的后期加工，即三螺旋端肽中賴(lài)氨酸殘基的羥基化對(duì)于I型膠原蛋白在骨骼中的交聯(lián)很重要[vanDijketal.,2012](PLOD2,FKBP10)和裂解C前肽(BMP1)[Martínez-Glez等，2012]（圖1）。此外，在編碼Osterix的SP7（一種成骨細(xì)胞特異性轉(zhuǎn)錄因子）、可能參與骨形成和重建的SERPINF1[vanDijk等，2012]和編碼三聚體細(xì)胞內(nèi)陽(yáng)離子通道的TMEM38B[Shaheen等,2012;Volodarsky等,2013]。最近描述的WNT1突變，編碼參與成骨細(xì)胞分化和增殖的信號(hào)肽[Fahiminiya等，2013；Keupp等，2013；Laine等，2013]以及與FRIZZLED及其配體LRP5的相互作用，其中后者的突變已知會(huì)導(dǎo)致患有嚴(yán)重綜合征性成骨不全癥(OI)的患者，預(yù)測(cè)對(duì)來(lái)自?xún)?nèi)婚人群的嚴(yán)重成骨不全癥(OI)患者的進(jìn)一步研究將揭示突變機(jī)制在WNT-β連環(huán)蛋白信號(hào)通路的后續(xù)步驟中。最近，在一個(gè)具有嚴(yán)重進(jìn)行性畸形成骨不全癥(OI)表型的家族中發(fā)現(xiàn)了CREB3L1的純合缺失。CREB3L1編碼內(nèi)質(zhì)網(wǎng)應(yīng)激傳感器OASIS，該傳感器已在小鼠模型中顯示可與Col1a1啟動(dòng)子中的成骨細(xì)胞特異性UPRE（未折疊蛋白反應(yīng)元件）調(diào)節(jié)區(qū)結(jié)合。這一發(fā)現(xiàn)擴(kuò)大了成骨不全癥(OI)的遺傳異質(zhì)性，并說(shuō)明了ER應(yīng)激在成骨不全癥(OI)病理生理學(xué)中的作用[Symoensetal.,2013]。在隱性基因中發(fā)現(xiàn)的致病性突變（Dalgleish，R：成骨不全變異數(shù)據(jù)庫(kù)（https://oi.gene.le.ac.uk，2013年4月1日訪問(wèn)），主要是純合子或復(fù)合雜合子功能喪失突變，導(dǎo)致在兩個(gè)無(wú)效等位基因中，正常蛋白質(zhì)的產(chǎn)生嚴(yán)重減少或沒(méi)有。X連鎖成骨不全癥(OI)骨質(zhì)疏松癥和骨折的X連鎖遺傳僅在D.Sillence的論文（Pedigree41，附錄）[Sillence，1980]中有過(guò)一次報(bào)道。最近，發(fā)現(xiàn)編碼plastin-3的PLS3中的功能喪失突變是一種形式的X連鎖骨質(zhì)疏松癥伴骨折的原因[vanDijk等，2013]。在半合子男性中，PLS3的致病性突變與通常在兒童時(shí)期發(fā)生的中軸和四肢骨骼的骨質(zhì)疏松癥和骨質(zhì)疏松性骨折有關(guān)。雜合子女性成員的臨床表現(xiàn)是多變的，范圍從正常的骨礦物質(zhì)密度和沒(méi)有骨折到早發(fā)性骨質(zhì)疏松癥。受影響的男性沒(méi)有成骨不全癥(OI)的骨骼外特征，但表型在許多其他類(lèi)型的成骨不全癥(OI)患者中無(wú)法區(qū)分，它可能最適合常見(jiàn)變量成骨不全癥(OI)（OI類(lèi)型4）組，其中不到50%的患者具有頭骨中的Wormian骨和鞏膜等特征，顏色正常，兒童期呈藍(lán)色，成人后逐漸褪色。結(jié)論從醫(yī)學(xué)遺傳學(xué)家的角度來(lái)看，核心原則是個(gè)體的表型分析（畸形學(xué)）以及這些家族在遺傳模式和表型變異性方面的研究。1979年的成骨不全癥(OI)分類(lèi)是畸形學(xué)的重要性和可能性的典型例子，因?yàn)樗鶕?jù)臨床/放射學(xué)特征和遺傳，結(jié)合成骨不全癥(OI)具有遺傳異質(zhì)性的假設(shè)，對(duì)四種成骨不全癥(OI)綜合征進(jìn)行了描述，許多人證實(shí)了這一點(diǎn)多年后通過(guò)分子遺傳學(xué)研究。目前，據(jù)推測(cè)，下一代測(cè)序等分子技術(shù)將減少對(duì)表型分析的需求。然而，本文描述的新成骨不全癥(OI)命名法和嚴(yán)重程度分級(jí)量表強(qiáng)調(diào)了表型分析對(duì)于診斷、分類(lèi)和評(píng)估成骨不全癥(OI)嚴(yán)重程度的重要性。這將使患者及其家人深入了解疾病的可能病程，并使醫(yī)生能夠評(píng)估治療效果。結(jié)合對(duì)特定分子遺傳原因的了解，仔細(xì)的臨床描述是開(kāi)發(fā)和評(píng)估包括成骨不全癥(OI)在內(nèi)的遺傳性疾病患者治療的起點(diǎn)。后者是我們?cè)谖磥?lái)十年面臨的最大挑戰(zhàn)。SEVERITYGRADINGINOSTEOGENESISIMPERFECTASYNDROMESIntheyearsfollowingthediscoveryofCOL1A1/2mutationsinallOItypes,thefourOItypeswereoftenusedinclinicalpracticetoreflectseveritywithmild(OItype1),lethal(OItype2),severelydeforming(OItype3),andmoderatelydeforming(OItype4).AlthoughtheINCDSagreedtoretaintheSillenceclassificationas“theprototypicanduniversallyacceptedwaytoclassifythedegreeofseverityinOI”[Warmanetal.,2011],theneedforinternationallyagreedcriteriaforgradingseveritybetweenaffectedindividualswasproposedandadopted,reflectingalsotheimprovedtreatmentpossibilities(surgical,pharmacologicalandconservative)forpatientswithOI.Theseveritygradingscaleproposedherereliesonclinical,historicaldata,fracturefrequency,bonedensitometry,andlevelofmobility(Table(Table3).3).ThisseveritygradingwasadoptedforthePOISE(PediatricOsteogenesisImperfectaSafetyandEfficacystudy)ofRisedronateinosteogenesisimperfectain231childrenascertainedfrom22investigatorsdrawnfrom11countries[MunnsandSillence,2013;Bishopetal.,2013].ThegradingforthePOISEstudyismodifiedherebytheauthorswithadditionofageneralguidelinetoprenatalclinicalandultrasonographicfindings.ThescalewillrequirefurthervalidationbycollaborationbetweenCentresofExpertisewithsufficientpatientsandaccesstofacilitiesforcomprehensiveassessmentinordertofurtherconfirmandclarifyitsclinicalutility.CLINICALPRESENTATIONSANDFEATURESOFOSTEOGENESISIMPERFECTAClinicalPresentationsandFeaturesofOIinGeneralPrimaryfeature:liabilitytofracturesandosteoporosisWhileliabilitytofracturesthroughoutlifeisthesinglemostimportantclinicalfeature,experiencewithfamilieswithOItype1indicatethatperhaps10%ofaffectedindividualshavenothadalongbonefractureduringchildhood[Sillence,1980].However,newertechniquesformeasuringbonedensity,suchasdualenergyX-rayabsorptiometry(DXA)oftheskeleton[Luetal.,1994]and/ormorerecentlyperipheralquantativecomputerizedtomography(pQCT)[Gattietal.,2003;Folkestadetal.,2012]offorearmandleg,frequentlyrevealsignificantlyreducedbonedensityinaleastoneareaoftheskeletoninthoseindividualswhobyformalgeneticanalysishaveOI(Table3).Netbonefragilityisthefinalresultofcontributionsfromprimarybonefragilityandthesecondaryfragilityresultingfromosteoporosis.OsteoporosisdevelopsinthemajorityofpatientswithOI.ThefindingofelevatedserumandurinemarkersofboneturnoverinpatientswithOIconsideredalongwiththefindingsofbonehistomorphometry,isbestexplainedbyacombinationofincreasedboneformationandincreasedboneresorption[RauchandGlorieux,2004].Theneteffectisasmallprogressivebonelosssinceboneresorptionisoftengreaterthanboneformation,withimmobilizationalsoexertinganegativeeffectonboneformation.Bisphosphonatetreatmentaimedatreductionofosteoclastactivity,isinitiatedinmanychildrenwithOIaftercarefulassessmentbythetreatingphysician.InthatregardcyclicaltreatmentwithintravenousbisphosphonateshasbecomethegoldstandardfortreatmentofchildrenwithmoderatetosevereOI.Averyrecentrandomized,double-blind,placebo-controlledtrialoforalRisedronateinchildrenwithOI,includingalargeproportionofmoremildtomoderatelyaffectedchildren,demonstratedasignificantreductioninfracturerisk,thusextendingthetherapeuticbenefitsofthistherapyinchildrenwithOI[Bishopetal.,2013].AssociatedfeaturesingeneralAssociatedfeaturesinsomeaffectedindividuals,butnotothers,includedistinctbluenessofthesclerae,youngadultonsethearingloss,dentinogenesisimperfect(DI),jointhypermobility,shortstature,andprogressiveskeletaldeformity.CardiovascularcomplicationssuchasvalvulardysfunctionandaorticrootdilatationhavebeenreportedinadultOIpatients,moreofteninpatientswithOItype3[Radunovicetal.,2011].Severalassociatedfeaturesaremoreelaboratelydescribedbelow.BlueScleraeSeveralmajorreviewsandatleastonemonograph[Smars,1961;Sillenceetal.,1979;Sillenceetal.,1993]concludedthatinpatientswith“bluesclerae”thecolorofthescleraeissimilartoWedgewoodblueinhueandissoverydistinctivethatthescleraeappearpainted.When“bluesclerotics”arepresent,theyremaindistinctlybluethroughoutlife.BerfenstamandSm?rsinapopulationbasedstudy[1956]showedthattherewerestatisticallysignificantdifferencesinpatternsofphenotypicsymptomsandmusculoskeletalcomplicationsbetweentwogroupsofpatientswithOI,thosewithblue-greyscleraeandthosewithnormalsclerae.Datafromacohortof95patientswithOItype1andOItype4inthe1979Victorianpopulationstudywerereanalysedtoconfirmthatfinding[Sillenceetal.,1993].Attentionwasalsodrawntothemisconceptionthattheblue-grayscleraeinOItype1areduetothethinningofthesclerae.EichholtzandMuller[1972]hadreportedthatoverallthicknessofthescleraeinOItype1wasnormalandtherewasincreasedelectrondensegranularmaterialbetweenscleralcollagenfibers.ItwasproposedthatinthepathogenesisofOItype1,thehearingimpairment,easybruisingandpossiblythemarkedjointhypermobilitywouldbebestexplainedbysecondarydysregulationofconnectivetissuecomposition.Thereisfurtherevidencethatthehighprevalenceofprematuretermination/nonsense/splicingmutationswhichcausetheOItype1phenotypeareassociatedwithalterationsinmatrixcomposition[ByersandCole,2002].DentinogenesisimperfectaDentinogenesisimperfectaproducesadistinctiveyellowingandapparenttransparencyoftheteeth,whichareoftenwornprematurelyorbroken.Someteethmayhaveaparticularlygreyishhue.Radiologicstudiesofaffectedteethshowthattheyhaveshortrootswithconstrictedcorono-radicularjunctions[Bailleul-Forestieretal.,2008].SecondarydeformationsSkeletaldeformitiessuchasscoliosisandbasilarimpressionareregardedassecondarydeformationsratherthanprimarymalformations.Althoughtheabsenceofdeformityoflongboneshasbeenadvancedasadiagnosticcriterion,thepresenceofdeformityseemsatleastpartlysignificantlyinfluencedbyqualityofcare.Indevelopingcountries,deformitymaybeevidenceofsub-optimalcarereflectinglackofprimarycareservicesformanagingfractures,ratherthanevidenceofanintrinsicprocessofbonedeformation.Non-DeformingOIWithBlueSclerae—OIType1OItype1ischaracterizedbyincreasedbonefragility,whichisusuallyassociatedwithlowbonemass,distinctlyblue-graysclerae,andsusceptibilitytoconductivehearinglosscommencinginadolescenceandyoungadultlife.Deformityoflongbonesorspineisuncommonandwherescoliosisdevelopsitiscommonlyanidiopathicscoliosis.OItype1isthemostcommonvarietyofOIinEuropeanderivedcommunitiesandhasabirthprevalenceintheorderof1:25,000livebirthsandasimilarpopulationfrequency[Steineretal.,2013].Fracturefrequencyandusuallymildlongboneandspinedeformitymeanthatitisgenerallyperceivedtobeofmildseveritybutoccasionallyitismoderatelysevere,particularlywhenDIispresent[Patersonetal.,1983].DIisobservedinsomefamilieswiththistraitandnotothers.PatersonandcolleaguesshowedthatpatientswithOItype1andDIaremorelikelytohavefracturesatbirth(25%vs.6%)thanthosewithoutDI.Furthermore,patientswithOItype1andDIhaveahigherfracturefrequency,moresevereshortstature,andmoreskeletaldeformity.Bothsubgroupshaveasimilarfrequencyofjointhypermobility,bruising,deafness,andjointdislocations[Patersonetal.,1983].Hearingimpairmentresultingfrombothconductiveandsensorineurallossisdetectableinover50%ofpatientswithOItype1by40yearsofage[Kuurilaetal.,2002;Swinnenetal.,2011].VertigoisatroublesomesymptominmanypeoplewithOIincludingOItype1[Kuurilaetal.,2003].Familieswithautosomaldominantinheritanceandvariableexpressivityhavebeenreportedinmanystudies.Penetranceforbluescleraeiscloseto100%butfrequencyofclinicalfracturesisonly90–95%[Smars,1961;Sillenceetal.,1979].CommonVariableOI—OIType4Thesepatientshaverecurrentfractures,osteoporosisandvariabledegreesofdeformityoflongbonesandspinebutnormalsclerae.Thescleraemaybebluishatbirthbutthebluetingefadesduringchildhood.Hearingimpairmentisnotoftenencountered.Posteriorfossacompressionsyndromesduetobasilarimpressionwithelevationoftheflooroftheposteriorcranialfossaareincreasedinprevalence.PatientswithOItype4whohaveDIhaveafivetimeshigherrelativeriskforbasilarimpression[Sillence,1994].Some30%ofpatientswithOItype4havebasilarimpressiononscreeningbutonly16%ofthesearesymptomatic[Sillence,1994].Commonvariableosteogenesisimperfectawithnormalscleraeshowsoccasionallyautosomalrecessive[vanDijketal.,2010]andX-linkedinheritance[vanDijketal.,2013]butitisusuallyinheritedasanautosomaldominantdisorder(Table1).Severityishighlyvariablewithinfamilies.ItisnotuncommontofindfamilieswheretherearemanyaffectedwithmildOIbutafewindividualsinthesamefamilywithmoderatelysevereOI[Holcomb,1931;Seedorf,1949].ProgressivelyDeformingOI–OIType3IndividualswithOItype3usuallyhavenewbornorinfantpresentationwithbonefragilityandmultiplefracturesleadingtoprogressivedeformityoftheskeleton.Theyaregenerallybornatorneartermandhavenormalbirthweightandoftennormalbirthlength,althoughthismaybereducedbecauseofdeformitiesofthelowerlimbsatbirth.Althoughthescleraemaybeblueatbirth,observationofmanypatientswiththissyndromedocumentsthatthescleraebecomeprogressivelylessbluewithage[Sillenceetal.,1986].Persistingbluescleraeareusuallyanindicationofnonsenseorframeshiftmutationsintype1collagengenescharacteristicofnon-deformingOItype1whereaspatientswiththevariousautosomalrecessivedisorderswillusuallyhavegrey-whitesclerae[ByersandPyott,2012].Allpatientshavepoorlongitudinalgrowthandfallwellbelowthethirdcentileinheightforageandsex.Progressivekyphoscoliosisdevelopsduringchildhoodandprogressesintoadolescence.Hearingimpairmenthasnotbeenreportedinchildrenwiththissyndromebuthearinglossismorefrequentinadults.DIisavariablefeature.Atbirth,radiographicstudiesshowgeneralizedosteopeniaandmultiplefractures.Bowingandangulationdeformitiesexisttoavariabledegreewithfrequentover-modelingoftheshaftsofthelongbones.Withinweekstomonths,insomeinfants,under-modelingoftheshaftsoflongbonesresultsina“broad-bone”appearance.Fromseveralyearsofage,metaphysesdevelopincreasingdensityandirregularity.Thesemetaphysealchangesdesignateda“pop-corn”appearancemayevolveonlytoresolvecompletelyafterpuberty.Theribsarethin,osteopenic,andprogressivelycrowdedasplatyspondylyincreases.TheskullshowsmultipleWormianbones,althoughthesemaynotbeevidentuntilseveralweekstomonthsofage[Sillenceetal.,1979;Sillenceetal.,1986;Sprangeretal.,2003;vanDijketal.,2011].Inthepast,approximatelytwo-thirdsofthepatientsdiedbytheendoftheseconddecade.Deathusuallyresultedfromthecomplicationsofskeletalchestwalldeformityincludingkyphoscoliosis,pulmonaryhypertension,andcardio-respiratoryfailure.Withthepresenttherapeuticoptions,specificallybisphosphonatetreatmentwithcyclicintravenousPamidronate[Glorieuxetal.,1998]commencedininfancy,itcanbeexpectedthattodaythemajorityofpatientswithOItype3willsurviveintoadultlife.SeveralstudiesdemonstratethatcentersofexpertisethatmanagechildrenwithsevereOI,achieveveryreducedfracturefrequencyandnearnormalgrowthvelocityininfantscommencedoncyclicintravenouspamidronateby3yearsofage[Plotkinetal.,2000;DiMeglioetal.,2004;Munnsetal.,2005;Astrometal.,2007].Arecentpublicationconfirmedthattreatmentappearstobewelltoleratedandassociatedwithanincreaseinbonedensity,reducedfracturefrequencyandimprovedvertebralshape[Alcausinetal.,2013].PerinatallyLethalOISyndromes—OIType2Theskeletal,joint,andextraskeletalfeaturesofthisgroupoffetusesandchildrenareextremelysevere.Perinatallethalityisanoutcomeratherthanadiagnosticfeature.Fetusesdetectedat18–20weeksgestationhaveshortcrumpledlongbones,bowingorangulationdeformitiesoflongbonesandmarkeddeficiencyofossificationoffacialandskullbones.Atthisearlygestation,theremaybefewribfracturesbutwitheachmonthinuterothereisprogressivefracturingofribsresultinginthecontinuouslybeadedappearancecombinedwithcrumpled(accordion-like)longbonesthatischaracteristicoftheextremelysevereendofthespectrumrepresentedbyOItype2(OItype2-A)[Sillenceetal.,1984].Inourexperience,treatmentwithcyclicintravenouspamidronateisnotindicatedasboneformationissoimpairedandjointrestrictionsoseverethereisvirtuallynochanceofanynormalchildhoodlifeexperience.Painreliefwithsimpleanalgesicsorsubcutaneousmorphineisparticularlyvaluable,improvingcomfortandbreathing.AmongtheextraskeletalfeaturesinOItype2,neuropathologicalfindingssuchasbrainmigrationaldefectsand/orwhitematterchangeshavebeenreportedinalimitednumberofcases[Emeryetal.,1999].Somebabieshaveaphenotypewhichisalittlelessseverewithfewerribfractures(OItype2-B)[Sillenceetal.,1984]andassuchtheycanshowoverlapwithOItype3[Spranger,1984].Rarelythesebabiessurvive,eventoadultlifeandcanbe“rescued”withtreatmentwithcyclicintravenouspamidronate.Indevelopedcountries,manyormostchildrenwithOItype2areatpresentdiagnosedprenatally(byultrasoundandDNAanalysis),oftenresultinginterminationofpregnancy.Meanbirthlengthandweightarelessthanthefiftiethcentile[Sillenceetal.,1984].Thethighsareheldabductedandinexternalrotation.Thechestissmallforgestationandrespiratoryexcursionmaybedepressedbecauseofthepainfrommultipleribfracturesandtheabnormalbiomechanicalpropertiesofsemicontinuousbeadingfromfracturecallusalongeachribinthemostseverelyaffected.SeveralclinicalfeaturessuggestthatnewbornswithOItype2areinconstantpain.Theymayhaveexcessiveperspiration,pallor,showanxietyatbeingtouchedandmovetheirlimbsverylittlebecauseofmultiplefractures.One-fiftharestillbornand90%dieby4weeksofage[Sillenceetal.,1984].OIWithCalcificationinInterosseousMembranes—OIType5OItype5withmoderatetoseverebonefragilitywasoriginallydefinedbyBattleandShattock[1908]asatypeofOIwithprogressivecalcificationoftheinter-osseousmembranesintheforearmsandlegs.Independentlyitwasidentifiedbyincreasedpropensitytodevelophyperplasticcallus.ThesyndromewasdelineatedinsomedetailbyBauzeetal.[1975],whoobservedthat10%ofpatientswithmoderatetosevereOIandnormalsclerae,hadOItype5[Bauzeetal.,1975].InahistomorphometricstudyofmoderatelysevereOItype4,7of26cases(25%)weredetectedwithabnormalbonehistomorphometrywhichischaracteristicofOItype5[Glorieuxetal.,2000].Inclinicalstudiesitaccountsforapproximately5%ofindividualswithOIseeninahospitalsetting.Calcificationoftheinter-osseousmembraneintheforearmsisobservedfromearlyinlife,whichleadstorestrictionofpronationandsupination,andeventualdislocationoftheradialheads.ThescleraearewhiteandDIandWormianbonesarenotpresent.Thoseaffectedtendtohavehigherserumalkalinephosphatasevaluesandhaveanincreasedriskofdevelopinghyperplasticcallusfollowingafractureororthopaedicsurgery.Adistinctpathogenesisisfurthersupportedbycharacteristicbonehistomorphometrywhichshowscoarsemesh-likelamellationwhichdistinguishesOItype5fromOItype4[Glorieuxetal.,2000].HyperplasticcallusisararemedicalemergencyoccurringinpatientswithOItype5.Thisischaracterizedbymassivecalluswithswellingandpainatthesiteofafracture,whichmaybeasminorasastressfracture.Promptuseofindomethacin,ananti-inflammatoryCOX-1andCOX-2prostaglandininhibitorhasbeenrecommendedtoavertprogressalthoughofthecallusalthougharandomizedclinicaltrialhasnotbeenreported[Glorieuxetal.,2000;ChoandMoffat,2014].MOLECULARGENETICSOFOICurrently,morethan1,000heterozygousCOL1A1/2mutationshavebeenidentified(https://oi.gene.le.ac.uk,accessedApril12013)[Dalgleish,1997,1998].Mutationtypeandpositioninfluencethephenotypeandassuchgenotype–phenotyperelationsexisttosomeextent.AutosomalDominantOI(OITypes1-5)InthemajorityofaffectedindividualsfromEuropeandescent,OItypes1–4resultfromheterozygousmutationsintheCOL1A1/2genesencodingrespectivelythealpha1andalpha2chainsofcollagentypeI(Fig.1).ThebiosynthesisofcollagentypeIhasbeendepictedinTable?Table3.3.Siblingrecurrencewithoutanaffectedparentmayoccurduetogonadalmosaicismforheterozygousdominantmutationsinoneoftheparents[ByersandCole,2002].PatientswithOItype1andsometimesOItype4haveanapproximately50%reduction(quantitativeorhaploinsufficiencyeffect)inthesynthesisoftype1procollagenoftenduetoheterozygousmutationsinoneCOL1A1allele(nonsense,frameshift,andsplicesitealterations)leadingtomRNAinstabilityandhaploinsufficiency.OthercausesaredeletionsofthewholeCOL1A1alleleorsubstitutionsforglycinebysmallaminoacids(cysteine,alanine,andserine)neartheamino-terminalendsofthetriplehelicaldomainsineitheroneCOL1A1orCOL1A2allele[vanDijketal.,2012].Notwithstandingthe50%reductionincollagensynthesisfromindividualcells,thesepatientshaveaboveaveragenewboneformation,theresultofhomeostaticmechanisms,whichincreasethenumberofboneformingunits.Thisincreasednewboneformationislinkedtoincreasedboneturnoversothattheneteffectisasmallannualboneloss,whichisexaggeratedifthereisimmobilizationbecauseoffracturesorpain[RauchandGlorieux,2004].ThemajorityofcasesofOItype2–4inNorthAmericaandEuropearedominantlyinheritedandmostcasesareduetoheterozygousCOL1A1/2mutationsthatresultinsubstitutionsforglycine.Ingeneral,glycinesubstitutionsnearthecarboxyl-terminalendappeartoresultintheseverestphenotype.Lesscommonmutationsincludesplicesitealterations,insertion/deletion/duplicationeventsthatleadtoin-framesequencealterationsandvariantsinthecarboxyl-terminalpropeptidecoding-domains[vanDijketal.,2012]TheheterozygousmutationsdisrupttriplehelicalassemblyoftypeIcollagenpolypeptides,resultinginoverprocessingbytheenzymesresponsibleforpost-translationalmodificationof(pro)collagentypeIandconsequentlyproductionofabnormalcollagentypeI.Thispost-translationalover-modificationisdemonstrablebySDS–polyacrylamidegelelectrophoresis.TheintertwiningofmutatedandnormalcollagentypeIchainsresultinproductionofabnormalcollagentypeIprotein,whichisrapidlydegraded(dominant-negativeeffect).Recently,thegeneticcauseofOItype5hasbeenelucidatedintwoindependentpublications[Choetal.,2012;Semleretal.,2012]andconsistsofaheterozygousC＞Ttransitioninthe5′UTR(untranslatedregion)ofIFITM5(c.-14C＞T).IFITM5encodesInterferoninducedtransmembraneprotein5,theexpressionofthisproteinhasbeenshowntopeakduringosteoblastformationintheearlymineralizationstageinmiceandrats[Hanagataetal.,2011].AutosomalRecessiveOI(OItypes2-4)Asevere,autosomalrecessiveformofOItype3withacomparativelyhighfrequencyhadalreadybeenrecognizedinthepastintheblackpopulationsofsouthernAfrica[Wallisetal.,1993](Table?(Table3).3).Nowadays,itisalsoknownthatafoundermutationinLEPRE1iscarriedby1.5%ofWestAfricansand0.4%ofAfricanAmericans[Cabraletal.,2012].RecessivemutationsingenesinvolvedincollagentypeIbiosynthesisandpost-translationalmodificationhavebeenidentifiedinOItypes2–4inthelast6years.Thesewererecentlyreviewedindepth[ByersandPyott,2012].TherecessivemutationsconcerngenesencodingproteinsinvolvedincollagentypeIbiosynthesis,canbesubdividedinto(i)anenzymaticcomplexresponsiblefor3-prolylhydroxylationofonespecificresidue(P986)inthealpha1chain[vanDijketal.,2012]andprobablyforinitiatingchainalignmentandhelicalfolding[Pyottetal.,2011](CRTAP,LEPRE1,PPIB);(ii)qualitycontrolcheckofthecollagentriplehelix(SERPINH1,FKBP10);(iii)lateprocessingoffolded(pro)collagentypeIchainsi.e.hydroxylationoflysineresiduesintriplehelicaltelopeptidesimportantforcollagentypeIcross-linkinginbone[vanDijketal.,2012](PLOD2,FKBP10)andcleavageoftheC-propeptide(BMP1)[Martínez-Glezetal.,2012](Fig.1).Furthermore,recessivemutationshavebeenreportedinSP7encodingOsterix,anosteoblastspecifictranscriptionfactor,inSERPINF1possiblyinvolvedinboneformationandremodeling[vanDijketal.,2012]andinTMEM38Bencodingatrimericintracellularcationchannel[Shaheenetal.,2012;Volodarskyetal.,2013].TherecentdelineationofmutationsinWNT1,encodingasignalingpeptideinvolvedinosteoblastdifferentiationandproliferation[Fahiminiyaetal.,2013;Keuppetal.,2013;Laineetal.,2013]andtheinteractionwithFRIZZLEDanditscoligandLRP5,inwhichmutationsinthelatterareknowntoresultinpatientswithseveresyndromicOI,predictthatfurtherstudyofpatientswithsevereOIfromendogamouspopulationswilluncovermutationalmechanismsinthesubsequentstepsoftheWNT-BetaCateninsignalingpathway.Mostrecently,ahomozygousdeletionofCREB3L1wasidentifiedinafamilywithasevereprogressivelydeformingOIphenotype.CREB3L1encodestheER-stresstransducerOASISthathasbeenshowninamurinemodeltobindtotheosteoblast-specificUPRE(unfoldedproteinresponseelement)regulatoryregionintheCol1a1promotor.ThisfindingexpandsthegeneticheterogeneityinOIandillustratestheroleofER-stressinthepathophysiologyofOI[Symoensetal.,2013].Pathogenicmutationsfoundinrecessivegenes(Dalgleish,R:OsteogenesisImperfectaVariantDatabase(https://oi.gene.le.ac.uk,accessedApril12013),aremostlyhomozygousorcompoundheterozygousloss-of-functionmutationsthatresultintwonullalleleswithseverelydecreasedornoproductionofnormalprotein.X-linkedOIX-linkedinheritanceofosteoporosisandfractureshadbeenreportedonlyonceinthethesisofD.Sillence(Pedigree41,Appendix)[Sillence,1980].Recently,loss-of-functionmutationsinPLS3encodingplastin-3werediscoveredasacauseofoneformofX-linkedosteoporosiswithfractures[vanDijketal.,2013].Inhemizygousmen,pathogenicmutationsinPLS3wereassociatedwithosteoporosisandosteoporoticfracturesoftheaxialandappendicularskeletonusuallydevelopinginchildhood.Theclinicalpictureinheterozygousfemalememberswasvariableandrangedfromnormalbonemineraldensityandanabsenceoffracturestoearly-onsetosteoporosis.NoextraskeletalfeaturesofOIwerepresentinaffectedmen,butthephenotypeisindistinguishableinmanypatientswithothertypesofOI,itwouldprobablyfitbestinthecommonvariableOI(OItype4)group,ofwhomlessthan50%ofpatientshavefeaturessuchasWormianbonesintheskullandthescleraearenormalinhue,bluishinchildhoodandfadingtonormaladulthue.CONCLUSIONFromamedicalgeneticistpointofview,thecoreprincipleisphenotypingofindividuals(dysmorphology)andthestudyofthesefamilieswithregardtoinheritancepatternandphenotypicvariability.TheOIclassificationfrom1979isaclassicexampleoftheimportanceandpossibilitiesofdysmorphologysinceitledtothedelineationoffourOIsyndromesbasedonclinical/radiologicalfeaturesandinheritance,incombinationwiththeassumptionthatOIwasgeneticallyheterogeneous,whichwasconfirmedmanyyearslaterbymoleculargeneticstudies.Atpresenttime,ithasbeenpostulatedthatmoleculartechniquessuchasNext-GenerationSequencingwilldecreasetheneedforphenotyping.However,thenewOInomenclatureandtheSeverityGradingScaledescribedinthispaper,emphasizetheimportanceofphenotypinginordertodiagnose,classifyandassessseverityofOI.Thiswillprovidepatientsandtheirfamilieswithinsightintotheprobablecourseofthedisorderanditwillallowphysicianstoevaluatetheeffectoftherapy.AcarefulclinicaldescriptionincombinationwithknowledgeofthespecificmoleculargeneticcauseisthestartingpointfordevelopmentandassessmentoftherapyinpatientswithheritabledisordersincludingOI.Thelatteristhebiggestchallengewefaceintheupcomingdecade(s).Osteogenesisimperfecta:clinicaldiagnosis,nomenclatureandseverityassessmentAbstractRecently,thegeneticheterogeneityinosteogenesisimperfecta(OI),proposedin1979bySillenceetal.,hasbeenconfirmedwithmoleculargeneticstudies.Atpresent,17geneticcausesofOIandcloselyrelateddisordershavebeenidentifiedanditisexpectedthatmorewillfollow.UnlikemostreviewsthathavebeenpublishedinthelastdecadeonthegeneticcausesandbiochemicalprocessesleadingtoOI,thisreviewfocusesontheclinicalclassificationofOIandelaboratesonthenewlyproposedOIclassificationfrom2010,whichreturnedtoadescriptiveandnumericalgroupingoffiveOIsyndromicgroups.ThenewOInomenclatureandthepre-andpostnatalseverityassessmentintroducedinthisreview,emphasizetheimportanceofphenotypinginordertodiagnose,classify,andassessseverityofOI.Thiswillprovidepatientsandtheirfamilieswithinsightintotheprobablecourseofthedisorderanditwillallowphysicianstoevaluatetheeffectoftherapy.AcarefulclinicaldescriptionincombinationwithknowledgeofthespecificmoleculargeneticcauseisthestartingpointfordevelopmentandassessmentoftherapyinpatientswithheritabledisordersincludingOI.?2014TheAuthors.AmericanJournalofMedicalGeneticsPublishedbyWileyPeriodicals,Inc.ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-NonCommercial-NoDerivsLicense,whichpermitsuseanddistributioninanymedium,providedtheoriginalworkisproperlycited,theuseisnon-commercialandnomodificationsoradaptationsaremade.Keywords:classification;collagentypeI;fractures;heterogeneity;osteogenesisimperfecta.FIG.1.OverviewofcollagentypeIbiosynthesis.CollagentypeIconsistsoftwoa1-chainsandonea2-chain.Aftertranslation,pro-a1-chainsandpro-a2chainsareprocessedintheroughEndoplasmicreticulum(rER).Thesechainshavetoaligninordertostartthefoldingprocessof(pro)collagentypeIintoatriplehelix.Thenextstepisalignmentofthethreechainsinordertocommencefoldingintoatriplehelicalstructure.Duringthisfoldingprocess,post-translationalmodificationbyspecificproteinstakesplace.Thegenesencodingproteinsinvolvedinpost-translationalmodificationandinwhichmutationshavebeenreportedtocauseOI,aredepictedinthisfigure.AftertransportofprocollagentypeItotheGolgicomplexandfollowingexocytosisintotheextracellularmatrix,cleavageoftheC-andN-propeptidesresultsinformationofcollagentypeI.Subsequently,cross-linkingofcollagentypeImoleculesleadstoformationoffibrils.MultiplecollagentypeIfibrilsformintocollagenfibers,importantconstituentsofbone.TABLEIII.Pre-andPostnatalSeverityGradingScaleofOsteogenesisImperfectaMildOI(PatientswithmildOImostoftenhaveOItype1or4)Ultrasoundfindingsat20weeksofpregnancyNointra-uterinelongbonefracturesorbowingPostnatalRarelycongenitalfracturesNormalornearnormalgrowthvelocityandheightStraightlongbonesi.e.nointrinsiclongbonedeformityFullyambulantotherthanattimesofacutefractureMinimalvertebralcrushfracturesLumbarspinebonemineraldensityZ-scoreusually＞1.5(1.5to?1.5)Annualizedfracturerateoflessthanorequalto1.Absenceofchronicbonepainorminimalpaincontrolledbysimpleanalgesics.Regularschoolattendance,i.e.,doesnotmissschoolduetopain,lethargy,orfatigue.ModerateOIUltrasoundfindingsat20weeksofpregnancyRarelyfetallongbonefracturesorbowing(butmayincreaseinthelasttrimester)Postnatal(Notmodifiedbybisphosphonatetherapy)OccasionallycongenitalfracturesDecreasedgrowthvelocityandheightAnteriorbowingoflegsandthighsBowingoflongbonesrelatedtoimmobilizationforrecurrentfracturesVertebralcrushfracturesLumbarspinebonemineraldensityZ-scoreusually＞2.5to＜1.5)butawiderangeAnnualizedprepubertalfracturerategreaterthan1(average3withawiderange)Absentfromschoolduetopainmorethan5daysperyear.SevereOIUltrasoundfindingsat20weeksofpregnancyShorteningoflongbonesFracturesand/orbowingoflongboneswithsomeunder-modelingSlenderribswithabsentordiscontinuousribfractures(casesintermediatebetweensevereandextremelyseverehavefewribfracturesbutcrumpledlongbones)DecreasedmineralizationPostnatal(notmodifiedbybisphosphonatetherapy)MarkedimpairmentoflineargrowthWheel-chairdependentProgressivedeformityoflongbonesandspine(unrelatedtofractures)MultiplevertebralcrushfracturesLumbarspinebonemineraldensityZ-scoreusually＜3.0(widerangewithagecomparisonasmeasurementissize/heightdependent)Annualizedprepubertalfracturerategreaterthan3fracturesperannum(agedependent)ChronicbonepainunlesstreatedwithbisphosphonatesSchoolattendancecharacterizedbyabsencesforfracturecareandfatigueorpainExtremelySevereOIUltrasoundfindingsat20weeksofpregnancyShorteningoflongbonesFracturesand/orbowingoflongboneswithsevereunder-modelingleadingtocrumpled(concertina-like)longbonesThickcontinuouslybeadedribsduetomultiplesitesoffractureorthinribs(previouslydescribedasOItype2-Aand2-B,respectively)DecreasedmineralizationPostnatalThighsheldinfixedabductionandexternalrotationwithlimitationofmovementofmostjointsClinicalindicatorsofseverechronicpain(pallor,sweatiness,whimperingorgrimacingonpassivemovement)Decreasedossificationofskull,multiplefracturesoflongbonesandribs.Smallthorax.Shortenedcompactedfemurswithaconcertina-likeappearanceAllvertebraehypoplastic/crushedRespiratorydistressleadingtoperinataldeathPerinatallylethalcourse文獻(xiàn)出處：FSVanDijk1,DOSillence.Osteogenesisimperfecta:clinicaldiagnosis,nomenclatureandseverityassessmentReview,AmJMedGenetA.2014Jun;164A(6):1470-81.doi:10.1002/ajmg.a.36545.