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瓷娃娃，鋼筋鐵骨 (2)：成骨不全綜合征(OI)：臨床診斷、命名和嚴重程度評估：2014年瓷娃娃，鋼筋鐵骨(2)：成骨不全綜合征(OI)：臨床診斷、命名和嚴重程度評估：2014年作者：FSVanDijk1,DOSillence作者單位:DepartmentofClinicalGenetics,CenterforConnectiveTissueDisorders,VUUniversityMedicalCenter,Amsterdam,TheNetherlands.譯者：陶可（北京大學人民醫(yī)院骨關節(jié)科）合作：任寧濤（解放軍總醫(yī)院第四醫(yī)學中心骨科）摘要最近，Sillence等于1979年提出的成骨不全癥(OI)的遺傳異質(zhì)性已通過分子遺傳學研究得到證實。目前，已經(jīng)確定了17種成骨不全癥(OI)和密切相關疾病的遺傳原因，預計還會有更多。與過去十年發(fā)表的關于導致成骨不全癥(OI)的遺傳原因和生化過程的大多數(shù)評論不同，這篇評論側(cè)重于成骨不全癥(OI)的臨床分類，并詳細闡述了2010年新提出的成骨不全癥(OI)分類，回歸到描述性和數(shù)字分組：五個成骨不全癥(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)后嚴重程度評估，強調(diào)了表型分析對于診斷、分類和評估成骨不全癥(OI)嚴重程度的重要性。這將使患者及其家人深入了解疾病的可能病程，并使醫(yī)生能夠評估治療效果。結(jié)合對特定分子遺傳原因的了解，仔細的臨床描述是開發(fā)和評估包括成骨不全癥(OI)在內(nèi)的遺傳性疾病患者治療的起點。關鍵詞：分類；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。這些鏈必須對齊才能開始將I型（原）膠原蛋白，折疊成三股螺旋。下一步是對齊三個鏈，以便開始折疊成三螺旋結(jié)構(gòu)。在此折疊過程中，會發(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)報道其中的突變會導致成骨不全癥(OI)，如圖所示。在I型前膠原轉(zhuǎn)運到高爾基復合體并胞吐進入細胞外基質(zhì)后，C和N前肽的裂解導致I型膠原的形成。隨后，I型膠原分子的交聯(lián)導致原纖維的形成。多個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)后嚴重程度分級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周時的超聲檢查結(jié)果無子宮內(nèi)長骨骨折或弓形產(chǎn)后罕見先天性骨折正常或接近正常的生長速度和身高直的長骨，即沒有固有的長骨畸形除了急性骨折的時候，完全可以走動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沒有慢性骨痛或通過簡單鎮(zhèn)痛藥控制的輕微疼痛正常上學，即不會因疼痛、嗜睡或疲勞而缺課。中度成骨不全癥(OI)懷孕20周時的超聲檢查結(jié)果很少有胎兒長骨骨折或弓背（但在最后三個月可能會增加）產(chǎn)后（未被雙膦酸鹽治療改變）偶見先天性骨折生長速度和身高下降腿部和大腿前弓形與復發(fā)性骨折固定相關的長骨彎曲椎骨擠壓性骨折腰椎骨礦物質(zhì)密度Z評分通常＞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。嚴重的成骨不全癥(OI)懷孕20周時的超聲檢查結(jié)果長骨縮短長骨骨折和/或弓形，伴有一些生長發(fā)育不足肋骨細長，肋骨骨折不存在或不連續(xù)（中間病例，介于嚴重和極嚴重之間，肋骨骨折很少，但長骨皺折）礦化減少產(chǎn)后（未被雙膦酸鹽治療改變）線性增長明顯受損依賴輪椅長骨和脊柱進行性畸形（與骨折無關）多發(fā)椎體粉碎性骨折腰椎骨礦物質(zhì)密度Z評分通常＜3.0（范圍寬年齡比較，因為測量值取決于尺寸/身高）每年超過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校出勤率下降。極度嚴重的成骨不全癥(OI)懷孕20周時的超聲檢查結(jié)果長骨縮短骨折和/或長骨彎曲伴有嚴重的生長發(fā)育不足導致皺巴巴的（類似手風琴的）長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)關節(jié)活動受限嚴重慢性疼痛的臨床指標（臉色蒼白、出汗、嗚咽或做鬼臉）被動運動顱骨骨化減少，長骨和肋骨多處骨折，胸闊小。縮短的緊實股骨具有類似手風琴的外觀所有椎骨發(fā)育不全/壓碎呼吸窘迫導致圍產(chǎn)兒死亡圍產(chǎn)期致死過程。成骨不全綜合征(OI)的嚴重程度分級在所有成骨不全癥(OI)類型中發(fā)現(xiàn)COL1A1/2突變后的幾年里，臨床實踐中經(jīng)常使用四種成骨不全癥(OI)類型來反映其嚴重程度：輕型（OI1型）、致死性（OI2型）、嚴重畸形（OI3型）和中等程度畸形(OI4型)。盡管INCDS同意將Sillence分類保留為“對成骨不全癥(OI)嚴重程度進行分類的原型和普遍接受的方法”[Warman等2011年]，但有人提出需要國際商定的受影響個體嚴重程度分級標準，并且采納，也反映了成骨不全癥(OI)患者治療的改進可能性（手術(shù)、藥物和保守治療）。這里提出的嚴重程度分級量表依賴于臨床、歷史數(shù)據(jù)、骨折頻率、骨密度測定和活動水平（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）采用了這種嚴重程度分級，該研究確定了來自11個國家的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，增加了產(chǎn)前臨床和超聲檢查結(jié)果的一般指南。該量表將需要通過專業(yè)中心與足夠患者的合作進一步驗證，并使用設施進行全面評估，以進一步確認和闡明其臨床實用性。注：利塞膦酸鈉屬于第三代雙膦酸鹽，是一種骨吸收抑制劑，用于治療各類骨質(zhì)疏松。利塞膦酸鈉是與羥基磷灰石有非常強的親和力，能夠沉積于骨骼及關節(jié)骨質(zhì)中，它不僅能夠抑制破骨細胞活性，也能促進破骨細胞出現(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)驗表明，可能有10%的受影響個體在童年時期沒有發(fā)生過長骨骨折[Sillence，1980年]。然而，用于測量骨密度的更新技術(shù)，例如骨骼的雙能X線吸收測定法(DXA)[Luetal.,1994]和/或最近的外周定量計算機斷層掃描(pQCT)[Gattietal.,2003];Folkestad等2012]的前臂和下肢，經(jīng)常顯示在那些通過正式遺傳分析患有成骨不全癥(OI)的個體中，至少一個骨骼區(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)換血清和尿液標志物升高的發(fā)現(xiàn)與骨組織形態(tài)學的發(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解釋[Rauch和Glorieux，2004]。凈效應是小的進行性骨質(zhì)流失，因為骨吸收通常大于骨形成，固定也對骨形成產(chǎn)生負面影響。許多成骨不全癥(OI)兒童在經(jīng)主治醫(yī)師仔細評估后開始使用旨在降低破骨細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)兒童的金標準。最近一項針對成骨不全癥(OI)兒童口服利塞膦酸鹽的隨機、雙盲、安慰劑對照試驗（包括大部分受輕度至中度影響的兒童）表明骨折風險顯著降低，從而擴大了該療法的治療益處成骨不全癥(OI)兒童[Bishop等2013]。一般相關的功能一些受累個體（而非其他個體）的相關特征包括明顯的鞏膜發(fā)藍、年輕成人發(fā)作的聽力損失、牙本質(zhì)發(fā)育不全(DI)、關節(jié)活動過度、身材矮小和進行性骨骼畸形。據(jù)報道，成人成骨不全癥(OI)患者會出現(xiàn)心臟瓣膜功能障礙和主動脈根部擴張等心血管并發(fā)癥，更常見于3型成骨不全癥(OI)患者[Radunovic等，2011]。下面更詳細地描述了幾個相關的特征。藍鞏膜幾篇主要評論和至少一部專著[Smars,1961;Sillence等，1979;Sillence等;1993]得出結(jié)論，在患有“藍色鞏膜”的患者中，鞏膜的顏色與Wedgewood藍色的色調(diào)相似，并且非常獨特，以至于鞏膜看起來像是涂了漆。當存在“藍色硬化”時，它們終生保持明顯的藍色。Berfenstam和Sm?rs在一項基于人群的研究中[1956]表明，兩組成骨不全癥(OI)患者（具有藍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)計學顯著差異。對1979年維多利亞人口研究中95名1型和4型成骨不全癥(OI)患者隊列的數(shù)據(jù)進行了重新分析，以證實該發(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)中的藍灰色鞏膜是由于鞏膜變薄所致。Eichholtz和Muller[1972]曾報道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)病機制中，聽力障礙、容易瘀傷和可能明顯的關節(jié)過度活動最好用結(jié)締組織成分的繼發(fā)性失調(diào)來解釋。有進一步的證據(jù)表明，導致成骨不全癥(OI)1型表型的過早終止/無意義/剪接突變的高流行率與基質(zhì)組成的改變有關[Byers和Cole，2002]。牙本質(zhì)發(fā)育不全癥(DI)牙本質(zhì)發(fā)育不全癥會導致牙齒明顯變黃和明顯透明，這些牙齒通常會過早磨損或折斷。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為是繼發(fā)性畸形，而不是原發(fā)性畸形。盡管長骨無畸形已被作為診斷標準提出，但畸形的存在似乎至少在一定程度上受到護理質(zhì)量的顯著影響。在發(fā)展中國家，畸形可能是次優(yōu)護理的證據(jù)，反映出缺乏處理骨折的初級保健服務，而不是骨變形內(nèi)在過程的證據(jù)。具有藍色鞏膜的非變形成骨不全癥(OI)—成骨不全癥(OI)類型11型成骨不全癥(OI)的特征是骨脆性增加，這通常與低骨量、明顯的藍灰色鞏膜以及在青春期和青年期開始的傳導性聽力損失的易感性有關。長骨或脊柱的畸形并不常見，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)中最常見的成骨不全癥(OI)類型，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骨和脊柱畸形意味著它通常被認為是輕度嚴重的，但偶爾它是中度嚴重的，特別是當存在牙本質(zhì)發(fā)育不全癥(DI)時[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)的患者比沒有牙本質(zhì)發(fā)育不全癥(DI)的患者更容易在出生時發(fā)生骨折（25%對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，身材矮小更嚴重，骨骼畸形更多。兩個亞組都有相似的關節(jié)過度活動、瘀傷、耳聾和關節(jié)脫位的頻率[Patersonetal.,1983]。到40歲時，超過50%的1型成骨不全癥(OI)患者可檢測到由傳導性和感音神經(jīng)性損失引起的聽力損傷[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]。許多研究報告了具有常染色體顯性遺傳和可變表達的家族。藍鞏膜的外顯率接近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)類型4這些患者有反復骨折、骨質(zhì)疏松癥和不同程度的長骨和脊柱畸形，但鞏膜正常。鞏膜在出生時可能呈藍色，但在兒童時期藍色調(diào)會逐漸消失。聽力障礙并不常見。由于后顱窩底抬高的基底壓痕導致的后顱窩壓迫綜合征的患病率增加。患有牙本質(zhì)發(fā)育不全癥(DI)的4型成骨不全癥(OI)患者發(fā)生基底壓痕的相對風險高5倍[Sillence,1994]。約30%的4型成骨不全癥(OI)患者在篩查時有基底印象，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致骨骼進行性畸形。他們通常在足月或接近足月出生，出生體重正常，出生身長通常正常，但由于出生時下肢畸形可能會縮短。雖然鞏膜在出生時可能是藍色的，但對許多患有這種綜合征的患者的觀察表明，隨著年齡的增長，鞏膜的藍色逐漸變淡[Sillence等，1986年]。持續(xù)存在的藍色鞏膜通常表示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出現(xiàn)灰白色鞏膜[Byers和Pyott，2012]。所有患者的縱向生長都較差，身高遠低于年齡和性別的第三個百分位。進行性脊柱側(cè)凸在兒童時期發(fā)展并發(fā)展到青春期?；加写司C合征的兒童尚未報告聽力受損，但成人聽力損失更為常見。牙本質(zhì)發(fā)育不全癥(DI)是一個可變特征。出生時，放射學研究顯示全身性骨質(zhì)減少和多發(fā)性骨折。隨著長骨干的頻繁過度損傷與修復，弓形和成角畸形存在不同程度。在幾周到幾個月內(nèi)，在一些嬰兒中，長骨干的發(fā)育不足會導致“寬骨”外觀。從幾歲開始，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Wormian骨骼，盡管這些骨骼可能要到幾周到幾個月大時才會明顯[Sillence等,1979;Sillence等,1986;Spranger等,2003;vanDijk等,2011]。過去，大約三分之二的患者在20歲時死亡。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]在嬰兒期開始，可以預期今天大多數(shù)3型成骨不全癥(OI)患者將存活到成年生活。幾項研究表明，管理嚴重成骨不全癥(OI)兒童的專業(yè)中心在嬰兒3歲時開始循環(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，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[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、關節(jié)和骨骼外特征極為嚴重。圍產(chǎn)期致死率是一個結(jié)果，而不是一個診斷特征。在妊娠18-20周檢測到的胎兒長骨短而皺縮，長骨彎曲或成角畸形，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)每個月都會出現(xiàn)肋骨骨折，導致連續(xù)的串珠狀外觀和皺縮（手風琴狀）的長骨，這是極端嚴重的一端的特征，以成骨不全癥(OI)2型（成骨不全癥(OI)類型2-A）為代表[Sillence等,1984]。根據(jù)我們的經(jīng)驗，循環(huán)靜脈注射帕米膦酸治療并不適用，因為骨形成如此受損，關節(jié)受限如此嚴重，幾乎沒有任何正常童年生活經(jīng)歷的機會。使用簡單的鎮(zhèn)痛劑或皮下嗎啡來緩解疼痛特別有價值，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)量的病例中得到報道[Emeryetal.,1999]。有些嬰兒的表型不太嚴重，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，即使是成年，也可以通過循環(huán)靜脈注射帕米膦酸鹽治療“獲救”。在發(fā)達國家，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（通過超聲和DNA分析），通常導致妊娠終止。平均出生身長和體重小于第50個百分位數(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特性，因此妊娠期胸部較小，呼吸運動可能受到抑制。一些臨床特征表明，患有2型成骨不全癥(OI)的新生兒會持續(xù)疼痛。由于多處骨折，他們可能會出汗過多、臉色蒼白、被觸摸時表現(xiàn)出焦慮并且四肢很少活動。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行性鈣化的一種成骨不全癥(OI)。獨立地，它是通過增加增生性愈傷組織的傾向來識別的。Bauze等詳細描述了該綜合征[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]。在一項針對4型中重度成骨不全癥(OI)的組織形態(tài)學研究中，檢測到26例中有7例(25%)具有骨組織形態(tài)學異常，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，這會導致旋前和旋后受限，并最終導致橈骨頭脫位。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險增加。特征性骨組織形態(tài)學進一步支持了一種獨特的發(fā)病機制，該組織形態(tài)學顯示粗網(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)分開來[Glorieux等，2000]。增生性骨痂是5型成骨不全癥(OI)患者罕見的醫(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，可能與應力性骨折一樣輕微。及時使用消炎痛，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展，盡管尚未報告隨機臨床試驗[Glorieuxetal.,2000;Cho和Moffat，2014]。成骨不全癥(OI)的分子遺傳學目前，已鑒定出1,000多個雜合COL1A1/2突變（https://oi.gene.le.ac.uk，2013年4月1日訪問）[Dalgleish,1997,1998]。突變類型和位置影響表型，因此在一定程度上存在基因型-表型關系。常染色體顯性成骨不全癥(OI)（OI類型1-5）在大多數(shù)來自歐洲血統(tǒng)的受影響個體中，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，可能會發(fā)生沒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），通常是由于一個COL1A1等位基因的雜合突變（無意義、移碼和剪接位點改變）導致mRNA不穩(wěn)定性和單倍體不足。其他原因是整個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]。管單個細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，因此凈效應是每年的骨質(zhì)流失量很小，如果因骨折或疼痛不能活動，骨質(zhì)流失會加劇[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致最嚴重的表型。不太常見的突變包括剪接位點改變、插入/刪除/復制突變，這些突變導致框內(nèi)序列改變和羧基末端原肽編碼域的變異[vanDijk等，2012]雜合突變破壞了類型的三螺旋組裝I型膠原蛋白多肽，導致負責I型（原）膠原蛋白翻譯后修飾的酶過度加工，從而產(chǎn)生異常I型膠原蛋白。這種翻譯后過度修飾可通過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致異常I型膠原蛋白的產(chǎn)生，該蛋白迅速降解（顯性負效應）。最近，兩份獨立文獻闡明了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編碼干擾素誘導的跨膜蛋白5，該蛋白的表達已顯示在小鼠和大鼠早期礦化階段的成骨細胞形成過程中達到峰值[Hanagata等，2011]。常染色體隱性成骨不全癥(OI)（OI類型2-4）過去已經(jīng)在南部非洲的黑人人群中發(fā)現(xiàn)了一種相對較高頻率的嚴重的常染色體隱性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%的非裔美國人攜帶LEPRE1的創(chuàng)始人突變[Cabraletal.,2012]。在過去的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。最近對這些進行了深入審查[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，可細分為(i)負責alpha1鏈中一個特定殘基(P986)的3-脯氨酰羥基化的酶復合物[vanDijk等，2012]并且可能用于啟動鏈對齊和螺旋折疊[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，即三螺旋端肽中賴氨酸殘基的羥基化對于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]和編碼三聚體細胞內(nèi)陽離子通道的TMEM38B[Shaheen等,2012;Volodarsky等,2013]。最近描述的WNT1突變，編碼參與成骨細胞分化和增殖的信號肽[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導致患有嚴重綜合征性成骨不全癥(OI)的患者，預測對來自內(nèi)婚人群的嚴重成骨不全癥(OI)患者的進一步研究將揭示突變機制在WNT-β連環(huán)蛋白信號通路的后續(xù)步驟中。最近，在一個具有嚴重進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)應激傳感器OASIS，該傳感器已在小鼠模型中顯示可與Col1a1啟動子中的成骨細胞特異性UPRE（未折疊蛋白反應元件）調(diào)節(jié)區(qū)結(jié)合。這一發(fā)現(xiàn)擴大了成骨不全癥(OI)的遺傳異質(zhì)性，并說明了ER應激在成骨不全癥(OI)病理生理學中的作用[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（https://oi.gene.le.ac.uk，2013年4月1日訪問），主要是純合子或復合雜合子功能喪失突變，導致在兩個無效等位基因中，正常蛋白質(zhì)的產(chǎn)生嚴重減少或沒有。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]中有過一次報道。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。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)密度和沒有骨折到早發(fā)性骨質(zhì)疏松癥。受影響的男性沒有成骨不全癥(OI)的骨骼外特征，但表型在許多其他類型的成骨不全癥(OI)患者中無法區(qū)分，它可能最適合常見變量成骨不全癥(OI)（OI類型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，兒童期呈藍色，成人后逐漸褪色。結(jié)論從醫(yī)學遺傳學家的角度來看，核心原則是個體的表型分析（畸形學）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)分類是畸形學的重要性和可能性的典型例子，因為它根據(jù)臨床/放射學特征和遺傳，結(jié)合成骨不全癥(OI)具有遺傳異質(zhì)性的假設，對四種成骨不全癥(OI)綜合征進行了描述，許多人證實了這一點多年后通過分子遺傳學研究。目前，據(jù)推測，下一代測序等分子技術(shù)將減少對表型分析的需求。然而，本文描述的新成骨不全癥(OI)命名法和嚴重程度分級量表強調(diào)了表型分析對于診斷、分類和評估成骨不全癥(OI)嚴重程度的重要性。這將使患者及其家人深入了解疾病的可能病程，并使醫(yī)生能夠評估治療效果。結(jié)合對特定分子遺傳原因的了解，仔細的臨床描述是開發(fā)和評估包括成骨不全癥(OI)在內(nèi)的遺傳性疾病患者治療的起點。后者是我們在未來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文獻出處：FSVanDijk1,DOSillence.Osteogenesisimperfecta:clinicaldiagnosis,nomenclatureandseverityassessmentReview,AmJMedGenetA.2014Jun;164A(6):1470-81.doi:10.1002/ajmg.a.36545.