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嚴(yán)重脛腓骨彎曲畸形治療前成人成骨不全癥患者骨骼畸形矯正困難，軟組織攣縮嚴(yán)重，骨骼發(fā)育差，髓腔封閉。截骨后愈合困難。聯(lián)合外固定支架分期手術(shù)可以有效的解決這一難題治療中先利用外固定支架矯正攣縮的畸形然后再進(jìn)行髓內(nèi)固定手術(shù)治療后治療后3年畸形獲得糾正，恢復(fù)正常行走功能任秀智醫(yī)生的科普號(hào)
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，并詳細(xì)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(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；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，以便開始折疊成三螺旋結(jié)構(gòu)。在此折疊過程中，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)患者最常患有1型或4型成骨不全癥(OI)】懷孕20周時(shí)的超聲檢查結(jié)果無子宮內(nèi)長(zhǎng)骨骨折或弓形產(chǎn)后罕見先天性骨折正?；蚪咏５纳L(zhǎng)速度和身高直的長(zhǎng)骨，即沒有固有的長(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沒有慢性骨痛或通過簡(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)明顯受損依賴輪椅長(zhǎng)骨和脊柱進(jìn)行性畸形（與骨折無關(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)類型來反映其嚴(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分類保留為“對(duì)成骨不全癥(OI)嚴(yán)重程度進(jìn)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(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。該量表將需要通過專業(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)期沒有發(fā)生過長(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)作的聽力損失、牙本質(zhì)發(fā)育不全(DI)、關(guān)節(jié)活動(dòng)過度、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，聽力障礙、容易瘀傷和可能明顯的關(guān)節(jié)過度活動(dòng)最好用結(jié)締組織成分的繼發(fā)性失調(diào)來解釋。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(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始的傳導(dǎo)性聽力損失的易感性有關(guān)。長(zhǎng)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(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(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。聽力障礙并不常見。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?；加写司C合征的兒童尚未報(bào)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(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)兒童的專業(yè)中心在嬰兒3歲時(shí)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(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，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(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，它是通過增加增生性愈傷組織的傾向來識(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(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）[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(guān)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(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(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)胞形成過程中達(dá)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(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)來自內(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），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)無效等位基因中，正常蛋白質(zhì)的產(chǎn)生嚴(yán)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(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(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)谖磥硎昝媾R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.陶可醫(yī)生的科普號(hào)
關(guān)注“瓷娃娃”一、問：有一種寶寶被人稱為“瓷娃娃”，您能給大家介紹一下這是什么樣的寶寶嗎？姜海：大家好，“瓷娃娃”是患成骨不全癥的兒童，形容患兒骨骼像瓷器一樣容易摔碎，輕微的外力即可引起四肢骨折，嚴(yán)重的病例咳嗽，翻身等簡(jiǎn)單的日常行為都有可能引起肋骨骨折，脊柱骨折。該病是最常見的單基因遺傳性骨病，以骨量低下、骨骼脆性增加和反復(fù)骨折為主要特征。該病已列入國(guó)家衛(wèi)生健康委員會(huì)等5部門聯(lián)合制定的《第一批罕見病目錄》。二、問：哦，這是一種病，名稱叫“成骨不全癥”，還是罕見病。既然罕見，那這種患病的寶寶應(yīng)該不多吧。姜海：該病雖然為罕見病，它的發(fā)病率新生兒在一萬五至兩萬分之一。但中國(guó)的新生兒一年的數(shù)量巨大。2021年中國(guó)的新生兒為1062萬，按照這個(gè)患病率，2021年可能的成骨不全癥兒童有大約708至531人。十年下來，中國(guó)的成骨不全癥兒童應(yīng)該有五千至一萬人左右。三、問：那這個(gè)病是怎么得得了？是和父母有遺傳關(guān)系嗎？姜海：該病是由多種致病基因突變所致。目前已報(bào)道的致病基因至少有21種。其遺傳模式只要呈常染色體顯性遺傳。有可能父母各攜帶一個(gè)突變基因，父母不發(fā)病，生出來的寶寶結(jié)合了父母的兩個(gè)突變基因，就發(fā)病了。也有可能父母都是正常的，僅是寶寶在發(fā)育過程中出現(xiàn)了基因的突變導(dǎo)致發(fā)病。四、問：這個(gè)病有什么臨床表現(xiàn)？作為父母，如何能早期發(fā)現(xiàn)寶寶患了這個(gè)病？姜海：成骨不全癥常幼年發(fā)病，輕微創(chuàng)傷后反復(fù)發(fā)生骨折，病情嚴(yán)重者在宮內(nèi)或出生時(shí)即骨折，可導(dǎo)致脊柱側(cè)凸，胸廓塌陷，四肢彎曲等畸形?；純哼€可伴有聽力下降，關(guān)節(jié)韌帶松弛，心臟瓣膜病變等骨骼外表現(xiàn)。該病危害大，具有較高的致殘率。作為父母，如果發(fā)現(xiàn)寶寶輕微外力下就容易骨折，同時(shí)一年內(nèi)多次骨折，一定要警惕患這種病。同時(shí)注意觀察寶寶的鞏膜，看是否鞏膜是藍(lán)色的。患者典型X線表現(xiàn)及常見體征如箭頭所示,A:長(zhǎng)骨纖細(xì),皮質(zhì)菲薄,多發(fā)陳舊性骨折;B:脊柱側(cè)凸畸形,胸郭塌陷;C:骨盆畸形,長(zhǎng)骨彎曲畸形;D:顱板薄,枕骨縫間骨;E:藍(lán)鞏膜;F:牙本質(zhì)發(fā)育不全;G:指間關(guān)節(jié)韌帶松馳;五、問：如何來確診寶寶患了這個(gè)病呢？姜海：主要依據(jù)臨床表現(xiàn)和影像學(xué)特點(diǎn)，包括自幼發(fā)病，反復(fù)脆性骨折史；藍(lán)鞏膜；聽力下降；陽(yáng)性骨折家族史；骨骼X線影像特征。此外，應(yīng)注意排除多種遺傳性及代謝性骨骼疾病，如軟骨發(fā)育不全、低血磷性佝僂病、維生素D依賴性佝僂病、骨纖維異樣增殖癥、低磷酸酶血癥、腫瘤相關(guān)骨病和關(guān)節(jié)活動(dòng)過度綜合征等?；蛟\斷對(duì)發(fā)現(xiàn)該病的病因、做好遺傳咨詢和優(yōu)生優(yōu)育具有積極意義。由于尚未發(fā)現(xiàn)呈成骨不全癥的所有致病基因,因此基因診斷不能代替臨床診斷,基因檢測(cè)陰性者不能完全排除罹患該病的可能。有生育需求的成骨不全癥患者或已育有成骨不全癥患兒的夫婦擬再生育者，建議行基因診斷，為遺傳咨詢和產(chǎn)前基因診斷做準(zhǔn)備。目前成骨不全癥的產(chǎn)前診斷需通過羊膜穿刺獲得胎兒基因組DNA樣本。羊膜穿刺有3個(gè)時(shí)機(jī)：妊娠第11~13周取絨毛組織；或妊娠第16~24周取羊水細(xì)胞；或妊娠第23周后取臍血。建議選擇有條件的醫(yī)院婦產(chǎn)科行羊膜穿刺，盡早獲得胎兒基因組DNA樣本，進(jìn)行基因診斷。六、問：目前這個(gè)病能治愈嗎？該如何治療？姜海：該病目前還不能完全治愈，但通過綜合性的治療，可以改善患兒的活動(dòng)能力，提高生活質(zhì)量。適量的鈣劑和維生素D有助于提供骨骼發(fā)育所需的營(yíng)養(yǎng)。目前廣泛使用的治療成骨不全癥的藥物主要是雙膦酸鹽類。雙膦酸鹽屬于骨吸收抑制劑，能夠與骨骼羥基磷灰石結(jié)合，有效抑制破骨細(xì)胞活性，減少骨吸收，從而增加骨密度，降低骨折風(fēng)險(xiǎn)。第二代帕米膦酸二鈉，第三代唑來膦酸臨床運(yùn)用治療成骨不全癥兒童安全性較好。兒童一旦確診成骨不全癥，應(yīng)當(dāng)盡早給予雙膦酸藥物治療，能增加患兒的骨密度，降低骨折風(fēng)險(xiǎn)，改善疾病預(yù)后。西北婦女兒童醫(yī)院骨科已采用第二代帕米膦酸二鈉靜脈輸液治療成骨不全癥兒童數(shù)年，具有良好的安全性，臨床效果滿意。通過治療后，患兒的骨密度明顯增強(qiáng)，不再容易發(fā)生骨折，打破了以往的“骨折-臥床-骨質(zhì)疏松加重-再骨折”的惡性循環(huán)，減輕了患兒的痛苦和家庭的負(fù)擔(dān)。今年科室開展了第三代唑來膦酸注射液治療成骨不全癥兒童，輸液時(shí)間明顯縮短，住院時(shí)間也進(jìn)一步縮短，花費(fèi)更低，具有良好的臨床推廣價(jià)值。姜海醫(yī)生的科普號(hào)