張 婭 方曉燕 徐 虹 沈 茜

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·論著·

Dent病1型5例病例系列報告并文獻復習

張 婭 方曉燕 徐 虹 沈 茜

目的 報告5例Dent病1型患兒的臨床資料，提高對其認識。方法 分析5例Dent病1型患兒病史、實驗室檢查，對先證者進行Dent病相關(guān)基因CLCN5、OCRL外顯子及附近調(diào)控區(qū)域的直接測序，驗證先證者父母有無相應位點突變，系統(tǒng)復習國內(nèi)外文獻報告的Dent病1型，歸納臨床表型與突變類型。結(jié)果 5例患兒實驗室檢查發(fā)現(xiàn)24 h尿蛋白定量33.0～68.9 mg·kg-1，尿α1微球蛋白、尿白蛋白和尿免疫球蛋白均明顯升高，均伴有高鈣尿癥，其中鏡下血尿1例、腎鈣質(zhì)沉著2例，行CLCN5、OCRL基因測序各發(fā)現(xiàn)了1個CLCN5突變，分別為R637X、Y479X、G530V、W103fsX104和R707X，其中Y479X、G530V和W103fsX104為新發(fā)現(xiàn)的突變位點。系統(tǒng)文獻檢索260篇Dent病相關(guān)文獻，逐篇篩選，共有72篇Dent病1型病例報告和病例系列報告進入本文分析，均為病例報道或病例系列報道，歐美人群422例，亞洲人群176例。歐美與亞洲國家Dent病1型臨床表型低分子量蛋白尿表現(xiàn)一致，差異無統(tǒng)計學意義，高鈣尿癥、腎鈣質(zhì)沉著、腎積石、佝僂病和腎功能異常差異均有統(tǒng)計學意義，不同的臨床表型沒有突出顯現(xiàn)突變類型(錯義、無義、移碼、剪切和缺失突變)的優(yōu)勢。結(jié)論 臨床提示Dent病1型可能的患兒可通過基因檢測以明確診斷，避免不必要的免疫抑制劑治療。CLCN5突變具有高度異質(zhì)性，臨床表型與CLCN5突變類型沒有顯現(xiàn)較好的關(guān)聯(lián)性。

兒童； 低分子量蛋白尿； Dent病1型；CLCN5基因突變； 慢性腎臟病

蛋白尿是兒童腎臟疾病就診的常見原因，隨著對蛋白尿認識的深入，發(fā)現(xiàn)兒童期起病的蛋白尿除了常見的腎小球病變外，腎小管性蛋白尿也并不少見，所以對于首診為蛋白尿的患兒，要了解尿蛋白的來源。Dent病是小管性蛋白尿中研究較多的一類疾病，屬于X連鎖隱性遺傳疾病，所以就診人群中多為男性，女性攜帶者癥狀輕微不易發(fā)現(xiàn),對于有臨床表現(xiàn)或家族史的患兒最終可通過基因測序確診Dent病，CLCN5和OCRL基因突變分別為1型和2型Dent病，未檢測出突變的則記為Dent-NI(Dent-not identified)[1]。全球?qū)ent病有非常多的病例報告或病例系列報告，本課題組前期對Dent病2型做過系統(tǒng)的文獻復習，本文報道5例Dent病1型并對相關(guān)文獻進行復習，以進一步提高對Dent1型的認識。

1 方法

1.1 研究對象 納入2011年1月以來至復旦大學附屬兒科醫(yī)院(我院)臨床診斷Dent病并行相關(guān)基因突變檢測確診的Dent病1型的病例。

1.2 資料采集 截取入我院后與Dent病相關(guān)的第1次血液、尿液生化指標和泌尿系超聲結(jié)果，Dent病1型相關(guān)基因突變檢測結(jié)果，基于倫理考量外院已經(jīng)行腎活檢的結(jié)果也進入本文分析，同時截取外院行免疫抑制劑使用情況。

1.3 Dent病相關(guān)基因檢測方法 取得患兒家長或監(jiān)護人知情同意后，采集患兒及父母外周血2 mL，送北京德易東方轉(zhuǎn)化醫(yī)學研究中心行相關(guān)基因檢測。提取基因組DNA(德國QIAGEN公司血液基因DNA抽提試劑盒)。PCR擴增CLCN5和OCRL所有編碼序列，擴增引物序列參考文獻[2,3]。PCR反應條件：95℃預變性3 min，94℃ 30 s，55～60℃ 35 s，72℃ 40～50 s；35個循環(huán)，72℃再延伸5 min。PCR產(chǎn)物經(jīng)1%瓊脂糖凝膠電泳初步鑒定擴增條帶是否為目的條帶，若為目的條帶則進行測序。使用ABI 3730測序列分析儀(美國ABI公司)進行測序，測序結(jié)果與美國國家生物技術(shù)信息中心(NCBI)GenBank中的序列進行對比。

1.4 文獻檢索策略 以“Dent Disease” OR “Dent's Disease”在PubMed網(wǎng)站檢索，以“Dent病”關(guān)鍵詞在萬方數(shù)據(jù)庫檢索，檢索起于建庫至2016年7月，手工去除Dent病2型。

1.5 文獻提取數(shù)據(jù) Dent病臨床表型：蛋白尿(泡沫尿)、低分子量蛋白尿(LMWP)、高鈣尿癥、腎鈣質(zhì)沉著、佝僂病、腎結(jié)石、腎功能和CLCN5基因突變類型。

1.6 統(tǒng)計學分析 分類資料(臨床表型、CLCN5基因突變類型)應用卡方檢驗進行統(tǒng)計，病例數(shù)不滿足卡方檢驗要求，則使用Fisher確切概率法，統(tǒng)計數(shù)據(jù)均用SPSS Statistics 22軟件進行分析。

2 結(jié)果

2.1 病例報告 我院經(jīng)CLCN5基因檢測確診的Dent病1型5例，均為男性，起病年齡為生后至5.4歲，4例以泡沫尿就診、1例為體檢發(fā)現(xiàn)，確診年齡為4.5～6.8歲，無特殊面容和指趾畸形，無其他系統(tǒng)異常表現(xiàn)，生長發(fā)育正常。5例患兒尿液及其他檢查結(jié)果見表1。

表1 5例Dent病1型實驗室、超聲和腎活檢等檢查結(jié)果

注 1)25～50mg·kg-1為中等量蛋白尿，>50mg·kg-1為大量蛋白尿；“-”：陰性；“+”：陽性；NA為缺失值

2.2 基因檢測及家系驗證結(jié)果 5例患兒均為CLCN5基因突變。例1：10號外顯子c.1909C>T突變(p.637R>X)，為CLCN5基因突變熱點[4]；例2 ：9號外顯子c.1437C>A突變(p.479Y>X)；例3：10號外顯子c.1589G>T突變(p.G530V)，SIFT和Polyphen-2軟件預測其蛋白結(jié)構(gòu)有害；例4：4號外顯子c.308缺失G突變(p.103，W>Xfsl)；例5：13號外顯子c.2119C>T(p.707R>X)。均未發(fā)現(xiàn)OCRL相關(guān)突變，5例患兒母親均為相應位點的雜合攜帶者，父未檢測出相關(guān)突變。Y479X、G530V和W103fsX104(例2～4)均未在Human Gene Mutation Database和ExAC Browser網(wǎng)站上查閱到為新發(fā)現(xiàn)的突變位點，Mutation Taster網(wǎng)站查找，顯示均為高度保守。

2 .3 文獻復習

2.3.1 文獻檢索結(jié)果 共檢索到260篇Dent病相關(guān)文獻，逐篇篩選，共有72篇Dent病1型病例報告和病例系列報告?？紤]到女性為攜帶者，目前發(fā)病人數(shù)相對較少，所以有癥狀的女性患者未納入；家系報告中經(jīng)基因驗證證實CLCN5突變的男性患者也納入；可識別的重復病例只記錄1次；共有598例Dent病1型患者進入本文分析，根據(jù)作者醫(yī)院所在國家劃分為美歐和亞洲，歐美人群422例包括意大利、西班牙、德國、英國、法國、奧地利、芬蘭、葡萄牙、黑山共和國、比利時、塞爾維亞、瑞士、烏克蘭、美國、南美、加拿大、烏拉圭、阿根廷、玻利維亞，亞洲人群176例[5～76]包括中國、日本、韓國、以色列、印度。

2.3.2 臨床表型 復習598例Dent病1型臨床診斷發(fā)現(xiàn)，以低分子量蛋白尿+以下任意一項，高鈣尿癥、腎鈣質(zhì)沉著、腎結(jié)石、腎功能異常、鏡下血尿、低磷酸鹽血癥作為臨床診斷為180例，以低分子量蛋白尿和高鈣尿癥+以下任意一項腎鈣質(zhì)沉著、腎結(jié)石、腎功能異常、鏡下血尿、低磷酸鹽血癥作為臨床診斷為120例，298例沒有具體描述臨床診斷的相關(guān)癥狀無法歸類。

表2顯示歐美與亞洲國家Dent病1型臨床表型高鈣尿癥、腎鈣質(zhì)沉著、腎結(jié)石、佝僂病(低磷酸鹽血癥導致)和腎功能異常差異均有統(tǒng)計學意義。歐美人群有無腎鈣質(zhì)沉著導致腎功能不全38.2%(21/55)和14.3%(8/56)，差異有統(tǒng)計學意義(χ2=8.209，P=0.005)，亞洲人群有無腎鈣質(zhì)沉著導致腎功能不全24.1%(7/29)和12.9%(4/31)，差異無統(tǒng)計學意義(精確檢驗，P=0.327)。歐美人群有無CLCN5突變導致高鈣尿癥97.1%(68/70)和40.0%(24/60)，差異有統(tǒng)計學意義(精確檢驗，P=0.009)。

表2 不同地區(qū)Dent病1型臨床表現(xiàn)[n/N(%)]

2.3.3 歐美與亞洲人群Dent病1型CLCN5突變類型比較 圖1顯示，歐美與亞洲人群間錯義、無義、移碼、剪切和缺失突變差異均無統(tǒng)計學意義，Dent病1型CLCN5突變以錯義、無義、移碼為主要類型，鑒于無義、移碼突變均可導致蛋白截短，在統(tǒng)計臨床表型與突變類型時歸為截短突變，表3顯示，在歐美人群和亞洲人群不同的臨床表型沒有突出顯現(xiàn)突變類型的優(yōu)勢。

圖1 不同地區(qū)CLCN5突變類型

注：錯義突變組(χ2=1.142，P=0.285)，無義突變組(χ2=0.734,P=0.392)，移碼突變組(χ2=0.385,P=0.535)，剪切突變組(χ2=0.087,P=0.769)，缺失突變組(χ2=1.686,P=0.694)

表3 不同地區(qū)CLCN5突變類型與臨床表型關(guān)系[n/N(%)]

3 討論

隨著對蛋白尿認識的深入，腎小管病因?qū)е碌牡鞍啄蛞苍絹碓绞艿疥P(guān)注，也提醒蛋白尿不僅是量的問題，尿蛋白成分的定性也顯得尤為重要。Dent病1型屬于罕見病，大部分Dent病1型患者在兒童時期臨床表現(xiàn)不明顯，甚至進展為慢性腎衰竭才被發(fā)現(xiàn)，而且Dent病1型表現(xiàn)各異，即使是同一患病家庭的成員，臨床表型也可不同，所以早期診斷存在一定的難度[76]。

Dent病1型國內(nèi)外報道的就診原因基本一致，包括泡沫尿、多飲多尿、佝僂病、感染、多發(fā)性骨折、生長受限和體檢發(fā)現(xiàn)等。多數(shù)患兒在初診時被診斷為腎病綜合征、腎小球腎炎、抑或是Bartter綜合征等，部分患兒使用了不同的免疫抑制劑治療。當Dent病1型患者出現(xiàn)腎病水平的蛋白尿或混合型蛋白尿時，往往是在腎小管病變后出現(xiàn)的繼發(fā)性改變，所以Dent病1型的早期發(fā)現(xiàn)就顯得尤為重要，日本多以尿液篩查形式發(fā)現(xiàn)尿蛋白，進而分析尿蛋白成分，從而有助于診斷Dent病1型，所以推薦行尿液篩查，以降低漏診誤診的發(fā)生[48]。

典型的Dent病1型臨床診斷包括以下2種標準，一是2 項必備加任意一項，必備項：①低分子蛋白尿至少升高5 倍，包括尿α1微球蛋白、β2微球蛋白和視黃醇結(jié)合蛋白，或尿蛋白電泳提示低分子蛋白﹥50%；②高鈣尿癥：隨機尿鈣/肌酐>0.25，或24 h尿鈣定量>4.0 mg·kg-1;任意項：③腎鈣鹽沉著癥、④腎結(jié)石、⑤腎功能異常、⑥鏡下血尿、⑦低磷血癥[19]。二是有日本學者認為，只需符合上述必備項之一加任意項之一即可診斷。由于診斷不一致，日本降低了總體亞洲人群高鈣尿癥的發(fā)生率[77]。

對于高鈣尿癥是否能夠提示CLCN5突變存在爭議，歐美病例系列報道數(shù)據(jù)匯總發(fā)現(xiàn)，在有高鈣尿癥的Dent病1型患者中，更能發(fā)現(xiàn)CLCN5突變，但沒有高鈣尿癥的患者也不能否定Dent病1型的可能，尤其是已經(jīng)進展為慢性腎臟病的患者中[19, 45, 66]。根據(jù)之前報道的腎穿結(jié)果，Dent病1型患者主要表現(xiàn)為腎小管萎縮、腎間質(zhì)纖維化、小管或間質(zhì)鈣化管型和腎小球非特異性改變，發(fā)現(xiàn)局灶節(jié)段性腎小球硬化可能是Dent病1型的表現(xiàn)之一，所以推測如果患者出現(xiàn)不明原因的大量蛋白尿或混合型蛋白尿，沒有原發(fā)性腎小球疾病、腎活檢與上述表現(xiàn)一致，應該考慮是否存在Dent病1型，尤其是不伴有水腫和低蛋白血癥的患者[51, 52, 63]。圖2顯示的Dent病1型診斷流程。臨床診斷的Dent病1型最終需要通過基因檢測確診。

歐美人群和亞洲人群低分子蛋白尿是相似的，而高鈣尿癥、腎鈣質(zhì)沉著、腎結(jié)石、佝僂病以及腎功能異常，亞洲人群發(fā)病較歐美人群是明顯減少。目前對于Dent病1型主要是對癥治療，包括低鈣飲食、氫氯噻嗪藥物治療，國內(nèi)外文獻都有報道氫氯噻氫類藥物有助于降低尿鈣、鈣鹽沉積，部分患者腎鈣質(zhì)沉著可消退，而有些患者停用藥物后有鈣質(zhì)反跳現(xiàn)象，所以推測腎鈣質(zhì)沉著和腎結(jié)石發(fā)病的差異可能與不同的生活習慣有關(guān)，歐美人群多飲用富含礦物質(zhì)水和奶制品，進而增加了Dent病1型患者鈣質(zhì)排泄的風險，促進了腎鈣質(zhì)沉著和腎結(jié)石的發(fā)生[11, 56, 74]。目前Dent病1型腎功能進展的確切機制尚不明確，對于腎鈣質(zhì)沉著是否與腎功能異常有關(guān)存在爭議，由于亞洲人群腎鈣質(zhì)沉著和腎功能異常較歐美人群明顯少，考慮兩者是否存在相關(guān)性，歐美人群腎功能不全更易出現(xiàn)在腎鈣質(zhì)沉著的患者中，而亞洲人群沒有發(fā)現(xiàn)兩者相關(guān)[55]。歐美文獻報道30%～80%的Dent病1型患者將在其30～50歲發(fā)展為慢性腎功能不全，考慮到目前亞洲人群隨訪年限較短，進展為慢性腎臟病的比例和年限的觀察還需要大量的隨訪資料予以證實[78]。

圖2 Dent病1型診斷流程圖

注 基于文獻[78]改編

歐美人群和亞洲人群CLCN5突變類型分布一致，比較不同人群臨床表型與突變類型的相關(guān)性，沒能發(fā)現(xiàn)不同的突變類型凸顯出不同臨床表型的優(yōu)勢。雖然各研究團隊都在尋找 Dent病1型臨床表型和基因型的關(guān)聯(lián)性，但是結(jié)果都沒有給出明確的提示，還需要更多的基礎(chǔ)研究、進而指導后續(xù)的臨床診療。

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(本文編輯：張崇凡)

Five case series of Dent-1 disease and literature review

ZHANG Ya, FANG Xiao-yan, XU Hong, SHEN Qian

(Department of Nephrology, Children's Hospital of Fudan University, Shanghai Kidney Development & Pediatric Kidney Disease Research Center, Shanghai 201102, China)

SHEN Qian，E-mail: shenqianjing@aliyun.com

Objective To summarize the clinical data of five cases of Dent-1 disease so as to improve our understanding of the disease. MethodsClinical data of five cases with Dent-1 disease were summarized, including clinical manifestations, laboratory findings and renal pathological changes. Mutation analysis onCLCN5 andOCRLgenes was performed by direct sequencing in these families. Related literatures of Dent-1 disease were reviewed and the phenotypes and genotypes were summarized.ResultsLaboratory findings of five patients showed 24-hr urine protein ranged from 33.0 to 68.9 mg·kg-1, and high levels of urinary α1-microglobulin, albuminuria, immunoglobulin G and hypercalciuria, and one patient with microscopic haematuria and other two patients with nephrocalcinosis. FiveCLCN5 mutations were detected, including R637X, Y479X, G530V, W103fsX104 and R707X, respectively. Y479X, G530V and W103fsX104 were novel mutations. Among 260 articles related to Dent's disease, we found 72 case reports or case series of Dent-1 disease including 598 patients, 422 from Europe and America and 176 from Asia. Except low-molecular-weight proteinuria, the incidence between Europe and America cases and Asia cases of hypercalciuria, nephrocalcinosis, rickets and renal insufficiency were statistically significantly different. No significant correlations between phenotypes and genotypes in all cases were found, including nonsense mutations, missense mutations and frameshift mutations. ConclusionClinical diagnosis of Dent-1 disease should be confirmed byCLCN5 mutation test to avoid unnecessary immunosuppressants therapy.CLCN5 mutations show high heterogenetic, and the relationships between the phenotypes and genotypes of Dent-1 disease are not found yet.

Children； Low-molecular-weight proteinuria； Dent-1 disease；CLCN5 gene mutation ； Chronic renal disease

復旦大學附屬兒科醫(yī)院腎臟科,上海市腎臟發(fā)育和兒童腎臟病研究中心 上海,201102

沈茜，E-mail: shenqianjing@aliyun.com

10.3969/j.issn.1673-5501.2016.05.014

2016-08-13

2016-10-08)