Abstract
原发性纤毛运动障碍(primary ciliary dyskinesia,PCD)是一种以气道黏液纤毛清除功能障碍为主要表现的遗传性运动型纤毛病。PCD的患病率为1꞉10 000~1꞉20 000。在儿童中与呼吸道相关的主要表现有咳嗽、咳痰、慢性鼻炎、鼻窦炎和分泌性中耳炎,在成人中主要表现为慢性鼻窦炎、支气管扩张症和不孕不育。在某些基因突变的PCD患者中大约50%伴有内脏反位,先天性心脏病的发生率也较高。基因突变导致呼吸道与其他器官的运动型纤毛发生不同严重程度的结构或运动功能障碍,从而发展成一系列异质性的临床表现,对PCD的早期识别和诊断造成了一定的困难。综合使用不同的疾病筛查工具,理解基因型和表型的关联及相关机制有利于PCD患者的早期诊治。
Keywords: 原发性纤毛运动障碍, 临床表型, 疾病筛查, 基因型, 运动型纤毛病
Abstract
Primary ciliary dyskinesia (PCD) is a hereditary disease characterized by airway mucociliary clearance dysfunction. The estimated prevalence of PCD is 1꞉10 000 to 1꞉20 000. The main respiratory manifestations in children are cough, expectoration, chronic rhinitis, sinusitis, and chronic otitis media, while the most common symptoms in adults are chronic sinusitis, bronchiectasis, and infertility. About 50% of patients with certain PCD-related gene variants are combined with situs inversus, and the incidence of congenital heart disease is also high. The pathogenesis behind PCD is that gene variants cause structural or functional disorders of respiratory cilia and motile cilia of other organs, leading to a series of heterogeneous clinical manifestations, which makes it difficult to identify and diagnose PCD. Combining different disease screening tools and understanding the relationship between genotypes and phenotypes may facilitate early diagnosis and treatment for PCD.
Keywords: primary ciliary dyskinesia, clinical phenotype, disease screening, genotype, motile ciliopathies
原发性纤毛运动障碍(primary ciliary dyskinesia,PCD)主要累及具有运动型纤毛或类似结构的器官,以呼吸道症状为主要表现[1]。目前已知超过50个PCD相关的致病基因[2],其遗传模式主要为常染色体隐性遗传,X染色体连锁隐性(RPGR、OFD1和DNAAF6基因)及常染色体显性遗传(FOXJ1基因)[3-8]。不同基因突变会导致不同严重程度的PCD,但均有呼吸道纤毛功能受累的表现:包括足月儿出现新生儿呼吸窘迫,自幼出现的咳嗽、咳痰、慢性鼻炎、鼻窦炎、分泌性中耳炎和支气管扩张[9]。其他器官的运动型纤毛受累则会出现内脏反位、先天性心脏病和不孕不育等表现[10]。一项大型的欧洲调查研究[11]显示在5~14岁儿童中PCD的患病率为1꞉10 000~1꞉20 000。PCD临床表现较为多样,诊断较为复杂,目前未见PCD在中国的患病率数据。
近些年来随着二代测序技术的发展,新的致病基因不断被发现,PCD的遗传异质性和临床表型的异质性越来越明显,同时基因型与表型的关联也得到了深入的研究。本文重点关注PCD的临床表型、疾病筛查、基因型与表型关联的研究进展,以帮助理解不同PCD患者表型差异背后的遗传学基础,促进PCD患者的早期诊治。
1. PCD的临床表型
1.1. 呼吸道表现
呼吸道纤毛具有转运中耳(咽鼓管)、支气管和鼻旁窦黏液的功能,PCD患者由于呼吸道纤毛功能缺陷易发生呼吸道慢性感染,主要表现为以下几个方面。
1.1.1. 足月新生儿呼吸窘迫
PCD患者最早的呼吸道症状为足月新生儿呼吸窘迫,大约55%的PCD患儿会出现此症状[10, 12],表现为出生约12 h后出现呼吸困难,多数患儿需要长时间的氧疗,其发生机制可能与肺内液体吸收及清除延迟、肺叶不张或新生儿肺炎有关[13-14]。由于大多数成年患者对自己出生时的情况不了解及相关医疗记录的缺失,因此该表型对于成年PCD患者的提示作用有限。
1.1.2. 鼻部症状
慢性鼻炎症状(如鼻充血和流涕)出现的时间也较早,通常起自新生儿期[15-16]。在一项荟萃分析[10]中,75%的PCD患者有慢性鼻炎的症状,超过一半的PCD患者伴有慢性鼻窦炎,19%的PCD患者伴有鼻息肉。有研究[17]显示73%的PCD患者存在额窦或蝶窦发育不良,因此鼻窦发育不良也可能是PCD的表型之一。既往的研究多基于儿童PCD患者,成年PCD患者鼻部症状的发生率及严重程度可能更高。
1.1.3. 耳部症状
PCD患者的耳部症状通常开始于2岁[18],包括分泌性中耳炎以及急性或慢性中耳炎。反复耳部感染会导致暂时或永久性听力下降[19]。由于幼年时期的听力丧失会导致语言和学习能力下降,因此需要定期对听力进行监测[20]。随着年龄的增加,耳部症状会逐渐得到缓解,但少数患者在成年后仍需要使用听力辅助设备[1]。
1.1.4. 下呼吸道表现
PCD患者由于黏液纤毛清除功能障碍易发生反复肺部感染,使支气管壁结构遭到破坏而最终导致支气管扩张。两项分别针对45例和20例PCD患者的高分辨率CT研究[21-22]均表明支气管扩张的严重程度与年龄呈正相关,成年PCD患者中支气管扩张的发生率为100%,而在儿童中为56%~71%。支气管扩张主要分布在中叶和舌叶,其次为下叶,而上叶较少受累,可能与中叶和下叶黏液的引流较为困难有关[21-24]。肺部的其他影像学特征还包括肺叶或肺段不张、黏液栓塞、磨玻璃或实变影、支气管管壁增厚及空气潴留等[21-23, 25]。PCD患者的主要死亡原因是肺部感染和呼吸衰竭[24],详细评估PCD患者的肺部情况,进行早期干预是改善患者预后的关键。
1.2. 偏侧发育缺陷
基因(如DNAH5、DNAH11、DNAH9等)突变可影响胚胎节点纤毛的运动,从而干扰人体的发育,导致内脏器官沿身体垂直轴的排列出现异常,大约一半的基因突变患者会出现内脏反位,在孕20周时即可经超声检查发现[26-27]。偏侧发育缺陷主要分为全内脏反位(situs inversus totalis)和内脏异位(situs ambiguous/heterotaxy)。后者又包括左侧内脏异构(left isomerism)、右侧内脏异构(right isomerism)、胸腔内脏反位、腹腔内脏反位、心脏与血管的位置及结构异常等[28-29]。全内脏反位最常见。PCD患者出现支气管扩张、鼻窦炎和内脏反位时,称为Kartagener 综合征。内脏位置对于急性创伤的评估或急诊手术时内脏器官的定位具有很重要的参考意义,右侧内脏异构合并无脾易发生重度感染和凶险性脓毒症,因此需要积极进行管理并预防感染[30-31]。此外,PCD患者先天性心脏病的发生率至少比普通人高200倍(分别为1꞉50和1꞉10 000)[29],因此建议对所有PCD患者行心脏和腹部彩色多普勒超声波检查。
1.3. 不孕不育
精子鞭毛具有与呼吸道纤毛类似的轴丝结构,因而多数(75.5%)PCD男性患者伴有不育的表现[32],主要表现为弱精子症(精子运动能力下降)、少精子症(精子数量减少)和畸形精子症(精子形态异常)[33-34]。呼吸道纤毛与精子鞭毛在蛋白质组成上存在一定的差异,因此男性不育与基因型有较大关系。最近有研究[35-37]发现一些PCD致病基因可同时导致精子鞭毛多发形态异常(一种特殊的遗传性男性弱畸精子症)。PCD女性患者也有不孕的表现,但很少有异位妊娠的报道[32, 38]。尽管输卵管纤毛与呼吸道纤毛在动力蛋白质组成、摆动模式及摆动频率上相似,但一项队列研究[32]表明女性不孕的发生率比男性低且未观察到异位妊娠,提示输卵管纤毛不是卵子运输的主要驱动力量,卵子运输可能更多依赖于输卵管肌肉的收缩运动[39]。最近发表的一项研究[40]支持了这一假设,输卵管的功能主要包括拾卵、精子和受精卵的转运,输卵管纤毛缺失后主要影响拾卵功能,而对精子和受精卵的转运无影响。研究不同基因突变对拾卵功能的影响可促进女性不孕的准确预测及评估。
1.4. 脑积水
脑积水是指脑脊液在脑室内异常聚集导致脑室扩大,伴或不伴脑室内压力升高[41]。在PCD动物模型中,室管膜纤毛运动缺陷导致的脑积水很常见,然而在PCD患者中,脑积水的报道却不多。如DNAH5基因突变的纯合小鼠模型均发生脑积水,但在DNAH5基因突变的PCD患者中脑积水的发生率仅为2.5%(2/80),这可能与人类的中脑水管更宽更短有关[42],脑脊液流动障碍仅部分增加了脑积水的风险。大部PCD患者表现为无症状的静止性脑积水[43-45],但FOXJ1基因突变的PCD患者脑积水较为严重,往往需要降颅压治疗[6]。最近有学者[45]提出除室管膜纤毛运动缺陷引起的脑脊液流动障碍外,脑积水的发生还可能与脉络丛上皮细胞纤毛出现异常从而引起脉络膜增生和脑脊液分泌过多有关。PCD患者脑积水的发生机制可能涉及多个环节,具体机制仍需要进一步研究。
1.5. 其他
除了上述较为常见的表型外,基因突变同时累及初级纤毛时,PCD患者也会出现相应的表现,如色素性视网膜炎、神经性耳聋、肾发育不良、多囊肾、脊柱侧凸、胸廓畸形、多指等[8, 10, 21, 46-48]。但由于缺乏系统性研究,这些表型的发生率、病程、对患者生活质量及预后的影响程度尚不清楚。
2. PCD高危人群的筛查
由于PCD表型的多样性及异质性,诊断也较为复杂[49],除内脏反位外,其他症状特异性不高,因此未合并内脏反位的患者非常容易漏诊及误诊。通过简易方法初步筛查患者进行进一步检查以明确诊断尤为重要,现已有多种症状筛查工具被国外指南推荐。
Mullowney等[13]通过比较具有新生儿呼吸窘迫症状的46例PCD患儿和46例对照足月儿,提出当足月儿出现新生儿呼吸窘迫,合并以下3条中的任意1条时应该考虑PCD的诊断:1)肺叶不张;2)需要氧疗超过2 d;3)内脏反位。在合并新生儿呼吸窘迫的足月儿中,该标准诊断PCD的灵敏度和特异度分别为87%和96%[13]。虽然该方法可以对新生儿进行快速筛查、评估,但仅适用于合并有新生儿呼吸窘迫且具有详细新生儿医疗记录的患儿,因此临床上应用不多。
2016年,4个临床特征被用来识别PCD的高危人群[50],包括新生儿期出现不明原因的足月儿呼吸窘迫,6月龄内出现持续性咳嗽,6月龄内出现持续性鼻塞、偏侧发育缺陷。当以满足2个特征作为临界值时,诊断PCD的敏感度和特异度分别为80%和72%,该筛查方法被2018年美国胸科协会制订的PCD诊断指南所采纳[51]。
PICADAR(Primary Ciliary Dyskinesia Rule)评分用于评估自幼有慢性咳嗽、咳痰症状的人群,预测PCD的可能性,包括7个临床变量:1)是否为足月儿(2分);2)新生儿期是否存在呼吸系统症状(2分);3)是否入住过新生儿病房(2分);4)是否存在内脏位置异常(4分);5)是否有先天性心脏病(2分);6)是否存在持续性鼻炎(1分);7)是否存在慢性耳部或听力症状(1分)。以PICADAR评分≥5为临界值时,诊断PCD的灵敏度和特异度分别为90%和75%[52],可用PICADAR评分简易判断下一步是否需要进行PCD相关的检查。PICADAR评分于2017年被欧洲呼吸协会制订的PCD诊断指南推荐用于识别可疑人群[9]。
2017年有学者[53]对PICADAR评分进行了改良,用于成人支气管扩张症的PCD筛查,由于大多数成年人不知道自己的胎龄和出生后的具体情况,因此从评分标准中删除了“是否为足月儿”,并把“新生儿期是否存在呼吸道症状”和“是否住入过新生儿病房”合并为“新生儿呼吸窘迫”,其他评分项目与PICADAR相同。以≥2分作为临界值时,改良后的PICADAR评分对PCD的敏感度和特异度分别为100%和89%[53],但由于缺乏外部验证,该评分的临床应用还需要更多的数据进行确认。
最近一项研究[54]通过对比PCD和非PCD成年支气管扩张症患者的肺部CT,构建了PCD-CT评分,使用该评分可通过肺部CT筛查支气管扩张症患者中可疑的PCD患者。PCD-CT评分由4个指标构成:1)既往通过手术切除中/下肺叶或中/下肺叶不张(2分);2)树芽征(2分);3)支气管扩张以中/下肺叶分布为主(2分);4)无纤维化或肺气肿的表现(3分)。PCD-CT评分的曲线下面积为0.90,以>6分为临界值时判定PCD的灵敏度和特异度均为83%。因此当未合并内脏反位的支气管扩张症患者PCD-CT评分>6时,推荐进一步进行针对PCD的专科检查。
使用上述筛选工具可以快速锁定高危人群,进一步转诊至有专业诊疗条件的中心。由于大多筛查工具都是针对儿童开发的,没有纳入成人PCD中较常出现的不孕不育及经鼻一氧化氮(nasal nitric oxide,nNO)检测,且很多成人无法回忆起儿时的具体情况,因此这些筛查工具的适用人群需要进一步评估。
3. PCD基因型与表型的关联
目前已发现超过50个基因与PCD相关,根据不同基因在纤毛中的位置及作用,最近有多项研究建立了部分基因型与表型之间的关联。
呼吸道症状主要包括上呼吸道和下呼吸道症状,均与呼吸道纤毛的受累程度有直接关系。早期研究[19, 55-56]表明在电镜下表现为中央微管对结构缺失的PCD患者,其耳部症状和呼吸道症状可能更重,但症状出现较晚,治疗效果较好。与DNAH5基因突变或其他外动力蛋白臂缺失的患者相比,CCDC39或CCDC40基因突变的患者肺功能状态和生长发育情况(体重指数)更差,肺功能下降更快[57-58],影响纤毛数量的CCNO和MCIDAS基因突变患者肺部病变也较严重[44],而DNAH11、DNAH9和RSPH1基因突变的PCD患者呼吸道症状往往较轻[59-62]。呼吸道表型往往与患者的预后直接相关,因此,对于严重呼吸道表型相关基因突变的患者需要更加积极的监测及干预。
内脏反位是最容易被观察及描述的表型,因此其与基因型的关联研究较为明确。内脏反位被认为与胚胎时期节点纤毛的摆动缺陷有关,胚胎节点纤毛是9+0结构,与呼吸道纤毛或精子鞭毛的9+2结构不同,没有中心微管和辐射轴,且每个细胞仅有一根纤毛,因此与纤毛中心微管(HYDIN、STK36、CFAP221、SPEF2)、辐射轴(RSPH1、RSPH4A、RSPH9、RSPH3、DNAJB13)及纤毛数量和长度相关的基因(CCNO、MCIDAS、NEK10)突变的患者不会影响胚胎节点纤毛,无内脏反位的表现[2, 56, 63]。虽然在胚胎节点纤毛中有微管连接蛋白表达,但其可能在早期胚胎左右不对称发育过程中对节点纤毛摆动产生的液体流动影响较小,因此未见微管连接蛋白相关基因如DRC1(CCDC164)、CCDC65(DRC2)和GAS8(DRC4)突变患者出现内脏反位的报道[64]。
关于不孕不育的基因型和表型研究较少,已有研究[65-66]表明ODAD1(即CCDC114基因,与外动力蛋白在微管上的锚定有关)突变似乎不会影响男性和女性患者的生育功能。虽然ODAD1在精子编码中也有表达,ODAD1突变患者呼吸道纤毛外动力蛋白臂缺失,但精子的结构和功能却不受影响,推测可能是由于睾丸中组织特异性表达的CCDC63蛋白部分补偿了ODAD1蛋白的功能[65]。与纤毛数量相关的基因(CCNO、MCIDAS)虽然不会影响男性生育,但会导致女性不孕[43],这可能与精子为单根鞭毛而输卵管纤毛细胞为多根纤毛有关。一项包含85例成人PCD患者的队列研究[32]对不孕不育的基因型和表型进行了分析,虽然由于样本量太少未出现统计学差异,但结果显示存在CCDC39、CCDC40、DNAAF1或LRRC6突变的患者几乎都有男性不育和女性不孕的表现。尽管目前已有研究把PCD与精子鞭毛多发形态异常表型关联起来,但大多数研究仅观察了精子的运动能力而没有关注其形态,因此大多数PCD致病基因是否导致精子鞭毛多发形态异常尚不明确。目前的研究在纤毛功能缺陷导致女性不孕的机制上已取得突破性进展,但对PCD患者女性不孕的表型仍然缺乏关注及系统性的总结。
目前已知的FOXJ1基因突变患者均存在脑积水,而且均有颅内压升高,需要手术干预[6]。与纤毛数量减少相关的基因(CCNO、MCIDAS)突变患者脑积水较常见(4/39,10%),但表现为无临床症状的静止性脑积水[44-45]。其他基因型虽然明显会影响室管膜纤毛的运动,但这类患者很少伴有脑积水。因此,基因突变导致不同严重程度脑积水仅用室管膜纤毛运动缺陷这一机制难以解释,后续研究需要进一步揭示基因型与脑积水关联的机制。
积极寻找基因型和表型之间的关联有助于对PCD患者进行长期管理,更精准地预测其预后。目前虽然已发现多个基因型与表型之间存在关联,但即使同一基因(如DNAH5、CCDC39/CCDC40、CCDC103)突变,具有不同突变位点患者的呼吸道表现也轻重不一[46, 59, 67],提示可能存在多个影响表型严重程度的因素。
4. 结 语
PCD作为一种具有较大遗传异质性的疾病,尚无诊断金标准,临床表型及其严重程度的多样化也增加了其诊断的困难性。随着研究的深入,未来还会发现越来越多PCD相关的基因和表型。利用已有筛查工具有助于对PCD高危患者的早期诊断和优化管理,但前提是增加临床医生对该疾病的认识。已有的基因型和表型之间的关联研究不仅有助于患者的个体化管理及预后的评估,还有助于对致病基因的判读,如对于伴有内脏反位的患者,需要谨慎解读与偏侧发育缺陷无关的基因突变。目前关于基因型和表型的关联仅局限于部分较为常见的基因及表型,其他基因和表型的关联、关联背后的机制及不同临床表型的影响因素等问题需进一步研究。
基金资助
国家自然科学基金(81900002,81770002)。
This work was supported by the National Natural Science Foundation of China (81900002, 81770002).
利益冲突声明
作者声称无任何利益冲突。
作者贡献
雷诚 撰写和修改论文,王荣春、杨丹晖、郭婷、罗红 指导并修改论文。
原文网址
http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202201116.pdf
参考文献
- 1. Lucas JS, Davis SD, Omran H, et al. Primary ciliary dyskinesia in the genomics age[J]. Lancet Respir Med, 2020, 8(2): 202-216. 10.1016/S2213-2600(19)30374-1. [DOI] [PubMed] [Google Scholar]
- 2. Wallmeier J, Nielsen KG, Kuehni CE, et al. Motile ciliopathies[J]. Nat Rev Dis Primers, 2020, 6(1): 77. 10.1038/s41572-020-0209-6. [DOI] [PubMed] [Google Scholar]
- 3. Paff T, Loges NT, Aprea I, et al. Mutations in PIH1D3 cause X-linked primary ciliary dyskinesia with outer and inner dynein arm defects[J]. Am J Hum Genet, 2017, 100(1): 160-168. 10.1016/j.ajhg.2016.11.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Olcese C, Patel MP, Shoemark A, et al. X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3[J]. Nat Commun, 2017, 8: 14279. 10.1038/ncomms14279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Hannah WB, DeBrosse S, Kinghorn B, et al. The expanding phenotype of OFD1-related disorders: Hemizygous loss-of-function variants in three patients with primary ciliary dyskinesia[J]. Mol Genet Genomic Med, 2019, 7(9): e911. 10.1002/mgg3.911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Wallmeier J, Frank D, Shoemark A, et al. De novo mutations in FOXJ1 result in a motile ciliopathy with hydrocephalus and randomization of left/right body asymmetry[J]. Am J Hum Genet, 2019, 105(5): 1030-1039. 10.1016/j.ajhg.2019.09.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Moore A, Escudier E, Roger G, et al. RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa[J]. J Med Genet, 2006, 43(4): 326-333. 10.1136/jmg.2005.034868. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Bukowy-Bieryllo Z, Rabiasz A, Dabrowski M, et al. Truncating mutations in exons 20 and 21 of OFD1 can cause primary ciliary dyskinesia without associated syndromic symptoms[J]. J Med Genet, 2019, 56(11): 769-777. 10.1136/jmedgenet-2018-105918. [DOI] [PubMed] [Google Scholar]
- 9. Lucas JS, Barbato A, Collins SA, et al. European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia[J]. Eur Respir J, 2017, 49(1): 1601090. 10.1183/13993003.01090-2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Goutaki M, Meier AB, Halbeisen FS, et al. Clinical manifestations in primary ciliary dyskinesia: systematic review and meta-analysis[J]. Eur Respir J, 2016, 48(4): 1081-1095. 10.1183/13993003.00736-2016. [DOI] [PubMed] [Google Scholar]
- 11. Kuehni CE, Frischer T, Strippoli MP, et al. Factors influencing age at diagnosis of primary ciliary dyskinesia in European children[J]. Eur Respir J, 2010, 36(6): 1248-1258. 10.1183/09031936.00001010. [DOI] [PubMed] [Google Scholar]
- 12. Goutaki M, Halbeisen FS, Barbato A, et al. Late diagnosis of infants with PCD and neonatal respiratory distress[J]. J Clin Med, 2020, 9(9): E2871. (2020-09-04)[2021-06-01] 10.3390/jcm9092871. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Mullowney T, Manson D, Kim R, et al. Primary ciliary dyskinesia and neonatal respiratory distress[J]. Pediatrics, 2014, 134(6): 1160-1166. 10.1542/peds.2014-0808. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Ferkol T, Leigh M. Primary ciliary dyskinesia and newborn respiratory distress[J]. Semin Perinatol, 2006, 30(6): 335-340. 10.1053/j.semperi.2005.11.001. [DOI] [PubMed] [Google Scholar]
- 15. Coren ME, Meeks M, Morrison I, et al. Primary ciliary dyskinesia: age at diagnosis and symptom history[J]. Acta Paediatr, 2002, 91(6): 667-669. 10.1080/080352502760069089. [DOI] [PubMed] [Google Scholar]
- 16. Knowles MR, Daniels LA, Davis SD, et al. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease[J]. Am J Respir Crit Care Med, 2013, 188(8): 913-922. 10.1164/rccm.201301-0059CI. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Pifferi M, Bush A, Caramella D, et al. Agenesis of paranasal sinuses and nasal nitric oxide in primary ciliary dyskinesia[J]. Eur Respir J, 2011, 37(3): 566-571. 10.1183/09031936.00068810. [DOI] [PubMed] [Google Scholar]
- 18. Sommer JU, Schäfer K, Omran H, et al. ENT manifestations in patients with primary ciliary dyskinesia: prevalence and significance of otorhinolaryngologic co-morbidities[J]. Eur Arch Otorhinolaryngol, 2011, 268(3): 383-388. 10.1007/s00405-010-1341-9. [DOI] [PubMed] [Google Scholar]
- 19. Prulière-Escabasse V, Coste A, Chauvin P, et al. Otologic features in children with primary ciliary dyskinesia[J]. Arch Otolaryngol Head Neck Surg, 2010, 136(11): 1121-1126. 10.1001/archoto.2010.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Shapiro AJ, Zariwala MA, Ferkol T, et al. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review[J]. Pediatr Pulmonol, 2016, 51(2): 115-132. 10.1002/ppul.23304. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Kennedy MP, Noone PG, Leigh MW, et al. High-resolution CT of patients with primary ciliary dyskinesia[J]. AJR Am J Roentgenol, 2007, 188(5): 1232-1238. 10.2214/AJR.06.0965. [DOI] [PubMed] [Google Scholar]
- 22. Santamaria F, Montella S, HAWM Tiddens, et al. Structural and functional lung disease in primary ciliary dyskinesia[J]. Chest, 2008, 134(2): 351-357. 10.1378/chest.07-2812. [DOI] [PubMed] [Google Scholar]
- 23. Jain K, Padley SP, Goldstraw EJ, et al. Primary ciliary dyskinesia in the paediatric population: range and severity of radiological findings in a cohort of patients receiving tertiary care[J]. Clin Radiol, 2007, 62(10): 986-993. 10.1016/j.crad.2007.04.015. [DOI] [PubMed] [Google Scholar]
- 24. Shah A, Shoemark A, MacNeill SJ, et al. A longitudinal study characterising a large adult primary ciliary dyskinesia population[J]. Eur Respir J, 2016, 48(2): 441-450. 10.1183/13993003.00209-2016. [DOI] [PubMed] [Google Scholar]
- 25. Dettmer S, Ringshausen F, Vogel-Claussen J, et al. Computed tomography in adult patients with primary ciliary dyskinesia: typical imaging findings[J]. PLoS One, 2018, 13(2): e0191457. (2018-02-06)[2021-06-01] 10.1371/journal.pone.0191457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. 原壮壮, 黄皓, 杨一峰, 等. 纤毛与人体左右不对称发育研究进展[J]. 生命科学研究, 2018, 22(5): 412-421. 10.16605/j.cnki.1007-7847.2018.05.011. [DOI] [Google Scholar]; YUAN Zhuangzhuang, HUANG Hao, YANG Yifeng, et al. Cilia and human left-right asymmetric patterning[J]. Life Sci Res, 2018, 22(5): 412-421. 10.16605/j.cnki.1007-7847.2018.05.011. [DOI] [Google Scholar]
- 27. Burwick RM, Govindappagari S, Sanchez-Lara PA. Situs inversus totalis and prenatal diagnosis of a primary ciliary dyskinesia[J]. J Clin Ultrasound, 2021, 49(1): 71-73. 10.1002/jcu.22862. [DOI] [PubMed] [Google Scholar]
- 28. Fliegauf M, Benzing T, Omran H. When Cilia go bad: Cilia defects and ciliopathies[J]. Nat Rev Mol Cell Biol, 2007, 8(11): 880-893. 10.1038/nrm2278. [DOI] [PubMed] [Google Scholar]
- 29. Kennedy MP, Omran H, Leigh MW, et al. Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia[J]. Circulation, 2007, 115(22): 2814-2821. 10.1161/CIRCULATIONAHA.106.649038. [DOI] [PubMed] [Google Scholar]
- 30. Kennedy MP, Plant BJ. Primary ciliary dyskinesia and the heart: Cilia breaking symmetry[J]. Chest, 2014, 146(5): 1136-1138. 10.1378/chest.14-0722. [DOI] [PubMed] [Google Scholar]
- 31. Rubin LG, Schaffner W. Clinical practice care of the asplenic patient[J]. N Engl J Med, 2014, 371(4): 349-356. 10.1056/NEJMcp1314291. [DOI] [PubMed] [Google Scholar]
- 32. Vanaken GJ, Bassinet L, Boon M, et al. Infertility in an adult cohort with primary ciliary dyskinesia: phenotype-gene association[J]. Eur Respir J, 2017, 50(5): 1700314. 10.1183/13993003.00314-2017. [DOI] [PubMed] [Google Scholar]
- 33. Sironen A, Shoemark A, Patel M, et al. Sperm defects in primary ciliary dyskinesia and related causes of male infertility[J]. Cell Mol Life Sci, 2020, 77(11): 2029-2048. 10.1007/s00018-019-03389-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Tu CF, Wang WL, Hu TY, et al. Genetic underpinnings of asthenozoospermia[J]. Best Pract Res Clin Endocrinol Metab, 2020, 34(6): 101472. 10.1016/j.beem.2020.101472. [DOI] [PubMed] [Google Scholar]
- 35. Tu CF, Nie HC, Meng LL, et al. Novel mutations in SPEF2 causing different defects between flagella and Cilia bridge: the phenotypic link between MMAF and PCD[J]. Hum Genet, 2020, 139(2): 257-271. 10.1007/s00439-020-02110-0. [DOI] [PubMed] [Google Scholar]
- 36. Sha YW, Wei XL, Ding L, et al. Biallelic mutations of CFAP74 may cause human primary ciliary dyskinesia and MMAF phenotype[J]. J Hum Genet, 2020, 65(11): 961-969. 10.1038/s10038-020-0790-2. [DOI] [PubMed] [Google Scholar]
- 37. Guo T, Tu CF, Yang DH, et al. Bi-allelic BRWD1 variants cause male infertility with asthenoteratozoospermia and likely primary ciliary dyskinesia[J]. Hum Genet, 2021, 140(5): 761-773. 10.1007/s00439-020-02241-4. [DOI] [PubMed] [Google Scholar]
- 38. Blyth M, Wellesley D. Ectopic pregnancy in primary ciliary dyskinesia[J]. J Obstet Gynaecol, 2008, 28(3): 358. 10.1080/01443610802058742. [DOI] [PubMed] [Google Scholar]
- 39. Raidt J, Werner C, Menchen T, et al. Ciliary function and motor protein composition of human fallopian tubes[J]. Hum Reprod, 2015, 30(12): 2871-2880. 10.1093/humrep/dev227. [DOI] [PubMed] [Google Scholar]
- 40. Yuan SQ, Wang ZQ, Peng HY, et al. Oviductal motile cilia are essential for oocyte pickup but dispensable for sperm and embryo transport[J]. Proc Natl Acad Sci USA, 2021, 118(22): e2102940118. 10.1073/pnas.2102940118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Kahle KT, Kulkarni AV, Limbrick DD, et al. Hydrocephalus in children[J]. Lancet, 2016, 387(10020): 788-799. 10.1016/S0140-6736(15)60694-8. [DOI] [PubMed] [Google Scholar]
- 42. Ibañez-Tallon I, Pagenstecher A, Fliegauf M, et al. Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation[J]. Hum Mol Genet, 2004, 13(18): 2133-2141. 10.1093/hmg/ddh219. [DOI] [PubMed] [Google Scholar]
- 43. Amirav I, Wallmeier J, Loges NT, et al. Systematic analysis of CCNO variants in a defined population: implications for clinical phenotype and differential diagnosis[J]. Hum Mutat, 2016, 37(4): 396-405. 10.1002/humu.22957. [DOI] [PubMed] [Google Scholar]
- 44. Boon M, Wallmeier J, Ma LN, et al. MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia[J]. Nat Commun, 2014, 5: 4418. 10.1038/ncomms5418. [DOI] [PubMed] [Google Scholar]
- 45. Robson EA, Dixon L, Causon L, et al. Hydrocephalus and diffuse choroid plexus hyperplasia in primary ciliary dyskinesia-related MCIDAS mutation[J]. Neurol Genet, 2020, 6(4): e482 (2020-07-13)[2021-06-01]. 10.1212/NXG.0000000000000482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46. Guan YH, Yang HM, Yao XF, et al. Clinical and genetic spectrum of children with primary ciliary dyskinesia in China[J]. Chest, 2021, 159(5): 1768-1781. 10.1016/j.chest.2021.02.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Li P, He YN, Cai GY, et al. CCDC114 is mutated in patient with a complex phenotype combining primary ciliary dyskinesia, sensorineural deafness, and renal disease[J]. J Hum Genet, 2019, 64(1): 39-48. 10.1038/s10038-018-0514-z. [DOI] [PubMed] [Google Scholar]
- 48. Reiter JF, Leroux MR. Genes and molecular pathways underpinning ciliopathies[J]. Nat Rev Mol Cell Biol, 2017, 18(9): 533-547. 10.1038/nrm.2017.60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49. 孙晓燕, 陈亚红, 孙永昌. 原发性纤毛运动障碍诊断的方法和流程[J]. 中华结核和呼吸杂志, 2020, 43(9): 811-815. 10.3760/cma.j.cn112147-20200307-00269. [DOI] [Google Scholar]; SUN Xiaoyan, CHEN Yahong, SUN Yongchang. Methods and procedures for the diagnosis of primary ciliary dyskinesia[J]. Chinese Journal of Tuberculosis and Respiratory Diseases, 2020, 43(9): 811-815. 10.3760/cma.j.cn112147-20200307-00269. [DOI] [PubMed] [Google Scholar]
- 50. Leigh MW, Ferkol TW, Davis SD, et al. Clinical features and associated likelihood of primary ciliary dyskinesia in children and adolescents[J]. Ann Am Thorac Soc, 2016, 13(8): 1305-1313. 10.1513/AnnalsATS.201511-748OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Shapiro AJ, Davis SD, Polineni D, et al. Diagnosis of primary ciliary dyskinesia. an official American thoracic society clinical practice guideline[J]. Am J Respir Crit Care Med, 2018, 197(12): e24-e39. [2021-06-01] 10.1164/rccm.201805-0819ST. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52. Behan L, Dimitrov BD, Kuehni CE, et al. PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia[J]. Eur Respir J, 2016, 47(4): 1103-1112. 10.1183/13993003.01551-2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Rademacher J, Buck A, Schwerk N, et al. Nasal nitric oxide measurement and a modified PICADAR score for the screening of primary ciliary dyskinesia in adults with bronchiectasis[J]. Pneumologie, 2017, 71(8): 543-548. 10.1055/s-0043-111909. [DOI] [PubMed] [Google Scholar]
- 54. Rademacher J, Dettmer S, Fuge J, et al. The Primary Ciliary Dyskinesia Computed Tomography Score in Adults with Bronchiectasis: A Derivation und Validation Study[J]. Respiration. 2021, 100(6): 499-509. 10.1159/000514927. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55. Tamalet A, Clement A, Roudot-Thoraval F, et al. Abnormal central complex is a marker of severity in the presence of partial ciliary defect[J]. Pediatrics, 2001, 108(5): E86. (2001-11-01)[2021-06-01] 10.1542/peds.108.5.e86. [DOI] [PubMed] [Google Scholar]
- 56. Vallet C, Escudier E, Roudot-Thoraval F, et al. Primary ciliary dyskinesia presentation in 60 children according to ciliary ultrastructure[J]. Eur J Pediatr, 2013, 172(8): 1053-1060. 10.1007/s00431-013-1996-5. [DOI] [PubMed] [Google Scholar]
- 57. Davis SD, Rosenfeld M, Lee HS, et al. Primary ciliary dyskinesia: longitudinal study of lung disease by ultrastructure defect and genotype[J]. Am J Respir Crit Care Med, 2019, 199(2): 190-198. 10.1164/rccm.201803-0548OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58. Davis SD, Ferkol TW, Rosenfeld M, et al. Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype[J]. Am J Respir Crit Care Med, 2015, 191(3): 316-324. 10.1164/rccm.201409-1672OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59. Shoemark A, Rubbo B, Legendre M, et al. Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia[J]. Eur Respir J, 2021, 58(2): 2002359. 10.1183/13993003.02359-2020. [DOI] [PubMed] [Google Scholar]
- 60. Knowles MR, Ostrowski LE, Leigh MW, et al. Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype[J]. Am J Respir Crit Care Med, 2014, 189(6): 707-717. 10.1164/rccm.201311-2047OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61. Loges NT, Antony D, Maver A, et al. Recessive DNAH9 loss-of-function mutations cause laterality defects and subtle respiratory ciliary-beating defects[J]. Am J Hum Genet, 2018, 103(6): 995-1008. 10.1016/j.ajhg.2018.10.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Fassad MR, Shoemark A, Legendre M, et al. Mutations in outer dynein arm heavy chain DNAH9 cause motile Cilia defects and situs inversus[J]. Am J Hum Genet, 2018, 103(6): 984-994. 10.1016/j.ajhg.2018.10.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63. Best S, Shoemark A, Rubbo B, et al. Risk factors for situs defects and congenital heart disease in primary ciliary dyskinesia[J]. Thorax, 2019, 74(2): 203-205. 10.1136/thoraxjnl-2018-212104. [DOI] [PubMed] [Google Scholar]
- 64. Olbrich H, Cremers C, Loges NT, et al. Loss-of-function GAS8 mutations cause primary ciliary dyskinesia and disrupt the nexin-dynein regulatory complex[J]. Am J Hum Genet, 2015, 97(4): 546-554. 10.1016/j.ajhg.2015.08.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65. Onoufriadis A, Paff T, Antony D, et al. Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia[J]. Am J Hum Genet, 2013, 92(1): 88-98. 10.1016/j.ajhg.2012.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66. Knowles MR, Leigh MW, Ostrowski LE, et al. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia[J]. Am J Hum Genet, 2013, 92(1): 99-106. 10.1016/j.ajhg.2012.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67. Shoemark A, Moya E, Hirst RA, et al. High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations[J]. Thorax, 2018, 73(2): 157-166. 10.1136/thoraxjnl-2017-209999. [DOI] [PMC free article] [PubMed] [Google Scholar]