Primary ciliary dyskinesia diagnosed on nasal mucosal biopsy in two newborns

Primary ciliary dyskinesia (PCD) is a genetic disease that causes abnormalities in ciliary structure and/or function. Ciliated cells line the upper and lower respiratory tracts and the Eustachian tube. Impairment of mucus clearance at these sites leads to sinusitis, repeated pulmonary infections, bronchiectasis, and chronic otitis media. Situs inversus occurs randomly in approximately 50% of subjects with PCD. The triad of situs inversus, bronchiectasis and sinusitis is known as Kartagener syndrome. PCD is usually an autosomal recessive disease, but occasional instances of X‐linked transmission have been reported. Specific diagnosis requires examination of ciliary function or structure on light and electron microscopy. Early diagnosis and respiratory management are important in order to prevent the development of bronchiectasis and deterioration in lung function. We report early diagnosis of PCD on nasal mucosal biopsy in two newborns who presented with prolonged respiratory distress and rhinorrhea.     

Neonatal respiratory distress syndrome – a sign of primary ciliary dyskinesia?

Primary ciliary dyskinesia (PCD) is a clinically heterogeneous disease. In most cases, its clinical manifestation in children is rather unspecific: chronic infectious rhinosinusitis, recurrent acute infections of the upper and lower airways and chronic otitis media with effusion. Between 1990 and 1998 ten patients were diagnosed as PCD. Nine presented a neonatal respiratory distress syndrome (NRDS) of unknown cause. Six of these patients were newborns treated in the intensive care unit, one of them needed mechanical ventilation. The few cases already described in the literature and the experience with our patients support the possible association of NRDS with PCD. Conclusion Neonatal respiratory distress syndrome of unknown cause should be added to the list of clinical presentation of primary ciliary dyskinesia, and if further signs and symptoms are indicative of primary ciliary dyskinesia, investigations to explore this disorder are warranted. Received: 8 December 1999 and in revised form: 13 May and 13 June 2000 / Accepted: 14 June 2000     

Periodic breathing cycle duration in preterm infants

Periodic breathing cycle duration (PCD), the time interval from the beginning of one respiratory pause to the beginning of the next pause within an episode of periodic breathing (PB), was measured by examination of 24-h impedance pneumograms in 51 preterm infants. Calculations of the SD of PCD within a given PB episode (approximately 3 s) and comparison of PCD values between two PB episodes in each infant (r = 0.68) revealed considerable variability in PCD. This variability was not related to the number of cycles in the PB episode or to the amount of PB in the recording. Contrary to the decrease in PCD from 15.0 s at 1 wk to 12.4 s at 12 wk in term infants reported previously, PCD did not vary as a function of postconceptional, gestational, or postnatal age in our preterm population. PCD has limited value as an indicator of chemoreceptor maturation in the preterm infant, and most likely reflects transient adjustments in respiratory system control.     

Primary ciliary dyskinesia: age at diagnosis and symptom history

Age at diagnosis and the symptom history of children with primary ciliary dyskinesia (PCD) are described by reviewing the case notes in the paediatric PCD clinic. Mean age at diagnosis was 4.4 y despite a history of neonatal respiratory distress in 37/55 cases, situs inversus in 38/55 cases and early onset troublesome rhinitis in 42/55. Conclusion : Diagnosis of PCD is often delayed despite the presence of typical symptoms early in life. The key clinical features of unexplained neonatal respiratory distress, early onset rhinitis, situs inversus and a productive cough are highlighted, which, especially when occurring in combination, makes early referral for specific testing for PCD mandatory.     

儿童原发性纤毛运动障碍的临床研究

目的 系统性研究儿童原发性纤毛运动障碍(primary ciliarydyskinesia,PCD)的临床特点,探讨PCD的诊断和鉴别诊断流程.方法 对PCD患儿的临床资料进行分析.结果 确诊PCD患儿26例,男11例,女15例.来自25个家族,1个家族诊断2例Kartagener综合征同胞姐弟.起病年龄为生后第2天～15岁,确诊时病程中位数为3.5年.所有患儿有咳嗽症状,24例有咯痰,7例有体格发育落后.23例接受支气管黏膜和(或)鼻黏膜的电镜检查,可见纤毛动力臂缺失6例,动力臂数目减少、微管排列紊乱、外周微管和(或)中央微管异常各4例,1例纤毛结构正常.经胸部CT证实,支气管扩张症8例,肺实变6例.20例存在鼻窦炎.15份痰或支气管肺泡灌洗液培养阳性标本中,铜绿假单胞菌8份,肺炎链球菌5份,白色念珠菌2份.其中1例培养出2种微生物.肺功能检查的16例中9例为阻塞性通气功能障碍.4例听力检测中3例异常,食管24 h pH值测定的5例患儿中3例有胃食管反流.结论 PCD起病年龄从新生儿期到青春期,呈慢性病程.主要临床表现为咳嗽、咯痰,可出现体格发育落后.PCD患儿中最多见的纤毛结构异常是动力臂缺失.部分患儿纤毛结构正常.影像学异常包括肺实变、支气管扩张症和鼻窦炎.常见的细菌病原为铜绿假单胞菌、肺炎链球菌,并可能存在混合感染.PCD患儿肺功能异常主要为阻塞性通气功能障碍,听力损害、胃食管反流出现率较高.     

Postnatal development of periodic breathing cycle duration in term and preterm infants

Previous studies of the maturation of periodic breathing cycle duration (PCD) with postnatal age in infants have yielded conflicting results. PCD is reported to fall in term infants over the first 6 mo postnatally, whereas in preterm infants PCD is reported either not to change or to fall. Contrary to measured values, use of a theoretical respiratory control model predicts PCD should increase with postnatal age. We re-examined this issue in a longitudinal study of 17 term and 22 preterm infants. PCD decreased exponentially from birth in both groups, reaching a plateau between 4 and 6 mo of age. In preterm infants, PCD fell from a mean of 18.3 s to 9.8 s [95% confidence interval (CI) is +/- 3.2 s]. In term infants, PCD fell from 15.4 s to 10.1 s (95% CI is +/- 3.1 s). The higher PCD at birth in preterm infants, and the similar PCD value at 6 mo in the two groups, suggest a more rapid maturation of PCD in preterm infants. This study confirms that PCD declines after birth. The disagreement between our data and theoretical predictions of PCD may point to important differences between the respiratory controller of the infant and adult.     

Pierwotna dyskineza rzęsek – nowe możliwości diagnostyczne i aktualne zalecenia opieki nad pacjentem na przykładzie przypadku klinicznego

Primary ciliary dyskinesia (PCD) presents a diagnostic challenge. Coexistence of multiorgan abnormalities may facilitate the diagnosis. In this article, we present a case of a patient with a complex congenital heart disease and recurrent severe lower respiratory tract infections, in whom further diagnostics confirmed PCD with CCDC39 gene mutation. In recent years, genetic testing for PCD forms a valuable completion of the ciliary biopsy with electron microscopy. Once diagnosis of PCD is established, proper clinical care will have to be rendered to reduce the complications of the disease. In this article, the current recommendations for patient's clinical visits’ regimen, laboratory testing and suggested prophylactic methods are presented.     

原发性纤毛不动综合征诊断方法研究进展

原发性纤毛不动综合征是一种常染色体隐性遗传或X染色体相关的遗传疾病,国外发病率为1∶50 000~1∶10 000,国内尚无相关流行病学资料。该病发生机制为纤毛的双等位基因突变,导致组织器官的结构和/或功能改变,从而引起一系列相关临床表现,其中约50%为Kartagener综合征。目前常用的检查方法有鼻呼出气一氧化氮检测、透射电镜法、免疫荧光分析法、高频数字视频成像和基因诊断,但每种检查方法均有其优点及弊端。同时,统一的诊断思路及确切有效的治疗方案也处于探索研究阶段。     

Skeletal muscle metabolism in cystic fibrosis and primary ciliary dyskinesia

Previous studies have reported differences in muscle function and metabolism between patients with cystic fibrosis (CF) and healthy controls (HC), but it is currently unknown whether these abnormalities are specific to CF or also seen in other airway diseases. In this study, we used magnetic resonance spectroscopy (MRS) during exercise to assess muscle metabolism in CF patients. Twenty patients with CF and 20 age, gender, and habitual activity-matched HCs and a respiratory disease comparison group with primary ciliary dyskinesia (PCD; n = 10) were studied. Phosphorus MRS (P-MRS) was used to characterize muscle bioenergetic metabolism at rest and after high-, moderate-, and low-intensity exercise. CF patients exhibited lower resting ATP/phosphocreatine (PCr) ratio and significantly higher end-exercise pH values compared with both HC and PCD patients. Both CF and PCD patients demonstrated significantly slower PCr recovery time constants after high-intensity exercise. Our results suggest that not only there are specific abnormalities of muscle metabolism in CF patients but also there is a nonspecific impact of respiratory disease on muscle function.     

Primary ciliary dyskinesia: current state of the art

Primary ciliary dyskinesia (PCD) is usually inherited as an autosomal recessive disorder and presents with upper and lower respiratory tract infection, and mirror image arrangement in around 50% of cases. Cilia dysfunction is also implicated in a wider spectrum of disease, including polycystic liver and kidney disease, central nervous system problems including retinopathy and hydrocephalus, and biliary atresia. Cilia are complex structures, containing more than 250 proteins; recent studies have begun to locate PCD genes scattered throughout the genome. Screening tests for PCD include nasal nitric oxide and in vivo tests of ciliary motility such as the saccharin test. Specific diagnosis requires examination of cilia by light and electron microscopy, with epithelial culture in doubtful cases. This is only available in supra-regional centres, recently centrally funded by the National Commissioning Group. Treatment is not evidence based and recommendations are largely extrapolated from cystic fibrosis and other suppurative lung diseases.     

Primary ciliary dyskinesia: current state of the art.

Primary ciliary dyskinesia (PCD) is usually inherited as an autosomal recessive disorder and presents with upper and lower respiratory tract infection, and mirror image arrangement in around 50% of cases. Cilia dysfunction is also implicated in a wider spectrum of disease, including polycystic liver and kidney disease, central nervous system problems including retinopathy and hydrocephalus, and biliary atresia. Cilia are complex structures, containing more than 250 proteins; recent studies have begun to locate PCD genes scattered throughout the genome. Screening tests for PCD include nasal nitric oxide and in vivo tests of ciliary motility such as the saccharin test. Specific diagnosis requires examination of cilia by light and electron microscopy, with epithelial culture in doubtful cases. This is only available in supra-regional centres, recently centrally funded by the National Commissioning Group. Treatment is not evidence based and recommendations are largely extrapolated from cystic fibrosis and other suppurative lung diseases.     

Diagnostik der primären ziliären Dyskinesie

Characteristics

Primary ciliary dyskinesia (PCD) is a rare congenital disease of the cilia which is mostly manifested in the respiratory system.

Diagnostics

When there is a clinical suspicion of the presence of PCD and/or a positive screening result with reduced nasal nitrogen oxide (NO) values, further diagnostic measures should be initiated as soon as possible. In centers where high-frequency video microscopy analyses (HVMA) of beating of cilia are available, an initial nasal NO measurement for screening must not necessarily be carried out. As the first diagnostic measure for confirmation or exclusion of PCD, HVMA should be carried out. If the findings are conspicuous transmission electron microscopic analysis (TEM) of the ciliary structure and high-resolution immunofluorescence (IF) microscopic analysis of the cilia should follow. Mandatory for diagnosis are at least two congruent pathological findings from HVMA, TEM or IF. When a PCD variant with no evidence of ultrastructural defects is present, an identical pathological beating of cilia must be demonstrated with HVMA on three independent occasions. Following that a targeted genetic clarification should be attempted based on the findings for HVMA, TEM and IF. A clear genetic result can also confirm the diagnosis.

Approach

When PCD is suspected contact with a diagnostic center should be made. A reference center for PCD diagnostics will evaluate uncertain findings.     

Psychological, cognitive and maternal stress assessment in children with primary ciliary dyskinesia

Background

Primary ciliary dyskinesia (PCD) is a rare disorder due to structure and functional abnormalities of respiratory cilia. There are no reports on the behavioral and psychological aspects of children and adolescents with PCD. This study was undertaken to assess the cognitive and behavioural characteristics, and the parental stress of a population of school-aged children with PCD.

Methods

Ten PCD and 34 healthy school-aged children underwent Wechsler Intelligence Scale for Children-III edition, Child Behavior Check-List questionnaire (CBCL), Parenting Stress Index-Short Form tests in order to perform a behavioural and psychological evaluation.

Results

PCD children showed significant behavioral and social competent problems in CBCL scale than control children, in particular with regard to internalizing problems score (P<0.001). Parental distress, parent-child interaction and total stress in the mothers of PCD patients were higher than those in the controls’ parents (P<0.001).

Conclusion

Our findings pinpoint the importance of specific psychological support in the clinical management of children with PCD.     

Dyskinésie ciliaire congénitale : qui et comment explorer ?

Primary ciliary dyskinesia (PCD) is a rare genetic disease associated with abnormal ciliary structure and function, which results in retention of mucus and bacteria in the respiratory tract, leading to chronic oto-sino-pulmonary disease from early childhood, situs abnormalities and abnormal sperm motility. The diagnosis of PCD can be difficult and is based on the presence of the characteristic clinical phenotype, evidence of abnormal ciliary function and specific ultrastructural ciliary defects identified by transmission electron microscopy. Because prognosis of the disease is related to the age of diagnosis, we suggest in this article, elements that should early orientate diagnostic evaluation of patients suspected of having PCD.     

儿童原发性纤毛运动障碍鼻窦CT影像学特征临床观察

目的　探讨儿童原发性纤毛运动障碍（primary ciliary dyskinesia,PCD）的鼻窦CT影像学特征。方法　回顾性分析2018年7月至2021年3月复旦大学附属儿科医院诊治的24例PCD患儿的临床资料,包括病史、鼻窦CT、鼻内镜、胸片、胸部CT、心脏超声、腹部B超及基因检测结果等。计算PCD患儿的Lund-Mackay鼻窦CT评分,与行功能性内窥镜鼻窦手术（FESS）的慢性鼻窦炎患儿的Lund-Mackay评分对比。 并应用Stata软件对PCD患儿的Lund-Mackay评分与年龄进行相关性分析。结果　24例患儿中21例行鼻窦CT检查,其中男15例,女6例,年龄1～17岁,平均年龄（7.4±4.3）岁。21例（100.0%）均伴鼻窦炎,4例（19.0%）伴腺样体肥大,18例（85.7%）伴中耳炎。5例行鼻内镜检查,未见鼻息肉。11例（52.4%）伴全内脏反位,11例（52.4%）伴肺实变肺不张,8例（38.1%）伴不同程度的支气管扩张。12例（57.1%）出生时有新生儿呼吸窘迫,其中仅1例为早产儿。1例（4.8%）伴房间隔室间隔缺损。PCD患儿Lund-Mackay评分平均（15.1±3.8）分,普通慢性鼻窦炎患儿Lund-Mackay评分平均（12.1±6.0）分,差异有统计学意义（P＜0.05）。PCD患儿鼻窦炎症在窦口鼻道复合体受累最重。与普通的慢性鼻窦炎患儿相比,PCD患儿在窦口鼻道复合体、蝶窦、后组筛窦的CT评分更高（P＜0.05）。PCD患儿年龄与Lund-Mackay评分呈负相关（r＝-0.5270,P＜0.05）。结论　绝大多数PCD患儿有慢性鼻窦炎。 与普通的慢性鼻窦炎患儿相比,PCD 患儿鼻窦炎症更重,后组鼻窦受累更重。临床遇到顽固性鼻窦炎伴反复下呼吸道感染或既往有新生儿呼吸窘迫的足月产患儿,要考虑PCD可能。     

Diagnostic approach to primary ciliary dyskinesia: a review

Primary ciliary dyskinesia (PCD) is a heterogeneous disease with impaired mucociliary transport leading to respiratory disorders, hearing impairment and male infertility. PCD can be diagnosed by clinical features together with functional and structural analysis of the cilia. To prevent bronchiectasis with a marked reduction in quality of life, early diagnosis is essential. The rarity of PCD and the costs of ultrastructural analysis of cilia require a rational diagnostic concept. We therefore reviewed the literature and compared clinical manifestations as well as functional and structural analyses of the cilia in 28 patients (23 children, 5 adults) investigated between 1990 and 1998. All were thoroughly examined for other possible diseases before biopsy, and ten patients (35.7%; eight children, two adults) were diagnosed as having PCD. From the literature review and our findings we conclude that ciliary investigation is indicated (a) in patients who remain suspected of having PCD despite thorough clinical examination and exclusion of other disorders such as cystic fibrosis, allergy, immunologic disorders and α₁-antitrypsin deficiency; (b) in patients with situs inversus suffering from chronic and/or recurrent airway infections; and (c) in patients with neonatal respiratory distress syndrome of “unknown” cause (i.e. after exclusion of hyaline membrane disease, aspiration syndromes, neonatal pneumonia, and pneumothorax as well as cardiovascular and metabolic diseases). Conclusion The combination of extensive clinical examination with functional and ultrastructural analysis of the cilia results in a high degree of accuracy in diagnosing PCD. Received: 30 November 1998 / Accepted: 20 July 1999     

Axonemal localization of the dynein component DNAH5 is not altered in secondary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is a heterogeneous genetic disorder characterized by recurrent airway infections and situs inversus in half of affected individuals. Diagnosis currently relies on demonstration of abnormal ciliary ultrastructure or altered ciliary beat. Alterations encountered in secondary ciliary dyskinesia (SCD) caused by inflammation often complicate the diagnostic workup. We have recently shown that in respiratory epithelial cells from PCD patients with outer dynein arm defects the dynein protein DNAH5 is mislocalized and either completely or partially absent from the ciliary axoneme. In this study, we addressed the question whether SCD might affect axonemal DNAH5 localization in respiratory cells. To induce SCD in vitro, we treated primary human respiratory epithelial cell cultures with interleukin-13 (IL-13). Ciliary function and ultrastructure were assessed by high-speed videomicroscopy and transmission electron microscopy, respectively. For in vivo localization of DNAH5, we performed nasal brushing biopsies in patients with evidence of SCD. Expression of DNAH5 was analyzed by immunofluorescence microscopy. IL-13-treated cells showed evidence of SCD. Ciliary beat frequency was significantly reduced and ultrastructural analyses showed axonemal disorganization compared with control cells. High-resolution immunofluorescence studies of respiratory epithelial cells with SCD identified in vitro and in vivo normal axonemal DNAH5 localization. DNAH5 localization is not altered by SCD, indicating a high potential for immunofluorescence analysis as a novel diagnostic tool in PCD.     

Ciliary defects and genetics of primary ciliary dyskinesia

Cilia are evolutionarily conserved structures that play key roles in diverse cell types. Motile cilia are involved in the most prominent ciliopathy called primary ciliary dyskinesia (PCD) that combines respiratory symptoms, male infertility, and, in nearly 50% cases, situs inversus. The diagnosis of PCD relies on the identification of ciliary abnormalities that mainly concern outer and/or inner dynein arms (ODA, IDA). PCD is a genetic condition, usually inherited as an autosomal recessive trait. To date, six genes have been clearly implicated in PCD. Two “major” genes, DNAI1 and DNAH5, underlie PCD in nearly half of the patients with ODA defects, whereas RPGR, DNAH11 and TXNDC3 are implicated in rare families with specific phenotypes (retinitis pigmentosa, abnormal beating of structurally normal cilia, and situs ambiguous, respectively). The relative contribution of DNAI2 is currently being assessed. In all the other patients with ODA or other ultrastructural defects, the causative genes remain to be identified.     

Primary ciliary dyskinesia: Diagnosis in children with inconclusive ultrastructural evaluation

The purpose of this study was to distinguish between acquired and genetically determined ciliary abnormalities in children with severe chronic respiratory diseases. Samples of nasal ciliated epithelium from 50 subjects (25 male, 25 female; age-range 2–19 years) with severe chronic respiratory diseases were examined using transmission electron microscopy (TEM). Based on TEM findings, patients were divided into two groups: A and B. Group A comprised 39 children with ciliary alterations compatible with a condition probably occuring secondary to chronic inflammation (alterations of peripheral pairs, swollen cilia, and compound cilia). The other 11 patients, Group B, exhibited a greater number of alterations of the central pair and dynein arms (p< 0.001), which were qualitatively similar to, but less numerous than, those observed in primary ciliary dyskinesia (PCD). In both groups, analysis of ciliary beat frequency and waveform was performed by phase contrast microscopy (PCM). All the children with a ciliary beat frequency of < 7 Hz were treated with daily physiotherapy and with antibiotics, as recommended for PCD, for a 6-month period. After this treatment, the children were reexamined by PCM. Almost 50% of the children from Group B (i.e. those with a small proportion of specific ultrastructural defects) showed permanence of low ciliary beat frequency. This was also observed in two children of Group A. These children were considered to be affected by PCD. Our study describes a method for the diagnosis of PCD in the absence of specific ultrastructural defects or when these defects are present in only a small proportion of the cilia.     

Respiratory support in the absence of abdominal muscles: A case study of ventilatory management in prune belly syndrome

Prune belly syndrome (PBS) results in a total lack of abdominal musculature. Abdominal muscles have an important function during inspiration and expiration. This puts the patient at risk for respiratory complications since they have a very limited ability to cough up secretions. Patients in an intensive care unit (ICU) with PBS who receive mechanical ventilation are at even greater risk for respiratory complications. We review the function of the abdominal muscles in breathing and delineate why they are important in the ICU. We include an illustrative case of a long-term ventilated patient with PBS and offer respiratory management options.