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Primary Ciliary Dyskinesia

PCD

Primary ciliary dyskinesia is a genetic disorder in which impaired development and function of cilia leads to recurrent respiratory infections, hearing deficits and congenital heart malformations. Symptoms are present from birth, and the diagnosis is often missed, primarily because of the lack of clinical suspicion. Patient history, clinical criteria and a range of laboratory, as well as genetic tests, are used to confirm the diagnosis.


Presentation

Primary ciliary dyskinesia (PCD) is a genetic disorder of abnormal ciliary function and/or structure, thus the signs and symptoms are related to their respective locations - the upper and lower respiratory tracts, the middle ear, and the reproductive tract [1] [2] [3] [4]. Symptoms start shortly after birth, when the majority of patients suffer from recurrent bacterial infections of the paranasal sinuses and the lungs, as cilia are unable to perform their function of moving mucus and bacteria [1] [2] [3]. A wet cough, rhinorrhea, respiratory distress, tachypnea, hypoxia and the development of neonatal pneumonia are prominent symptoms [2] [3] [5]. Many reports have stressed that the diagnosis is frequently delayed until adulthood, despite the persistent presence of respiratory complaints and recurrent infections [1] [3] [5]. In addition, virtually all children (85-95%) suffer from a severe inflammation of the inner ear (otitis media) with effusion manifesting as conductive hearing impairment [2] [3]. Ciliary dysfunction is also responsible for male infertility and female subfertility, due to the fact that cilia are pivotal for motility of the sperm and the function of the fallopian tubes, respectively [1] [2] [3] [4]. Interestingly, about 50% of all individuals suffering from PCD are diagnosed with situs inversus, which arises because of the important roles of cilia in the formation of cardiac structures during embryogenesis, and often predisposes to a number of congenital heart diseases (CHDs) [1] [2] [4] [5] [6]. Other less common features are dextrocardia, heterotaxy (isomerism of the atrial appendages), hydrocephalus and atresia of the biliary tree [2].

Recurrent Infection
  • It is important to recognize the association and to question patients with retinitis pigmentosa about their respiratory functions, because an early diagnosis of PCD can prevent recurrent infections and development of bronchiectasis with daily physiotherapy[ncbi.nlm.nih.gov]
  • People with PCD may have persistent or recurrent infections, which can significantly disrupt their quality of life and sometimes lead to permanent damage and life-threatening complications.[chop.edu]
  • Primary ciliary dyskinesia: The immotile cilia syndrome, a condition in which poorly functioning cilia (hairlike projections from cells) in the respiratory tract contribute to retention of secretions and recurrent infection.[medicinenet.com]
Recurrent Respiratory Infections
  • Recurrent respiratory infection, especially situs inversus could be the most important indicator of this disease. 2015 John Wiley & Sons Ltd.[ncbi.nlm.nih.gov]
Recurrent Otitis Media
  • Seven cases were complicated with recurrent otitis media and 15 cases were complicated with infertility. A total of 119 patients were diagnosed with situs inversus totalis (94%).[ncbi.nlm.nih.gov]
  • otitis media and 54% had significant sinus disease (1) Motile cilia on the embryonic node have an important role determining left-right symmetry approximately 50% of PCD patients having situs inversus (3) Reference: Noone PG, Leigh MW, Sannuti A, et[gpnotebook.co.uk]
  • Complications of PCD include respiratory difficulties and end-stage respiratory failure, permanent hearing loss due to recurrent otitis media, and rarely, hydrocephalus.[news-medical.net]
  • Ear symptoms (recurrent otitis media and glue ear) are a frequent complication (85% of patients) that can require multiple interventions, including repeated courses of antibiotics.[czytelniamedyczna.pl]
  • Children experience recurrent otitis media, glue ear and hearing loss. Unlike unaffected children with glue ear, grommet insertion is often unsuccessful and can result in offensive discharge and no improvement in hearing.[journals.rcni.com]
Recurrent Sinusitis
  • The clinical consequences of the immotile cilia syndrome include chronic cough and expectoration, bronchiectasis, chronic rhinitis and nasal polyposis, chronic or recurrent sinusitis, and often an agenesis of the frontal sinuses.[ommbid.mhmedical.com]
  • Many children experience recurrent sinusitis. In the ears, mucociliary clearance in the eustachian tubes is responsible for clearing the middle ear. Children experience recurrent otitis media, glue ear and hearing loss.[journals.rcni.com]
  • Lung India 2006;23:123-5 The Kartagener's syndrome comprises of classic triad of situs inversus, bronchiectasis and recurrent sinusitis. Male patients with this syndrome are almost invariably infertile because of immotile spermatozoa.[lungindia.com]
Recurrent Bronchitis
  • Diagnosis of PCD is frequently delayed 8, in part because patients present with symptoms (rhinitis, secretory otitis media, cough and recurrent bronchitis) that are common in healthy children 2.[erj.ersjournals.com]
  • Approximately 40 years later, Afzelius reported on four subjects with recurrent bronchitis and pneumonia associated with recurrent upper airways infections who also had SI in 50% of the cases, then known as Kartagener’s syndrome ( 6 ).[journal.frontiersin.org]
Cough
  • KEYWORDS: Primary Ciliary Dyskinesia [PCD]; chronic wet cough.; neonatal respiratory distress; persistent rhinosinusitis; situs inversus[ncbi.nlm.nih.gov]
  • One of the primary goals of treatment is to induce coughing, which helps the body rid itself of bacteria and reduces infections and illnesses. Chest physiotherapy is one technique frequently used to loosen mucus in the lungs so it can be coughed up.[childrenscolorado.org]
  • Exercise: Regular aerobic exercise can increase the airflow through the lungs and help loosen the mucus to be coughed up.[rbhh-specialistcare.co.uk]
Respiratory Distress
  • The infant had presented with respiratory distress and atelectasis almost immediately after birth.[ncbi.nlm.nih.gov]
Chronic Cough
  • Prolonged chronic cough represents an important symptom that is seen in most patients.[ncbi.nlm.nih.gov]
  • cough Causes - Immotile cilia syndrome- due to defective radial spokes * Asymptomatic * Chronic cough * Chronic inflammatory lung disease * Halitosis * Headache * Impaired hearing * Male infertility * Mouth breathing * Nasal congestion * Nasal polyps[checkorphan.org]
  • Other signs that may indicate PCD include: Chronic cough Respiratory distress as a newborn Chronic wheezing Excess mucus Difficulty clearing mucus Chronic nasal congestion Recurrent middle ear infections Recurrent cold symptoms Only genetic testing or[chop.edu]
  • The clinical consequences of the immotile cilia syndrome include chronic cough and expectoration, bronchiectasis, chronic rhinitis and nasal polyposis, chronic or recurrent sinusitis, and often an agenesis of the frontal sinuses.[ommbid.mhmedical.com]
Productive Cough
  • The patient experienced a chronic productive cough beginning in early childhood and had multiple episodes of pneumonia and otitis media with effusion and sinusitis. No situs inversus or other heterotaxias were reported.[ncbi.nlm.nih.gov]
  • The triad of productive cough, sinusitis, and otitis was a consistent finding in all. Situs inversus occurred in only half of the patients. Received July 22, 1980. Accepted September 26, 1980.[pediatrics.aappublications.org]
  • Case Report A 60 year old female from interior rural Maharashtra presented to our institute with productive cough and dyspnea for the last 8 to10 years. She had no past medical records.[mjdrdypu.org]
  • Despite retained secretions and a history of chronic productive cough in most patients, clinical examination may reveal few signs.[adc.bmj.com]
  • Productive cough, rhinitis and recurrent infections of the upper and lower respiratory tract have been described as leading symptoms [ 2 , 3 ].[erj.ersjournals.com]
Anosmia
  • Nasal polyps, bronchiectasis, segmental/lobar atelectasis, hear loss and anosmia were less frequent and more late. A detailed clinical feature is usefull for early diagnosis expecially in those pts without situs viscerum inversus.[nature.com]
  • Likewise, chronic upper airway symptoms, such as constant rhinitis (nasal discharge, episodic facial pain and anosmia).[czytelniamedyczna.pl]
  • Patients with the Kartagener syndrome may have anosmia (Goldstein, 1979). The sperm of males with Kartagener syndrome are immotile, which is the same as every cilliary cell in the body (Afzelius et al ., 1976).[scialert.net]
  • In addition, virtually all subjects show evidence of chronic upper airway symptoms, such as chronic rhinitis (nasal discharge, episodic facial pain and anosmia). This may be confirmed by physical examination and/or sinus imaging.[erj.ersjournals.com]
  • Chronic rhinorrhea complicated by anosmia, associated with recurrent secretory type otitis (glue ear), occur in 76–100% of PCD children ( 19, 28 ) and may lead to sleep-disordered breathing ( 29, 30 ).[journal.frontiersin.org]
Halitosis
  • * Nasal congestion * Impaired hearing * Wheezing * Respiratory problems * Bronchiectasis * Headache * Chronic cough Causes - Immotile cilia syndrome- due to defective radial spokes * Asymptomatic * Chronic cough * Chronic inflammatory lung disease * Halitosis[checkorphan.org]
  • […] as for childhood Bronchiectasis more evident in adulthood (83%) Chronic mucopurulent sputum production is common Digital clubbing may also be found Pulmonary function tests usually show a progressive obstructive or mixed pattern Nasal polyposis and halitosis[czytelniamedyczna.pl]
Hearing Impairment
  • Primary ciliary dyskinesia (PCD) is a rare, genetic disorder of the motile cilia characterised by chronic lung disease, nasal and sinus disease, chronic ear infections with glue ear leading to possible hearing impairment, and subfertility.[ncbi.nlm.nih.gov]
  • In addition, virtually all children (85-95%) suffer from a severe inflammation of the inner ear (otitis media) with effusion manifesting as conductive hearing impairment.[symptoma.com]
  • Hearing impairment was reported in 14 (27%) studies and prevalence ranged from 8% to 100% (weighted mean 36; figure 3 ).[erj.ersjournals.com]
Headache
  • * Chronic cough Causes - Immotile cilia syndrome- due to defective radial spokes * Asymptomatic * Chronic cough * Chronic inflammatory lung disease * Halitosis * Headache * Impaired hearing * Male infertility * Mouth breathing * Nasal congestion * Nasal[checkorphan.org]
  • […] uncommon–1:20 000 AR disease of childhood onset due to defective or afunctional cilia in the respiratory tract, resulting in chronic sinusitis, defective mucociliary transport and bronchial clearance, bronchiectasia, chronic otitis media and incapacitating headaches[medical-dictionary.thefreedictionary.com]
  • Symptoms of hydrocephaly include: Neurological Digestive and Urinary Movement Increased sleepiness/fatigue Nausea Altered pattern of walking (gait) Seizures Vomiting Poor coordination Headaches Loss of bladder control Generalized slowing of arm/leg movement[study.com]
  • Individuals with PCD may also have situs inversus or situs ambiguous, headaches or hydrocephalus. All the causative genes identified thus far have roles in the development and function of cilia and flagella.[flystocks.bio.indiana.edu]
  • Many families also report frequent headaches, both sinus-related and non-sinus related, stomach and GI complaints, failure to gain weight and unusual fevers, although these are not known to be specifically relate to PCD at this time.[medifitbiologicals.com]

Workup

Although prevalence rates estimate PCD to affect about 1 in 10,000-15,000 individuals, several studies have concluded that the condition is both underreported and underdiagnosed, thus assuming its more frequent in clinical practice [1] [2] [5]. For this reason, PCD must be included in the differential diagnosis of unexplained recurrent respiratory and otogenic symptoms, particularly in neonates. To establish a diagnosis, a detailed patient history and a complete physical examination are an absolute necessity. Apart from evaluating the onset and progression of symptoms, family history is of essential importance, keeping in mind the autosomal recessive pattern of inheritance (some reports also indicate an X-linked pattern) [2] [3]. During the physical exam, sensorineural hearing loss and confirmation of respiratory complaints are noted, while cardiac auscultation may reveal situs inversus or dextrocardia, in which case additional studies should be performed to determine the underlying cause. Plain radiography and computed tomography (CT) are useful tools in PCD patients, as thickening of the bronchial wall, lung hyperinflation, and less commonly atelectasis and/or consolidation are typical signs [2] [4]. To make a definite diagnosis, several specific tests are described in the literature [1] [2] [3] [4] [5]:

  • Determination of nasal nitric oxide (NO) levels - is now considered to be one of the most reliable criteria. Nasal NO levels are almost universally lower in these patients compared to the general population, and its noninvasiveness is of great benefit [1] [2].
  • Examination of cilia with transmission electron microscopy (TEM) - Previously designated as the gold standard in diagnosing PCD, its complexity, and scarce availability are important limitations.
  • Analysis of ciliary function and structure - Although ciliary function may be apparently normal when examined under light microscopy, the combination of abnormal ciliary activity and alterations in their structure (confirmed by electron microscopy) is highly specific for PCD [2] [3].
  • Genetic testing - Various ciliary proteins and mutations of their respective genes have been implicated in the pathogenesis of PCD, and through immunofluorescence analysis and detection of specific mutations, the diagnosis can be established, but these tests are not widely available and are quite expensive [2] [3].
Atelectasis
  • The infant had presented with respiratory distress and atelectasis almost immediately after birth.[ncbi.nlm.nih.gov]
  • Close monitoring of the lower respiratory tract can often delay the onset of bronchiectasis and atelectasis. Surgical intervention may be necessary for severe cases of nasal polyposis, atelectasis and chronic otitis media.[path.upmc.edu]
  • Plain radiography and computed tomography (CT) are useful tools in PCD patients, as thickening of the bronchial wall, lung hyperinflation, and less commonly atelectasis and/or consolidation are typical signs.[symptoma.com]
  • Nasal polyps, bronchiectasis, segmental/lobar atelectasis, hear loss and anosmia were less frequent and more late. A detailed clinical feature is usefull for early diagnosis expecially in those pts without situs viscerum inversus.[nature.com]

Treatment

  • KEYWORDS: Bronchiectasis; Mucociliary clearance; Primary ciliary dyskinesia; Treatments[ncbi.nlm.nih.gov]
  • LEARN MORE TREATMENT PCD treatment requires a multi-disciplinary approach. LEARN MORE CLINICAL CENTERS Clinical centers are crucial to accelerating access to better therapies and ultimately cure(s) for individuals with PCD.[pcdfoundation.org]

Prognosis

  • CONCLUSION: Precocious diagnosis and regular treatment may enhance the PCD prognosis.[ncbi.nlm.nih.gov]
  • Prognosis The prognosis depends on timely diagnosis and appropriate treatment. Life expectancy is likely somewhat shortened, although quantitative estimates are not currently available.[orpha.net]

Etiology

  • Together, these findings support an oligogenic disease model with broad relevance for further interrogating the genetic etiology of human ciliopathies.[ncbi.nlm.nih.gov]
  • Children up to 18 years of age with established PCD Children with suspected PCD suggested by the following findings: Dextrocardia with respiratory symptoms Triad of chronic ear infections, sinusitis and lower airways disease Bronchiectasis of unknown etiology[sickkids.ca]
  • This study can include term neonates with respiratory distress of unknown etiology and features of PCD, particular laterality defects (situs inversus or heterotaxy).[centerwatch.com]
  • Etiology/Pathophysiology: Due to deficiency of dynein arms of cilia which leads to immotility of respiratory, auditory, and sperm cilia. Pathology: Electron microscopy reveals the deficient dynein arms of the cilia.[virtualpediatrichospital.org]

Epidemiology

  • Fundamental data on epidemiology, clinical presentation, course and treatment strategies are lacking in PCD.[ncbi.nlm.nih.gov]
  • Our understanding of the epidemiology, genetics, pathophysiology, and clinical manifestations of primary ciliary dyskinesia has rapidly advanced since the disease was linked to ultrastructural defects of the ciliary axoneme more than four decades ago.[thoracic.org]
  • Research Prizes to BEAT-PCD members at European Respiratory Society Congress, September 2015 Congratulations to Panayiotis Kouis who won the Respiratory Paediatric Assembly Epidemiology prize for his abstract “Diagnostic accuracy of nasal nitric oxide[beatpcd.org]
  • Summary Epidemiology PCD has an estimated incidence of 1/15,000-1/30,000 live births, but this is probably an underestimate. Prevalence is difficult to determine.[orpha.net]
Sex distribution
Age distribution

Pathophysiology

  • Here, we will describe the genetics and pathophysiology of ciliopathies in children, focusing on PCD, review emerging genotype-phenotype relationships, and diagnostic tools available for the clinician.[ncbi.nlm.nih.gov]
  • Etiology/Pathophysiology: Due to deficiency of dynein arms of cilia which leads to immotility of respiratory, auditory, and sperm cilia. Pathology: Electron microscopy reveals the deficient dynein arms of the cilia.[virtualpediatrichospital.org]

Prevention

  • Author information 1 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland Both authors contributed equally. 2 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. 3 PCD Centre, NIHR Southampton[ncbi.nlm.nih.gov]

References

Article

  1. Lucas JS, Burgess A, Mitchison HM, Moya E, Williamson M, Hogg C. Diagnosis and management of primary ciliary dyskinesia. Arch Dis Child. 2014;99(9):850-856.
  2. Popatia R, Haver K, Casey A. Primary Ciliary Dyskinesia: An Update on New Diagnostic Modalities and Review of the Literature. Pediatr Allergy Immunol Pulmonol. 2014;27(2):51-59.
  3. Olm MAK, Caldini EG, Mauad T. Diagnosis of primary ciliary dyskinesia. J Bras Pneumol. 2015;41(3):251-263.
  4. Leigh MW, Pittman JE, Carson JL, et al. Clinical and Genetic Aspects of Primary Ciliary Dyskinesia / Kartagener Syndrome. Genet Med. 2009;11(7):473-487.
  5. Mullowney T, Manson D, Kim R, Stephens D, Shah V, Dell S. Primary Ciliary Dyskinesia and Neonatal Respiratory Distress. Pediatrics. 2014;134(6):1160-1166.
  6. Horani A, Ferkol TW, Dutcher SK, Brody SL. Genetics and Biology of Primary Ciliary Dyskinesia. Paediatr Respir Rev. 2016;18:18-24.

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Last updated: 2019-06-28 10:02