Primary Ciliary Dyskinesia (PCD)

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: DNAI1 (HGNC:2954) DNAH5 (HGNC:2950) DNAH11 (HGNC:2942) CCDC39 (HGNC:25244) CCDC40 (HGNC:26090) SPAG1 (HGNC:11212) CCNO (HGNC:18576) DNAAF3 (HGNC:30492) DNAI2 (HGNC:18744) HYDIN (HGNC:19368) RSPH1 (HGNC:12371) RSPH4A (HGNC:21558) FOXJ1 (HGNC:3816) MCIDAS (HGNC:40050) CCDC103 (HGNC:32700) CFAP300 (HGNC:28188) ODAD1 (HGNC:26560) ODAD2 (HGNC:25583) ODAD4 (HGNC:25280)
• Literature Search: 11/15/2022
• Curation Status: Released (1.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
DNAI1	primary ciliary dyskinesia 1 (0009484)	244400	Moderate Actionability
DNAH5	primary ciliary dyskinesia 3 (0012085)	603335	Moderate Actionability
DNAH11	primary ciliary dyskinesia 7 (0012748)	611884	Moderate Actionability
CCDC39	primary ciliary dyskinesia 14 (0013434)	613807	Moderate Actionability
CCDC40	primary ciliary dyskinesia 15 (0013435)	613808	Moderate Actionability
SPAG1	primary ciliary dyskinesia 28 (0014216)	615505	Moderate Actionability
CCNO	primary ciliary dyskinesia 29 (0014378)	615872	Moderate Actionability
DNAAF3	primary ciliary dyskinesia 2 (0011718)	606763	Moderate Actionability
DNAI2	primary ciliary dyskinesia 9 (0012906)	612444	Moderate Actionability
HYDIN	primary ciliary dyskinesia 5 (0012088)	608647	Moderate Actionability
RSPH1	primary ciliary dyskinesia 24 (0014202)	615481	Moderate Actionability
RSPH4A	primary ciliary dyskinesia 11 (0012978)	612649	Moderate Actionability
FOXJ1	ciliary dyskinesia, primary, 43 (0032874)	618699	Moderate Actionability
MCIDAS	ciliary dyskinesia, primary, 42 (0032872)	614086	Moderate Actionability
CCDC103	primary ciliary dyskinesia 17 (0013854)	614677	Moderate Actionability
CFAP300	ciliary dyskinesia, primary, 38 (0054843)	618063	Moderate Actionability
ODAD1	primary ciliary dyskinesia 20 (0014030)	615067	Moderate Actionability
ODAD2	primary ciliary dyskinesia 23 (0014193)	615451	Moderate Actionability
ODAD4	primary ciliary dyskinesia 35 (0014910)	617092	Moderate Actionability

Actionability Assertion Rationale

• Although the suggested assertion based on the scores for heterotaxy was strong, there was consensus in the group about the lack of evidence for effectiveness of the intervention for that outcome-intervention pair. For both pairs, there was extrapolation for effectiveness from other conditions.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from respiratory tract manifestations / Evaluation by specialist(s) to guide diagnostic confirmation and treatment	2	3A	2C	2	9AC
Morbidity and mortality from heterotaxy / Evaluation by imaging/echocardiogram	2	2N	3N	3	10NN

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of primary ciliary dyskinesia (PCD; aka immotile cilia syndrome) is estimated to be between 1:2000 and 1:40,000 live births. PCD is one of the most common causes of non-cystic fibrosis bronchiectasis in children and accounts for 7% of total cases. Kartagener syndrome (KS) constitutes up to 50% of the PCDs; the prevalence of KS is estimated at 1:32,000.

Clinical Features (Signs / symptoms)

The clinical manifestations of PCD include pulmonary disease, nasal congestion and sinus infections, chronic/recurrent ear infection, infertility in males, situs abnormalities, and hydrocephalus (rare). Ciliary dyskinesia may lead to other organ anomalies such as biliary atresia, intestinal malrotation, asplenia, and polysplenia. The four key clinical features in childhood include unexplained neonatal respiratory distress; laterality defect; early-onset, year-round wet cough; and early-onset, year-round nasal congestion. More than 75% of full-term neonates with PCD experience neonatal respiratory distress requiring supplemental oxygen for days to weeks. Most children with PCD experience year-round wet cough, sputum production, and chronic wheezing or shortness of breath. Chronic airway infection results in bronchiectasis that may be evident in some young children and is commonly present in adulthood on chest computerized tomography (CT) examination. Chronic sinusitis and nasal congestion typically begin in the first months of life, usually at birth. Chronic rhinitis symptoms include nasal discharge, episodic facial pain, and anosmia. Sinus infections persist through adulthood, and nearly all patients with PCD demonstrate pansinusitis on CT. Nasal polyps can occur in PCD. Chronic/recurrent ear infection is apparent in most young children with PCD but often improves by school age. In many infants and young children, chronic otitis media is associated with transient hearing loss that may affect speech development. If untreated, infections of the middle ear may result in irreversible hearing loss. Hydrocephalus may occur on rare occasion in individuals with PCD.KS constitutes about 50% of the PCDs and is characterized by a triad of symptoms including sinusitis, bronchiectasis, and situs inversus. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is observed in 40-50% of individuals with PCD. Heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures) is present in approximately 12% of individuals with PCD. In those with heterotaxy, congenital cardiovascular malformations (e.g., atrial isomerism, transposition of the great vessels) occur in approximately 4% of individuals with PCD. Pulmonary isomerism, stomach displacement, abnormal rotation of the intestinal loop, CNS, skeletal, and genitourinary malformations may also be observed. Virtually all males with PCD are infertile as a result of abnormal sperm motility. Some females with PCD have normal fertility; others experience impaired fertility and increased risk for ectopic pregnancy.

Natural History (Important subgroups & survival / recovery)

Clinical symptoms in PCD affect the entire respiratory tract; the majority of symptoms occur on a chronic, daily basis and start soon after birth. The progression and severity of lung disease varies among individuals. Chronic airway infection is evident by early childhood. A subset of adults with chronic airway infection experience calcium deposition in the lung and expectorate small calcium stones. Some develop end-stage lung disease in mid-adulthood. Life expectancy is likely somewhat shortened, although quantitative estimates are not currently available.

Likelihood of Outcome

Mode of Inheritance

Autosomal recessive, with the exception of FOXJ1 which is autosomal dominant.

Prevalence of Genetic Variants

To date, pathogenic variants in 45 genes are known to be associated with PCD. However, 20-30% of individuals with well-characterized PCD do not have identifiable pathogenic variants.

Penetrance (Includes any high-risk racial or ethnic subgroups)

A systematic review and meta-analysis (k=42) evaluated clinical manifestations in children and adults with PCD (diagnosis of PCD included a wide range of inclusion criteria ranging from a clinical diagnosis to those with positive results from diagnostic tests such as electron microscopy, light or high-speed video microscopy, nasal nitric oxide, or molecular testing). They reported the following prevalence rates (weighted means):

• Sputum production – 89%

• Cough – 88%

• Rhinitis, rhinorrhea, or nasal congestion – 75%

• Otitis media – 74%

• Lower respiratory infections – 72%

• Sinusitis – 69%

• Bronchiectasis – 56%

• Neonatal respiratory distress – 55%

• Situs anomalies – 49%

• Hearing impairment – 36%

• Nasal polyps – 19%

• Congenital heart disease – 5%

• Female infertility – 58%

• Male infertility – 100%

Tier 1

A multi-center service evaluation of care provided by the English National Management PCD Service included 333 children with PCD (diagnosis based on clinical diagnostic criteria). Median age at diagnosis of PCD was 2.6 years, significantly lower in children with situs inversus (1.0 vs 6.0 years, p<0.001). 333 children with PCD reviewed in the Service Compared with national data from the CF Registry (n=2970), mean (SD) % predicted forced expiratory volume in one second (FEV1) was 76.8% in PCD (n=240) and 85.0% in CF, and FEV1 was lower in children with PCD up to the age of 15 years. Approximately half of children had some hearing impairment, with 26% requiring hearing aids. Children with a lower body mass index (BMI) had lower FEV1 (p<0.001). One-third of children had positive respiratory cultures at review, 54% of these grew Haemophilus influenzae.

Tier 5

Expressivity

All clinical features may not be seen in each individual patient with PCD; however, most patients have three or more clinical features.

Tier 4

PCD is likely to include a small number of milder phenotypes that may be manifest in subtle or no apparent structural defects and ciliary dysfunction

Tier 4

Approximately 50% of patients, even within the same family, have situs inversus.

Tier 3

Intervention Effectiveness

Patient Management

The following tests are recommended to confirm the diagnosis and rule out other potential conditions, such as cystic fibrosis:

• Nasal nitric oxide measurement. Testing should be performed at baseline and repeated if there is any question about health status.

• Ciliary biopsy with electron microscopy

• Functional ciliary beat/waveform analysis with high-speed video microscopy

• Immunofluorescence testing

Tier 2

Additional evaluations recommended at the time of diagnosis of PCD include:

• Audiology evaluation

• Allergic bronchopulmonary aspergillosis (ABPA) testing: IgE levels +/- evidence of aspergillus specificity

• Chest radiography to assess the extent and severity of lung abnormalities

Tier 2

Additional evaluations to establish the extent of disease and needs in an individual recently diagnosed with PCD include:

• Respiratory cultures to define infecting organisms and to direct antimicrobial therapy. Specific cultures for non-tuberculous mycobacteria should be included for older children and adults.

• Pulmonary function tests to determine severity of obstructive impairment.

• Pulse oximetry, with overnight saturation studies if borderline.

• Sinus imaging (sinus x-rays or preferably sinus CT examination).

Tier 4

There are no randomized trials of PCD treatment and therefore all treatment recommendations are based on a very low-level of evidence or extrapolated from cystic fibrosis (CF) guidelines. Consensus guidelines for the treatment of PCD recommend the following:

• Treatment should be started as soon as possible to prevent deterioration in lung function, and in some cases improve it.

• Patients should be seen at a multidisciplinary care center specializing in PCD.

• Daily airway clearance by combinations of physiotherapy and physical exercise should be encouraged and regularly prescribed in children.

• Acute airway infection should be promptly treated with antibiotics of adequate duration, based upon evidence from other conditions with similar pathophysiology (including bacterial bronchitis, CF, and non-CF bronchiectasis).

• Inhaled hyperosmolar agents (e.g., nebulized hypertonic saline) can be used on a case- by-case basis to promote cough clearance and alter mucus rheology to favor increased cough clearance.

• All patients should receive pneumococcal immunization.

Tier 2

A recent systematic review (k=21) evaluated the effectiveness of nebulized hypertonic saline (HS) for muco-obstructive lung diseases, including PCD and CF. The evidence for effectiveness of nebulized HS on PCD was limited and results were inconsistent. For CF, forced expiratory volume and forced vital capacity did not improve significantly in the HS group compared to controls. However, the clearance capability of lung and quality of life improved significantly in the HS group. Most adverse events of nebulized HS were mild and transient.

Tier 1

Lobectomy is not routinely suggested as therapy in patients with PCD, though it may be beneficial in rare cases to decrease infection burden and limit the damage to the remaining lung. The decision to perform lobectomy requires multi-disciplinary discussion. Similarly, lung transplantation could be considered in rare cases (advanced pulmonary disease), but situs anomalies may surgically complicate this procedure.

Tier 2

Consensus guidelines differ on the use of pressure equalization tubes (PET) in children with PCD. Some guidelines recommend they should be avoided where possible due to the potential for prolonged post-operative otorrhea (ear drainage). Other guidelines advocate for the use of PET in children who have hearing deficits or speech delay and middle ear effusions. All patients undergoing PET insertion should be counseled on the likelihood of multiple insertions, post-operative otorrhea, and the possibility of a permanent tympanic membrane perforation. Although several systematic reviews have cast doubt on the utility of PET in otitis media with effusion, these studies are not necessarily generalizable to a PCD population, where individuals are expected to have greater portion of their prelingual life with conductive hearing loss. In studies assessing hearing children with PCD post-PET placement, hearing normalized in 80-100% of patients. In another study examining surgical treatment with PET versus medical management alone in PCD, children with PET had larger hearing improvements postoperatively than those treated with medical therapy

Tier 2

Speech therapy and hearing aids may be necessary for children with hearing loss and delayed speech.

Tier 4

Nasal endoscopy (as permitted by age) can be used to identify polyps which may be exacerbating already poor mucociliary clearance. Daily saline irrigation may be beneficial for chronic rhinosinusitis , but studies demonstrating their efficacy are lacking. Antibiotics and nasal steroids may be used in acute exacerbations of rhinosinusitis. Endoscopic sinus surgery is often performed in PCD and may improve lower respiratory tract disease in some patients.

Tier 2

These guidelines are specific to KS but may also apply to PCD more generally.

• Local or regional anesthesia are preferred to general anesthesia.

• Prior to surgery, optimization of respiratory functions is recommended which may require respiratory physiotherapy, postural drainage of secretions, bronchodilator treatment to prevent airway reactivity, or antibiotic therapy to treat or prevent infections.

• In patients with congenital heart disease comorbidity, endocarditis prophylaxis and measures to prevent air embolism should be performed along with its treatment.

• Central or peripheral nerve blocks should be preferred with the aim to minimize the need for opioids, which are associated respiratory depression.

• Recommended preoperative procedures include lung function tests, chest radiography, and electrocardiogram.

Tier 4

It is recommended that patients are educated about infection control including attention to hand washing, avoidance of sick contacts, proper cleaning/disinfecting of respiratory devices, and early use of antibiotics for respiratory illnesses.

Tier 4

Consensus guidelines recommend the following:

• Seminal analysis is recommended in males with PCD so that accurate counseling about reproductive capability may be given.

Tier 2

For females with PCD, any pulmonary infections and pulmonary functional status should be rigorously evaluated by an expert in PCD or CF to define the risk associated with childbearing.

Tier 4

Surveillance

Consensus guidelines recommend the following:

• A protocolized shared-care system is recommended to ensure close follow-up and prevent eventual lung damage. Long-term follow-up should be in a multidisciplinary care center with specialization in PCD.

• Outpatient visits with a pulmonologist experienced in management of chronic suppurative lung disease 2-4 times annually.

• Airway microbiology cultures 2-4 times/year plus non-tuberculosis mycobacterial cultures every 2 years and with unexplained clinical decline.

• Pulmonary function test via spirometry using American Thoracic Society/European Respiratory Society criteria two to four times annually.

• Chest radiography during respiratory exacerbations, as indicated. Otherwise, chest radiography should be performed every 2-4 years in stable patients.

• Chest CT at least once after age 5-7 years old (when sedation not required); use lowest possible radiation doses.

• ABPA testing with new onset wheezing or unexplained clinical decline

• Pediatric patients should visit a pediatric otolaryngologist at least once to twice annually, while adult patients should have otolaryngology care as needed. Otolaryngologists should monitor for chronic rhinosinusitis in PCD patients.

• Audiology clinical visits as needed.

Tier 2

Circumstances to Avoid

Exposure to respiratory pathogens, tobacco smoke, and other pollutants and irritants that may damage airway mucosa and stimulate mucus secretion should be avoided.

Tier 2

Inhaled corticosteroids are not routinely recommended and should be reserved for patients with PCD with associated asthma or airway reactivity.

Tier 2

Nasotracheal intubation is contraindicated given likelihood of chronic sinusitis, nasal polyp, and chronic otitis media.

Tier 4

Cough suppressants should not be used because cough is critical for clearing secretions.

Tier 4

Nature of Intervention

Nature of Intervention

Approaches to enhance mucus clearance are similar to those used in the management of CF, including chest percussion, postural drainage, oscillatory vest, and breathing maneuvers to facilitate clearance of distal airways. Because cough is an effective clearance mechanism, patients should be encouraged to cough and engage in activities that promote deep breathing and cough (e.g., vigorous exercise).

Context: Adult Pediatric

One systematic review (k=14) evaluated the patient’s experience of PCD and found that frustration related to treatment burden was a prominent theme in the pediatric group. Additionally, self-reported (adults with PCD and parents of children with PCD) adherence ranged from 39% for eardrops, to 71% for antibiotics, and 89% for physiotherapy. For adolescents, 57% agreed that their PCD team do not understand how difficult it is to follow treatments. Parents expressed how other commitments, such as siblings and employment, could limit their ability to complete daily treatments.

Context: Adult Pediatric

Chance to Escape Clinical Detection

Diagnosis of PCD is frequently delayed, in part because patients present with symptoms (rhinitis, otitis media, cough, and recurrent bronchitis) that are common in healthy children. Many physicians incorrectly diagnosis PCD or eliminate PCD from their differential diagnosis due to inexperience with diagnostic methods. Differential diagnoses include CF, immunodeficiency, asthma, pulmonary aspiration, allergic rhinitis, and protracted bacterial bronchitis. Few physicians outside multidisciplinary care centers specializing in the condition are skilled in recognizing the characteristic clinical phenotype and interpreting diagnostic tests. Patients often receive false-positive or false-negative PCD diagnoses. Furthermore, PCD is often missed when respiratory symptoms are present in patients with other complex diseases involving cilia, such as heterotaxy and various genetic conditions. Prognosis depends on timely diagnosis and appropriate treatment.

Context: Adult Pediatric

Tier 2

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			DNAI1			244400	0009484
DNAH5			603335	0012085
DNAH11			611884	0012748
CCDC39			613807	0013434
CCDC40			613808	0013435
SPAG1			615505	0014216
CCNO			615872	0014378
DNAAF3			606763	0011718
DNAI2			612444	0012906
HYDIN			608647	0012088
RSPH1			615481	0014202
RSPH4A			612649	0012978
FOXJ1			618699	0032874
MCIDAS			614086	0032872
CCDC103			614677	0013854
CFAP300			618063	0054843
ODAD1			615067	0014030
ODAD2			615451	0014193
ODAD4			617092	0014910

References List

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Behan L, Rubbo B, Lucas JS, Dunn Galvin A. (2017) The patient's experience of primary ciliary dyskinesia: a systematic review. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation. 26(1573-2649):2265-2285.

CILIARY DYSKINESIA, PRIMARY, 1; CILD1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 244400, (2019) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 11; CILD11. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 612649, (2022) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 14; CILD14. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 613807, (2022) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 15; CILD15. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 613808, (2022) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 17; CILD17. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 614679, (2017) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 2; CILD2. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 606763, (2021) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 20; CILD20. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 615067, (2019) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 23; CILD23. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 615451, (2017) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 24; CILD24. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 615481, (2017) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 28; CILD28. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 615505, (2013) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 29; CILD29. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 615872, (2017) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 3; CILD3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 608644, (2022) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 35; CILD35. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 617092, (2016) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 38; CILD38. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 618063, (2018) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 42; CILD42. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 618695, (2019) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 43; CILD43. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 618699, (2020) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 5; CILD5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 608647, (2022) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 7; CILD7. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 611884, (2022) World Wide Web URL: http://omim.org/

CILIARY DYSKINESIA, PRIMARY, 9; CILD9. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 612444, (2022) World Wide Web URL: http://omim.org/

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