Goal 1.

Describe the clinical characteristics of primary ciliary dyskinesia.

Goal 2.

Review the genetic causes of primary ciliary dyskinesia.

Goal 3.

Provide an evaluation strategy to identify the genetic cause of primary ciliary dyskinesia in a proband.

Goal 4.

Review management of primary ciliary dyskinesia.

Goal 5.

Inform genetic counseling of family members of an individual with primary ciliary dyskinesia.

Clinical Manifestations of Primary Ciliary Dyskinesia

Establishing the Clinical Diagnosis of Primary Ciliary Dyskinesia

Recently published consensus recommendations [Shapiro et al 2018] have defined a panel of tests for the diagnosis of PCD including key clinical features, nasal nitric oxide measurement, and transmission electron microscopy. The four key clinical features for detection in childhood include the following [Leigh et al 2016]:

• Unexplained neonatal respiratory distress
• Laterality defect
• Early-onset, year-round wet cough
• Early-onset, year-round, nasal congestion

The diagnosis of PCD is highly likely if two or more of these key clinical features are present. Identification of a specific mendelian form by molecular genetic testing (see Table 1) may confirm the diagnosis; however, 20%-30% of individuals with well-characterized PCD do not have identifiable pathogenic variants in any of associated genes. Transmission electron microscopic analysis of ciliary biopsy can also be performed; however, it should be noted that an estimated 30% of individuals with PCD do not have ultrastructural abnormalities of the cilia. Nasal nitric oxide measurement can be performed as an adjunctive test in children older than age five years to provide additional support for the diagnosis of PCD.

Differential Diagnosis of Primary Ciliary Dyskinesia

Other Testing

Ciliary Ultrastructural Analysis

Transmission electron microscopy to identify ciliary ultrastructural defects requires a biopsy of the respiratory epithelium, typically obtained by brushing or scraping the inferior surface of the nasal turbinate or brushing the bronchial surface via bronchoscopy [MacCormick et al 2002, Chilvers et al 2003]. Approximately 30% of individuals with a clinical phenotype strongly suggestive of PCD and low levels of nasal nitric oxide have normal ciliary ultrastructure (in many of whom the diagnosis has been confirmed by identification of biallelic pathogenic variants in one of the genes listed in Table 1) [Knowles et al 2013].

The dynein arm defects are often specific for the mutated gene (see Table 1). The most prevalent of the defined ultrastructural defects in primary ciliary dyskinesia are the following (Figure 1) [Knowles et al 2013, Davis et al 2015]:

Figure 1.

Cross section of the cilia A. Schematic diagram of a cilium revealing "9+2" arrangement of nine peripheral microtubule doublets surrounding a central microtubule pair

• Shortening and/or absence of outer dynein arms alone (~55% with defined ultrastructural defects, or 38.5% of all PCD)
• Shortening or absence of both outer and inner dynein arms (~15% with defined ultrastructural defects, or 10.5% of all PCD)
• Microtubular (axonemal) disorganization associated with absence of the inner dynein arm and central apparatus defect (5%-20% of defined ultrastructural defects, or ~14% of all PCD)
• Absence or disruption of the central apparatus (central microtubule pair and/or radial spokes) (~10% of defined ultrastructural defects, or 7% of all PCD)
• Shortening and/or absence of inner dynein arms alone (rare)
• Oligocilia (presence of only few cilia) with or without normal ultrastructure (rare).

Note: (1) Expertise in evaluation of ciliary ultrastructure is needed to distinguish primary (genetic) defects from acquired defects that result from exposure to different environmental and infectious agents.

Other Tests Under Evaluation as Supportive Tests for PCD

High-speed videomicroscopy of ciliary motility. Evaluation of ciliary beat frequency and ciliary beat pattern requires high-speed videomicroscopy of freshly obtained ciliary biopsies that are maintained in culture media under controlled conditions. Specific immotility/dysmotility patterns associated with PCD can be identified [Chilvers et al 2003, Toskala et al 2005, Raidt et al 2014]. Note: It is now recognized that ciliary videos must to be repeated multiple times (including studies on cultured ciliary cells) in order to establish the diagnosis of PCD using ciliary waveform analyses.

Mucociliary clearance analysis of radiolabeled particles. Mucociliary clearance has been measured by assessing clearance of radiolabeled particles from the nasal passages or from the lower airways [De Boeck et al 2005, Marthin et al 2007]. For these studies, an aerosol containing radiolabeled particles is inhaled and a gamma camera is used to track deposition and clearance of these insoluble particles.

Immunofluorescent staining of ciliary biopsy. Immunofluorescent assays using antibodies specific to the ciliary components can be used to identify the specific ciliary ultrastructural defect. For example, individuals with outer dynein arm (ODA) defects on electron microscopic analysis and/or biallelic pathogenic variants in ODA-related genes such as DNAH5 or DNAI2 show absence of ciliary staining using anti-DNAH5 or anti-DNAI2 antibodies [Fliegauf et al 2005, Loges et al 2008]. Inner dynein arm (IDA) defects, nexin-dynein regulatory complex defects, and radial spokes/central pair defects can be ascertained using IDA-specific anti-DNALI1, nexin-related anti-GAS8/GAS11 antibodies, and radial spokes-related anti-RSPH1, anti-RSPH4A, and anti-RSPH9, respectively [Becker-Heck et al 2011, Merveille et al 2011, Frommer et al 2015]. Limited information is available about utility of immunoflourescent staining as a diagnostic test [Shoemark et al 2017].

Semen analysis. Sperm count is typically normal, but sperm are immotile or motility is severely limited [Afzelius 2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with primary ciliary dyskinesia (PCD), the following evaluations are recommended:

• Pulmonary disease
  • Respiratory cultures (typically sputum cultures) to define infecting organisms and to direct antimicrobial therapy. Specific cultures for non-tuberculous mycobacteria should be included for older children and adults.
  • Chest radiographs and/or chest CT to define distribution and severity of airway disease and bronchiectasis
  • Pulmonary function tests (spirometry) to define severity of obstructive impairment
  • Pulse oximetry, with overnight saturation studies if borderline
• Nasal congestion and/or sinus symptoms. Sinus imaging (sinus x-rays or preferably sinus CT examination)
• Chronic/recurrent ear infections. Formal hearing evaluation (See Genetic Hearing Loss Overview for hearing evaluations available at different ages.)
• Other. Clinical genetics consultation

Treatment of Manifestations

To date, no specific therapies can correct ciliary dysfunction. The therapies described in this section are empiric and aimed at treating consequences of dysfunctional cilia and sperm flagella. Little evidence supports use of specific therapeutic modalities in PCD.

Pulmonary disease. Management of individuals with PCD should include aggressive measures to enhance clearance of mucus, prevent respiratory infections, and treat bacterial infections.

Approaches to enhance mucus clearance are similar to those used in the management of cystic fibrosis, including chest percussion and 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).

Routine immunizations to protect against respiratory pathogens:

• Pertussis
• Haemophilus influenzae type b
• Pneumococcal vaccine
• Annual influenza virus vaccine

Prompt institution of antibiotic therapy for bacterial infections of the airways (bronchitis, sinusitis, and otitis media) is essential for preventing irreversible damage. Sputum culture results may be used to direct appropriate choice of antimicrobial therapy. In those individuals in whom symptoms recur within days to weeks after completing a course of antibiotics, extended use of a broad-spectrum antibiotic or even prophylactic antibiotic coverage may be considered. (Consideration of chronic antibiotic therapy must include assessing the risk of selecting for multiresistant organisms.)

For individuals with localized bronchiectasis, lobectomy has been performed in an attempt to decrease infection of the remaining lung. This approach, however, is controversial; consultants with expertise in PCD should be involved in the decision-making process.

Lung transplantation has been performed in persons with end-stage lung disease.

Nasal congestion and sinus infections. In some persons with extensive sinus disease, sinus surgery can facilitate drainage and relieve symptoms.

Chronic/recurrent ear infection. For chronic otitis media unresponsive to antibiotic therapy, PE tube placement may be helpful; however, some individuals with PCD have persistent mucoid discharge following PE tube placement [Hadfield et al 1997].

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

Male infertility. A couple in which the male has PCD-related infertility has the option of in vitro fertilization using ICSI (intracytoplasmic sperm injection). In this procedure, spermatozoa retrieved from ejaculate (in males with oligozoospermia) or extracted from testicular biopsies (in males with obstructive azoospermia) are injected into a harvested egg by in vitro fertilization [Sha et al 2014].

Another option is artificial insemination by donor sperm.

Situs abnormalities. Typically, situs abnormalities do not require intervention unless physiologic dysfunction (e.g., congenital heart disease) requiring surgical intervention is present.

Prevention of Secondary Complications

Appropriate preventive measures:

• Routine immunizations (including influenza vaccine and pneumococcal vaccine) to prevent respiratory infections
• Education 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 (directed by prior respiratory cultures)

Surveillance

Follow up by a pulmonologist to monitor lung function and pathogens in sputum cultures as well as to assess pulmonary disease extent/progression is indicated.

For young children with chronic otitis media, routine hearing evaluation is essential, and should be continued until the teenage years, by which time hearing is usually normal [Majithia et al 2005]. Typically, the ear disease improves in later childhood and hearing screening is not necessary.

Agents/Circumstances to Avoid

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

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

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

• If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known, a rigorous clinical history and physical examination accompanied by chest imaging and nasal nitric oxide measurements can be used to clarify the disease status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For a female with PCD, any pulmonary infections and pulmonary functional status should be rigorously evaluated by an expert in PCD (or cystic fibrosis) to define the risk associated with childbearing.

Mode of Inheritance

Primary ciliary dyskinesia (PCD) is usually inherited in an autosomal recessive manner. PIH1D3-PCD and OFD1-PCD are inherited in an X-linked manner. FOXJ1-PCD is inherited in an autosomal dominant manner.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one PCD-causing pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a PCD-causing pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a PCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with autosomal recessive PCD are obligate heterozygotes (carriers of a PCD-related pathogenic variant).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a PCD-related pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the PCD-related pathogenic variants in the family.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the PIH1D3 or OFD1 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo PIH1D3 or OFD1 pathogenic variant, in which case the mother is not a carrier.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a either PIH1D3 or OFD1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and will usually not be affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PIH1D3 or OFD1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males transmit the PIH1D3 or OFD1 pathogenic variant to:

• All of their daughters who will be (heterozygotes) carriers and will usually not be affected;
• None of their sons.

Other family members. A male proband's maternal aunts may be at risk of being carriers for the pathogenic variant and the aunts' offspring, depending on their sex, may be at risk of being carriers for the pathogenic variant or of being affected.

Heterozygote detection. Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the PIH1D3 or OFD1 pathogenic variant in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• To date, all individuals with FOXJ1-PCD whose parents have undergone molecular genetic testing have had the disorder as the result of a de novo FOXJ1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband; another possible explanation is germline mosaicism in a parent.
• The family history of some individuals diagnosed with FOXJ1-PCD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for PCD because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with FOXJ1-PCD has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the FOXJ1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the PCD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Author Notes

Websites:
UNC – Department of Pathology and Laboratory Medicine
UNC – Pulmonary Diseases and Critical Care Medicine – PCD
UNC – Department of Pediatrics

Acknowledgments

We are grateful to the patients and their families for their participation. We also thank the US PCD foundation. We would like to thank Dr Johnny Carson for the assistance with the figure.

Funding research support

• NIH/NCATS/NHLBI U54 HL096458
• NIH/NHLBI R01 HL071798
• NIH/NHLBI R01 HL117836

The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH.

Revision History

• 5 December 2019 (sw) Comprehensive update posted live; scope change: now an overview
• 3 September 2015 (me) Comprehensive update posted live
• 15 September 2011 (me) Comprehensive update posted live
• 6 October 2009 (me) Comprehensive update posted live
• 24 January 2007 (me) Review posted live
• 19 July 2006 (mbz) Original submission

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