Sections

Primary Ciliary Dyskinesia (Kartagener Syndrome)

Sections Primary Ciliary Dyskinesia (Kartagener Syndrome)
Overview
Presentation
DDx
Workup
Treatment
Medication
Questions & Answers
Media Gallery
Tables
References

Workup

Laboratory Studies

The initial diagnostic workup is started after suggestive findings are encountered during the history and physical examination. The only standardized definitive diagnostic tool is electron microscopy, which is used to visualize ciliary ultrastructure. The sample of these respiratory cilia is obtained from a nasal scrape or brush biopsy. Some research centers use high-speed videomicroscopy to observe ciliary beats.^[23]

Semen analysis in postpubescent males may reveal abnormal sperm motility and ultrastructure.

Multiple diagnostic tests have emerged, but none has been fully standardized. These include nasal nitric oxide measurement, mucociliary clearance, and immunofluorescent analysis. The stimulation tests should be conducted when patients are at a stable respiratory baseline, owing to the altered motility during illness.

All of these novel diagnostic tools have caused a large expansion into the field of genetic testing and isolation of Kartagener syndrome mutations. Studies have recently discovered multiple new genes related to Kartagener syndrome. These studies are motivated by the hypothesis that additional ciliary mutations may exist that do not manifest themselves as ultrastructural defects. These discoveries have created the potential for future genetic testing as part of disease diagnosis. It has been posited that in the near future, more than 80% of patients will be able to be identified by genetic testing.^[26]

Imaging Studies

Sinus radiographs (which largely have been supplanted by CT scans) typically demonstrate mucosal thickening, opacified sinus cavities, and hypoplastic frontal and/or sphenoid sinuses.^[17]

Chest radiographs may illustrate bronchial wall thickening as an early manifestation of chronic infection, hyperinflation, atelectasis, bronchiectasis, and situs inversus (in 50% of patients with primary ciliary dyskinesia). The presence of situs inversus strongly suggests Kartagener syndrome (KS).^[27]

Bronchiectasis occurs in the lower lobes in patients with Kartagener syndrome and immunoglobulin deficiency, while bronchiectasis predominantly occurs in the upper lobes of patients with cystic fibrosis.

High-resolution CT scan of the chest is the most sensitive modality for documenting early and subtle abnormalities within airways and pulmonary parenchyma when compared to routine chest radiographs. Consideration should be given to this imaging technique early in the presentation of primary ciliary dyskinesia (PCD) syndromes, when a chest radiograph may not be sensitive enough to identify disease processes or when another differential is being considered. See the images below.

Axial CT image showing dextrocardia and situs inversus in a patient with Kartagener syndrome. Image courtesy of Wikimedia Commons.

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Axial CT image showing situs inversus (liver and inferior vena cava on the left, spleen and aorta on the right) in a patient with Kartagener syndrome. Image courtesy of Wikimedia Commons.

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Other Tests

Screening tests include the saccharin test and the measurement of nasal and exhaled nitric oxide, as follows:

Saccharine test: Saccharin or another substance is placed in the nose, and the speed of transport into the nasopharynx is measured to calculate mucociliary clearance (used infrequently because of awkwardness and dubious reliability).
Nitric oxide: Measuring exhaled nasal nitric oxide, which is mostly reduced in primary ciliary dyskinesia, is a good screening test for immotile-cilia syndrome with a good negative predictive value.^[15]This study is generally more reliable in children older than 5 years and in adults, as they are more likely to cooperate with actions required in testing.^[22]Studies have demonstrated a relationship between nasal nitric oxide levels, nasal oxide synthase mRNA expression, and ciliary beat frequency.^[28]There is also a significant inverse correlation between the degree of aplasia and/or hypoplasia of the paranasal sinus and nasal nitric oxide values in primary ciliary dyskinesia patients.^[17]
Pulmonary radioaerosol mucociliary clearance: Mucociliary transport, which is reduced in these patients, can be measured in situ by administering an inhalation aerosol of colloid albumin or colloid sulfur tagged with technetium Tc 99. This test is generally not recommended owing to the high rate of false-positive results.^{[15, 29]}

Audiologic testing usually demonstrates a flat tympanogram and bilateral conductive hearing loss secondary to thick middle-ear effusion.

Pulmonary function studies are as follows:

Spirometry often reveals an obstructive ventilatory defect with decreases in the ratio of forced expired volume in 1 second to forced vital capacity, reduced forced expired volume in 1 second, and a reduced forced expiratory flow of 25-75%.
Static lung volumes also may demonstrate hyperinflation.
The response to bronchodilators is variable in patients with primary ciliary dyskinesia.

Procedures

For mucosal biopsy, the specimen should come from ciliated epithelium, preferably when the patient is not acutely ill. Infectious processes can alter cilia and cause secondary ciliary dyskinesia, even in a healthy host. Tracheal biopsies require general anesthesia but provide excellent specimens. Nasal mucosa is more readily available. Although nasal brushing is least invasive, it frequently yields an inadequate specimen. Children with suspected primary ciliary dyskinesia often require an adenoidectomy. Because adenoid tissue has a ciliated surface, adequate material is available for histopathologic and electron microscope examination. Knowledge of this fact should eliminate the need for other invasive biopsies.

Nasal endoscopy is a sensitive indicator for nasal polyposis.

Histologic Findings

The mucosal biopsy specimen should be examined for ciliary movement using light microscopy. Light microscopic quantitation of ciliary beat frequency, coordination, and amplitude, although available in very few medical centers, can identify ciliary dyskinesia in patients with normal ultrastructure. Light microscopy alone offers a reliable and simple method of excluding primary ciliary dyskinesia, but light microscopy and electron microscopy in combination provide a higher degree of accuracy.

A ciliary beat frequency(CBF) of less than 11 beats per second (< 11 Hz) has been suggested as a cutoff value for patients to proceed to electron microscopy(EM).^[30]However, CBF as a laboratory screening test to determine which patients should undergo EM results in a number of patients with primary ciliary dyskinesia being missed. The use of beat-pattern analysis appears to be a more sensitive and specific test, with higher positive and negative predictive values.^[30]

Quantitative diagnostic criteria do not exist for EM; however, ciliary ultrastructure is examined qualitatively for abnormalities in dynein arms (inner and outer), radial spokes, central sheaths, nexin links, and ciliary transposition and orientation. The most common ultrastructural defect is an absence or decrease in the number of inner or outer dynein arms. A radial spoke deficiency commonly appears with a dynein arm deficiency. Other ultrastructural abnormalities with nexin links, central sheaths, and ciliary transposition and orientation are considered nonspecific for primary ciliary dyskinesia because they can occur in healthy people and as a consequence of recurrent respiratory infections.

Electron microscopic diagnosis of ciliary ultrastructure is expensive, time consuming, and described by some experts as inadequate. Patients with Kartagener syndrome also may have normal ultrastructure, which decreases the sensitivity of electron microscopy.^{[31, 32]}

Efforts have been undertaken to standardize the clinical criteria for the diagnosis of Kartagener syndrome. These criteria include dextrocardia, a ciliary beat frequency of less than 10 Hz/s, and a mean cross-section dynein arm count of less than two. If the patient does not have dextrocardia, primary ciliary dyskinesia presents a much greater diagnostic challenge. Genetic testing ultimately may become the principal means of establishing this diagnosis.

Treatment & Management

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Camner P, Mossberg B, Afzelius BA. Evidence of congenitally nonfunctioning cilia in the tracheobronchial tract in two subjects. Am Rev Respir Dis. 1975 Dec. 112(6):807-9. [QxMD MEDLINE Link].
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Cho DY, Hwang PH, Illek B. Characteristics of chloride transport in nasal mucosa from patients with primary ciliary dyskinesia. Laryngoscope. July 2010. 120(7):1460-1464. [QxMD MEDLINE Link].
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Geremek M, Bruinenberg M, Ziętkiewicz E, Pogorzelski A, Witt M, Wijmenga C. Gene expression studies in cells from primary ciliary dyskinesia patients identify 208 potential ciliary genes. Hum Genet. March 2011. 129:283-293. [QxMD MEDLINE Link].
Becker-Heck A, Zohn IE, Okabe N, Pollock A, Lenhart KB, Sullivan-Brown J, et al. The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nat Genet. Jan 2011. 43(1):79-84. [QxMD MEDLINE Link].
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. Am J Hum Genet. 2013 Jan 10. 92(1):88-98. [QxMD MEDLINE Link]. [Full Text].
Milara J, Armengot M, Mata M, Morcillo EJ, Cortijo J. Role of adenylate kinase type 7 expression on cilia motility: possible link in primary ciliary dyskinesia. Am J Rhinol Allergy. May 2010. 24(3):181-185. [QxMD MEDLINE Link].
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Pifferi M, Bush A, Caramella D, Di Cicco M, Zangani M, Chinellato I, et al. Agenesis of paranasal sinuses and nasal nitric oxide in primary ciliary dyskinesia. Eur Respir J. March 2011. 37(3):566-571. [QxMD MEDLINE Link].
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Media Gallery

Axial CT image showing dextrocardia and situs inversus in a patient with Kartagener syndrome. Image courtesy of Wikimedia Commons.
Axial CT image showing situs inversus (liver and inferior vena cava on the left, spleen and aorta on the right) in a patient with Kartagener syndrome. Image courtesy of Wikimedia Commons.
Normal cilia (A) compared with cilia in Kartagener syndrome with missing dynein arms (B). Image courtesy of Wikimedia Commons.

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Table. Mutations in the Genes that Cause Human Primary Ciliary Dyskinesia^[14]

Table. Mutations in the Genes that Cause Human Primary Ciliary Dyskinesia ^[14]

Human Gene	Human Chromosomal Location	Chlamydomonas Ortholog	Ciliary Ultrastructure in Subjects with Biallelic Mutations	Presence of Laterality Defects	Percentage of Individual with Biallelic Mutations	MIM No.
DNAH5	5p15.2	DHC ?	ODA defect	Yes	15-21% of all PCD, 27-38% of PCD with ODA defects	608644
DNAI1	9p21-p13	IC78	ODA defect	Yes	2-9% of all PCD, 4-13% of PCD with ODA defects	244400
DNAI2	17q25	IC69	ODA defect	Yes	2% of all PCD, 4% of PCD with ODA defects	612444
DNAL1	14q24.3	LC1	ODA defect	Yes	na	614017
CCDC114	19q13.32	DC2	ODA defect	Yes	6% of PCD with ODA defects	615038
TXNDC3 (NME8)	7p14-p13	LC5	Partial ODA defect (66% cilia defective)	Yes	na	610852
DNAAF1 (LRRC50)	16q24.1	ODA7	ODA + IDA defect	Yes	17% of PCD with ODA + IDA defects	613193
DNAAF2 (KTU)	14q21.3	PF13	ODA + IDA defect	Yes	12% of PCD with ODA + IDA defects	612517, 612518
DNAAF3 (C19ORF51)	19q13.42	PF22	ODA + IDA defect	Yes	na	606763
CCDC103	17q21.31	PR46b	ODA + IDA defect	Yes	na	614679
HEATR2	7p22.3	Chlre4 gene model 525994 Phytozyme v8.0 gene ID Cre09.g39500.t1	ODA + IDA defect	Yes	na	614864
LRRC6	8q24	MOT47	ODA + IDA defect	Yes	11% of PCD with ODA + IDA defects	614930
CCDC39	3q26.33	FAP59	IDA defect + axonemal disorganization	Yes	36-65% of PCD with IDA defects + Axonemal disorganization	613798
CCDC40	17q25.3	FAP172	IDA defect + axonemal disorganization	Yes	24-54% of PCD with IDA defects + Axonemal disorganization	613808
RSPH4A	6q22.1	RSP4, RSP6	Mostly normal, CA defects in small proportion of cilia	No	na	612649
RSPH9	6p21.1	RSP9	Mostly normal, CA defects in small proportion of cilia	No	na	612648
HYDIN	16q22.2	hydin	Normal, very occasionally CA defects	No	na	610812
DNAH11	7p21	DHC ß	Normal	Yes	6% of all PCD, 22% of PCD with normal ultrastructure	603339
RPGR	Xp21.1	na	Mixed	No	PCD cosegregates with X-linked retinitis pigmentosa	300170
OFD1	Xq22	OFD1	nd	No	PCD cosegregates with X-linked mental retardation	312610
CCDC164 (C2ORF39)	2p23.3	DRC1	Nexin (N-DRC) link missing; axonemal disorganization in small proportion of cilia	No	na	312610
CA = central apparatus; IDA = inner dynein arm; MIM = Mendelian Inheritance in Man; na = not available; N-DRC = nexin–dynein regulatory complex; ODA = outer dynein arm; PCD = primary ciliary dyskinesia.

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Author

Elena B Willis, MD Resident Physician, Department of Otorhinolaryngology, Albert Einstein College of Medicine, Montefiore Medical Center

Elena B Willis, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Medical Student Association/Foundation, Wilderness Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Margo Rose Tanghetti, DO Chief Resident, Department of Otolaryngology, Oklahoma State University College of Osteopathic Medicine

Margo Rose Tanghetti, DO is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Osteopathic Colleges of Ophthalmology and Otolaryngology-Head and Neck Surgery

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director, Pulmonary Medicine General Practice Unit (F2), Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, Society of Critical Care Medicine

Disclosure: Received research grant from: Sanofi Pharmaceutical.

Chief Editor

John J Oppenheimer, MD Clinical Professor, Department of Medicine, Rutgers New Jersey Medical School; Director of Clinical Research, Pulmonary and Allergy Associates, PA

John J Oppenheimer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, New Jersey Allergy, Asthma and Immunology Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Amgen; GSK; Aquestive; Aimmune<br/>Clinical Adjudication/Data Safety Monitoring Board for AZ, GSK, Abbvie, Sanofi; Executive Editor for Annals of Allergy, Asthma & Immunology; Editor for Medscape; Reviewer for UpToDate; Honoraria from American Board of Allergy and Immunology.

Additional Contributors

Ryland P Byrd, Jr, MD Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Ryland P Byrd, Jr, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

John P Bent, III, MD Professor, Director of Pediatric Otolaryngology, Departments of Otolaryngology-Head and Neck Surgery and Pediatrics, Albert Einstein School of Medicine; Director, Airway Clinic, Cochlear Implant Program, Children's Hospital at Montefiore

John P Bent, III, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Society of Pediatric Otolaryngology, Society for Ear, Nose and Throat Advances in Children, Society of University Otolaryngologists-Head and Neck Surgeons, Triological Society

Disclosure: Nothing to disclose.

Arvind K Badhey, MD Clinical Assistant Professor , Attending Surgeon, Head and Neck Surgical Oncology and Microvascular Reconstructive Surgery, Department of Otolaryngology, UMass Memorial Health, University of Massuchusetts Medical School

Arvind K Badhey, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Matthew Olearczyk, MD and Esther X Vivas, MD, to the development and writing of this article.