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Kartagener Syndrome Workup

  • Author: John P Bent, III, MD; Chief Editor: Ryland P Byrd, Jr, MD  more...
 
Updated: Feb 28, 2014
 

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.[15]

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.[24]

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Imaging Studies

Sinus radiographs (which largely have been supplanted by CT scans) typically demonstrate mucosal thickening, opacified sinus cavities, and hypoplastic frontal sinuses.

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).[25]

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 inve 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 i 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. [18] Studies have demonstrated a relationship between nasal nitric oxide levels, nasal oxide synthase mRNA expression, and ciliary beat frequency. [26] 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. [9]
  • Mucociliary transport, which is reduced in these patients, can be measured in situ by administering an inhalation aerosol of colloid albumin tagged with technetium Tc 99. [18]

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.
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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. Nasal brushing is least invasive but 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.

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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 PCD, 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).[27] However, CBF as a laboratory screening test to determine which patients should undergo EM results in a number of patients with PCD being missed. The use of beat-pattern analysis appears to be a more sensitive and specific test, with higher positive and negative predictive values.[27]

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 those with 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.[28, 29]

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 2. 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.

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Contributor Information and Disclosures
Author

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, Society of University Otolaryngologists-Head and Neck Surgeons, American Society of Pediatric Otolaryngology, Society for Ear, Nose and Throat Advances in Children, Triological Society

Disclosure: Nothing to disclose.

Coauthor(s)

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.

Arvind K Badhey, MD Resident Physician, Department of Otolaryngology, Icahn School of Medicine at Mount Sinai

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; Chair of the Clinical Competency Committee, Pulmonary and Critical Care Fellowship Program, Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Health System; Chair, Guideline Oversight Committee, American College of Chest Physicians

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

Disclosure: Nothing to disclose.

Chief Editor

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.

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.

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.

References
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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.
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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