Primary Ciliary Dyskinesia (Kartagener Syndrome) Workup

Updated: Jun 12, 2020
  • Author: Elena B Willis, MD; Chief Editor: John J Oppenheimer, MD  more...
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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]

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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 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 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. [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.

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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. 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.

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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 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.

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