Kartagener Syndrome Workup
- Author: John P Bent, III, MD; Chief Editor: Ryland P Byrd, Jr, MD more...
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.
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.
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).
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.
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.  Studies have demonstrated a relationship between nasal nitric oxide levels, nasal oxide synthase mRNA expression, and ciliary beat frequency.  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. 
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. 
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.
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.
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). 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.
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.
Kartagener M. Zur pathogenese der bronchiectasien. I Mitteilung:bronchiectasien bei situs viscerum inversus. Betr Klin Tuberk. 1933. 83:498-501.
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. [Medline].
Afzelius BA. A human syndrome caused by immotile cilia. Science. 1976 Jul 23. 193(4250):317-9. [Medline].
Eliasson R, Mossberg B, Camner P, Afzelius BA. The immotile-cilia syndrome. A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility. N Engl J Med. 1977 Jul 7. 297(1):1-6. [Medline].
Rossman CM, Forrest JB, Lee RM, Newhouse MT. The dyskinetic cilia syndrome. Ciliary motility in immotile cilia syndrome. Chest. 1980 Oct. 78(4):580-2. [Medline].
Sturgess JM, Chao J, Wong J, Aspin N, Turner JA. Cilia with defective radial spokes: a cause of human respiratory disease. N Engl J Med. 1979 Jan 11. 300(2):53-6. [Medline].
Pedersen M. Specific types of abnormal ciliary motility in Kartagener's syndrome and analogous respiratory disorders. A quantified microphoto-oscillographic investigation of 27 patients. Eur J Respir Dis Suppl. 1983. 127:78-90. [Medline].
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. [Medline].
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. [Medline].
Campbell R. Managing upper respiratory tract complications of primary ciliary dyskinesia in children. Curr Opin Allergy Clin Immunol. 2012 Feb. 12(1):32-8. [Medline].
Sommer JU, Schäfer K, Omran H, Olbrich H, Wallmeier J, Blum A, et al. ENT manifestations in patients with primary ciliary dyskinesia: prevalence and significance of otorhinolaryngologic co-morbidities. Eur Arch Otorhinolaryng. March 2011. 268(3):383-388. [Medline].
Pifferi M, Bush A, Pioggia G, et al. Evaluation of pulmonary disease using static lung volumes in primary ciliary dyskinesia. Thorax. 2012 Nov. 67(11):993-9. [Medline].
Magnin ML, Cros P, Beydon N, et al. Longitudinal lung function and structural changes in children with primary ciliary dyskinesia. Pediatr Pulmonol. 2012 Aug. 47(8):816-25. [Medline].
Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med. 2013 Oct 15. 188(8):913-22. [Medline].
Leigh MW, Pittman JE, Carson JL, Ferkol TW, Dell SD, Davis SD, et al. Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet Med. 2009 Jul. 11(7):473-87. [Medline]. [Full Text].
Greenstone M, Stanley P, Cole P, Mackay I. Upper airway manifestations of primary ciliary dyskinesia. J Laryngol Otol. 1985 Oct. 99(10):985-91. [Medline].
Prulière-Escabasse V, Coste A, Chauvin P, Fauroux B, Tamalet A, Garabedian EN, et al. Otologic features in children with primary ciliary dyskinesia. Arch Otolaryngology Head and Neck Surg. Nov 2010. 136(11):1121-1126. [Medline].
Skeik N, Jabr Fl. Kartagener syndrome. Int J Gen Med. Jan/2011. 12:41-43. [Medline].
Bush A, Chodhari R, Collins N, Copeland F, Hall P, Harcourt J. Primary ciliary dyskinesia: current state of the art. Arch Dis Child. 2007 Dec. 92(12):1136-40. [Medline].
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. [Medline].
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. [Medline].
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. [Medline]. [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. [Medline].
Leigh MW, O'Callaghan C, Knowles MR. The challenges of diagnosing primary ciliary dyskinesia. Proc Am Thorac Soc. 2011 Sep. 8(5):434-7. [Medline].
Nadel HR, Stringer DA, Levison H, Turner JA, Sturgess JM. The immotile cilia syndrome: radiological manifestations. Radiology. 1985 Mar. 154(3):651-5. [Medline].
Pifferi M, Bush A, Maggi F, Michelucci A, Ricci V, Conidi ME, et al. Nasal nitric oxide and nitric oxide synthase expression in primary ciliary dyskinesia. Eur Respir J. March 2011. 37:572-577. [Medline].
Stannard WA, Chilvers MA, Rutman AR, Williams CD, O'Callaghan C. Diagnostic testing of patients suspected of primary ciliary dyskinesia. Am J Respir Crit Care Med. Feb 2010. 181(4):307-314. [Medline].
Kupferberg SB, Bent JP, Porubsky ES. The evaluation of ciliary function: electron versus light microscopy. Am J Rhinol. 1998 May-Jun. 12(3):199-201. [Medline].
Mierau GW, Agostini R, Beals TF, Carlén B, Dardick I, Henderson DW, et al. The role of electron microscopy in evaluating ciliary dysfunction: report of a workshop. Ultrastruct Pathol. 1992 Jan-Apr. 16(1-2):245-54. [Medline].
Barbato A, Frischer T, Kuehni CE, Snijders D, Azevedo I, Baktai G. Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children. Eur Respir J. 2009 Dec. 34(6):1264-76. [Medline].
Desai M, Weller PH, Spencer DA. Clinical benefit from nebulized human recombinant DNase in Kartagener's syndrome. Pediatr Pulmonol. 1995 Nov. 20(5):307-8. [Medline].
Strippoli MP, Frischer T, Barbato A, et al. Management of primary ciliary dyskinesia in European children: recommendations and clinical practice. Eur Respir J. 2012 Jun. 39(6):1482-91. [Medline].
Elwany S, Ibrahim AA, Mandour Z, Talaat I. Effect of passive smoking on the ultrastructure of the nasal mucosa in children. Laryngoscope. 2012 May. 122(5):965-9. [Medline].
Leopold PL, O'Mahony MJ, Lian XJ, Tilley AE, Harvey BG, Crystal RG. Smoking is associated with shortened airway cilia. PLoS One. 2009. 4(12):e8157. [Medline].
Parsons DS, Greene BA. A treatment for primary ciliary dyskinesia: efficacy of functional endoscopic sinus surgery. Laryngoscope. 1993 Nov. 103(11 Pt 1):1269-72. [Medline].
Marthin JK, Petersen N, Skovgaard LT, Nielsen KG. Lung function in patients with primary ciliary dyskinesia: a cross-sectional and 3-decade longitudinal study. Am J Respir Crit Care Med. 2010 Jun 1. 181(11):1262-8. [Medline].
Bent JP 3rd, Smith RJ. Intraoperative diagnosis of primary ciliary dyskinesia. Otolaryngol Head Neck Surg. 1997 Jan. 116(1):64-7. [Medline].
Merveille AC, Davis EE, Becker-Heck A, Legendre M, Amirav I, Bataille G, et al. CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet. Jan 2011. 43(1):72-78. [Medline].
Mishra M, Kumar N, Jaiswal A, Verma AK, Kant S. Kartagener's syndrome: A case series. Lung India. 2012 Oct. 29(4):366-9. [Medline].
Philpott CM, McKiernan DC. Bronchiectasis and sino-nasal disease: a review. J Laryngol Otol. 2008 Jan. 122(1):11-5. [Medline].
|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|
|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.|