Primary Ciliary Dyskinesia (Kartagener Syndrome)

Updated: Mar 03, 2017
  • Author: John P Bent, III, MD; Chief Editor: John J Oppenheimer, MD  more...
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Overview

Background

Siewert first described the combination of situs inversus, chronic sinusitis, and bronchiectasis in 1904. [1] However, Manes Kartagener [1] first recognized this clinical triad as a distinct congenital syndrome in 1933. Because Kartagener described this syndrome in detail, it bears his name. Kartagener syndrome (KS) is inherited via an autosomal recessive pattern. Symptoms result from defective cilia motility.

Also see Primary Ciliary Dyskinesia.

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Pathophysiology

Camner and coworkers [2] first suggested ciliary dyskinesia as the cause of Kartagener syndrome in 1975. They described two patients with Kartagener syndrome who had immotile cilia and immotile spermatozoa. These patients had poor mucociliary clearance because the cilia that lined their upper airways were not functioning.

Later, Afzelius [3] discovered that bronchial mucosal biopsy specimens from patients with similar respiratory complaints showed cilia that appeared abnormal and were poorly mobile. In 1977, Eliasson and coworkers [4] used the descriptive phrase “immotile cilia syndrome” to characterize male patients with sterility and chronic respiratory infections. The image below illustrates missing dynein arms in Kartagener syndrome.

Normal cilia (A) compared with cilia in Kartagener Normal cilia (A) compared with cilia in Kartagener syndrome with missing dynein arms (B). Image courtesy of Wikimedia Commons.

In 1981, Rossman and coworkers [5] coined the term primary ciliary dyskinesia (PCD) because some patients with Kartagener syndrome had cilia that were not immobile but exhibited an uncoordinated and inefficient movement pattern. Current nomenclature classifies all congenital ciliary disorders as primary ciliary dyskinesias in order to differentiate them from acquired types. Kartagener syndrome is part of the larger group of disorders referred to as primary ciliary dyskinesias. Approximately one half of patients with primary ciliary dyskinesia have situs inversus and, thus, are classified as having Kartagener syndrome. Afzelius proposed that normal ciliary beating is necessary for visceral rotation during embryonic development. In patients with primary ciliary dyskinesia, organ rotation occurs as a random event; therefore, half the patients have situs inversus and the other half have normal situs.

Ciliated epithelium covers most areas of the upper respiratory tract, including the nasal mucosa, paranasal sinuses, middle ear, eustachian tube, and pharynx. The lower respiratory tract contains ciliated epithelium from the trachea to the respiratory bronchioles. Each ciliated cell gives rise to approximately 200 cilia that vary in length from 5-6 μm and decrease in size to 1-3 μm as the airway becomes smaller.

The typical ciliary axoneme consists of two central microtubules surrounded by 9 microtubular doublets. Each doublet has an A subunit and a B subunit attached as a semicircle. A central sheath envelops the two central microtubules, which attach to the outer doublets by radial spokes.

The outer doublets are interconnected by nexin links, and each A subunit is attached to two dynein arms that contain adenosine triphosphatase; one inner arm and one outer arm. The primary function of the central sheath, radial spokes, and nexin links is to maintain the structural integrity of the cilium, whereas the dynein arms are responsible for ciliary motion.

The cilium is anchored at its base by cytoplasmic microtubules and a basal body comprised of a basal foot and rootlet. The orientation of the basal foot indicates the direction of the effective cilial stroke. Just above the base, the cilium is composed of microtubular triplets (previously doublets) without associated structures, but at the tip, only the B subunits remain.

Cilia propel overlying mucus via a two-part ciliary beat cycle. First, the power stroke occurs when a fully extended cilium moves perpendicular to the cell surface in an arclike manner. Then, the recovery stroke follows, in which the entire cilium bends and returns to its starting point near the cell surface. Once a cilium starts to move, the complete beat cycle is obligatory.

The cycle is mediated by dynein arms from the A subunit that attach to the B subunit of the adjacent microtubule. Adenosine triphosphate is hydrolyzed by the dynein arms and the 9 microtubule doublets as they slide against each other.

Patients with primary ciliary dyskinesia exhibit a wide range of defects in ciliary ultrastructure and motility, which ultimately impairs ciliary beating and mucociliary clearance. The most common defect, first described by Afzelius, is a reduction in the number of dynein arms, which decreases the ciliary beat frequency.

Sturgess et al [6] described how the radial spoke, which serves to translate outer microtubular sliding into cilial bending, was absent in some patients with primary ciliary dyskinesia. Cilia in other patients lacked central tubules; however, instead of the central tubules, an outer microtubular doublet transposed to the cell of the axoneme was present that displayed an abnormal 8+1 doublet-to-tubule pattern. Both the radial spoke and the transposed doublet defects impaired mucociliary clearance.

Other ciliary defects include an abnormal basal cell apparatus with giant roots and double feet, cilia lacking all internal microtubular structures, and even cilia twice the normal length that beat in an uncoordinated undulating fashion. Pedersen [7] compared the type of ultrastructural defect to ciliary motility and found that dynein defects caused hypomotility and microtubular defects caused asynchrony. He also found that normal ciliary ultrastructure occasionally was associated with hypermotility or inefficient ciliary trembling.

Some patients with clinical features of primary ciliary dyskinesia have a ciliary ultrastructure that appears normal, but their arrangement and beat direction is disoriented, which causes inefficient mucociliary transport. These findings illustrate the importance of analyzing ciliary motility and ultrastructure when considering a diagnosis of primary ciliary dyskinesia.

Primary ciliary dyskinesia tissues have also been characterized by impaired chloride ion transport currents. This impaired current has been shown to persist even after application of a cAMP-elevating agonist. [8]

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Epidemiology

US frequency

The frequency of Kartagener syndrome is 1 case per 32,000 live births. Situs inversus occurs randomly in half the patients with primary ciliary dyskinesia; therefore, for every patient with Kartagener syndrome, another patient has primary ciliary dyskinesia but not situs inversus.

Sex

No sex predilection exists.

Age

Clinical manifestations of chronic sinusitis, bronchitis, and bronchiectasis are more severe during the first decade of life but remit somewhat by the end of adolescence.Kartagener syndrome is inherited via an autosomal recessive pattern.

 

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Prognosis

Chronic childhood infections can be very debilitating, but the range and severity of clinical symptoms is wide. In severe cases, the prognosis can be fatal if bilateral lung transplantation is delayed. [9] Fortunately, primary ciliary dyskinesia and Kartagener syndrome usually become less problematic near the end of the patient's second decade, and many patients have near normal adult lives. The prognosis of patients with Kartagener syndrome was outlined in a longitudinal study, which measured long-term outcomes and pulmonary function test results. Tests were conducted on an interval basis in a cohort of 74 patients. The study found that patients are at risk for decreased pulmonary function. The study did not come to a firm conclusion on age correlation with lung deterioration or disease progression. [10] However, cross-sectional data suggest that spirometry worsens in patients over time.

Clinical manifestations include chronic upper and lower respiratory tract disease resulting from ineffective mucociliary clearance. Males demonstrate infertility secondary to immotile spermatozoa.

Upper airway

Patients may exhibit chronic, thick, mucoid rhinorrhea from early in childhood. Examination usually reveals pale and swollen nasal mucosa, mucopurulent secretions, and an impaired sense of smell. Nasal polyps are noted in 30% of affected individuals.

Sinonasal disease in primary ciliary dyskinesia has been poorly studied; however, these patients often have recurrent chronic sinusitis with sinus pressure headaches in the maxillary and periorbital regions. Sinus radiographs (which largely have been supplanted by CT scans) typically demonstrate mucosal thickening, opacified sinus cavities, and aplastic or hypoplastic frontal and/or sphenoid sinuses. [11] Symptoms usually improve with antibiotic therapy but have a propensity for rapid recurrence. It appears that patients with chronic rhinosinusitis (CRS) may benefit from long-term macrolide therapy and endoscopic sinus surgery (ESS) in recalcitrant disease. Therapies targeted at improving mucociliary clearance have not been tested specifically in primary ciliary dyskinesia. [12] It has been shown that up to 59% of patients have recurring episodes of sinusitis and 69% of these patients require surgical intervention. [13]

Recurrent otitis media is a common manifestation of primary ciliary dyskinesia. Examination may reveal a retracted tympanic membrane with poor or absent mobility and a middle-ear effusion. Further testing usually demonstrates a flat tympanogram and bilateral conductive hearing loss secondary to thick middle-ear effusion. Many patients undergo repeated tympanostomy tube insertion, often complicated by chronic suppurative otitis media. Campbell et al found that ventilation tube insertion improves hearing in primary ciliary dyskinesia, but may lead to a higher rate of otorrhea when compared with the general population. [12] Other associated otologic disorders may include tympanosclerosis, cholesteatoma, and keratosis obturans.

Lower respiratory tract

Chronic bronchitis, recurrent pneumonia, and bronchiectasis are common conditions associated with primary ciliary dyskinesia. Patients presenting with bronchiectasis should be evaluated for Kartagener syndrome. Bronchiectasis usually occurs in the lower lobes in patients with Kartagener syndrome, while patients with cystic fibrosis have bronchiectasis predominantly in the upper lobes.

Chest radiographs may illustrate bronchial wall thickening (earliest manifestation), hyperinflation, atelectasis, bronchiectasis, and situs inversus (in 50% of patients with primary ciliary dyskinesia). High-resolution CT (HRCT) scanning, spirometry, and plethysmography may also be performed. Pifferi et al found that plethysmography better predicted HRCT abnormalities than spirometry by allowing recognition of different severities of focal air trapping, atelectasis, and extent of bronchiectasis in patients with primary ciliary dyskinesia. [14] Whether it might be a useful test to define populations of patients with primary ciliary dyskinesia who should or should not have HRCT scans requires further longitudinal studies. Magnin et al evaluated the longitudinal relationships between lung function tests (LFTs) and chest HRCT in children with primary ciliary dyskinesia and found significant correlation. It is possible that lung function follow-up can be used to reduce CT frequency to help minimize the radiation exposure in these children. [15]

Obstructive lung disease may be another component of Kartagener syndrome symptomatology. It probably results from elevated levels of local inflammatory mediators in a chronically irritated airway.

Other features

Other features include digital clubbing and diminished female fertility. Primary ciliary dyskinesia has been associated with esophageal problems and congenital cardiac abnormalities.

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