Primary Ciliary Dyskinesia (Kartagener Syndrome)

Updated: Jun 11, 2020
  • Author: Elena B Willis, 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 (pediatrics).

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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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Etiology

The cause of primary ciliary dyskinesia is genetic, with an autosomal recessive inheritance pattern. Genome analysis has found primary ciliary dyskinesia to be genetically heterogenous. Genes DNAH5 and DNA11 on bands 5p15.1 and 9p13,3 respectively, are known to cause primary ciliary dyskinesia. Both genes encode for dynein. [9] There are more than 200 genes, however, that are predicted to be involved in cilia biology and may play a role in primary ciliary dyskinesia and other ciliopathies. [10]

Recently a gene protein, CCDC40, has been characterized as playing an essential role in correct left-right patterning in mouse, zebrafish, and humans. In mouse and zebrafish, CCDC40 is expressed in tissues that contain motile cilia. Mutations in this protein result in cilia with reduced ranges of motility and likely result in a variant of primary ciliary dyskinesia characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes. [11]

Onoufriadis et al have described loss-of-function mutations in CCDC114 as causing primary ciliary dyskinesia with laterality malformations. The result of these mutations is a loss of the outer dynein arms. Fertility is apparently not greatly affected by CCDC114 deficiency. [12]

Adenylate kinase type 7 (AK7), the mediator of the reaction of ADP to ATP and AMP, is also diminished significantly in patients with primary ciliary dyskinesia compared with healthy controls. AK7 expression has also been correlated with ciliary beat frequency in this patient population. [13]

Table. Mutations in the Genes that Cause Human Primary Ciliary Dyskinesia [14] (Open Table in a new window)

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 intellectual disability

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.

MIM number is from the Online Mendelian Inheritance in Man Web site, which is a continuously updated catalog of human genes, genetic disorders, and traits, with particular focus on the molecular relationship between genetic variation and phenotype expression.

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Epidemiology

US frequency

The frequency of Kartagener syndrome is 1 case per 10,000-20,000 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.

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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. [15] 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. [16] 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. [17] 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. [18] It has been shown that up to 59% of patients have recurring episodes of sinusitis and 69% of these patients require surgical intervention. [19]

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. [18] 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. [20] 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. [21]

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, male infertility, and diminished female fertility. Primary ciliary dyskinesia has been associated with esophageal problems and congenital cardiac abnormalities.

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