Grand Rounds - Hammersmith Hospital Late presentation of Kartagener's syndrome Consequences of ciliary dysfunctionBMJ 1994; 308 doi: https://doi.org/10.1136/bmj.308.6927.519 (Published 19 February 1994) Cite this as: BMJ 1994;308:519
Primary ciliary dyskinesia provides a unique insight into the role of cilia in the human body. It is usually diagnosed in childhood, when prompt treatment of respiratory infections can minimise irreversible damage to the lungs.
A 48 year old man presented with a four month history of cough productive of green sputum, a two month history of night sweats, and a two day history of left sided pleuritic chest pain. He had previously had recurrent chest infections, recurrent purulent rhinosinusitis, and had produced more than one cupful of sputum a day for many years. He smoked 20 cigarettes a day.
On examination he had a fever (38°C), a regular pulse (100 beats/min), and blood pressure of 130/80 mm Hg. He was not clubbed. His apex beat was localised to the right fifth intercostal space and he had signs of consolidation in the left mid-zone. He had complete situs inversus viscerum.
He had a haemoglobin concentration of 140 g/l and a peripheral leucocyte count of 11.8x109/l with 88% neutrophils. His erythrocyte sedimentation rate (34 mm in the first hour) and C reactive protein concentration (15 mg/l) were raised. Routine biochemistry tests gave normal results. Blood cultures were sterile but sputum culture grew Streptococcus pneumoniae. Culture was negative for acid fast bacilli. Chest radiography confirmed dextrocardia, with the aortic arch lying on the right side of the trachea (fig 1). The left lung had three lobes with consolidation in the middle lobe. A gastric air bubble was noted on the right side. The plain film showed no evidence of bronchiectasis but computed tomography of the chest after his pneumonia had resolved showed bronchiectasis in the left middle lobe and right lower lobe (fig 2).
Kartagener's syndrome with an acute left sided pneumonia was diagnosed clinically. He was treated with intravenous benzylpenicillin and physiotherapy and advised to stop smoking. His symptoms rapidly improved and he was discharged taking low dose antibiotics in rotation.
He had further tests to confirm the diagnosis. Lung function tests showed mild airways obstruction (forced expiratory volume in one second/vital capacity was 62% predicted). The saccharin test of mucociliary clearance gave a time of 60 minutes (normal result less than 15 minutes). Nasal cilia (obtained by the brush technique and analysed by light microscopy and photometric techniques) were totally immotile. Analysis of a fresh semen ejaculate showed a viability of 40%, but all the sperm were immotile. Transmission electron microscopy of the nasal cilia and sperm tails showed an identical ultrastructural defect - namely, complete absence of the inner and outer dynein arms on the microtubular doublets of the axoneme (fig 3).
The triad of bronchiectasis, sinusitis, and situs inversus was first described by Siewert in 1903,1 although its usual eponym, Kartagener's syndrome, derives from the Swiss paediatrician who described four cases with similar features in 1933.2
By the 1960s over 300 cases had been reported and the concept of a disease with congenital and generalised non-functioning of the cilia evolved. Men with bronchiectasis and sinusitis were noted to have immotile sperm with generalised defects in sperm tails and the cilia in the respiratory tract. 3 About half of these men also had situs inversus and so fitted the criteria of Kartagener's syndrome. Since not all those affected had situs inversus the term immotile cilia syndrome was proposed.4 However, further work showed that cilia are often not completely immotile but show abnormal and ineffective motility. Therefore the syndrome is also referred to as primary ciliary dyskinesia.5
The clinical features of primary ciliary dyskinesia have been ascribed to primary ultrastructural defects in cilia. Ultrastructurally cilia and dspermatozoa are similar. The axoneme is the key component of the cytoskeleton and has a characteristic nine plus two array of microtubules (fig 3). The nexin links and spokes seem to provide structural rigidity to the axoneme. Dynein arms extend from one side of a doublet in a clockwise direction when viewed from the base toward the tip of the cilium. They contain most of the ATPase activity of the axoneme and are important in releasing energy for sliding and bending of microtubules and ciliary motion.6
The tracheobronchial tree is ciliated to the level of the respiratory bronchioles, each ciliated cell having about 200 cilia. Mucociliary transport in the respiratory tract is important for normal respiratory function and resistance to respiratory infection.
The typical clinical picture of primary ciliary dyskinesia is a chronic productive cough, which can usually be traced back to early childhood orinfancy; chronic rhinitis often with nasal polyposis (so that an affected baby may be born with a running nose); chronic or recurrent maxillary sinusitis; and frequent ear infections in childhood. Bronchiectasis is not present at birth but may develop early, sometimes even in childhood. The most common respiratory pathogens are Haemophilus influenzae and Streptococcus pneumoniae. Colonisation with pseudomonas is much less common than in cystic fibrosis. Most men are sterile and many women have a lowered fertility. About half of patients have situs inversus viscerum.
Patients with suspected primary ciliary dyskinesia should have their mucociliary clearance measured and the cilia should be examined by microscopy. Nasal mucociliary clearance can be measured by the saccharin test, in which a saccharin particle is placed on the anterior end of the inferior turbinate and the time taken for the subject to notice the taste is recorded. This test requires some patient cooperation and is not reliable in children under 10 years old.
Nasal cilia are easily accessible and can be obtained from the inferior turbinate without anaesthesia by a non-invasive brush technique. Ciliary beat frequency can then be assessed by light microscopy and photometric techniques and the cilia fixed for electron microscopy. The motility of sperm can be examined simply in men, and electron microscopy may show the characteristic ultrastructural defects.
Rationale of treatment
Treatment of primary ciliary dyskinesia is aimed at relieving symptoms and preventing complications. Early recognition facilitates prompt antibiotic treatment in patients with recurrent infections and is the key to minimising irreversible lung damage. Physiotherapy with postural drainage and stopping smoking are also important. Coughing should not be suppressed since it acts as a substitute for mucociliary clearance; huffing from mid to low lung volume with a forced expiratory manoeuvre helps improve clearance.7
Despite the chronic respiratory disease, life expectation seems to be normal. Infertile patients may benefit from advanced micromanipulation techniques that allow non-motile or poorly motile sperm to penetrate the oocyte.
The prevalence of primary ciliary dyskinesia has been estimated to be 1 in 16 000.8 Segregation analysis of proband sibships is consistent with autosomal recessive inheritance9 but the ultrastructural abnormality is variable. The most common abnormality is absence or reduced number of dynein arms. Defects in the radial spokes, nexin links, cilial length, and orientation of the cilia have also been described.3 There are thus likely to be several genes which may cause the manifestations of the disease. However, no clinical differences have emerged to distinguish different defects.
Although ultrastructural abnormalities often occur in both cilia and sperm flagella, patients with ultrastructural axonemal anomalies of only one cell type have been reported.9,10 Men with primary ciliary dyskinesia should therefore have seminal analysis before being told they are infertile.
Situs inversus occurs randomly in about 50% of patients with primary ciliary dyskinesia but may also occur without associated respiratory disease. Parents of children with primary ciliary dyskinesia usually have no history of chronic lung disease. The risk of another child being affected is about 25%.
The causes of lateralisation of organs are unknown but a network of genes and their products is likely to be involved. Ciliary function may be critical to the directional organ movements that produce lateralisation. Brown et al suggested that handedness may be signalled by a molecule which is itself handed and can be fixed in a particular orientation in relation to the anteroposterior and dorsoventral axes.11 Cells may become polarised with respect to the midline, perhaps as a response to a diffusible substance produced by midline cells. Dynein is capable of asymmetrical transport and Brown et al postulated that situs may be associated with a defect in cytoplasmic rather than ciliary dynein. However, this does not explain why patients with defects of the microtubules other than the dynein arms also develop situs inversus.
MW: These patients are teaching us something about left-right asymmetry. The obvious explanation is that if your cilia don't beat then your heart doesn't move to the correct side. It may not be as simple as that. In Polynesian bronchiectasis there is bronchiectasis and ciliary dysfunction but no situs inversus. An alternative hypothesis is that dynein has a role in intracellular asymmetry. In this hypothesis the molecule can be visualised as an F shaped structure which orientates according to the polarity of the cell and sets up intracellular gradients. Interestingly, it is very common for only one of conjoint twins to show abnormalities of symmetry.
CO: Not all patients with dextrocardia and situs inversus have Kartagener's syndrome; but all patients with isomerism (whereby you have mirror image structures) have complex cardiac defects.
JS: The cilia and the dynein always have the same geometric relationship, which may imply an asymmetrical moiety. Is there one dynein gene?
MW: There seems to be one dynein gene. However, there are probably several different mutations within this gene.
SB: If it produces infertility why is it so common?
MW: Theoretically, primary ciliary dyskinesia ought to breed out, but that is going to take a long time as it is a rare recessive. Selection against the homozygous is very slow and inefficient. The genetics of our patient's family are interesting because he has a nephew with Kartagener's syndrome and no dominant examples of this syndrome have ever been described. There is no history of consanguinity in this family.
DB: Is there an increased incidence of left handedness in these patients?
MW: As far as we know there is not, and this implies different genes for cerebral lateralisation.
I thank Dr Kevin Lindsay, Queen Charlotte's and Chelsea Hospital, for the sperm tail analysis and electron micrographs, and Professor Cole and Dr Charlotte Raynor, Royal Brompton National Heart and Lung Institute, for the nasal ciliary studies.