Mini-Symposium: Primary Ciliary Dyskinesia
Primary ciliary dyskinesia: when to suspect the diagnosis and how to confirm it

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Summary

Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive condition. The signs and symptoms are due to congenital abnormalities of ciliary structure and function, resulting in impaired mucociliary clearance. This affects the ciliated epithelium lining the nose, sinuses, Eustachian tube and airways. As a consequence, the patient typically presents with a range of features, including recurrent upper and lower respiratory tract infections, persistent glue ear and possible hearing deficit. Around half of all patients will have situs anomalies, most typically situs inversus totalis. The most significant morbidity results from the development of bronchiectasis. Access to early diagnosis and effective treatment is essential to reduce disease progression and to alleviate the burden of symptoms. This review aims to provide a clinical guide to what to look for and when to suspect the diagnosis. Recent advances in the screening and diagnostic tests available will be outlined, as well as some future directions that aim to enhance the current diagnostic techniques.

Section snippets

Historical background

Although Sievert first described the triad of sinusitis, bronchiectasis and situs inversus, and Kartagener recognized it as a genetic entity, ciliary immotility was first described by the electron microscopist Afzelius in the 1970s.7 Afzelius first reported immotile cilia in the sperm tails of infertile males, some cases occurring in the same family, and half of these also had the triad associated with Kartagener syndrome. This observation was soon applied by Sturgess,8, 9 another electron

Cilial structure and function

Cilia are complex and highly specialized organelles made up of over 360 proteins.10 The respiratory cilia are about 6 μm long and 200−250 nm in diameter. Each respiratory cilium is composed of microtubules arranged in a 9+2 formation, with nine peripheral microtubule pairs arranged around a central pair. This is known as an axoneme. The peripheral pairs consist of a complete microtubule, the A tubule, and a partial B microtubule. These pairs are connected to their neighbouring microtubular pairs

Ultrastructural abnormalities

Several ultrastructural defects have been identified in patients with PCD. Most common are those affecting the dynein arms, in particular the outer arms, but abnormalities in almost any part of the axonemal structure can occur. A range of such ultrastructural defects can be seen in Fig. 2. The various known ultrastructural defects are given in Table 1 and are listed in order of their reported frequency.4, 8, 11 Rarely, there is complete absence of cilia, a condition called ciliary aplasia, the

Genetics

PCD is nearly always inherited as an autosomal recessive disorder, although rarely there have been cases of X-linked or autosomal dominant inheritance.15, 16 The axoneme is made up of hundreds of different proteins and therefore the number of genes involved is by necessity very large. The genetic heterogeneity of PCD has made the identification of gene mutations a laborious process,17 although five recessive gene mutations have now been identified. These mutations, DNAH5, DNAH11, DNAI1, DNAI2

When to suspect primary ciliary dyskinesia: clinical signs and symptoms

In the absence of specific findings, such as situs inversus, the presentation in PCD is often non-specific. Common childhood conditions such as upper respiratory tract infections, rhinitis and middle ear pathology are so typical in the preschool child that consideration of PCD may be delayed and late referral is common. One review of 55 patients diagnosed at a tertiary referral centre records the median age at referral to be 4 years.5 There is little evidence that early diagnosis improves

Diagnostic testing for Primary Ciliary Dyskinesia

PCD is usually considered as one of a number of differential diagnoses, unless absolutely typical features of PCD are present. Therefore, investigations to exclude other more common conditions have often been undertaken during the initial phase of the work-up. These investigations may include sweat test, immunological investigation and exclusion of gastro-oesophageal reflux and pulmonary aspiration amongst others. Following the exclusion of other causes, or where typical features of PCD exist,

Conclusion

Although PCD could once be considered a rare and, perhaps, overlooked condition, the tide has turned and readily available diagnostics and treatment in specialized centres have led to a surge in interest in this best known of the ciliopathies. PCD is an important cause of progressive lung disease and a key aim of any paediatric respiratory unit must be to establish an early diagnosis and introduce treatment strategies prior to the onset of bronchiectasis. In the majority of cases, diagnostic

Practice points

  • 1.

    Presentation in PCD is often non-specific, or has features typical of many childhood illnesses. A high index of suspicion should be exercised when examining patients with prolonged or unremitting symptoms of both upper and lower airway infection.

  • 2.

    PCD is an important cause of progressive lung disease and our key aim is to establish an early diagnosis and institute treatment strategies prior to the onset of irreversible lung damage.

  • 3.

    Patients presenting with ‘difficult’ asthma or other conditions

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