Primary ciliary dyskinesia is a rare syndrome, characterised by extensive genetic heterogeneity and clinical variability. Mutations in over 40 genes have been reported to cause this syndrome, and genes continue to be discovered. Abnormal ciliary function leads to unexpected neonatal respiratory distress in term infants, persistent wet cough from early infancy, bronchiectasis, chronic rhinosinusitis, and conductive hearing impairment; 50% of patients have situs inversus, and infertility is common.1 Disease progression is highly variable, with some patients maintaining reasonably good lung function and quality of life into later adulthood, whereas other patients have worse outcomes.2, 3, 4, 5 Evidence shows that mutations in different genes lead to variable phenotypes; for example, some genes are never associated with situs anomalies, and variants in other genes are more likely to cause infertility.6, 7 A few studies have suggested an association between some genes and the severity of pulmonary disease, but the evidence remains scarce.8, 9, 10, 11
Primary ciliary dyskinesia is estimated to affect 1 in 10 000 to 1 in 15 000 Europeans and is more common in populations with closed genetic pools;12, 13, 14 interestingly, genetic heterogeneity is seen in socially isolated consanguineous populations.15, 16 Estimates of prevalence are scarce outside of Europe, but primary ciliary dyskinesia is expected to be more common in certain populations (eg, in Arab countries).17, 18 A survey of specialists in Europe reported that only a small proportion of patients estimated to have primary ciliary dyskinesia have been diagnosed, and that 37% of patients reported in an international survey that they had visited a doctor for primary ciliary dyskinesia-related symptoms more than 40 times before being referred for testing.12, 19 The reasons for underdiagnosis are multifactorial, including difficulty accessing diagnostic services and the lack of awareness of the syndrome among general physicians.19 Symptoms are non-specific, and patients with situs inversus, which is rare in the general population, are diagnosed earlier than those with normal organ positioning.12 Clinical tools have been developed to help physicians identify patients for testing,20, 21 but these tools are based on typical symptoms; however, awareness of genotypes associated with atypical presentations is increasing.
As with other rare diseases, the evidence for treating patients with primary ciliary dyskinesia is scarce. In addition to the few small studies for this syndrome, consensus guidelines are based on evidence from more common disorders, such as cystic fibrosis and chronic rhinosinusitis.22, 23
Key messages
- •
Primary ciliary dyskinesia is a syndrome caused by mutations in genes responsible for structure and function of motile cilia; although mutations have been identified in more than 40 responsible genes, the genetic cause of this syndrome is not known in approximately 25% of patients
- •
A diagnosis of primary ciliary dyskinesia can be confirmed by identification of a hallmark ultrastructural defect by transmission electron microscopy or bi-allelic pathogenic mutations in a known primary ciliary dyskinesia gene
- •
Genetic advances are identifying patients with atypical presentations of primary ciliary dyskinesia and have confirmed some overlaps with non-motile ciliopathies
- •
No diagnostic test is perfect for primary ciliary dyskinesia; therefore, diagnosis relies on a combination of tests and no test can be used in isolation
- •
Some genotype–phenotype associations have been described in small studies. International collaborations and prospective registries are needed to properly understand these associations
- •
In the absence of disease-specific evidence, respiratory management of primary ciliary dyskinesia is based on evidence from cystic fibrosis. Guidelines for primary ciliary dyskinesia recommend regular airway clearance and treatment of pulmonary exacerbations with antibiotics for all patients. Early steps towards personalised medicine are being taken in light of genetic understanding
In this Review, we discuss the information available regarding the underlying mechanisms of primary ciliary dyskinesia and how this knowledge might inform our understanding of clinical presentation and natural disease progression. We review current diagnostic and management strategies for patients with primary ciliary dyskinesia. We will discuss how the improving knowledge of primary ciliary dyskinesia genetics is affecting the understanding of the phenotype, the conduct of diagnostic testing, and management of patients. We reflect on the expanding phenotype, and how this challenges the definition of primary ciliary dyskinesia.