Mini-symposium: Primary Ciliary DyskinesiaCongenital Heart Disease and Primary Ciliary Dyskinesia
Introduction
Primary Ciliary Dyskinesia (PCD) is a genetically heterogenous, autosomal recessive disorder of ciliary motility resulting in defective mucociliary clearance. The prevalence of PCD is not well defined but has been estimated to be approximately 1 in 16,000 based on extrapolating the incidence from population-based studies screening chest radiographs for organ laterality defects and bronchiectasis [1], [2].
The disorder classically includes neonatal respiratory compromise, chronic sinusitis, recurrent otitis media, male infertility, and recurrent pneumonia with bronchiectasis. The original description of the disorder in 1933 by Kartagener describes a triad of situs inversus totalis, bronchiectasis and sinusitis [3]. While this early description of PCD included situs inversus totalis, it was not until many years later that a connection was established between PCD and other organ laterality defects, including congenital heart disease (CHD) [4], [5]. The association between PCD and CHD is supported by studies demonstrating an increased incidence of CHD in murine models of PCD [6]. Increased awareness of this link amongst clinicians, with improved radiology imaging modalities, has resulted in detection of increasing numbers of cases of congenital heart disease amongst patients with ciliary disorders. Recent studies have shown that approximately 50% of patients with PCD have organ laterality defects [4], [7], [8], with approximately 3.5-6% having cardiovascular malformations [4], [8] and at least 2.6% having a complex cardiovascular defect [8]. This review explores a number of aspects of CHD in PCD, including definitions and nomenclature, genetic associations, diagnosis, management, prognosis and potential future directions for these two related conditions.
Section snippets
Defining CHD and heterotaxy in PCD
Congenital heart disease represents one manifestation of the many organ laterality defects seen in patients with PCD (see Figure 1). The study of these laterality defects, and comparison of previous studies regarding CHD in PCD, is made more difficult by discordance in the published literature regarding the nomenclature and categorisation of the variety of defects that may exist. Previous studies in non-PCD populations have classified patients with organ laterality defects based on the presence
Pathogenesis
The prevalence of heterotaxy in the general population has been reported as approximately 1 in 10,000 pregnancies, [14] which represents approximately 3% of all births with CHD [15]. This prevalence is estimated using data extracted from an American population-based registry of congenital malformations including live births, stillbirths at greater than 20 weeks and elective terminations in the second trimester. Spontaneous abortions at less than 20 weeks gestation were not included in this
Genetics
The polygenic nature and the high locus heterogeneity of the individual genetic mutations responsible for PCD have hindered progress towards comprehensive understanding of the genetic basis for the disease. In recent years, the development of robust PCD animal models coupled with the advent of whole exome DNA-sequencing techniques have resulted in significant advances in our understanding of the genetic basis for PCD, and consequently, heterotaxy in PCD. Genetic mutations causing ciliary
Diagnosis
In the absence of a comprehensive genetic test for PCD-causing mutations, establishing a PCD diagnosis often begins with clinical suspicion based on a classic phenotype, or the detection of incidental laterality defects on radiological imaging. Clinical features of CHD resulting in complex cardiovascular disease may be the first clue to an underlying ciliopathy and should prompt further PCD investigations with nasal nitric oxide measurement, ciliary electron microscopy, or functional ciliary
Cardiovasular lesions in CHD in PCD
There is a paucity of published literature examining CHD in PCD. In the only published prospective study, Shapiro et al, report a prevalence of SA in 37 out of 305 cases (12.1%) with classic PCD, with 8 (2.6%) of these having heterotaxy (defined as SA plus complex cardiovascular defects). (see Table 3)
In a retrospective study of 337 patients with PCD, Kennedy et al, report 21 patients (6.3%) with PCD and either SA or heterotaxy (defined as any thoracoabdominal asymmetry that differs from SS or
Management and Prognosis
The recommended management of CHD in patients with PCD is not affected by the presence of PCD, and surgical correction for complex and non-complex congenital heart disease is indicated as for patients without PCD. This is particularly true in younger children where established bronchiectasis is less likely to be found, and so represent a lower risk during general anaesthetic. There are no evidence-based, PCD–specific therapies for the non-cardiovascular manifestations of PCD, and recommended
Future Research Directions
Given the potential short-term and long-term benefits of early diagnosis of PCD, continued pursuit of comprehensive genotyping of all known PCD cases is key for development of a commercially viable genetic diagnostic tool for PCD.
Longitudinal studies are required to provide a clearer picture of the natural history of patients with PCD and heterotaxy, and to examine the effect of PCD-specifc peri-operative therapeutic interventions in patients undergoing corrective surgery.
Increased awareness by
Educational aims
The reader will come to understand the importance:
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Association between PCD and congenital heart disease (CHD), including complex cardiovascular defects.
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Mechanism by which ciliary dysfunction leads to heterotaxic CHD.
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Importance of screening for CHD in patients with PCD, especially those with organ laterality defects.
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Importance of screening for ciliary disorders, including PCD, in patients with CHD, particularly in the context of potential surgical correction of the congenital heart defect.
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Cited by (34)
Bronchoscopy findings in children with congenital lung and lower airway abnormalities
2024, Paediatric Respiratory ReviewsRole of cilia in the pathogenesis of congenital heart disease
2021, Seminars in Cell and Developmental BiologyCitation Excerpt :In fact, PCD is well described to be associated with male infertility and situs inversus, a spectrum of phenotypes previously referred to as Kartagener’s syndrome [25]. However, the link between PCD and CHD was not discovered until more recent studies showed PCD patients can exhibit heterotaxy and in such PCD-heterotaxy patients, CHD is commonly observed [26,27]. It is interesting to note that while many of our mutations in PCD genes caused immotility or weak flickering dyskinetic ciliary motion in the airway, ciliary motion in the brain ependyma is often preserved, albeit the cilia waveform and beat frequency may be abnormal [13].
De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry
2019, American Journal of Human GeneticsCitation Excerpt :Affected individuals OP-2950 II1, US-1 II1, and US-2 II1 exhibited situs inversus, consistent with previous observations in mice, Xenopus laevis, and zebrafish, indicating that FOXJ1 has an important functional role in left/right body asymmetry determination during early embryogenesis.9,11,28–30 Of note, OP-1933 II1 presented with a ventricular septal cardiac defect, which might reflect the increased incidence of congenital heart defects in motile ciliopathies associated with randomization of left/right body asymmetry compared to the healthy population.31,32 OP-2950 II1 was unable to become pregnant even after in vitro fertilization.
Respiratory physiology for intensivists
2018, Critical Heart Disease in Infants and ChildrenMutations in PIH1D3 Cause X-Linked Primary Ciliary Dyskinesia with Outer and Inner Dynein Arm Defects
2017, American Journal of Human GeneticsCitation Excerpt :Ineffective mucociliary clearance causes mucus stasis in the entire respiratory tract, leading to recurrent infections and chronic inflammation. Dysfunctional cilia at the embryonic node give rise to laterality defects such as situs inversus of the internal organs in about half of the individuals.9 In addition, PCD-affected individuals often suffer from sub- or infertility caused by dysfunction of fallopian tube cilia and sperm flagella.