Primary ciliary dyskinesia: Overlooked and undertreated in children

Abstract

Primary ciliary dyskinesia (PCD) is a multi-organ disorder associated with chronic oto-sino-pulmonary disease, neonatal respiratory distress, situs abnormalities and reduced fertility. Repeated respiratory tract infections leads to the almost universal development of bronchiectasis. These clinical manifestations are a consequence of poorly functioning motile cilia. However, confirming the diagnosis is quite difficult and is often delayed, so the true incidence of PCD may be significantly higher than current estimates. Nasal nitric oxide has been earmarked as a useful screening tool for identifying patients, but its use is limited in pre-school-aged children. Due to the rarity of PCD, the evidence base for management is somewhat limited, and treatment regimens are extrapolated from other suppurative lung disorders, like cystic fibrosis.

Cilia distribution and polarity in the epithelial lining of the mouse middle ear cavity

“…Our study supports the justification to expand upon the capacity of current tests for PCD and other ciliopathy-related diseases, which are considered to significantly underestimate the cases, to include the ability to reveal defects in PCP genes and cilia polarity10657778. The inclusion of PCP and cilia polarity genes in the genetic and pathological-morphological tests will likely lend support to the idea of PCP genes as a novel class of susceptibility genes for COME and other respiratory diseases, caused by a reduction or ablation of mucociliary functions of the motile cilia.…”

“…The demonstration of motile cilia PCP in the middle ear points to the possibility that defective PCP signaling may lead to respiratory diseases and chronic OM with effusion, which is commonly associated with PCD and other ciliopathy diseases67126465667677. Our study supports the justification to expand upon the capacity of current tests for PCD and other ciliopathy-related diseases, which are considered to significantly underestimate the cases, to include the ability to reveal defects in PCP genes and cilia polarity10657778.…”

“…In the respiratory epithelium of the trachea, motile cilia are uniformly orientated to generate an outward flow for mucociliary clearance27. Cilia dysfunctions have been implicated in a number of conditions, including neonatal respiratory distress, chronic nasal congestion, bronchiectasis and sinusitis, and chronic otitis media with effusion67810111263646566. Despite the significant association and likely contributory role of cilia in OM671112636667, the most common childhood disease, only a sparse number of studies examined ciliation in the epithelium that lines the middle ear cavity and thus have provided only a partial understanding of ciliation in the middle ear13141617686970.…”

Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review

“…[1][2][3] Recently, significant progress has been made in PCD diagnosis, 4 yet few physicians outside of highly experienced PCD centers are skilled in recognizing the characteristic clinical phenotype and interpreting diagnostic tests. [5][6][7][8][9] Patients often receive false-positive or false-negative PCD diagnoses, as physicians are unaware of the pitfalls commonly encountered with ciliary electron microscopy, 10,11 PCD molecular genetic panels, 12,13 ciliary motility studies, [14][15][16] and nasal nitric oxide testing. 17,18 Furthermore, PCD is often missed when respiratory symptoms are present in patients with other complex diseases involving cilia, such as heterotaxy and various genetic syndromes.…”

“…Testing should be performed at baseline health status and repeated if there is any question about health status 2. Reference.18 3 The risk of false positive result is moderately increased with secondary changes from infectious processes or pollutant exposures, improper specimen handling and processing, or inexperience with electron microscopy interpretation.4 4 Several PCD-causing genetic mutations can result in normal electron microscopy10 or subtle changes which are not readily apparent.38 5 Misinterpretation of genetic panel result (e.g., variants of unknown significance or single mutations in two different PCD genes interpreted as "diagnostic") 6. Genetic panel testing may miss large insertions, deletions, and mutations in novel genes, since approximately 30% of PCD do not have identifiable mutations in the currently known PCD associated genes, but this risk should decrease with broader range of genetic analysis provided by NGS panels 7.…”