children Review Respiratory Distress in the Newborn with Primary Ciliary Dyskinesia Evans Machogu * and Benjamin Gaston Section of Pediatric Pulmonology, Allergy and Sleep Medicine, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN 46202, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-317-948-7208; Fax: +1-317-944-7247 Abstract: Primary ciliary dyskinesia (PCD) is inherited in a predominantly autosomal recessive manner with over 45 currently identified causative genes. It is a clinically heterogeneous disorder that results in a chronic wet cough and drainage from the paranasal sinuses, chronic otitis media with hearing impairment as well as male infertility. Approximately 50% of patients have situs inversus totalis. Prior to the development of chronic oto-sino-pulmonary symptoms, neonatal respiratory distress occurs in more than 80% of patients as a result of impaired mucociliary clearance and mucus impaction causing atelectasis and lobar collapse. Diagnosis is often delayed due to overlapping symptoms with other causes of neonatal respiratory distress. A work up for PCD should be initiated in the newborn with compatible clinical features, especially those with respiratory distress, consistent radiographic findings or persistent oxygen requirement and/or organ laterality defects Keywords: primary ciliary dyskinesia; neonatal respiratory distress Citation: Machogu, E.; Gaston, B. 1. Neonatal Respiratory Distress Respiratory Distress in the Newborn Respiratory distress develops in about 7% of all newborn infant deliveries [1]. Respi- with Primary Ciliary Dyskinesia. ratory distress syndrome (RDS) develops in 1% of all newborn infant deliveries primarily Children 2021, 8, 153. https://doi. in premature babies due to surfactant deficiency, and its prevalence is inversely associated org/10.3390/children8020153 with gestational age. More than 50% of infants born at <28 weeks’ gestation develop RDS Academic Editors: Roberto W. Dal compared to <5% of those greater than 37 weeks gestation. In 2014, nearly 10 of every 100 Negro and Rita Marie Ryan infants were delivered at <37 completed weeks’ gestation. Neonatal RDS contributes to significant morbidity and mortality and is ranked in the top 10 leading causes of infant Received: 29 December 2020 mortality. It is the leading cause of mortality in premature infants and contributes to 2% of Accepted: 10 February 2021 all causes of infant deaths [2]. Published: 18 February 2021 Clinical symptoms of respiratory distress in neonates include tachypnea, nasal flaring, grunting, retractions and cyanosis. The differential diagnosis for neonatal respiratory Publisher’s Note: MDPI stays neutral distress is broad and includes RDS, transient tachypnoea of the newborn (TTN), neonatal with regard to jurisdictional claims in pneumonia, pulmonary air leak such as pneumothorax and pneumomediastinum, pul- published maps and institutional affil- monary arterial hypertension, congenital heart disease, interstitial lung diseases such as iations. those due to surfactant protein deficiencies and other non-pulmonary systemic disorders such as neonatal sepsis, hypothermia and metabolic acidosis. Primary ciliary dyskinesia (PCD) presents with neonatal respiratory distress in majority of patients and should be considered in the differential diagnosis, especially in term infants with respiratory distress. Copyright: © 2021 by the authors. Given the long-term complications related to chronic airway inflammation and infection, Licensee MDPI, Basel, Switzerland. making the diagnosis in the neonatal period is critical. This article is an open access article distributed under the terms and 2. The Motile Cilia conditions of the Creative Commons Primary ciliary dyskinesia is characterized by impaired function of motile cilia that Attribution (CC BY) license (https:// leads to chronic inflammation and infection in the middle ear, sinuses and lungs among creativecommons.org/licenses/by/ other clinical manifestations. Motile cilia are highly specialized organelles that exist in 4.0/). Children 2021, 8, 153. https://doi.org/10.3390/children8020153 https://www.mdpi.com/journal/children Children 2021, 8, x FOR PEER REVIEW 10 of 12 2. The Motile Cilia Primary ciliary dyskinesia is characterized by impaired function of motile cilia that leads to chronic inflammation and infection in the middle ear, sinuses and lungs among other clinical manifestations. Motile cilia are highly specialized organelles that exist in select cells in the upper and lower respiratory epithelium, the ependymal cells in the cer- ebral ventricles, in the female reproductive tract and in spermatozoa. Each motile cilium consists of a cytoskeleton referred to as an axoneme that is com- posed of nine longitudinal microtubule doublets that surround a central pair of single microtubules in a 9+2 axonemal conformation. The outer microtubules are linked to each Children other2021, 8, 153 through nexin links and have two attachments, the inner and outer dynein2 ofarms 12 (IDA and ODA). The dynein arms are anchored to the central microtubules via radial spokes [3]. The cilium is attached to the cell via a basal body and, in the airway lumen, extends through aselect periciliary cells in theliquid upper (PCL and lower) layer respiratory with the epithelium, tip reaching the ependymal a mucus cellslayer. in theEach ciliated cell in thecerebral respiratory ventricles, epithelium in the female has reproductive approximately tract and in 200 spermatozoa. cilia that beat at a fre- Each motile cilium consists of a cytoskeleton referred to as an axoneme that is com- quency of 5–20 hzposed. The ofcoordinated nine longitudinal and microtubule synchronized doublets bending that surround of the a cilia central produces pair of single wave like movements thatmicrotubules function in to a 9+2 propel axonemal bacteria conformation. and trapped The outer particles microtubules on arethe linked mucus to each layer of the airway surfaceother [4] through. Nodal nexin cilia links are and also have motile two attachments, cilia that theonly inner exist and in outer embryogenesis. dynein arms (IDA and ODA). The dynein arms are anchored to the central microtubules via radial Nodal cilia lack radialspokes spokes [3]. The and cilium central is attached microtubules to the cell via and a basal therefore body and, have in the a airway9+0 axonemal lumen, conformation. Theextends outer through microtubules a periciliary are liquid linked (PCL) to layer each with other the tip and reaching do have a mucus dynein layer. Each arms. These cilia have a ciliatedrotary cellmotion in the that respiratory through epithelium chemical has approximatelygradients help 200 ciliaguide that organ beat at growth a fre- quency of 5–20 hz. The coordinated and synchronized bending of the cilia produces wave and laterality. like movements that function to propel bacteria and trapped particles on the mucus layer Approximatelyof the 70% airway of patients surface [4]. with Nodal PCD cilia are have also motilebiallelic cilia thatmutations only exist in in embryogenesis.a known gene associated with theNodal disease. cilia lack Mutations radial spokes in and the centralse genes microtubules that code and thereforefor the haveproteins a 9+0 axonemalthat make conformation. The outer microtubules are linked to each other and do have dynein arms. up the ciliary axonemeThese ciliaresult have in a rotaryultrastructural motion that through and/or chemical functional gradients abnormalities help guide organ of growth the mo- tile cilia resulting andin the laterality. PCD disorder [5]. However, many of the disease-causing genes do not result from genesApproximately encoding 70% ciliary of patients ultrastructure: with PCD have biallelicadditional mutations genes in a are known involved gene associated with the disease. Mutations in these genes that code for the proteins that make with ciliagenesis, uptrafficking the ciliary of axoneme ciliary result proteins in ultrastructural, ciliary function and/or functional and other abnormalities cellular ofmecha- the nisms not evidentmotile by electron cilia resulting microscopy in the PCD. disorderThese ultrastructural [5]. However, many defects of the disease-causing can be visualized genes on transmission electrondo not result microscopy from genes encoding (TEM) ciliaryand include ultrastructure: ODA additional defects, genes OD areA+ involvedIDA defects, with ciliagenesis, trafficking of ciliary proteins, ciliary function and other cellular mechanisms IDA with microtubularnot evident disorganization by electron microscopy. (MTD) These, radial ultrastructural spoke defects defects or can central be visualized apparatus on defects (Figure 1).transmission However, electron not all microscopy gene mutations (TEM) and result include in ODA obvious defects, ultrastructural ODA+IDA defects, de- fects on TEM. In fact,IDA approximately with microtubular disorganizationa third do not. (MTD), For example, radial spoke normal defects or ciliary central apparatusultrastruc- defects (Figure1). However, not all gene mutations result in obvious ultrastructural defects ture is found in mutationson TEM. In fact,of the approximately CCDC65 a thirdprotein do not. [6] For while example, mutations normal ciliary in genes ultrastructure such as GAS8 result in veryis found subtle in mutations changes of that the CCDC65 are not protein easily [6 ]recognizable while mutations on in genes TEM such [7] as. Further, GAS8 because of chronicresult inflammation