Elsevier

Seminars in Perinatology

Volume 30, Issue 6, December 2006, Pages 335-340
Seminars in Perinatology

Primary Ciliary Dyskinesia and Newborn Respiratory Distress

https://doi.org/10.1053/j.semperi.2005.11.001Get rights and content

Primary ciliary dyskinesia is an autosomal recessive genetic disease that results in impaired mucociliary clearance causing progressive involvement of the upper and lower respiratory tract, characterized by airway obstruction and recurrent infections of the lungs, middle ear and paranasal sinuses. Other clinical manifestations include situs inversus totalis and male infertility. Recently, neonatal respiratory distress has been found to be a common clinical presentation of patients with primary ciliary dyskinesia, indicating that this is an important symptom complex in early life for this condition. The diagnosis requires a high index of suspicion, but primary ciliary dyskinesia must be considered in any term neonate who develops respiratory distress or persistent hypoxemia and has situs inversus or an affected sibling. Moreover, further evaluation is warranted in children who had transient respiratory distress in newborn period and subsequently develop persistent cough or chronic otitis media.

Section snippets

Ciliary Structure and Function

The respiratory epithelium in the nasopharynx, middle ear, paranasal sinuses, and conducting airways (including trachea, bronchi, and bronchioles) is lined by a ciliated, pseudostratified columnar epithelium that is essential for mucociliary clearance. Each mature ciliated epithelial cell has approximately 200 uniform cilia (5 to 6 μm in length and 0.2 μm diameter) that are functionally and anatomically oriented in the same direction. With a beating frequency of 5 to 20 Hz, cilia play a central

Role of Cilia in Pulmonary Defense

The human lung is exposed daily to inhaled pathogens and airborne irritants. Innate host defenses are critical in acute pulmonary injury and infection. Complex, local defenses have evolved to protect the airway, including mucociliary clearance. By this mechanism, inhaled particles are entrapped in mucus on the airway surface, then cleared by the coordinated action of cilia that sweeps mucus toward the pharynx. The volume and composition of airway surface liquid (ASL) influence the efficiency of

Primary Ciliary Dyskinesia

PCD is a human genetic disease associated with abnormal ciliary structure and function.6, 7, 8, 9, 10, 16, 17, 18, 19, 20 This genetically heterogeneous disorder involves multiple genes and usually is expressed in an autosomal recessive pattern with an estimated incidence of 1 in 15,000 to 30,000 births.21, 22 Ciliary dysfunction causes impaired mucociliary clearance, which results in the retention of inhaled particles, including bacteria, in the lung, paranasal sinuses, and middle ear (Table 1

Primary Ciliary Dyskinesia and Neonatal Respiratory Distress

Respiratory distress syndrome in newborn babies is the most common respiratory cause of death and morbidity in children in the first year of life,43 occurring at a rate of 25.1 cases per 100,000 births, based on 2001 data.44 Regardless of the cause, infants with respiratory distress present with similar clinical findings: tachypnea, increased work of breathing, and retractions. As respiratory distress progresses, gas exchange abnormalities develop, ultimately resulting in respiratory failure

Diagnosis of Primary Ciliary Dyskinesia

The diagnosis of PCD requires a high index of suspicion, and currently patients must have a compatible clinical phenotype and specific ultrastructural defects of the cilia detected by transmission electron microscopy.6, 10, 20 Expertise in evaluating ciliary ultrastructure is important to distinguish the primary (genetic) defects from acquired detects that result from exposure to different environmental and infectious agents.6, 71, 72 Absent (or shortened) dynein arms occur in up to 90% of

Genetics of Primary Ciliary Dyskinesia

As predicted from the complexity of ciliary structure and function, PCD is a genetically heterogeneous disorder that, in most cases, is autosomal recessive.81, 82 However, our understanding of the link between ultrastructural changes of cilia and the underlying genetic defect of PCD has lagged, which is in part related to the fact that mutations in any one of the 250 proteins that constitute a cilium could potentially cause PCD. For instance, the absence of a dynein arm may reflect a defect in

Management of Primary Ciliary Dyskinesia

Unfortunately, no specific therapeutic modalities are available to correct the ciliary dysfunction. Consequently, treatment focuses on facilitating the clearance of retained mucus secretions from the respiratory tract as well as aggressive therapy of bacterial infections.36 It is generally accepted that early diagnosis and institution of these therapies can limit early damage to these organs and slow the progression of disease. Unfortunately, little evidence exists showing the efficacy of

Prognosis

In contrast to cystic fibrosis, many individuals with PCD have experienced a normal or near-normal lifespan. However, the rate of lung disease progression is variable, and bronchiectasis may progress to severe pulmonary disability and eventually respiratory failure. Earlier diagnosis and institution of therapy could improve the overall health and prognosis for these patients.

Summary

PCD is a genetic disorder that results in dysfunction of motile cilia, resulting in chronic infections of the upper and lower respiratory tracts, male infertility, and situs inversus totalis in half of affected individuals. It has become increasingly clear that transient respiratory distress and hypoxemia in newborn period is highly prevalent in the PCD population, which suggests that cilia function may be important in transition from the fluid-filled fetal lung to air-filled neonatal lung.

Acknowledgments

Drs. Leigh and Ferkol are both members of the National Instuitutes of Health (NIH) Genetic Disorders of Mucociliary Clearance Consortium, and their work on primary ciliary dyskinesia is supported by NIH Grant Awards RR019480 (ML and TF) and HL079024 (TF). Dr. Ferkol is currently a member of a Speakers Bureau sponsored by Chiron Corporation.

References (89)

  • L. Jain

    Alveolar fluid clearance in developing lungs and its role in neonatal transition

    Clin Perinatol

    (1999)
  • C.W. Gowen et al.

    Electrical potential difference and ion transport across nasal epithelium of term neonates: correlation with mode of delivery, transient tachypnea of the newborn, and respiratory rate

    J Pediatr

    (1988)
  • R. Corbelli et al.

    Nasal nitric oxide measurements to screen children for primary ciliary dyskinesia

    Chest

    (2004)
  • G. Pennarun et al.

    Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia

    Am J Hum Genet

    (1999)
  • C. Guichard et al.

    Axonemal dynein intermediate-chain gene (DNAI1) mutations result in situs inversus and primary ciliary dyskinesia (Kartagener syndrome)

    Am J Hum Genet

    (2001)
  • A. Miralles et al.

    Heart-lung transplantation in situs inversusA case report in a patient with Kartagener’s syndrome

    J Thorac Cardiovasc Surg

    (1992)
  • P. Macchiarini et al.

    Double lung transplantation in situs inversus with Kartagener’s syndrome

    J Thorac Cardiovasc Surg

    (1994)
  • H. Date et al.

    Living-donor lobar lung transplantation for primary ciliary dyskinesia

    Ann Thorac Surg

    (2001)
  • P. Satir

    The cilium as a biological nanomachine

    FASEB J

    (1993)
  • M. Sleigh

    The nature and action of respiratory tract cilia

  • M.E.J. Holwill

    Dynein motor activity during ciliary beating

  • I. Ibanez-Tallon et al.

    To beat or not to beat: roles of cilia in development and disease

    Hum Mol Genet

    (2003)
  • H.C. Taylor et al.

    Assessment of inner dynein arm structure and possible function in ciliary and flagellar axonemes

    Cell Motil Cytoskeleton

    (1999)
  • M. Greenstone et al.

    Primary ciliary dyskinesia: cytological and clinical features

    Q J Med

    (1988)
  • R.U. de Iongh et al.

    Ciliary defects in healthy subjects, bronchiectasis, and primary ciliary dyskinesia

    Am J Respir Crit Care Med

    (1995)
  • R. Eliasson et al.

    The immotile-cilia syndromeA congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility

    N Engl J Med

    (1977)
  • P.G. Noone et al.

    Primary ciliary dyskinesia: diagnostic and phenotypic features

    Am J Respir Crit Care Med

    (2004)
  • A. Wanner et al.

    Mucociliary clearance in the airways

    Am J Respir Crit Care Med

    (1996)
  • R.C. Boucher

    Human airway ion transport (Part 2)

    Am J Respir Crit Care Med

    (1994)
  • R.C. Boucher

    Human airway ion transport (Part 1)

    Am J Respir Crit Care Med

    (1994)
  • M.R. Knowles et al.

    Mucus clearance as a primary innate defense mechanism for mammalian airways

    J Clin Invest

    (2002)
  • B.A. Afzelius

    A human syndrome caused by immotile cilia

    Science

    (1976)
  • B.A. Afzelius et al.

    Immotile-cilia syndrome (primary ciliary dyskinesia), including Kartagener syndrome

  • M.W. Leigh

    Primary ciliary dyskinesia

  • M.W. Leigh

    Primary ciliary dyskinesia

    Sem Resp Crit Care Med

    (2003)
  • A. Bush et al.

    Primary ciliary dyskinesia: diagnosis and standards of care

    Eur Respir J

    (1998)
  • J. Torgersen

    Situs inversus, asymmetry, and twinning

    Am J Hum Genet

    (1950)
  • A. Ellerman et al.

    Longitudinal study of lung function in a cohort of primary ciliary dyskinesia

    Eur Respir J

    (1997)
  • C.W. Corkey et al.

    The immotile cilia syndromeA longitudinal survey

    Am Rev Respir Dis

    (1981)
  • J. Hellinckx et al.

    Primary ciliary dyskinesia: evolution of pulmonary function

    Eur J Pediatr

    (1998)
  • D. Holzmann et al.

    Neonatal respiratory distress syndrome: a sign of primary ciliary dyskinesia?

    Eur J Pediatr

    (2000)
  • A. Whitelaw et al.

    Immotile cilia syndrome: a new cause of neonatal respiratory distress

    Arch Dis Child

    (1981)
  • T. Hossain et al.

    Primary ciliary dyskinesia as a cause of neonatal respiratory distress: implications for the neonatologist

    J Perinatol

    (2003)
  • R. Bromiker et al.

    Early diagnosis of primary ciliary dyskinesia in a newborn without situs inversus

    Acta Paediatr

    (2002)
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