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Primary ciliary dyskinesia (PCD)

Primary ciliary dyskinesia (PCD), also known as Kartagener syndrome is a rare motile ciliopathy that results in chronic oto-sinopulmonary disease.

Primary ciliary dyskinesia (PCD), also known as Kartagener syndrome is a rare motile ciliopathy that results in chronic oto-sinopulmonary disease.

  • Autosomal recessive inheritance

History:

Primary ciliary dyskinesia (PCD), formerly known as immotile cilia syndrome, was first described by Siewert as a combination of situs inversus, chronic sinusitis, and bronchiectasis in 1904. However, Manes Kartagener first recognized this clinical triad as a distinct congenital syndrome in 1933. Because Kartagener described this syndrome in detail, it bears his name. Kartagener’s syndrome (KS) is inherited via an autosomal recessive pattern. Its incidence is about 1 in 30,000 live births. Male patients with this syndrome are almost invariably infertile because of immotile spermatozoa. The immotility is due to variety of ultrastructural defects in respiratory cilia and sperm tail. Afzelius was the first to recognize the relationship between KS and male infertility when he observed lack of dynein arms in the sperms and cilia of four subjects, three with KS and a fourth one, brother of one of the three subjects.


Etiopathology

Ciliopathy:

Genetically heterogeneous group of disorders that are caused by mutations in genes with products that localize to the cilium–centrosome complex.
  • Ciliary functions:
    • Motile cilia: Respiratory epithelial function, fertility, and determination of left-right orientation
    • Primary (or sensory) cilia: Antennae for cells, sensing the extracullar environment and transducing signals back to the cell to facilitate its response. These functions are critically important in cell proliferation, differentiation, and maintenance.
Structures and functions of motile and non-motile cilia
Structures and functions of motile and non-motile cilia: All cilia extend from a basal body that typically consists of triplet microtubules, and subdistal and distal appendages. Distal appendages (also known as transition fibres) tether the basal body to the base of the ciliary membrane. Immediately distal to the basal body is the transition zone, which contains doublet microtubules that are connected to the ciliary membrane via Y-shaped structures. Axonemes (the ciliary backbone) are composed of doublet microtubules. In motile cilia, axonemes usually contain associated structures and proteins (for example, the central pair and axonemal dyneins) that are required for ciliary motility. Nodal cilia are an exception as they are motile but lack a central pair of microtubules. Cilia may contain additional subdomains, including singlet microtubules at the distal end, and regions with specific protein compositions or functions (for example, the inversin domain (INV; involved in signalling). Key cell signalling functions and roles in motility are summarized. | PKD, polycystin. | Reiter, J. F., & Leroux, M. R. (2017). Genes and molecular pathways underpinning ciliopathies. Nature reviews. Molecular cell biology, 18(9), 533–547. https://doi.org/10.1038/nrm.2017.60

Primary ciliary dyskinesia (PCD) “immotile cilia syndrome”:

Defects in the function of the motile cilia give rise to primary ciliary dyskinesia (PCD), or immotile cilia syndrome. PCD is the first human condition linked to abnormal ciliary function. Like other ciliopathies, PCD is genetically heterogeneous and patients demonstrate a spectrum of clinical manifestations with variable severity. Most patients demonstrate defective function of the outer dynein arms.
  • Respiratory tract: Abnormal ciliary movements cause impaired mucociliary clearance that results in recurrent and chronic oto-sinopulmonary infections.
  • Infertility: Sperm tail and fimbriae of fallopian tubes also have motile cilia therefore male and female infertility often results
  • Situs abnormalities: Abnormal thoracoabdominal orientation results since normal ciliary movement needed for the visceral rotation during embryogenesis

Clinical features

The majority of newborns with primary ciliary dyskinesia develop neonatal respiratory distress with atelectasis on chest radiographs. Unlike other causes of respiratory distress in newborns, which occurs in the first few hours after birth, the respiratory distress with primary ciliary dyskinesia patients occurs 12 to 24 hours after birth in term infants.

Clinical triad:

  1. Chronic recurrent rhinosinusitis (caused by pseudomonal infection)
  2. Bronchiectasis (caused by pseudomonal infection)
  3. Situs inversus (50% cases)

Other features:

  • Male infertility (100%)
  • Reduced female fertility or ectopic pregnancy

Diagnosis

Diagnostic criteria:

History of chronic bronchial infection and rhinitis from early childhood, combined with ≥ 1 features:
  1. Situs inversus or dextrocardia
  2. Alive but immotile spermatozoa
  3. Absent/impaired tracheobronchial clearance
  4. Cilia showing characteristic ultrastructural defect on electron microscopy

Imaging:

Kartagener’s syndrome: A) chest radiography with dextrocardia; B,C) face CT with mucosal thickening and material with soft tissue density in the paranasal sinuses, mastoid cells and in the middle and external ear cavities; D,E) axial chest CT showing bronchiectasis and centrilobular nodules (tree-in-bud sign); F) axial CT image showing liver (L) on the left and spleen (S) on the right | Queiroz, R. M., & Filho, F. B. (2018). Kartagener’s syndrome. The Pan African medical journal, 29, 160. https://doi.org/10.11604/pamj.2018.29.160.14927

Differential diagnosis:

  • Cystic Fibrosis
  • Foreign body aspiration
  • Idiopathic interstitial pneumonia
  • Idiopathic nasal polyposis
  • Immunosuppression
  • Malignancy
  • Post-infectious bronchiectasis
  • Severe atopy
  • Tracheobronchomegaly

Management

Treatment of Kartagener syndrome includes daily chest physiotherapy, antibiotics with good pseudomonal coverage, and supportive pulmonary care.

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