C. Both
Discussion
The clinical history for both Patient A and Patient B is concerning
for a diagnosis of primary ciliary dyskinesia (PCD). PCD is a genetic,
autosomal recessive disorder characterized by defective ciliary
structure and function.1
The diagnosis of PCD is challenging and typically relies on both
clinical history and diagnostic testing including nasal nitric oxide
(nNO), ciliary biopsy and genetic testing. Due to the variety of
diagnostic tests available, referral to a specialty center which can
provide a comprehensive evaluation and interpretation of tests is
recommended. In 2018, the American Thoracic Society released
Clinical Practice Guidelines which included a diagnostic algorithm for
evaluating a patient with suspected PCD. The diagnostic criteria for
primary ciliary dyskinesia include having two or more of the major
criteria plus at least one of the minor criteria.4
Major criteria:
- Unexplained neonatal respiratory distress in term infant
- Year-round daily cough beginning before 6 months of age
- Year-round daily nasal congestion beginning before 6 months of age
- Organ laterality defect
Minor criteria:
- nNO during plateau <77 nL/min on 2 occasions, >2 months apart, with CF excluded
- Diagnostic ciliary ultrastructure on EM
- Biallelic mutations in one PCD gene
- Persistent and diagnostic ciliary waveform abnormalities on high-speed video-microscopy, on multiple occasions
Both patients above have two major criteria for PCD and should
undergo further testing to evaluate for ciliary disease. While recurrent
episodes of acute otitis media and sinusitis can be seen in patients
with PCD and ciliopathies, currently it is not included as criteria in
the diagnostic guidelines published by the ATS. Genetic testing is a key
part of diagnosing PCD. There are currently 45 genes known to be
associated with PCD, with the most common being DNAI1 and DNAH5, however
approximately 20-30% of patients who fit the diagnostic criteria do not
have an identified genetic variant.3 While heterotaxy and
laterality defects can be seen in healthy, asymptomatic patients, their
presence should prompt further investigation to determine if testing for
PCD is warranted. Interestingly in the case above, while both siblings
have PCD, only one has laterality defects (Patient A), highlighting the
complex relationship between PCD, laterality defects and inheritance.
Nodal cilia, one of the three classes of cilia, are involved in
determining left-right body orientation. Abnormalities in the motility
of nodal cilia can result in laterality defects seen in approximately
50% of PCD patients.2 These can include both situs inversus
totalis and situs ambiguous. Situs inversus totalis, which is seen in
Figure 1, is the reversed lateralization of all visceral organs and
present in 40-50% of PCD patients.3 Heterotaxy, or situs
ambiguus, is characterized by the abnormal distribution, but not
complete reversed lateralization, of visceral organs within the chest
and abdomen and is seen in about 12% of PCD patients.3
Other organ systems can be affected in patients with heterotaxy, such
as the spleen, and further evaluation for asplenia or polyspenia are
warranted. There are, at this time, no therapies
specifically approved for patients with PCD. Recommended therapies
include airway clearance with nebulized hypertonic saline and chest
physiotherapy, with the goal of preventing exacerbations and slowing
disease progression.2
References
-
Kennedy MP, Omran H, Leigh MW, et al. Congenital Heart Disease and
Other Heterotaxic Defects in a Large Cohort of Patients with Primary
Ciliary Dyskinesia. Circulation.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.106.649038. Published May 21, 2007.
-
Mirra V, Werner C, Santamaria F. Primary Ciliary Dyskinesia: An
Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment
Strategies. Frontiers in Pediatrics.
https://pubmed.ncbi.nlm.nih.gov/28649564/. Published June 9, 2017.
-
Maimoona ZA, Knowles MR, Leigh MW. Primary Ciliary Dyskinesia. NCBI (National Center for Biotechnology Information).
https://www.ncbi.nlm.nih.gov/books/NBK1122/. Published January 24, 2007.
-
Diagnosis of Primary Ciliary Dyskinesia: An Official American
Thoracic Society Clinical Practice Guideline. American Journal of
Respiratory and Critical Care Medicine Volume 197 Number 12 | June 15,
2018
