(Chest. 2000;117:1207-1209.)
© 2000
American College of Chest Physicians
Primary Ciliary Dyskinesia Associated With a Novel Microtubule Defect in a Child With Down’s Syndrome*
Tom Kovesi, MD;
Brian Sinclair, MD;
Johnna MacCormick, MD;
Mary Ann Matzinger, MD and
Blair Carpenter, MD
*
Department of Pediatrics (Drs. Kovesi and Sinclair), the Department of Surgery (Dr. MacCormick), the Department of Diagnostic Imaging (Dr. Matzinger), and the Department of Pathology (Dr. Carpenter), Children’s Hospital of Eastern Ontario, Ottawa, Canada.
Correspondence to: Thomas Kovesi, MD, Department of Pediatrics, Children’s Hospital of Eastern Ontario, 401 Smyth Rd, Ottawa, Ontario, Canada, K1H 8L1; e-mail: kovesi{at}cheo.on.ca
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Abstract
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We present a child with Down’s syndrome, bilateral lower lobe
bronchiectasis, sinusitis, and severe ear disease who was found to have
a novel ciliary defect, with a frequent, partial absence of the walls
of the A subunits of some peripheral doublets. The defect caused the A
subunits to be "U-shaped" rather than "O-shaped." A nuclear
nasal mucociliary transport study confirmed that this defect was
associated with abnormal mucociliary transport. The ciliary defect was
not observed in a biopsy performed in a second patient who had Down’s
syndrome.
Key Words: bronchiectasis • ciliary motility disorders • Down’s syndrome
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Introduction
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Primary
ciliary dyskinesia (PCD) is characterized by chronic sinopulmonary
infection and eustachian tube dysfunction, due to impaired mucociliary
transport caused by absent or dyskinetic ciliary motion.1
The ultrastructure of normal cilia consists of nine outer microtubule
pairs and two single central microtubules. Each microtubule pair
includes two subunits, termed the A subunit and the
B subunit.2
We report the first case of PCD
associated with partial absence of the A subunit in a child with
Down’s syndrome (DS).
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Case Report
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The patient is an 8-year-old boy with DS (47 XY + 21
karyotype). He was first admitted at 4 months of age with wheezing and
dyspnea due to respiratory syncytial virus infection. Cardiac
evaluation showed a partial atrioventricular septal defect (primum
atrial septal defect [ASD]). He was readmitted several times between
1990 and 1992 with wheezing and pneumonia involving the right middle,
and sometimes lower lobes. He had recurrent otitis media and chronic
serous otitis, requiring bilateral myringotomy and tube placement in
1990. Bronchoscopy, performed in 1990, revealed diffuse bronchial
suppuration, and cultures grew Streptococcus pneumoniae,
Haemophilus influenzae, and Staphylococcus
aureus. Cardiac ultrasound and catheterization in 1992 established
the diagnosis of a moderate-sized primum ASD, cleft left
atrioventricular valve with moderate regurgitation, and a patent ductus
arteriosus. Repair of the ASD, and ligation of the patent ductus were
performed, although moderate residual left atrioventricular valvular
regurgitation and a small atrial shunt persisted.
The patient subsequently improved; however, chronic chest congestion,
green sputum production, and rhinorrhea with green or clear nasal
discharge persisted. In 1996, he underwent left atrioventricular valve
repair and closure of residual ASD. At thoracotomy, the cardiac surgeon
noted the lungs felt unusually "hard."
Symptoms of wheezing, cough, and severe exercise intolerance persisted,
with no response to salbutamol and fluticasone.
Physical examination revealed a well-looking male patient with the
stigmata of DS. Scarring of the right tympanic membrane, copious fluid
behind the left tympanic membrane, and rhinorrhea were present. The
chest was clear. There was no clubbing, and the remainder of the
examination was unremarkable.
Investigations included a normal sweat chloride and serum
concentrations of Ig and IgG subclasses. Radionuclide reflux study
showed mild gastroesophageal reflux to the mid-esophagus.
Video-fluoroscopic feeding study showed normal swallowing and no
tracheobronchial aspiration. CT of the chest demonstrated changes
consistent with mild congestive cardiac failure, bronchiectasis of both
lung bases, which was most marked in the posterior segment of the left
lower lobe, and multiple areas of plate-like atelectasis, possibly due
to dependent atelectasis. CT of the petrous temporal bones demonstrated
opacification of the left mastoid air cells and left middle ear cavity.
Tracheal mucosal biopsy from the carina was performed, and electron
microscopic examination of the specimen revealed a frequent, partial
absence of the walls of the A subunits of some peripheral doublets. The
defect, quite consistent in appearance and location, caused the A
subunits to be U-shaped rather than O-shaped.
There were also many nonspecific changes in the cilia, including
"blebbing" of the apical cytoplasm, presence of numerous compound
cilia, occasional disorganization of the tubules, and absence of the
central tubules. Inner and outer dynein arms and radial spokes were
identified (Fig 1
). A nasal ciliary transport study was performed, using technetium-99m
phytate placed on the left inferior turbinate.3
Although
the patient became agitated and cried, preventing the acquisition of
continuous images, images taken 20 min after placement of the
radiotracer showed no significant movement (Fig 2
, top). A normal control subject showed normal mucociliary
transport (Fig 2
, bottom). Electron microscopic examination
of the cilia in another child with DS and chronic pulmonary disease was
normal (data not shown). Following the diagnosis of PCD with a novel
ciliary defect, the patient received aggressive antibiotic therapy, and
chest physiotherapy was performed to the extent that he would
cooperate. This resulted in marked improvement in the patient’s
symptoms.
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Figure 1.. Abnormal cilia with frequent defects in the dynein
arm-bearing microtubules also known as A tubules or A subunits,
characterized by the absence of the outer wall giving rise to a
U-shaped opening (arrowheads; electron microscopy x 115,000).
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Figure 2.. Top: Nasal technetium-99m phytate
transit time in patient with DS (8 min postdynamic phase) showing
absence of movement of the radiotracer from its origin on the inferior
nasal turbinate. Bottom: Nasal technetium-99m phytate
transit time in a normal subject (10 min postdynamic phase) showing
normal movement of the radiotracer from its initial placement on the
inferior nasal turbinate.
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Discussion
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This patient presented with typical manifestations of PCD,
including bronchiectasis and recurrent right middle lobe pneumonia,
chronic rhinorrhea, and severe sinus and middle ear
disease.4
Diagnosis was complicated by the presence of an
atrial left to right shunt with increased pulmonary blood flow, which
can also cause recurrent wheezing and dyspnea. The diagnosis was
confirmed by demonstrating abnormal mucociliary transport. An increased
prevalence of nonspecific abnormalities in ciliary ultrastructure, as
seen in our patient, has previously been reported in association with
other types of PCD.1
While absence of the B subunit of the
microtubule doublets, in association with PCD, has been described in
one case,2
disease associated with defects of the A
subunit has not previously been reported. Complex congenital cardiac
defects have been described in several children with PCD.
PCD is believed to be an autosomal recessive inherited condition,
although the gene loci involved have not yet been identified. Candidate
genes, such as the heavy chain gene of human cytoplasmic dynein, mapped
to 14q, and the tubulin ß gene TUBB, mapped to
6p,5
do not appear to involve genes present on chromosome
21. Recurrent pneumonia and frequent sinus and ear infections are well
recognized in DS, and these are inconsistently related to immune
defects reported to be commoner in DS, such as IgG subclass
deficiency.6
The normal ciliary ultrastructure in a second
patient with DS suggests that the defect we describe is not a pervasive
defect in DS. However, examination of the cilia in more patients with
DS will be required to determine whether this defect is at least
partially responsible for the increased incidence of infection in these
patients.
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Acknowledgements
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The assistance of Dr. Mary Pothos
(Department of Pediatrics), Scott Walker, BSc, RTNM, MRT(N) (Department
of Diagnostic Imaging), and Ian Robb, MLT (Department of Pathology) is
gratefully acknowledged.
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Footnotes
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Abbreviations: ASD = atrial septal defect; DS = Down’s
syndrome; PCD = primary ciliary dyskinesia
Received for publication April 13, 1999.
Accepted for publication October 15, 1999.
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References
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-
Rossman, CM, Newhouse, MT (1988) Primary ciliary dyskinesia: evaluation and management. Pediatr Pulmonol 5,36-50[ISI][Medline]
-
de Iongh, RU, Rutland, J (1995) Ciliary defects in healthy subjects, bronchiectasis, and primary ciliary dyskinesia. Am J Respir Crit Care Med 151,1559-1567[Abstract]
-
Englender, M, Chamovitz, D, Harell, M (1990) Nasal transit time in normal subjects and pathologic conditions. Otolaryngol Head Neck Surg 103,909-912[ISI][Medline]
-
Nadel, HR, Stringer, DA, Levison, H, et al (1985) The immotile cilia syndrome: radiological manifestations. Radiology 154,651-655[Abstract/Free Full Text]
-
Alopez. 244400 Kartagener syndrome. National Center for Biotechnology Information [online]. Mendelian Inheritance in Man 1998 September 23 [cited 1998 November 18]; Available at: http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?244400. Accessed November 18, 1998
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Loh, RKS, Harth, SC, Hing Thong, Y, et al (1990) Immunoglobulin G subclass deficiency and predisposition to infection in Down’s Syndrome. Pediatr Infect Dis J 9,547-551[ISI][Medline]
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Abstract
Introduction
