Carpenter syndrome

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.

(CHEST 2000; 117:1207-1209)

Key words: bronchiectasis; ciliary motility disorders; Down's syndrome

Abbreviations: ASD = atrial septal defect; DS = Down's syndrome; PCD = primary ciliary dyskinesia

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).

CASE REPORT

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.

[Figures 1-2 ILLUSTRATION OMITTED]

DISCUSSION

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 [Beta] 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.

ACKNOWLEDGMENT: 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.

REFERENCES

[1] Rossman CM, Newhouse MT. Primary ciliary dyskinesia: evaluation and management. Pediatr Pulmonol 1988; 5:36-50

[2] de Iongh RU, Rutland J. Ciliary defects in healthy subjects, bronchiectasis, and primary ciliary dyskinesia. Am J Respir Crit Care Med 1995; 151:1559-1567

[3] Englender M, Chamovitz D, Harell M. Nasal transit time in normal subjects and pathologic conditions. Otolaryngol Head Neck Surg 1990; 103:909-912

[4] Nadel HR, Stringer DA, Levison H, et al. The immotile cilia syndrome: radiological manifestations. Radiology 1985; 154: 651-655

[5] 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

[6] Loh RKS, Harth SC, Hing Thong Y, et al. Immunoglobulin G subclass deficiency and predisposition to infection in Down's Syndrome. Pediatr Infect Dis J 1990; 9:547-551

(*) 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.

Manuscript received April 13, 1999; revision accepted October 15, 1999.

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@cheo.on.ca

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