Ming-Ren Chen

Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis

To find new candidate loci predisposing individuals to Kawasaki disease, an acute vasculitis that affects children, we conducted a genome-wide association study in 622 individuals with Kawasaki disease (cases) and 1,107 controls in a Han Chinese population residing in Taiwan, with replication in an independent Han Chinese sample of 261 cases and 550 controls. We report two new loci, one at BLK (encoding B-lymphoid tyrosine kinase) and one at CD40, that are associated with Kawasaki disease at genome-wide significance (P < 5 × 10−8). Our findings may lead to a better understanding of the role of immune activation and inflammation in Kawasaki disease pathogenesis.

Clinical characteristics and survival of trisomy 18 in a medical center in Taipei, 1988–2004†

Trisomy 18 is the second most common autosomal trisomy in newborns. The birth prevalence of this disorder is approximately 1 in 3,000 to 1 in 8,000, and the life span of the majority of patients is less than 1 year. As information regarding outcome in trisomy 18 is rather fragmentary in the literature, this study is aimed at investigating the survival and natural history of trisomy 18. We also evaluated the survival age and management of trisomy 18 in two different periods, before and after the implementation of National Health Insurance (NHI) program. Thirty‐nine cases of trisomy 18 were collected in Mackay Memorial Hospital in a 17‐year period, from 1988 to 2004. Delivery data, survival age, management before and after the implementation of NHI program, structural defects, image findings and cytogenetic results were analyzed by medical and nurses records. The diagnosis of trisomy 18 was based on the prenatal amniocentesis or postnatal chromosome analysis. Three patients had trisomy 18 mosaicism. Since cardiovascular and central nervous systems are the most common organ systems involved in this disorder, 31 patients received brain ultrasonography and heart ultrasonography for evaluation of their multiple anomalies after admission. All patients except one died in their first year due to severe malformations of the cardiovascular or central nervous systems. The median survival age was 6 days. We found a longer survival with female patients than with male patients (P < 0.05). Implementation of NHI program in the more recent decade of this study period was associated with longer survival of trisomy 18 (P < 0.05). The three most common structural defects were clenched hands (95%), rocker bottom feet (90%), and low set or malformed ears (90%). Low birth weight was present in 90%. By cardiac ultrasonography, the top four heart defects were ventricular septal defect (94%), patent ductus arteriosus (77%) and atrial septal defect (68%). However, ten cases (32%) had complex congenital heart defects. By brain ultrasonography, the most common brain lesion was cerebellar hypoplasia (32%), followed by brain edema (29%), enlarged cisterna magna (26%) and choroid plexus cysts (19%). Although most patients with trisomy 18 die within the first few weeks after birth, it is important to recognize that a small but notable percentage of these patients will survive the first year. When prenatal or postnatal decisions need to be made, the possibility of long‐term survival should be included in any discussion to enable families to make the most appropriate decision.

Clinical Features of Ehlers-Danlos Syndrome

BACKGROUND/PURPOSE Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous connective tissue disorder characterized by hyperextensibility of the skin, hypermobility of joints, and tissue fragility. This retrospective study analyzed the characteristics of patients with EDS. METHODS Review of medical records identified 16 cases of EDS during the study period from November 1997 to October 2002. Data on these patients, including clinical presentation, physical examinations, Beighton score, echocardiogram, bone mineral density findings and clinical classification, were analyzed. RESULTS The age of the patients ranged from 13 months to 36 years. All patients had skin hyperextensibility, joint hypermobility (Beighton score > 5 points), and tissue fragility. Complete bone mineral density study was performed in 11 patients and revealed that all had osteoporosis. Echocardiographic study was performed in 14 patients and showed aortic root dilatation/valve prolapse in 6/14 (43%). Other common features of EDS had the following prevalence: premature rupture of membranes in 3/16 (19%); prematurity in 3/16 (19%); neonatal hypotonia in 5/16 (31%); congenital hip dislocation in 3/16 (19%); unstable gait in 7/16 (44%); bone fracture(s) in 3/16 (19%); motor delay in 3/16 (19%); scoliosis in 3/16 (19%); short stature in 7/16 (44%); and positive family history in 8/16 (50%). All patients had a Beighton score of more than 5 points. CONCLUSION The results of this study emphasize the importance of echocardiographic monitoring of aortic size and valvular condition, and assessment of bone mineral density in patients with EDS. Clinical evaluation and counseling should be undertaken prior to pregnancy in patients with EDS because of the risk from labor and vaginal delivery in patients with type IV and the inability to distinguish EDS subtypes in Taiwan due to the unavailability of biochemical assay or molecular mutation analysis as part of standard care.

Polymorphism of Transmembrane Region of MICA Gene and Kawasaki Disease

Kawasaki disease is a febrile disease of children complicated with vasculitis of the coronary arteries and potential aneurysm formation. It has been recognized worldwide and appears to be increasing in frequency. Studies have found that Kawasaki disease is associated with major histocompatibility complex (MHC) class I B antigens. The MHC-class-I-chain-related gene A (MICA) is located near HLA-B. It has a triplet repeat microsatellite polymorphism in the transmembrane region. We investigated the microsatellite polymorphism in children with Kawasaki disease and controls. Seventy children (46 boys), age at diagnosis 1.68 ± 1.69 years, with Kawasaki who were treated with aspirin as well as intravenous gamma-globulin were enrolled. Control subjects consisted of 154 children (87 boys), age 2.81 ± 2.12 years. Phenotype frequency of allele A4 in patients with aneurysm formation was significantly lower than in patients without aneurysms [relative risk (RR) = 0.06, 95% confidence interval (CI) = 0.01–0.48, p = 0.00469, pc = 0.0232] and showed a similar tendency when compared with controls. Gene frequency of allele A4 was also significantly lower in patients who developed aneurysms than in patients who did not (RR = 0.07, 95% CI = 0.01–0.57, p = 0.0057, pc = 0.0282). Gene frequency of allele A5 showed a tendency to be higher in patients who developed aneurysms than in controls (RR = 2.35, 95% CI = 0.98–5.63, p = 0.0486, pc = 0.220). Allele A5.1 tended to be negatively associated with Kawasaki disease (RR = 0.57, 95% CI = 0.35–0.93, p = 0.022, pc = 0.105). Our study showed that allele A4 was negatively associated with coronary aneurysm formation in Kawasaki disease. This suggests that allele A4 protects the children with Kawasaki disease from developing coronary aneurysms after aspirin and gamma globulin therapy.

Clinical characteristics and survival of trisomy 13 in a medical center in Taiwan, 1985-2004.

Background: This study investigated the survival and natural history of trisomy 13 in a series of patients, comparing the management and outcome before and after the implementation of Taiwan’s National Health Insurance program (NHI).

Polysomnographic characteristics in patients with mucopolysaccharidoses

To evaluate the prevalence of obstructive sleep apnea (OSA) and to clarify sleep characteristics in patients with mucopolysaccharidoses (MPS), we performed overnight polysomnographic studies in 24 patients (22 males and 2 females; 3 with MPS I, 15 with MPS II, 1 with MPS III, 1 with MPS IV, and 4 with MPS VI; mean age, 10.8 ± 6.0 years; age range, 2.0–23.7 years; 2 patients ≥18 years of age). The nadir arterial oxygen saturation (SaO2) was 74.5 ± 12.3%, and the average percentage of sleep time with an SaO2 of <95% was 39.4%. The percentages of total sleep time spent in sleep stages N1, N2, N3, and R were 18.6 ± 10.8%, 50.3 ± 7.6%, 14.8 ± 8.1%, and 15.3 ± 4.6%, respectively. The respiratory disturbance index (RDI) was 21.8 ± 20.4/hr, and obstructive apnea–hypopnea index (OAHI) and central apnea index were 21.4 ± 19.9/hr and 0.4 ± 0.6/hr, respectively. The desaturation index was 17.6 ± 17.8/hr. All patients had some degree of OSA. For 22 children, the disorder was mild (OAHI 1.5–5) in 2, moderate (OAHI 5–10) in 7, and severe (OAHI > 10) in 13. Two patients with MPS II who received enzyme replacement therapy had reductions in RDI after treatment (38.9–10.8 and 3.5–2.0, respectively). The prevalence of moderate to severe OSA was 88% (21/24) in patients with MPS. The overnight polysomnography will help to determine the abnormalities of breathing during sleep more precisely and urge the clinicians to take necessary action for patients with severe manifestations. Pediatr Pulmonol. 2010;45:1205–1212.

ITPKC gene SNP rs28493229 and Kawasaki disease in Taiwanese children

Kawasaki disease (KD) is a systemic vasculitis caused by unknown infectious agents, host immune dysregulation and genetic susceptibility in children. Coronary artery lesions (CALs) complicate 15-25% of cases of untreated KD. The aim of this study was to investigate if the single-nucleotide polymorphism (SNP) rs28493229 of the ITPKC gene is associated with susceptibility to KD or with CALs in Taiwanese children. A total of 385 unrelated Taiwanese children (222 boys and 163 girls) with KD were included, 140 of whom had CALs. Mean age at diagnosis was 1.9 +/- 1.7 (0.1-10.2) years. Rs28493229 was genotyped in children with KD and 1158 ethnically matched healthy controls using the TaqMan Allelic Discrimination Assay. In 184 families with KD, both biological parents were available, constituting 184 trios with their children. They were assessed in a family-based study by means of a transmission/disequilibrium test (TDT). No significant differences in genotype (P = 0.29 and P = 0.29, respectively), allele (P = 0.14 and P = 0.22, respectively) and carrier (P = 0.22 and P = 0.25, respectively) frequencies of the SNP were found between healthy controls and children with KD or those with CALs. TDT in the 184 family trios and in 69 trios where the child had CALs did not reveal significant overtransmittion of the C allele. In conclusion, we did not find a statistically significant association between the ITPKC gene SNP rs28493229 and KD or CALs in Taiwanese children.

Evolution of coronary artery pattern according to short-axis aortopulmonary rotation: A new categorization for complete transposition of the great arteries

OBJECTIVES We studied the correlation between coronary artery pattern and aortopulmonary rotation in complete transposition of the great arteries. BACKGROUND Classifications of the coronary arteries in complete transposition are puzzling and incomplete. METHODS Coronary artery anatomy and relation of the great arteries were identified at angiography, echocardiography, surgical intervention or autopsy in 76 patients with complete transposition from 1988 to 1993. Five main types (type 0 and Shaher types 1,2,4 and 9) and their similar variants of epicardial configuration were categorized into five patterns (O, I, II, IV and IX). In addition, data from 568 cases from published reports were collected for analysis. RESULTS As the aorta rotated from a left anterior to a directly anterior location relative to the pulmonary trunk, the left anterior descending coronary artery arose from the left-hand sinus together with the right coronary artery (type 0, one case decreased to no cases); then it gradually shifted to the left to have the same origin as the left circumflex coronary artery from the right-hand sinus (type 1, 10 cases increased to 146, p < 0.0003). When the aorta rotated farther clockwise from directly anterior to right anterior (type 1, 146 cases increased to 235; type 2, 9 cases increased to 50, p < 0.0006) or from right anterior to right lateral (type 1, 235 cases decreased to 6 cases; type 2, 50 cases decreased to 20, p < 0.00000), the left circumflex coronary artery tended to move retropulmonically and originated from the left-hand sinus with the right coronary artery (type 2). When the aorta moved from right anterior to right lateral (type 2, 50 cases decreased to 20; type 4, 13 cases increased to 14, p < 0.031) or from right lateral to right posterior (type 2, 20 cases decreased to 1; type 4, 14 cases increased to 16, p < 0.0003), the right coronary artery shifted to the right-hand sinus anteaortically to join the left anterior descending coronary artery (type 4). Finally, the left anterior descending coronary artery combined with the left circumflex coronary artery (type 9, 12 cases increased to 21, p = 0.407) to become the usual pattern for normally related great arteries. Eta-square analysis showed that the evolution from pattern O to IX was dependent on clockwise aortopulmonary rotation. CONCLUSIONS The coronary arteries in complete transposition of the great arteries can be classified into five patterns and their evolution deduced on the basis of aortopulmonary rotation. Dependence of coronary artery type on aortopulmonary rotation made it possible to anticipate the coronary pattern from the relation of the great arteries in transposition.

Characterization of pulmonary function impairments in patients with mucopolysaccharidoses--changes with age and treatment.

The mucopolysaccharidoses (MPS) comprise a group of inherited lysosomal storage disorders characterized by deficiencies in enzymes catalyzing the degradation of glycosaminoglycans. Impairment of pulmonary function is an important health problem for patients with MPS. However, there are few published reports on the prevalence and severity of pulmonary dysfunction in relation to age and treatment in this disorder.

Modified arterial switch operation by spiral reconstruction of the great arteries in transposition

BACKGROUND Spiral relationship of the normally related great arteries (SRGA) has never been reconstructed in an arterial switch operation. METHODS From March 1998 to April 1999, 9 consecutive cases of transposition of the great arteries (TGA) family (from 2 days to 1.6 years old) underwent arterial switch operations with SRGA at our hospital. Two had a congenitally corrected TGA (plus atrial redirection). Lecompte maneuver was not used in all. The posterior wall of pulmonary trunk was not divided but three were reattached, two of whom had had previous pulmonary trunk banding. Thus the wall was shared between the great arteries facing each other. RESULTS All survived the operation. Supraaortic stenosis was balloon-dilated in 2 cases of early series, but technical modifications later were able to avoid it. Angiogram showed smooth flow into SRGA without upward and anterior tilting of the pulmonary bifurcation. All great and coronary arteries were patent. All were doing well on follow-up (16.5 +/- 4.2 months). CONCLUSIONS We concluded that the techniques to relocate the coronary arteries using common wall and in situ switch could also be applied to pulmonary arterial reconstruction, so that SRGA can be resumed in TGA.