Kawasaki Disease

A number sign (#) is used with this entry because of evidence that a functional polymorphism of the ITPKC gene (606476), which encodes inositol-1,4,5-trisphosphate 3-kinase C, is significantly associated with Kawasaki disease susceptibility and also with increased risk of coronary artery lesions.

Kawasaki disease is an acute, self-limited vasculitis of infants and children characterized by prolonged fever unresponsive to antibiotics, polymorphous skin rash, erythema of the oral mucosa, lips, and tongue, erythema of the palms and soles, bilateral conjunctival injection, and cervical lymphadenopathy (Kawasaki, 1967). Coronary artery aneurysms develop in 15 to 25% of those left untreated (Kato et al. (1975, 1996)), making Kawasaki disease the leading cause of acquired heart disease among children in developed countries. Treatment with intravenous immunoglobulin (IVIG) abrogates the inflammation in approximately 80% of affected individuals and reduces the aneurysm rate to less than 5%. Cardiac sequelae of the aneurysms include ischemic heart disease, myocardial infarction, and sudden death. Epidemiologic features such as seasonality and clustering of cases suggested an infectious trigger, although no pathogen had been isolated. Several lines of evidence suggested the importance of genetic factors in disease susceptibility and outcome. First, the incidence of Kawasaki disease is 10 to 20 times higher in Japan than in Western countries (Cook et al., 1989). Second, the risk of Kawasaki disease in sibs of affected children is 10 times higher than in the general population, and the incidence of Kawasaki disease in children born to parents with a history of Kawasaki disease is twice as high as that in the general population (Fujita et al., 1989; Uehara et al., 2003).

Hata and Onouchi (2009) reviewed current knowledge on Kawasaki disease, including epidemiology, genomewide linkage analysis, and molecular genetics.

Kawasaki (1967) described 50 children with an acute febrile mucocutaneous syndrome with lymphoid involvement and specific desquamation of the fingers and toes. The oldest patient was 9 years of age and more than one-half were less than 2 years of age. The primary symptoms included persistent fever, cervical adenopathy, conjunctival injection, nonvesicular erythematous rash particularly on palms and soles, edema of hands and feet, erosion/cracking of lips, diffuse congestion of oral mucosa, strawberry tongue, and membranous desquamation from the nail beds of fingers and toes. Kawasaki (1967) stated that the disease healed without intervention and without sequelae, that there was no recurrence, and that no contagion between sibs was observed. There was a family history of allergy in 46 of the 50 cases.

Kawasaki et al. (1974) noted that by 1973, 6,000 cases of Kawasaki disease had been reported in Japan. The case-fatality rate per year of 1.7% was due to sudden cardiac failure; at autopsy, all cases showed infantile periarteritis nodosa-like arteritis accompanied by coronary thrombosis and aneurysm.

Kato et al. (1975) performed coronary angiography in 20 patients who survived Kawasaki disease; 12 had abnormal angiograms, 7 of which involved coronary artery aneurysms. Complete regression of the coronary aneurysms was demonstrated in 2 patients on later angiography, 1 patient developed mitral regurgitation due to papillary muscle dysfunction, and 1 patient had a persistent but asymptomatic coronary artery aneurysm 2 years after the onset of illness.

Bell et al. (1981) reported 2 outbreaks of Kawasaki disease in the United States in 1979 and 1980. Questionnaire data showed that Kawasaki disease was more likely to occur in children of middle and upper socioeconomic status and that patients with Kawasaki disease had a higher incidence of an antecedent, primarily respiratory, illness than did controls matched for age, sex, and race. Laboratory studies did not identify an etiologic agent for Kawasaki disease or for the antecedent illness.

Dean et al. (1982) reported 33 cases of Kawasaki disease occurring over a 7-month period in Hawaii, occurring primarily in children of Japanese ancestry from families of high socioeconomic status. Four patients and 4 members of 26 immediate families had a history of atopic disease. One patient died with acute pancarditis. Although 44% of patients had a history of a respiratory infection in the preceding month, comprehensive epidemiologic and etiologic studies did not reveal the cause of Kawasaki disease.

Based on a Japanese survey of parents of children with Kawasaki disease, Fujita et al. (1989) reported that within 1 year after the onset of the first case in a family, the overall second-case rate was 2.1% for sibs, compared to an overall incidence of approximately 0.19% in the general population of children 0 to 4 years of age. For sibs younger than 1 year of age, the rate was 8.4%, and for those between 1 and 2 years of age, it was 9.3%. Fujita et al. (1989) noted that the high second-case rate in families might reflect more intimate exposure to an infectious agent within a family or genetically determined susceptibility, or both.

Kaneko et al. (1999) reported a 2-year-old Japanese girl with Kawasaki disease whose father had had the disease as a 10-month-old, 29 years earlier. Mori et al. (2001) reported a mother who had Kawasaki disease at 6 years of age whose daughter developed the disease at age 1. HLA haplotype analysis of these and other 2-generation cases was inconclusive.

Using Japanese epidemiologic survey data from 1999 to 2000, Uehara et al. (2003) found that the probability of a history of Kawasaki disease was significantly higher in parents whose children had the disease compared to parents in the general population (p less than 0.001).

Burns and Glode (2004) reviewed Kawasaki syndrome, with emphasis on early diagnosis and treatment with intravenous immunoglobulin to reduce the risk of coronary artery aneurysms.

Dergun et al. (2005) observed familial aggregation of Kawasaki syndrome in North America.

Wang et al. (2003) assessed CD40 ligand (CD40LG; 300386) expression in 43 patients with Kawasaki disease and in 43 age-matched febrile controls. CD40LG expression on CD4+ and CD8+ T cells and platelets from patients with Kawasaki disease was significantly higher than that of controls (p less than 0.001) and decreased significantly 3 days after treatment with IVIG (p less than 0.001). Serum CD40LG levels were also significantly higher in Kawasaki disease patients but were not affected by IVIG treatment. Expression of CD40LG on CD4+ T cells and platelets, but not on CD8+ T cells or in serum, correlated with the occurrence of coronary artery lesions in Kawasaki disease patients. Wang et al. (2003) concluded that CD40LG might play a role in the immunopathogenesis of Kawasaki disease, and that IVIG therapy might downregulate CD40LG expression, resulting in decrease of CD40LG-mediated vascular damage.

By microarray analysis of purified peripheral blood mononuclear cells and monocytes from patients with acute Kawasaki disease before and after high-dose IVIG therapy, Abe et al. (2005) identified 18 genes commonly downregulated by IVIG. Six of these genes, FCGR1A (146760), FCGR3A (146740), CCR2 (601267), ADM (103275), S100A9 (123886), and S100A12 (603112), were selected and the microarray results were confirmed by real-time RT-PCR analysis. Flow cytometric analysis demonstrated reduced monocyte expression of FCGR1 and FCGR3 following IVIG. In plasma, levels of the S100A8 (123885)/S100A9 heterocomplex, but not of S100A9, were elevated in acute Kawasaki disease patients compared with control febrile patients, and S100A8/S100A9 was rapidly downregulated in response to IVIG. Persistent elevation of S100A8/S100A9 after IVIG was found in patients who later developed coronary aneurysms. Abe et al. (2005) proposed that the effects of IVIG in Kawasaki disease are mediated by suppression of an array of immune activation genes, including those activating Fc gamma receptors and the S100A8/S100A9 heterocomplex.

Association with CD40LG

After screening the entire CD40LG gene and identifying 22 single-nucleotide polymorphisms (SNPs), Onouchi et al. (2004) performed an association study with 427 Japanese Kawasaki disease patients and 476 healthy Japanese controls. A SNP in intron 4 that was marginally overrepresented in Kawasaki disease patients was found to be significantly more frequent in male Kawasaki disease patients with coronary artery lesions compared to controls (OR, 2.0; 95% CI, 1.07-3.66; p = 0.030). This SNP was extremely rare in a control Caucasian population (0.7%). Onouchi et al. (2004) suggested that CD40LG has a role in the pathogenesis of coronary artery lesions and that this might explain the excess of males affected with Kawasaki disease.

Association with ITPKC

Onouchi et al. (2007) conducted an affected sib pair analysis of Kawasaki disease that demonstrated linkage to several chromosomal regions, including chromosome 19q13. Onouchi et al. (2008) reported results of linkage disequilibrium (LD) mapping carried out on 19q13.2, through which they identified a functional SNP in intron 1 of ITPKC (606476) that was significantly associated with risk of Kawasaki disease and the formation of coronary artery aneurysms in both Japanese and U.S. children. The functional SNP (606476.0001) was located in intron 1 of the ITTKC gene. Transfection experiments showed that the C allele of the SNP reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca(2+)/NFAT signaling pathway; the C allele may contribute to immune hyperreactivity in Kawasaki disease.

Chi et al. (2010) performed an association study with a total of 385 unrelated Taiwanese children with Kawasaki disease, 140 of whom had coronary artery lesions. The SNP rs28493229 was genotyped in children with Kawasaki disease and 1,158 ethnically matched healthy controls. There were 184 parent/affected child trios that were assessed by means of a transmission/disequilibrium test (TDT). No significant differences in genotype, allele and carrier frequencies of the SNP were found between healthy controls and children with Kawasaki disease or those with coronary artery lesions. TDT in the 184 family trios and in 69 trios where the child had coronary artery lesions did not reveal significant overtransmission of the C allele. The authors did not find a statistically significant association between the ITPKC gene SNP rs28493229 and Kawasaki disease or coronary artery lesions in Taiwanese children.

Associations Pending Confirmation

For discussion of a possible association between variation in the CASP3 gene and susceptibility to Kawasaki disease, see 600636.

Onouchi et al. (2012) performed a genomewide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease and 3,379 controls genotyped at 473,803 SNPs, and validated the association results in 2 independent replication panels totaling 754 cases and 947 controls. Onouchi et al. (2012) observed significant associations in the FAM167A (610085)-BLK (191305) region at 8p23-p22 (rs2254546) (p = 8.2 x 10 (-21)); in the HLA (see 142800) region at 6p21.3 (rs2857151) (p = 4.6 x 10 (-11)); and in the CD40 (109535) region at 20q13 (rs4813003) (p = 4.8 x 10 (-8)). Onouchi et al. (2012) also replicated the association of a functional SNP of FCGR2A (146790) (rs1801274) (p = 1.6 x 10 (-6)) identified by Khor et al. (2011) in a GWAS of Kawasaki disease.

Lee et al. (2012) conducted a GWAS in 622 individuals with Kawasaki disease 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. Lee et al. (2012) reported 2 new loci, 1 at BLK and 1 at CD40, that are associated with Kawasaki disease at genomewide significance (p less than 5 x 10 (-8)).

Stock et al. (2016) studied a mouse model of Kawasaki disease induced by intraperitoneal injection of Candida albicans water soluble (CAWS) fraction that elicited, within a month, cardiac vasculitis characterized by a cellular infiltrate localizing to the aortic root and coronary arteries. They found that Gmcsf (CSF2; 138960) was selectively and rapidly generated by cardiac fibroblasts after CAWS injection. Gmcsf acted locally within the heart, driving local inflammatory gene expression by cardiac macrophages. The resulting cascade of inflammatory cytokine, chemokine, and adhesion molecule expression induced cardiac inflammation that could be markedly reduced by blockade of Gmcsf. Stock et al. (2016) concluded that GMCSF is an essential initiating cytokine in cardiac inflammation and may be a therapeutic target in Kawasaki disease.