Case Report: Identification of a CARD8 variant in all three patients with PFAPA syndrome complicated with Kawasaki disease.

Background: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA syndrome), and Kawasaki disease (KD) are both considered to be disorders of the innate immune system, and the potential role of inflammasome activation in the immunopathogenesis of both diseases has been previously described. Case presentation: Herein, we report the clinical courses of three patients who presented a rare combination of PFAPA syndrome and KD. Two patients who presented KD later developed the PFAPA syndrome, of whom one developed recurrent KD 2 years after the initial diagnosis. The third patient developed KD one year after the onset of PFAPA syndrome. The presence of both of these conditions within individual patients, combined with the knowledge that inflammasome activation is involved in both PFAPA syndrome and KD, suggests a shared background of inflammatory dysregulation. To elucidate the mechanism underlying shared inflammatory dysregulation, we investigated the roles of Nod-like receptors (NLRs) and their downstream inflammasome-related genes. All the patients had a frameshift variant in CARD8 (CARD8-FS). A previous study demonstrated a higher frequency of CARD8-FS, whose product loses CARD8 activity and activates the NLRP3 inflammasome, in patients with the PFAPA syndrome. Additionally, the NLRP3 inflammasome is known to be activated in patients with KD. Together, these results suggest that the CARD8-FS variant may also be essential in KD pathogenesis. As such, we analyzed the CARD8 variants among patients with KD. However, we found no difference in the variant frequency between patients with KD and the general Japanese population. Conclusions: We report the clinical courses of three patients with a rare combination of PFAPA syndrome and KD. All the patients had the CARD8-FS variant. However, we could not find a difference in the variant frequency between patients with KD and the general Japanese population. As the frequency of KD is much higher than that of PFAPA among Japanese patients, and the cause of KD is multifactorial, it is possible that only a small portion of patients with KD harbor CARD8-FS as a causative gene.

Case report: Progressive pulmonary artery hypertension in a case of megalencephaly-capillary malformation syndrome.

Megalencephaly-capillary malformation syndrome (MCAP, OMIM # 602501) is caused by hyperactivity of the thephosphoinositide-3-kinase (PI3K)-Vakt murine thymoma viral oncogene homolog (AKT)-mammalian target of rapamycin (mTOR) pathway, which results in megalencephaly, capillary malformations, asymmetrical overgrowth, and connective tissue dysplasia. Herein, we report the case of a 7-month-old girl with MCAP due to a PIK3CA somatic mosaic variant who presented with atrial tachycardia, finally diagnosed as pulmonary arterial hypertension (PAH). Oxygen therapy and sildenafil decreased pulmonary blood pressure and improved atrial tachycardia. Previous studies reported an association between the PI3K/AKT/mTOR pathway and abnormal pulmonary arterial smooth muscle cell proliferation, which may be associated with PAH. PAH should be considered a potentially lethal complication in MCAP patients, even when no structural cardiac abnormalities are identified in the neonatal period.

A registry study of Kawasaki disease patients with coronary artery aneurysms (KIDCAR): a report on a multicenter prospective registry study three years after commencement.

The long-term prognosis of patients with Kawasaki disease (KD) complicated by coronary artery aneurysms (CAA) is still unclear. The present, multicenter registry study aimed to study the factors associated with coronary events (CE) and determine an appropriate management method for patients with KD complicated with CAA. Patients with KD with onset after 2015 and with a medium-sized or large CAA having an actual diameter ≥ 4 mm or a Z-score ≥ 5.0 at 30 days and later after KD onset were included in the annual survey. The primary endpoint was the time-dependent incidence of CE. Associated factors were also examined. In total, 179 patients from 53 centers were enrolled and followed up for a median of 501 days. The median age at KD onset was 2.2 years, 137 patients were male (77%), 47 had incomplete KD (26%), and 36 had large CAA (20%). CE occurred in 13 patients (7%; 95% confidence interval: 4-12%); eight (62%) experienced CE within 1 year, and all the patients experienced a CE within 2 years. All but one patient received antiplatelet drugs and warfarin. Patients with a large CAA had significantly more CAA (2.8 vs. 1.7, p < 0.001), more cases of warfarin use (86% vs. 43%, p < 0.001), and were more likely to have CE (28% vs. 2%, p < 0.001) than those with a medium-sized CAA. On univariate Cox regression analysis, the factors significantly associated with CE were large CAA (hazard ratio (HR): 17.0), three or more CAA (HR: 23.3), and beaded CAA (HR: 15.9). Multivariable Cox regression analysis revealed that the only associated factor was a large CAA. CONCLUSION: Patients with a large CAA were more likely to have a CE within 2 years. Antithrombotic therapy with warfarin did not eliminate the CE risk, and better therapies are desirable. WHAT IS KNOWN: • Coronary artery aneurysms are a serious complication of Kawasaki disease, and coronary events are sometimes fatal. • In previous, retrospective studies in Japan, large aneurysms, male sex, and refractoriness to initial immunoglobulin therapy were considered risk factors for coronary events. WHAT IS NEW: • Of 179 patients with a medium sized or large aneurysm, 13 (7%) experienced coronary events, all of which occurred within 2 years of onset. Factors significantly associated with coronary events were large aneurysms, three or more aneurysms, and beaded aneurysms.

Reproducibility between three-dimensional turbo spin-echo and two-dimensional dual inversion recovery turbo spin-echo for coronary vessel wall imaging in Kawasaki disease.

Magnetic resonance vessel wall imaging is desirable for evaluating Kawasaki disease (KD)-associated coronary arterial lesions. To evaluate the reproducibility of three-dimensional turbo spin-echo (3D-TSE) and two-dimensional dual inversion-recovery turbo spin-echo (2D-DIR-TSE) for coronary vessel wall imaging in KD. Ten patients were prospectively enrolled. Coronary vessel wall imaging with axial-slice orientation 3D-TSE and 2D-DIR-TSE were acquired for cross-sectional images in aneurysmal and normal regions. Lumen area (LA), wall area (WA), and normalized wall index (NWI) of cross-sectional images were measured in both regions. Reproducibility between 3D-TSE and 2D-DIR-TSE was evaluated via intraclass correlation coefficients (ICCs) and Bland-Altman plots. 48 points (aneurysmal, 27; normal, 21) were evaluated. There were high ICCs between 3D-TSE and 2D-DIR-TSE in LA (0.95) and WA (0.95). In aneurysmal regions, 95% limits of agreement were LA, WA, and NWI of - 29.9 to 30.4 mm2, - 18.8 to 15.0 mm2, and - 0.22 to 0.20, respectively. In normal regions, the 95% limits of agreement were LA, WA, and NWI of - 4.44 to 4.38 mm2, - 3.51 to 4.30 mm2, and - 0.14 to 0.16, respectively. No fixed and proportional biases between 3D-TSE and 2D-DIR-TSE images in aneurysmal and normal regions were noted. 3D-TSE was reproducible with conventional 2D-DIR-TSE for coronary vessel wall assessment on KD.

Increased Myosin light chain 9 expression during Kawasaki disease vasculitis.

Introduction: Kawasaki disease (KD) is an acute systemic vasculitis that predominantly afflicts children. KD development is known to be associated with an aberrant immune response and abnormal platelet activation, however its etiology is still largely unknown. Myosin light chain 9 (Myl9) is known to regulate cellular contractility of both non-muscle and smooth muscle cells, and can be released from platelets, whereas any relations of Myl9 expression to KD vasculitis have not been examined. Methods: Plasma Myl9 concentrations in KD patients and children with febrile illness were measured and associated with KD clinical course and prognosis. Myl9 release from platelets in KD patients was also evaluated in vitro. Myl9 expression was determined in coronary arteries from Lactobacillus casei cell wall extract (LCWE)-injected mice that develop experimental KD vasculitis, as well as in cardiac tissues obtained at autopsy from KD patients. Results and discussion: Plasma Myl9 levels were significantly higher in KD patients during the acute phase compared with healthy controls or patients with other febrile illnesses, declined following IVIG therapy in IVIG-responders but not in non-responders. In vitro, platelets from KD patients released Myl9 independently of thrombin stimulation. In the LCWE-injected mice, Myl9 was detected in cardiac tissue at an early stage before inflammatory cell infiltration was observed. In tissues obtained at autopsy from KD patients, the highest Myl9 expression was observed in thrombi during the acute phase and in the intima and adventitia of coronary arteries during the chronic phase. Thus, our studies show that Myl9 expression is significantly increased during KD vasculitis and that Myl9 levels may be a useful biomarker to estimate inflammation and IVIG responsiveness to KD.

Asymmetric Regional Work Contributes to Right Ventricular Fibrosis, Inefficiency, and Dysfunction in Pulmonary Hypertension versus Regurgitation.

BACKGROUND: Right ventricular (RV) pressure loading from pulmonary hypertension (PH) and volume loading from pulmonary regurgitation (PR) lead to RV dysfunction, a critical determinant of clinical outcomes, but their impact on regional RV mechanics and fibrosis is poorly characterized. The aim of this study was to test the hypothesis that regional myocardial mechanics and efficiency in RV pressure and volume loading are associated with RV fibrosis and dysfunction. METHODS: Eight PH, six PR, and five sham-control rats were studied. The PH rat model was induced using Sugen5416, a vascular endothelial growth factor receptor 2 inhibitor, combined with chronic hypoxia. PR rats were established by surgical laceration of the pulmonary valve leaflets. Six (n = 4) or 9 (n = 4) weeks after Sugen5416 and hypoxia and 12 weeks after PR surgery, myocardial strain and RV pressure were measured and RV pressure-strain loops generated. We further studied RV regional mechanics in 11 patients with PH. Regional myocardial work was calculated as the pressure-strain loop area (mm Hg ∙ %). Regional myocardial work efficiency was quantified through wasted work (ratio of systolic lengthening to shortening work). The relation of regional myocardial work to RV fibrosis and dysfunction was analyzed. RESULTS: In rats, PH and PR induced similar RV dilatation, but fractional area change (%) was lower in PH than in PR. RV lateral wall work was asymmetrically higher in PH compared with sham, while septal work was similar to sham. In PR, lateral and septal work were symmetrically higher versus sham. Myocardial wasted work ratio was asymmetrically increased in the PH septum versus sham. Fibrosis in the RV lateral wall, but not septum, was higher in PH than PR. RV fibrosis burden was linearly related to regional work and to measures of RV systolic and diastolic function but not to wasted myocardial work ratio. Patients with PH demonstrated similar asymmetric and inefficient regional myocardial mechanics. CONCLUSIONS: Asymmetric RV work and increased wasted septal work in experimental PH are associated with RV fibrosis and dysfunction. Future investigation should examine whether assessment of asymmetric regional RV work and efficiency can predict clinical RV failure and influence patient management.

Heart Rate Reduction Improves Right Ventricular Function and Fibrosis in Pulmonary Hypertension.

The potential benefit of heart rate reduction (HRR), independent of ß-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fibrosis and function in PH and RV pressure-loading models. Adult rats were randomized to 1) sham controls, 2) monocrotaline (MCT)-induced PH, 3) SU5416 + hypoxia (SUHX)-induced PH, or 4) pulmonary artery banding (PAB). Ivabradine (IVA) (10 mg/kg/d) was administered from 2 weeks after PH induction or PAB. Exercise tolerance, echocardiography, and pressure-volume hemodynamics were obtained at a terminal experiment 3 weeks later. RV myocardial samples were analyzed for putative mechanisms of HRR effects through fibrosis, profibrotic molecular signaling, and Ca++ handling. The effects of IVA versus carvedilol on human induced pluripotent stem cell-derived cardiomyocytes beat rate and relaxation properties were evaluated in vitro. Despite unabated severely elevated RV systolic pressures, IVA improved RV systolic and diastolic function, profibrotic signaling, and RV fibrosis in PH/PAB rats. RV systolic-elastance (control, 121 ± 116; MCT, 49 ± 36 vs. MCT+IVA, 120 ± 54; PAB, 70 ± 20 vs. PAB+IVA, 168 ± 76; SUHX, 86 ± 56 vs. SUHX +IVA, 218 ± 111; all P < 0.05), the time constant of RV relaxation, echo indices of RV function, and fibrosis (fibrosis: control, 4.6 ± 1%; MCT, 13.4 ± 6.5 vs. MCT+IVA, 6.7 ± 2.6%; PAB, 11.4 ± 4.5 vs. PAB+IVA, 6.4 ± 5.1%; SUHX, 10 ± 4.6 vs. SUHX+IVA, 3.9 ± 2.2%; all P < 0.001) were improved by IVA versus controls. IVA had a dose-response effect on induced pluripotent stem cell-derived cardiomyocytes beat rate by delaying Ca++ loss from the cytoplasm. In experimental PH or RV pressure loading, HRR improves RV fibrosis, function, and exercise endurance independent of ß-blockade. The balance between adverse tachycardia and bradycardia requires further study, but judicious HRR may provide a promising strategy to improve RV function in clinical PH.

Fulminant myocarditis following recurrent generalized erythrokeratoderma in a child with a heterozygous GJA1 variant.

Pathogenic germline variants in the gap junction protein alpha 1 (GJA1) gene have been identified in several congenital disorders affecting cutaneous, skeletal, and cardiac tissues. Here, we describe a 12-year-old patient with a GJA1 c.113G>A, p.(Gly38Glu) variant, who presented with fulminant myocarditis following recurrent generalized erythrokeratoderma. His mother and younger sister had the same clinical manifestations with the same GJA1 variant, but did not have cardiac dysfunction. GJA1 variants have been reported in patients with congenital cardiac malformations, while acute myocarditis in GJA1-related disorders has not been reported so far.

Identification of SAMD9L as a susceptibility locus for intravenous immunoglobulin resistance in Kawasaki disease by genome-wide association analysis.

Kawasaki disease (KD) is a systemic vasculitis affecting infants and children; it manifests as fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) treatment effectively attenuates the fever and systemic inflammation. However, 10-20% patients are unresponsive to IVIG. To identify genetic variants influencing IVIG non-response in KD, a genome-wide association study (GWAS) and a replication study were performed using a total of 148 IVIG non-responders and 845 IVIG-responders in a Korean population. rs28662 in the sterile alpha motif domain-containing protein 9-like (SAMD9L) locus showed the most significant result in the joint analysis of GWAS and replication samples (odds ratio (OR) = 3.47, P = 1.39 × 10-5). The same SNP in the SAMD9L locus was tested in the Japanese population, and it revealed a more significant association in a meta-analysis with Japanese data (OR = 4.30, P = 5.30 × 10-6). These results provide new insights into the mechanism of IVIG response in KD.

Coronary vessel wall visualization via three-dimensional turbo spin-echo black blood imaging in Kawasaki disease.

PURPOSE: To evaluate the feasibility of coronary vessel wall visualization using three-dimensional turbo spin-echo black blood imaging (3D-TSE) in children with Kawasaki disease. MATERIALS AND METHODS: Nine patients (6 girls and 3 boys; mean age ±â€¯standard deviation, 5.6 ±â€¯3.3 years; range, 1.4-10.3 years) were included. Coronary magnetic resonance angiography (MRA) with an axial slice orientation and 3D-TSE with axial and sagittal slice orientations (3D-TSE-axi and 3D-TSE-sag) were acquired for the whole heart. Coronary vessel walls were evaluated separately in aneurysm and normal-proximal regions. The internal diameter and wall thickness of the reformatted cross-sectional images were measured in both the regions. Reproducibility between MRA and 3D-TSE was evaluated via interclass correlation coefficients (ICCs) and Bland-Altman plots. RESULTS: In total, 164 points (aneurysmal regions, 73; normal-proximal regions, 64; normal-distal regions, 27) were evaluated. The ICC for 3D-TSE-axi was higher than that for 3D-TSE-sag (aneurysmal regions, ICC = 0.88 and 0.81; normal-proximal regions, ICC = 0.90 and 0.32, respectively). Bland-Altman plots of the internal diameter via MRA and 3D-TSE-axi showed a wide 95% limit of agreement (-0.13 to 2.89 mm) and significant fixed and proportional biases (P < 0.001 and P = 0.002) in the aneurysmal regions. However, the 95% limit of agreement was narrow (-0.14 to 0.57 mm) in the normal-proximal regions. If 1 mm was set as the cut-off for a thickened wall, wall thickness via 3D-TSE-axi was found to be abnormal across many points (84.0% of aneurysmal regions; 18.4% of normal-proximal regions). CONCLUSIONS: 3D-TSE imaging of the normal-proximal regions of the coronary vessel in individuals with Kawasaki disease was found to be feasible. However, in aneurysmal regions, larger aneurysmal diameters led to an increased bias between MRA and 3D-TSE.

Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (KAICA): a randomised controlled, open-label, blinded-endpoints, phase 3 trial.

BACKGROUND: Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. METHODS: We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. FINDINGS: We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25-0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). INTERPRETATION: Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. FUNDING: Japan Agency for Medical Research and Development (grant CCT-B-2503).

Sivelestat sodium hydrate treatment for refractory Kawasaki disease.

BACKGROUND: There is still no definite treatment for refractory Kawasaki disease (KD). In this pilot study, we evaluated the safety and efficacy of a new protocol consisting of sivelestat sodium hydrate (SSH) combined with additional i.v. immunoglobulin (IVIG) for KD resistant to initial IVIG therapy. METHODS: This study is a prospective non-randomized, open-label and single-arm study undertaken in a population of refractory KD patients at Chiba University Hospital from December 2006 to March 2016. The subjects had KD resistant to initial IVIG (2 g/kg) and received SSH (0.2 mg/kg/h for 5 days) combined with additional IVIG (2 g/kg) as a second-line therapy. We evaluated the safety and efficacy of the treatment during the study period. RESULTS: Forty-six KD patients were enrolled in this study and no serious adverse event was noted. Of these, 45 patients were evaluated for the incidence of coronary artery lesions, which occurred in one patient (2.2%; 95% CI: 0.5-15.2). Twenty-eight (62.2%) responded promptly and were afebrile after the therapy. The median total duration of fever was 8 days (range, 6-28 days). CONCLUSIONS: Additional IVIG combined with SSH as a second-line therapy for KD refractory to initial IVIG therapy was safe and well tolerated and could be a promising option for severe KD. Further investigations are expected to clarify the safety and timing of SSH treatment for KD.

Facial nerve palsy associated with atomoxetine-induced hypertension.

BACKGROUND: Peripheral facial nerve palsy is characterized by unilateral facial paresis due to ipsilateral facial nerve dysfunction. Most cases are idiopathic; however, some have specific etiologies, such as herpesvirus infection, immunological disorders, and hypertension. Atomoxetine is a norepinephrine reuptake inhibitor that is used in the treatment of attention deficit hyperactivity disorder (ADHD). This drug is known to cause adverse effects, such as nausea, appetite loss, headache, insomnia, and hypertension. CASE DESCRIPTION: We herein describe a case of sudden-onset right peripheral facial palsy in a 9-year-old Japanese boy. The patient's systolic blood pressure was as high as 200 mmHg, and he was therefore admitted to our hospital for investigation. Extensive surveillance including blood examination; endocrinological testing; imaging studies such as computed tomography, magnetic resonance imaging, and renography; and renal biopsy did not reveal any abnormalities. The patient had ADHD and was under treatment with atomoxetine. We discontinued treatment with atomoxetine; the patient showed gradual improvement. His hypertension and facial palsy resolved. We therefore diagnosed the patient with peripheral facial palsy associated with atomoxetine-induced hypertension. CONCLUSION: Although peripheral facial nerve palsy is usually benign and self-limiting, blood pressure should be monitored in children under treatment with atomoxetine and the possibility of drug-induced hypertension should be considered in order to prevent palsy associated with hypertension.

Identification of LEF1 as a Susceptibility Locus for Kawasaki Disease in Patients Younger than 6 Months of Age.

Kawasaki disease (KD) is an acute febrile vasculitis predominately affecting infants and children. The dominant incidence age of KD is from 6 months to 5 years of age, and the incidence is unusual in those younger than 6 months and older than 5 years of age. We tried to identify genetic variants specifically associated with KD in patients younger than 6 months or older than 5 years of age. We performed an age-stratified genome-wide association study using the Illumina HumanOmni1-Quad BeadChip data (296 cases vs. 1,000 controls) and a replication study (1,360 cases vs. 3,553 controls) in the Korean population. Among 26 candidate single nucleotide polymorphisms (SNPs) tested in replication study, only a rare nonsynonymous SNP (rs4365796: c.1106C＞T, p.Thr369Met) in the lymphoid enhancer binding factor 1 (LEF1) gene was very significantly associated with KD in patients younger than 6 months of age (odds ratio [OR], 3.07; pcombined = 1.10 × 10-5), whereas no association of the same SNP was observed in any other age group of KD patients. The same SNP (rs4365796) in the LEF1 gene showed the same direction of risk effect in Japanese KD patients younger than 6 months of age, although the effect was not statistically significant (OR, 1.42; p = 0.397). This result indicates that the LEF1 gene may play an important role as a susceptibility gene specifically affecting KD patients younger than 6 months of age.

Nationwide Survey of Patients With Giant Coronary Aneurysm Secondary to Kawasaki Disease 1999-2010 in Japan.

BACKGROUND: Giant coronary aneurysm is the most severe sequela in Kawasaki disease, occurring in approximately 0.2% of patients in Japan. Regression is rare, while myocardial infarction (MI) and sudden death are relatively common. Herein, we reviewed patients with giant coronary aneurysm in a 10-year period.Methods and Results:A nationwide questionnaire survey was conducted based on a national epidemiological database from 1999 to 2010. We identified 355 giant coronary aneurysm patients, of whom 209 were analyzed. The 5- and 10-year total cardiac event-free rates were 0.72 and 0.68, respectively. Twelve patients died, and MI was observed in 32 patients (18.1%). Five and 6 deaths were due to coronary rupture and MI, respectively. All ruptures occurred within 1 month of onset, while most MI occurred within 18 months. There was no death beyond 2 years. Aneurysm size was significantly related to the occurrence of MI in both the right and left coronary arteries. At the time of writing, 55% of patients had no exercise limitations. And including patients who cannot perform strenuous exercises, 81% of patients were leading ordinary lives. CONCLUSIONS: Severe cardiac events are likely to occur within 2 years from onset of Kawasaki disease, while no deaths occurred beyond this time. Hence, careful monitoring is needed especially for the first 2 years. Most patients with giant coronary aneurysms can lead ordinary lives with appropriate management.

Male-specific association of the FCGR2A His167Arg polymorphism with Kawasaki disease.

Kawasaki disease (KD) is an acute systemic vasculitis that can potentially cause coronary artery aneurysms in some children. KD occurs approximately 1.5 times more frequently in males than in females. To identify sex-specific genetic variants that are involved in KD pathogenesis in children, we performed a sex-stratified genome-wide association study (GWAS), using the Illumina HumanOmni1-Quad BeadChip data (249 cases and 1,000 controls) and a replication study for the 34 sex-specific candidate SNPs in an independent sample set (671 cases and 3,553 controls). Male-specific associations were detected in three common variants: rs1801274 in FCGR2A [odds ratio (OR) = 1.40, P = 9.31 × 10-5], rs12516652 in SEMA6A (OR = 1.87, P = 3.12 × 10-4), and rs5771303 near IL17REL (OR = 1.57, P = 2.53 × 10-5). The male-specific association of FCGR2A, but not SEMA6A and IL17REL, was also replicated in a Japanese population (OR = 1.74, P = 1.04 × 10-4 in males vs. OR = 1.22, P = 0.191 in females). In a meta-analysis with 1,461 cases and 5,302 controls, a very strong association of KD with the nonsynonymous SNP rs1801274 (p.His167Arg, previously assigned as p.His131Arg) in FCGR2A was confirmed in males (OR = 1.48, P = 1.43 × 10-7), but not in the females (OR = 1.17, P = 0.055). The present study demonstrates that p.His167Arg, a KD-associated FCGR2A variant, acts as a susceptibility gene in males only. Overall, the gender differences associated with FCGR2A in KD provide a new insight into KD susceptibility.

A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report.

BACKGROUND: According to previous KCNQ1 (potassium channel, voltage gated, KQT-like subfamily, member 1) gene screening studies, missense variants, but not nonsense or frame-shift variants, cause the majority of long QT syndrome (LQTS; Romano-Ward syndrome [RWS]) 1 cases. Several missense variants are reported to cause RWS by a dominant-negative mechanism, and some KCNQ1 variants can cause both Jervell and Lange-Nielsen Syndrome (JLNS; in an autosomal recessive manner) and LQTS1 (in an autosomal dominant manner), while other KCNQ1 variants cause only JLNS. The human KCNQ1 gene is known to have two transcript isoforms (kidney isoform and pancreas isoform), and both isoforms can form a functional cardiac potassium channel. CASE PRESENTATION: Here, we report a novel nonsense KCNQ1 variant causing not only JLNS, but also significant QTc prolongation identical to RWS in an autosomal dominant manner. Our case study supports that haploinsufficiency in the KCNQ1 gene is causative of significant QTc prolongation identical to RWS. Interestingly, the nonsense variant (NM_000218.2:c.115G > T [p.Glu39X]) locates in exon 1a of KCNQ1, which is a kidney-isoform specific exon. The variant is located closer to the N-terminus than previously identified nonsense or frame-shift variants. CONCLUSION: To the best of our knowledge, this is the first report showing that a nonsense variant in exon 1a of KCNQ1, which is the kidney-isoform specific exon, causes JLNS. Our findings may be informative to the genetic pathogenesis of RWS and JLNS caused by KCNQ1 variants.

Ellis-van Creveld syndrome associated with chronic intestinal pseudo-obstruction.

Ellis-van Creveld (EVC) syndrome is a rare autosomal recessive disorder characterized by hypoplastic nails, polydactyly, and achondroplasia. Patients usually exhibit normal cognitive function and no remarkable developmental delay. We herein present an unusual case of EVC syndrome. A Japanese 2-year-old boy was born at term, but immediately developed severe respiratory failure due to thorax deformity, postaxial polydactyly and nail hypoplasia. We identified a novel pattern of germinal compound heterozygous nonsense EVC2 mutations of c.1814C > A (p. S605X) and c.2653C > T (p. R885X), leading to the diagnosis of EVC syndrome. Interestingly, he also had severe developmental delay, and suddenly developed excessive abdominal distension at the age of 2. On surgery, extensive necrotic bowel with chronic intestinal pseudo-obstruction was noted. This is, to our knowledge, a most severe phenotype of EVC syndrome, illustrating that the specific pattern of EVC2 compound heterozygous mutations may cause severe developmental delay and intestinal malfunction.