Yoshifumi Kojima

Frequent association of 22q11.2 deletion with tetralogy of Fallot

Chromosome 22q11.2 deletion causes DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome with tetralogy of Fallot (TOF), and sporadic or familial TOF. To determine the prevalence and clinical importance of the 22q11.2 deletion in TOF, a series of 212 Japanese TOF patients was studied. The type of pulmonary blood supply, which may lead to various clinical outcomes, and other additional anomalies were evaluated clinically. The 22q11.2 deletion was diagnosed by fluorescence in situ hybridization with N25 and TUPLE1 probes. Of the 212 patients examined, 28 (13%) had a 22q11.2 deletion, the frequency being higher than that in TOF patients with trisomy 21. The prevalence of the deletion in TOF patients with pulmonary atresia (PA) plus major aortico-pulmonary collateral arteries (MAPCA) was significantly higher than the value in patients with PA plus patent ductus arteriosus (PDA) (P = 0.04) or with pulmonary stenosis (PS) (P < 0.0001). All 28 patients with 22q11.2 deletion had one or more extracardiac abnormalities. Four of 9 patients with the 22q11.2 deletion and TOF-PA-MAPCA suffered from bronchomalacia, while none of 19 patients with TOF-PA-PDA or TOF-PS manifested bronchomalacia (P = 0.006). These results indicate that 22q11.2 deletion is the most frequent cause of syndromic TOF, especially for TOF-PA-MAPCA, and bronchomalacia is the clinically most important associated anomaly in TOF-PA-MAPCA patients.

Phenotypic discordance in monozygotic twins with 22q11.2 deletion

We report on male monozygotic twins with 22q11.2 deletion and discordant phenotypes. The twins had twin-to-twin transfusion syndrome. Twin 1, the smaller of the pair, had Tetralogy of Fallot, a characteristic facial appearance, swallowing dysfunction, anal atresia, short stature, and mental retardation, whereas twin 2 had a characteristic facial appearance but no other signs of the 22q11 deletion syndrome. Fluorescence in situ hybridization analysis showed a microdeletion on chromosome 22q11.2 in both twins. Zygosity analysis gave a probability of monozygosity greater than 99.999%. These observations indicate that environmental factors or postzygotic events play a role in the phenotypic variability in the twins.

Bronchomalacia associated with pulmonary atresia, ventricular septal defect and major aortopulmonary collateral arteries, and chromosome 22q11.2 deletion

Respiratory distress is one of the major complications in young infants with pulmonary atresia, ventricular septal defect and major aortopulmonary collateral arteries (PA‐VSD‐MAPCA); however, its aetiology remains obscure. We have previously reported an association of bronchomalacia with PA‐VSD‐MAPCA in patients with a hemizygous deletion of chromosome 22q11.2 (del.22q11). To clarify the clinical relevance of bronchomalacia in patients with PA‐VSD‐MAPCA and del.22q11, we reviewed the clinical and laboratory records of four patients with PA‐VSD‐MAPCA who had del.22q11 and bronchomalacia. External bronchial compression by anomalous patterning of the aorta and MAPCA was documented in three of the four patients, using combinatorial examination of angiocardiography, bronchography, fibreoptic bronchoscopy and magnetic resonance imaging. One of the four patients died suddenly of severe respiratory distress at 4 years of age, while the remaining three were inoperable for complete surgical repair. Our study indicates that bronchomalacia as a result of external vascular compression may be an aetiology of early‐onset respiratory distress in some patients with PA‐VSD‐MAPCA and del.22q11, and can significantly affect the clinical outcome.

A de novo missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic long QT syndrome

Two missense mutations and a nine‐nucleotide deletion of the cardiac sodium channel (SCN5A) gene have been shown to cause long QT syndrome (LQTS) in several familial cases. We identified a novel missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic LQTS. We used polymerase chain reaction, single‐strand conformation polymorphism analysis and DNA sequence analysis to identify a mutation of the SCN5A gene in the patient. A single nucleotide substitution of guanine to adenine, in codon 1623, changed the coding sense of the SCN5A from arginine to glutamine (R1623Q) in the S4 segment of domain IV which is a highly conserved region of the SCN5A. This mutation was not identified in the unaffected biological parents and brother of the patient, and 100 normal, unrelated individuals. This finding is the first evidence of a de novo mutation in SCN5A associated with LQTS. Hum Mutat 11:481, 1998.

Behçet's disease presenting with a right atrial vegetation

Behçets disease (BD) is difficult to diagnose in children because patients often do not have characteristic symptoms and pediatricians have a low awareness of BD. We report on the case of BD in a 12-year-old boy that presented as endocarditis. Prednisolone, started after infective endocarditis had been ruled out, had a dramatic effect. Cardiac involvement in BD and the differential diagnosis of endocarditis are discussed.

Mechanisms underlying early development of pulmonary vascular obstructive disease in Down syndrome: An imbalance in biosynthesis of thromboxane A2 and prostacyclin.

Patients with Down syndrome (DS) and a left‐to‐right shunt often develop early severe pulmonary hypertension (PH) and pulmonary vascular obstructive disease (PVOD); the pathophysiological mechanisms underlying the development of these complications are yet to be determined. To investigate the mechanisms, we evaluated the biosynthesis of thromboxane (TX) A2 and prostacyclin (PGI2) in four groups of infants, cross‐classified as shown below, by measuring the urinary excretion levels of 11‐dehydro‐TXB2 and 2,3‐dinor‐6‐keto‐PGF1α: DS infants with a left‐to‐right shunt and PH (D‐PH, n = 18), DS infants without congenital heart defect (D‐C, n = 8), non‐DS infants with a left‐to‐right shunt and PH (ND‐PH, n = 12), and non‐DS infants without congenital heart defect (ND‐C, n = 22). The urinary excretion ratios of 11‐dehydro‐TXB2 to 2,3‐dinor‐6‐keto‐PGF1α in the D‐PH, D‐C, ND‐PH, and ND‐C groups were 7.69, 4.71, 2.10, and 2.27, respectively. The ratio of 11‐dehydro‐TXB2 to 2,3‐dinor‐6‐keto‐PGF1α was higher in the presence of DS (P < 0.001), independently of the presence of PH (P = 0.297). The predominant biosynthesis of TXA2 over PGI2, leading to vasoconstriction, was observed in DS infants, irrespective of the presence/absence of PH. This imbalance in the biosynthesis of vasoactive eicosanoids may account for the rapid progression of PVOD in DS infants with a left‐to‐right shunt.

Ventricular septal defect associated with microdeletions of chromosome 22q11.2.

Microdeletions of chromosome 22q11.2 (del.22q11) cause DiGeorge syndrome, velo‐cardio‐facial syndrome, and conotruncal anomaly face syndrome, which are commonly associated with conotruncal heart anomalies. Approximately 15% of the patients manifest ventricular septal defect (VSD), and the conal–septal type of VSD has been proposed to be associated with del.22q11, since it is categorized as a conotruncal anomaly. However, the types of VSD associated with del.22q11 remain poorly studied. The purpose of this study is to assess whether conal–septal VSD or other types of VSDs are associated with del.22q11. We analyzed the chromosomes of 22 consecutive patients with conal–septal VSD, prospectively, and evaluated the types of VSD observed in 3 patients with del.22q11, retrospectively. Del.22q11 was not detected in any of the 22 patients with conal–septal VSD. All the VSDs observed in the 3 patients with del.22q11 were a perimembranous type of VSD, which is not a conotruncal anomaly. Our results suggest that perimembranous VSD can be associated with del.22q11, but del.22q11 is not a common cause of conal–septal VSD.

Impaired Cardiorespiratory Response to Brief Sudden Strenuous Exercise in the Postoperative Tetralogy of Fallot Patients: A Ten-Second Pedaling Test

AbstractNo studies of cardiorespiratory response to brief, sudden, strenuous exercise in patients after tetralogy of Fallot (TOF) repair have been reported. We investigated the exercise capacity of TOF patients using a ten-second pedaling test designed to study cardiorespiratory responsiveness to brief, sudden, strenuous exercise. We assessed exercise capacity using a ten-second pedaling test (ten seconds maximal of voluntary cranking as fast as possible against an ergometers inertial resistance), coupled with a conventional ramp-type progressive exercise test at a constant rate to the limit of tolerance, in eight male postoperative TOF patients and eight male control subjects. In the ten-second pedaling test, there were no significant differences in the integrated areas of heart rate (HR) and oxygen uptake () responses between the TOF patients and controls, but there were significantly longer decreasing phase time constants of HR and responses in the TOF patients than in the controls. In the conventional exercise test, the endurance time, peak-HR, and peak- did not differ between the groups. The TOF group, with a normal exercise capacity assessed by a conventional exercise test, had an impaired cardiorespiratory response to brief, sudden, strenuous exercise assessed by a ten-second pedaling test.

White coat hypertension in two adolescents

Abstract We describe two adolescent boys with white coat hypertension. Both patients had significantly high blood pressure documented on more than three occasions at clinic. No cause for hypertension or target organ damage was demonstrated. Twenty-four-hour mean ambulatory blood pressure values were normal for height and sex, which led to the diagnosis.

A de novo missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic long QT sydrome. Mutations in brief no. 140. Online.

Two missense mutations and a nine‐nucleotide deletion of the cardiac sodium channel (SCN5A) gene have been shown to cause long QT syndrome (LQTS) in several familial cases. We identified a novel missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic LQTS. We used polymerase chain reaction, single‐strand conformation polymorphism analysis and DNA sequence analysis to identify a mutation of the SCN5A gene in the patient. A single nucleotide substitution of guanine to adenine, in codon 1623, changed the coding sense of the SCN5A from arginine to glutamine (R1623Q) in the S4 segment of domain IV which is a highly conserved region of the SCN5A. This mutation was not identified in the unaffected biological parents and brother of the patient, and 100 normal, unrelated individuals. This finding is the first evidence of a de novo mutation in SCN5A associated with LQTS. Hum Mutat 11:481, 1998.