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To establish a strategy for congenital cytomegalovirus (cCMV) screening and to establish confirmatory assays approved as in vitro diagnostics by the regulatory authorities, we evaluated the clinical risks and performance of diagnostic assays developed by commercial companies, since cCMV infection has significant clinical consequences.Newborns with clinical manifestations considered to be consequences of cCMV infection (n = 575) were screened for the presence of cytomegalovirus (CMV) DNA in urine specimens collected onto filter paper placed in their diapers using the polymerase chain reaction-based assay reported previously. Liquid urine specimens were obtained from all of 20 CMV-positive newborns and 107 of the CMV-negative newborns identified in the screening. We used these 127 specimens, as well as 12 from cCMV cases identified in a previous study and 41 from healthy newborns, to compare the performance of 2 commercial assays and 1 in-house assay.The risk-based screening allowed the identification of cCMV cases at least 10-fold more efficiently than our previous universal screening, although there appears to be a limit to the identification of asymptomatically infected newborns. Although CMV-specific IgM during pregnancy was found frequently in mothers of cCMV newborns, CMV-IgM alone is not an effective diagnostic marker. The urine-filter-based assay and the 3 diagnostic assays yielded identical results.Although risk-based and universal newborn screening strategies for cCMV infection each have their respective advantages and disadvantages, urine-filter-based assay followed by confirmatory in vitro diagnostics assays is able to identify cCMV cases efficiently.

Infants with Down Syndrome (DS) are at risk of developing a transient abnormal myelopoiesis (TAM). TAM is characterised by increased circulating blast cells but usually self-limiting. DS patients with TAM sometimes show fetal hydrops and effusion in body cavities, but the mechanism remains unclear. We report here a case of infant with DS who had pericardial effusion, TAM, and eosinophilia. In her pericardial effusion, white blood cell count was 6.0 × 103/µL, 41% of which were eosinophils. After administration of prednisolone, pericardial effusion gradually decreased, and TAM and eosinophilia improved. In order to elucidate the immunological mechanism, we measured the levels of 17 cytokines in her pericardial effusion fluid and serum. In her pericardial fluid, there were high levels of 12 cytokines, and they were higher than those in her serum. In particular, IL-6 (44,573 pg/mL), IL-8 (4,865 pg/mL), and IL-13 (579.41 pg/mL) were at extremely high levels in her pericardial fluid. After administration of prednisolone, the levels of 8 of the 12 elevated cytokines in her pericardial fluid decreased and all of the elevated cytokines decreased in her serum. Corticosteroids can be effective to reduce cytokine levels and the amount of effusion in patients with DS. It is presumed that effusion seen in DS with TAM could be related to an abnormal production of cytokines at the effusion site.

A crucial issue in neonatal medicine is the impact of preterm birth on the developmental trajectory of the brain. Although a growing number of studies have shown alterations in the structure and function of the brain in preterm-born infants, we propose a method to detect subtle differences in neurovascular and metabolic functions in neonates and infants. Functional near-infrared spectroscopy (fNIRS) was used to obtain time-averaged phase differences between spontaneous low-frequency (less than 0.1 Hz) oscillatory changes in oxygenated hemoglobin (oxy-Hb) and those in deoxygenated hemoglobin (deoxy-Hb). This phase difference was referred to as hemoglobin phase of oxygenation and deoxygenation (hPod) in the cerebral tissue of sleeping neonates and infants. We examined hPod in term, late preterm, and early preterm infants with no evidence of clinical issues and found that all groups of infants showed developmental changes in the values of hPod from an in-phase to an antiphase pattern. Comparison of hPod among the groups revealed that developmental changes in hPod in early preterm infants precede those in late preterm and term infants at term equivalent age but then, progress at a slower pace. This study suggests that hPod measured using fNIRS is sensitive to the developmental stage of the integration of circular, neurovascular, and metabolic functions in the brains of neonates and infants.

Complete urorectal septum malformation sequence (URSMS) is usually a lethal anomaly that is characterized by urethral obstruction, imperforate anus, ambiguous genitalia, renal agenesis or dysplasia, and mullerian duct maldevelopment. This anomaly is thought to be caused by the cessation of urorectal septum migration toward the caudal cloacal membrane. Teratogenic factors or a genetic abnormality is postulated as the etiology. To date, only 4 patients with URSMS have survived the neonatal period; however, 2 of these infants died before the age of 1 year. We report the survival in a case with complete URSMS who had moderate pulmonary hypoplasia and preserved left renal function. The cloacal remnant wasdilated more than expected because the wall of the muscle layer was torn, perhaps in early fetal life, and timely placement of vesico-amniotic shunts prevented severe pulmonary hypoplasia caused by oligohydramnios.

Mutations in ACTN1, the gene encoding the actin-crosslinking protein α-actinin-1, cause autosomal dominant macrothrombocytopenia. α-Actinin-1 exists as antiparallel dimers, composed of an N-terminal actin-binding domain (ABD), four spectrin-like repeats (SLRs), which form the spacer rod, and a C-terminal calmodulin-like (CaM) domain. All of the previously reported ACTN1 mutations associated with macrothrombocytopenia reside within the ABD and the CaM domain and not within the SLR domain. In this report, we describe a mutation in SLR2 of α-actinin-1 (p.Leu395Gln) associated with familial macrothrombocytopenia. A 3-year-old boy and his mother both had this mutation. They showed a mild form of thrombocytopenia without severe bleeding, accompanied by an elevated mean platelet volume. Consistent with the previous reports of mutations that reside in the ABD or the CaM domain, immunofluorescence examination revealed disorganization of the actin cytoskeleton in Gln395 mutant-transduced Chinese hamster ovary cells. Our findings suggest a novel mechanism for the pathogenesis of ACTN1-related macrothrombocytopenia that does not involve functional domain mutations.

Preterm infants are at significant risk of reduced bone mineral content and subsequent bone disease (metabolic bone disease of prematurity, MBDP). MBDP is frequently found in very low-birthweight (VLBW) infants, but long-term height prognosis is not well known.VLBW infants from two major neonatal intensive care units were studied. Medical records were reviewed. A total of 143 subjects were analyzed after excluding subjects who died, or who had severe complications that could affect linear growth, Silver-Russell syndrome, severe cholestasis, and/or chromosomal abnormality. The relationship between MBDP and height at age 3 was investigated.Height standard deviation score (SDS) at age 3 negatively correlated with peak serum alkaline phosphatase (ALP) activity in early life (r = -0.30, P = 0.0003) and positively correlated with serum phosphorus (P) at peak ALP (r = 0.33, P = 0.0002). In addition, serum P independently affected height SDS at 3 years of age (β = 0.19, P = 0.018), and was significantly different between infants with and without catch-up growth in height (difference: 0.23 mmol/L, 95%CI: 0.09-0.36, P = 0.0010).MBDP, particularly hypophosphatemia in the early period of life, is associated with linear growth until 3 years of age in VLBW infants.

Potent antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature. Background Angiotensin type 1 (AT1) receptor-deficient mice ( Agtr1 -/-), which selectively lack both AT1A and AT1B receptor genes, are characterized by marked intrarenal vascular thickening. In the present study, we explored the possible involvement of the kinin-kallikrein system in the development of this renal vascular hypertrophy. Methods Wild-type and Agtr1 -/- mice were examined for the developmental regulation pattern of the kinin-kallikrein system and treated with aprotinin (a kallikrein inhibitor), AcLys [D-b Nal 7 , Ile 8 ] des-Arg 9 -bradykinin (a bradykinin B1 receptor antagonist), or Hoe-140 (a bradykinin B2 receptor antagonist) from 3 to 14 days of age. Results The normal postnatal up-regulation of kininase II was organ-specifically suppressed in Agtr1 -/- kidneys at 2 and 3 weeks of age. Immunohistochemical staining in Agtr1 -/- mice revealed tissue kallikrein staining along the nephron from connecting tubules to cortical collecting tubules in proximity to the hypertrophic vasculature, whereas tissue kallikrein staining was confined to connecting tubules in wild-type mice. Aprotinin and Hoe-140 accelerated the vascular hypertrophy significantly as determined by wall thickness ratio, whereas B1 receptor antagonism had no effect. Conclusion The kinin-kallikrein system in the Agtr1 -/- mouse kidney is functionally activated by local suppression of kininase II and extensive redistribution of kallikrein to perivascular areas. This activation, specific to the kidney, serves to dampen a development of the marked vascular hypertrophy. These results demonstrate, to our knowledge for the first time, the antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature in vivo.

Near-infrared spectroscopy (NIRS) imaging studies have revealed the functional development of the human brain in early infancy. By measuring spontaneous fluctuations in cerebral blood oxygenation with NIRS, we can examine the developmental status of the functional connectivity of networks in the cortex. However, it has not been clarified whether premature delivery and/or chromosomal abnormalities affect the development of the functional connectivity of the cortex. In the current study, we investigated the spontaneous brain activity of sleeping infants who were admitted to a neonatal intensive care unit at term age. We classified them into the 3 following infant groups: (i) term-or-late-preterm, (ii) early-preterm, and (iii) Down's syndrome (DS). We used multichannel NIRS to measure the spontaneous changes in oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) at 10 measurement channels, which covered the frontal, temporal, and occipital regions. In order to reveal the functional connectivity of the cortical networks, we calculated the temporal correlations of the time-course signals among all of the pairs of measurement channels. The functional connectivity was classified into the 4 following types: (i) short-range, (ii) contralateral-transverse, (iii) ipsilateral-longitudinal, and (iv) control. In order to examine whether the local properties of hemodynamics reflected any pathological conditions, we calculated the phase differences between the oxy- and deoxy-Hb time-course signals in the 3 groups. The statistical analyses of the functional connectivity data showed main effects of group and the types of connectivity. For the group effect, the mean functional connectivity of the infants in the term-or-late-preterm group did not differ from that in the early-preterm group, and the mean functional connectivity of the infants in the DS group was lower than that in the other 2 groups. For the effect of types of connectivity, short-range connectivity was highest compared to any of the other types of connectivity, and the second highest connectivity was the contralateral-transverse one. The phase differences between the oxy- and deoxy-Hb changes showed that there were significant differences between the DS group and the other 2 groups. Our findings suggested that the development of the functional connectivity of cortical networks did not differ between term-or-late-preterm infants and early-preterm infants around term-equivalent ages, while DS infants had alterations in their functional connectivity development and local hemodynamics at term age. The highest short-range connectivity and the second highest contralateral-transverse connectivity suggested that the precursors for the basic cortical networks of functional connectivity were present at term age.

Several quantitative methods of urine microscopic examination for bacteriuria and pyuria on a blood cell counting-chamber have been found reliable for the diagnosis of urinary tract infection (UTI). However, no one technique has become popular or widely used because of laborious procedures associated with the method. We investigated the usefulness of microscopic examination of uncentrifuged urine on disposable counting-chambers. A total of 89 urine samples were obtained from 53 children (24 male and 29 female). Urine samples were examined for bacteriuria and pyuria using a disposable counting chamber and its reliability was analyzed in predicting significant bacteriuria defined by routine urine culture. Significant bacteriuria was diagnosed in 23 of 89 urine samples by urine culture. Microscopic urine examination on disposable counting-chambers was very easy without the need to set up or wash chambers and provided immediate information. Urine bacterial concentration determined by the counting-chamber method was closely correlated to that determined by bacterial culture. The counting-chamber method identified bacteriuria correctly in 21 of 23 urine samples diagnosed as significant bacteriuria (sensitivity = 91%) and also gave a correct diagnosis of 64 of 66 urine samples with non-significant bacteriuria (specificity = 98%). Nineteen of the 23 urine samples with significant bacteriuria also had pyuria. The positive predictive value of concomitant bacteriuria and pyuria was 100%. When neither bacteriuria nor pyuria was found, the negative predictive value was 100%. It was concluded that urine microscopy using disposable counting chambers was very easy, inexpensive, quick and reliable and thus an extremely useful method for diagnosing UTI.

Objective The increasingly younger age of onset of allergic rhinitis (AR) has recently become a problem. This study examined the prevalence of inhaled antigen sensitization and nasal eosinophils in children younger than two years old, with measurement of the serum concentrations of aeroallergen-specific IgE antibodies to house dust mites, cat fur, and Japanese cedar pollen, measurement of nasal eosinophil counts, and a questionnaire administered to the children's parents. Methods The subjects were a group of healthy children undergoing 18-month infant health checks provided by the local government, and sick children younger than two years old at the pediatric hospital. Results Among 408 healthy infants, 44 (10.7%) had antigen-specific IgE antibodies, 29 (7.1%) had nasal eosinophils, and eight (2.0%) had both specific IgE antibodies and nasal eosinophils. Nasal assessment revealed that 125 children had rhinorrhea. Of the infants who showed both sensitization to antigens and nasal eosinophils, six (1.5%) had confirmed rhinorrhea. Among 186 sick children younger than two years old at the pediatric hospital, aeroallergen-specific IgE antibodies were detected in five (2.6%). The presence of nasal eosinophils was confirmed in six children (3.2%), which percentage was smaller than that of the healthy group. No infant had either sensitization to antigens or nasal eosinophils. Conclusion The findings described above indicate that the minimum prevalence of AR might be 1.5% in 18-month-old children and that around 10% of affected children have aeroallergen-specific IgE antibodies in Japan. The incidence of AR in young children might increase further.

The effectiveness of intermittent low-dose trimethoprim-sulfamethoxazole (TMP-SMZ) for the prophylaxis of recurrent urinary infection is well established in adults. The present study assessed the effectiveness and safety of intermittent low-dose TMP-SMZ in 35 children (24 boys, 11 girls, aged 1 month to 9 years, median age 5 months) with vesicoureteral reflux; 18 children had bilateral reflux. A total of 53 refluxing ureters were graded as I in 2, II in 16, III in 19, IV in 14, and V in 2 cases. The children were given 1 mg/kg body weight of trimethoprim together with 5 mg/kg of sulfamethoxazole at bedtime every other day for 6-50 months (mean +/- SD, 22.9 +/- 11.7 months). None of the boys had a recurrence of urinary infection, while 2 of the 11 girls had a total of 7 recurrences during the prophylaxis period, with a recurrence rate of 0.027 per patient month in girls. Both girls were over 3 years and had a mildly unstable bladder. Transient neutropenia (1,000/microliter) developed in 2 infants during the prophylaxis period, but disappeared spontaneously. Intermittent low-dose TMP-SMZ seemed very effective for the prevention of recurrent urinary infection in children with ureteral reflux even of higher grades.

Objective: To clarify postnatal changes in urinary uric acid (UA) excretion in normal term infants and to examine the effects of prematurity or illness on the UA excretion. Methodology: Measurements of urinary UA were performed in term and premature infants at the ages of 1 and 7 days and at 1 and 4 months, as well as at 7 months in term infants. Results: Urinary UA levels were lowest on day 7 in term infants. The levels were highest on day 1 in premature infants and remained significantly higher compared to term babies during the first month of life. Respiratory failure requiring ventilation and oxygen supply resulted in further significant elevation of urinary UA in premature infants. Conclusions: With the reference values obtained in the study reported here, urinary UA can now be used for the diagnosis and monitoring of inherited disorders of purine metabolism and for the assessment of oxygen radical insult to sick infants.

Diagnosis of urinary infection in young children is often delayed, which may result in renal damage. However, it remains to be clarified how soon the treatment should be started to prevent renal changes. The present study prospectively enrolled young children with diagnosis of their first febrile urinary infection who underwent technetium-99m dimercaptosuccinate renal cortical scintigraphy within 120 h of initiation of treatment. Patients with abnormal renoscintigraphy received antibiotics for 2 weeks and scintigraphy was repeated 1 year later. Twenty-two children were enrolled from July 1995 through March 2000. Acute-phase renoscintigraphy identified focal defects in 0 of the 14 children who were treated within 24 h of the disease, 1 of the 3 treated in 24-48 h, and 2 of the 5 treated in 48-72 h. Repeat renoscintigraphy showed disappearance of the focal defects in all 3 children. The present study has shown that early treatment within 24 h of onset of the fever due to urinary infection should deter renal changes. Fever for more than 24 h prior to diagnosis indicates a high risk for renal changes and needs an immediate effective treatment to avoid renal damage.

Background: A genetic aberration in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (677 C to T substitution) has been shown to result in reduced enzyme activity. The hypothesis tested in the present study was that a higher proportion of Kawasaki disease (KD) patients with coronary artery lesions (CAL) would have the T677 allele compared with patients without CAL and healthy subjects. Methods: Genotypes for MTHFR were determined in 75 KD patients (male : female ratio 52:23) and 238 healthy subjects (male : female ratio, 110:128) by the polymerase chain reaction and restriction fragment length polymorphism method. Results: The results indicated that female KD patients had a significantly higher frequency of the TT genotype compared with female control subjects. In the female population, the frequency of the TT genotype in patients with initial coronary aneurysm was significantly lower than in patients without this manifestation. Analysis of the data for the male population showed that the frequency of the TT genotype in KD patients developing coronary stenosis, occlusion or myocardial infarction was higher than that in those without these manifestations, although the difference was statistically insignificant. Conclusions: The TT genotype may protect female KD patients against initial aneurysm formation and predispose male KD patients to severe coronary complications. Further large-scale studies may be required to confirm the contribution of homocysteine in the coronary sequelae of KD.

To evaluate in vivo nitric oxide production in Kawasaki disease (KD), urinary nitrite/nitrate (NOx) excretion was measured in 8 children with KD (age 1.1-2.7 years). Urinary NOx excretion was 0.66 +/- 0.22 mmol mmol-1 creatinine (mean +/- SD) in the 8 children with KD in the initial stages. The levels were significantly increased compared with those of 12 age-matched healthy control subjects (0.35 +/- 0.08 mmol mmol-1 creatinine). Urinary Nox excretion was serially determined in four patients. For each patient, there was a further rise in urinary NOx excretion from baseline levels coincident with the administration of intact-type gammaglobulin and aspirin. With clinical and laboratory improvement, however, urinary NOx excretion declined to the normal range. These findings suggest that endogenous nitric oxide production is enhanced in children with acute KD. Further studies are needed to clarify the role of nitric oxide in the pathogenesis and clinical course of KD.

Several less harmful methods than voiding cysto-urethrography for detecting significant ureteric reflux have been proposed. The present prospective study investigated whether ultrasonography was effective in identifying ureteric reflux in infants with their first febrile urinary infection. The subjects were 27 infants (24 boys and 3 girls) aged from 0 to 8 months. The urinary tract was scanned when the bladder was full, and before and during induced voiding. Infants with abnormal ultrasound findings underwent voiding cysto-urethrography. The other infants were followed and those who had a recurrence of urinary infection underwent voiding cystography. Ten children underwent cysto-urethrography, with eight refluxing ureters identified in six boys. Ultrasound revealed transient dilatation of the renal pelvis on voiding in five kidneys, transient dilatation of distal ureters in 12 and hydro-ureteronephrosis in two. Each of the five kidneys with pelvic dilatation on voiding was associated with ureteric reflux grades III or IV. Of the 17 children who did not undergo cysto-urethrography, only one had recurrence of urinary infection and was diagnosed with ureteric reflux. This girl was one of the three babies who were not scanned during voiding. More than half of the infants with febrile urinary infection were excluded from invasive examination without having recurrence of urinary infection. Thus, ultrasound scanning during voiding was effective for screening infants with their first urinary infection to detect significant ureteric reflux.

Three children were diagnosed as having acute renal failure due to acute tubulointerstitial nephritis (TIN) associated with Yersinia pseudotuberculosis infection. The kidneys were observed ultrasonically during the disease course. The subjects presented with remittent fever, vomiting or diarrhea, and nonoliguric acute renal failure with sterile pyuria and tubular reabsorptive dysfunction. Ultrasound examination delineated marked enlargement of the kidneys with diffuse hyperechogenicity in the cortex, suggesting the diagnosis of TIN. The renal swelling was marked in the descending order of width, depth and length, respectively, and reached more than 200% in volume in 1 of the children who was examined at the culminating stage of acute renal failure. The enlarged kidneys reduced in size in parallel as the elevated serum creatinine levels decreased. However, the enlarged kidneys did not seem to return to their original sizes: the kidney size in 1 of the children remained well above the upper allowance limit of the body-height-related normals and in the other 2 they were only a little smaller than the upper limits. These ultrasound findings should help with the diagnosis and follow-up of the disease.

We investigated by ultrasonography the bladders of 30 young children (26 boys, 4 girls) without established bladder control immediately before voiding cystourethrography. The anterior/posterior (D), superior/inferior (H) and transverse dimension (W) of the bladder were determined. The small children had a significantly greater H value compared with D and W than older children in our previous study in 1993. The regression equation for D x H x W and actual bladder volume in 30 infants was calculated as y = 0.49 x + 3 (Eq. 1). When bladder volume of the 30 infants was estimated from D x H x W, the mean percentage error was much lower with Eq. 1 than with Eq. 2 (y = 0.68 x + 4), which had been determined for older children (mean +/- SD 16.8% +/- 10.7% vs. 44.7% +/- 26.2%) (P0.01). Thus, infants have a different bladder shape than older children and their bladder volume should be estimated using a specific formula designed for them.

Dilatation of the renal pelvis has been observed as an ultrasonographic finding of ureteral reflux as well as hydronephrosis. However, little information is available on the prevalence of renal pelvis at dilatation in neonates. We measured the inner pelvis dimension of the kidneys in 511 apparently healthy neonates (279 boys and 232 girls) using an ultrasound scanner to determine the prevalence of renal pelvis dilatation. Ninety per cent of the neonates had an inner dimension of both renal pelvises below 5 mm. The prevalence of left renal pelvis dilatation of 5 mm or more was significantly higher in the boys than in the girls, 25 (9%) compared to 5 (2%). In contrast, no significant difference was found in the prevalence of right renal pelvis dilatation between the sexes. In the boys, the prevalence of renal pelvis dilatation of 6 mm or more was significantly higher on the left side than on the right. Moreover, the left renal pelvis dilatation of the male neonates had a tendency to persist at 1 month of age. These findings suggest that the left renal pelvis of the baby boy may be predisposed to dilatation.

A 4-year-old girl was diagnosed as having acute renal failure due to tubulointerstitial nephritis. The girl presented with remittent fever, vomiting and non-oliguric acute renal failure with sterile pyuria and tubular reabsorptive dysfunction. Ultrasound examination revealed that the kidneys were markedly enlarged with diffuse hyperechogenicity in the cortex when the abnormal renal function was present and were restored in size and echogenicity when the renal function normalised. A diagnosis of Yersinia pseudotuberculosis infection was based on a rise in haemagglutination titres against the organism.

Idiopathic low-molecular-weight (LMW) proteinuria is a newly described renal disease in Japan and Italy. We report on 7 patients who manifested bilateral or unilateral nephrocalcinosis, as demonstrated by abdominal computed tomography scans. Renal histology revealed calcinosis of renal tubules in 2 patients. Computed tomography is a reliable method for the detection of nephrocalcinosis in this disorder. Hypercalciuria was also seen in 6 patients. A calcium-loading test performed in 2 patients suggested that hypercalciuria was of renal origin. Although the true pathogenesis is still not known, hypercalciuria and nephrocalcinosis appear to be a common complication in patients with idiopathic LMW proteinuria. These complications and clinical features suggest that idiopathic LMW proteinuria in Japan is likely to be identical to Dent's disease in the United Kingdom.

Although ultrasound has been recently used to estimate bladder volume, several different formulae are used. We analysed the accuracy of ultrasound evaluation of bladder volume with an ultrasound scanner equipped with a videocassette recorder. We determined three dimensions of the bladder, i.e. depth (D), height (H) and width (W) by reviewing videotapes in 53 children. D x H x W (DHW) showed a good linear relationship with actual bladder volume (r = 0.96). Estimation of bladder volume by the regression equation gave errors of 12.5 +/- 8.6% (mean +/- SD) with errors above 25% in only 6% of children. Estimation of the volume by simply multiplying DHW by a correction factor of 0.80 gave a greater error of 18.9 +/- 14.0% (P0.001) with errors above 25% in 24% of children. Thus, the use of the formula volume (ml) = DHW (cm3) x 0.68+4 was sufficiently accurate in the ultrasound estimation of bladder volume in children.

The following is a case of a family with a pair of identical twins and a family history of insulin-dependent diabetes mellitus (IDDM). A 2 year old identical twin was first admitted to our hospital and diagnosed as IDDM based on diabetic ketoacidosis. His father has been treated with insulin since the diagnosis of IDDM at the age of 17. All family members had the HLA-DR4 and DQA1*0301 alleles, which are strongly associated with IDDM. The DR-DQ haplotypes of the father and both twins were DR4-DQW8 (DQB1*0302), which increases susceptibility to IDDM. Islet cell antibodies were positive only in the index twin at the time of diagnosis. The co-twin was considered to have beta-cell dysfunction based on the result of an intravenous glucose tolerance test.