Urinary L-FABP as a mortality predictor in <5-year-old children with sepsis in Bangladesh.

BACKGROUND: Although sepsis is often associated with high mortality in severely malnourished children, data are very limited on appropriate diagnostic tools to predict mortality. We examined the role of urinary liver-type fatty acid-binding protein (L-FABP) in children <5 years old with sepsis who died. METHODS: This prospective observational study was conducted at the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh. Children aged 6-59 months admitted with sepsis from April 2010 to December 2011 were enrolled. Comparison of clinical and laboratory characteristics was made between children who survived (n = 83) and those who did not survive (n = 22). RESULTS: On multiple Poisson regression analysis, after adjusting for potential confounders such as mid-upper arm circumference < 115 mm, plasma albumin < 2.5 g/dL, potassium > 5.0 mmol/L, and blood urea nitrogen > 20 mg/dL on admission, first urine L-FABP ≥ 370 ng/mL (relative risk [RR], 2.76; 95%CI: 1.22-6.25), weight-for-length/height z score < -3 (RR, 2.54; 95%CI: 1.26-5.09), capillary refilling time > 2.0 s (RR, 5.16; 95%CI: 1.46-18.3), and sodium > 160 mmol/L (RR, 2.72; 95%CI: 1.07-6.90) were identified as significant risk factors of mortality in children with sepsis. Diagnostic performance of first urine L-FABP was analyzed using receiver operating characteristic curve, and the area under the curve was 0.647 (95%CI: 0.500-0.795). CONCLUSION: Urinary L-FABP may be a useful predictor of mortality in septic children. Urinary examination is non-invasive and easy to apply at the bedside.

Japanese boy with maturity-onset diabetes of the young type 3 who developed diabetes at 19 months old.

Maturity-onset diabetes of the young type 3 (MODY3) is caused by hepatocyte nuclear factor 1α gene mutation and is clinically characterized by young onset and insufficient insulin secretion. We report a 19-month-old Japanese boy with a family history of young-onset diabetes who was initially diagnosed with type 1 diabetes. Mutational analysis of the hepatocyte nuclear factor 1α gene revealed a novel heterozygous frameshift mutation (c.593delA p.Lys198fs) resulting in a truncated protein in the patient and his father. The patient was diagnosed as having MODY3 and was successfully treated with insulin glargine. We could not determine the genetic or environmental factors to explain the difference in the age of disease onset within the same family. This is the youngest case of a MODY3 child presenting with overt diabetes. Our experience suggests that clinicians should always consider the possible diagnosis of MODY3 in a diabetic child with a family history of young-onset diabetes and should perform molecular investigations.

Hypophosphatemia among severely malnourished children with sepsis in Bangladesh.

BACKGROUND: The interaction between hypophosphatemia (HP) and severe malnutrition has received little attention. This study investigated the prevalence, severity, and risk factors of HP among severely malnourished children with sepsis in Bangladesh. METHODS: Children aged 6-59 months admitted with sepsis to Dhaka Hospital from April 2010 to December 2011 were enrolled in the study and divided into two groups: severe acute malnutrition (SAM) and non-SAM groups. Plasma phosphate and the related biochemical parameters were measured upon admission and on the second and fourth days for both groups and the 10th day or discharge day for the SAM group. RESULTS: The prevalence of HP (plasma phosphate <3.7 mg/dL) was 72.9% and 62.5% (P = 0.26) for 48 SAM and for 56 non-SAM patients, respectively; that of moderate-severe HP (phosphate <2 mg/dL) was 25.0% and 19.6%, respectively (P = 0.51). The plasma phosphate level of 21 SAM patients was significantly lower on the second and fourth days than upon admission (P = 0.03, P = 0.01, respectively); it then recovered on the 10th day or discharge day. On multiple logistic regression analysis, plasma potassium <2.5 mmol/L upon admission was found to be a risk factor for moderate or severe HP (adjusted odds ratio, 7.21; 95% confidence interval: 1.88-27.7). CONCLUSION: HP is common among children with sepsis. Potassium <2.5 mmol/L upon admission is considered a risk factor for moderate or severe HP in children with sepsis.

Association of adiponectin polymorphism with cord blood adiponectin concentrations and intrauterine growth.

To assess whether adiponectin gene (ADIPOQ) polymorphism is associated with intrauterine fetal growth and cord blood adiponectin, we investigated eight single-nucleotide polymorphisms (SNPs; rs182052, rs710445, rs16861205, rs12495941, rs1501299, rs3774261, rs2082940 and rs266729) in ADIPOQ and birth weight and cord blood adiponectin in 526 healthy neonates. We found that the neonates carrying the G allele of rs266729 had a significantly greater birth weight s.d. score than those homozygous for the C allele (CC: -0.06±0.75 versus CG: 0.20±0.64 versus GG: 0.07±0.78; P=1.65 × 10(-3), adjusted P=9.90 × 10(-3)). However, this difference was not significant after adjustment for cord blood adiponectin (P=0.04, adjusted P=0.26). The rs266729 SNP was strongly associated with cord blood adiponectin; neonates with rs266729 GG had the highest adiponectin (CC: 34.1±20.2 versus CG: 44.3±26.1 versus GG: 54.1±36.7 µg ml(-1), P=2.80 × 10(-9), adjusted P=1.68 × 10(-8)). This association remained after adjustment for birth weight s.d. score (P=6.63 × 10(-8), adjusted P=3.98 × 10(-7)). Our results suggest that the influence of the rs266729 SNP in ADIPOQ on birth weight may be dependent on circulating adiponectin.

A Japanese boy with adenine phosphoribosyltransferase (APRT) deficiency caused by compound heterozygosity including a novel missense mutation in APRT gene.

UNLABELLED: We describe a 2-year-old Japanese boy with radiolucent urolithiasis and recurrent urinary tract infection. Urinalysis showed typical 2,8-dihydroxyadenine (2,8-DHA) crystals, leading to a diagnosis as adenine phosphoribosyltransferase (APRT) deficiency. The sensitivity of proliferating T cells to an adenine analogue, whose cytotoxicity is dependent on APRT, showed that he was homozygous or compound heterozygous for the APRT gene mutation. A genetic analysis revealed a compound heterozygous state for M136T and a novel missense mutation L33P, not previously reported in patients with APRT deficiency. CONCLUSION: Adenine phosphoribosyltransferase deficiency should be suspected in all patients with radiolucent kidney stones, urinary 2,8-DHA crystals were an important finding for an early diagnosis of APRT deficiency. Appropriate treatment should be initiated to prevent the development of urolithiasis or renal failure in APRT-deficient children. The T cell method was useful to detect a homozygote or a compound heterozygote of the pathogenic allelic gene in APRT deficiency, and a genetic analysis revealed a novel mutation L33P.

Serum resistin concentrations in children with Kawasaki disease.

OBJECTIVE: Human resistin is expressed strongly in monocytes or macrophages rather than in adipocytes and may play a pivotal role in inflammation. We hypothesize that resistin levels are elevated in patients with Kawasaki disease (KD) in the acute phase and may be associated with the disease severity. DESIGN AND SUBJECTS: Serum resistin concentrations were measured in 44 Japanese children with KD and 17 age-matched healthy children. All the KD patients were given both aspirin and a single dose of intravenous immunoglobulin (IVIG). RESULTS: The serum resistin levels at baseline in KD children were significantly higher than those in controls [33.0 (21.6-45.3) vs. 14.8 (12.4-18.6) ng/mL, P < 0.001]. After IVIG therapy, serum resistin levels were significantly decreased to normal control levels. No significant difference in baseline resistin levels was found between the high-risk group and the low-risk group of coronary artery aneurysms. CONCLUSIONS: We confirmed that resistin was an acute inflammatory protein, but its concentrations were unlikely to predict the prognosis of disease in acute KD patients.

Novel compound heterozygous ATP6V0A4 mutations in an infant with distal renal tubular acidosis.

A Japanese infant presenting with vomiting, failure to thrive, metabolic acidosis, and hyperammonemia was finally diagnosed with autosomal recessive distal renal tubular acidosis (dRTA). Hyperchloremic metabolic acidosis, hypokalemia, a normal serum anion gap, a positive urine anion gap, nephrocalcinosis, and high urine pH despite systemic acidemia were consistent with the cardinal manifestations in dRTA. Mutational analysis of the ATP6V0A4 gene revealed novel compound heterozygous mutations: Ile549fsX580 and Ile557Leu558del. The father was found to be heterozygote for the former mutation, the mother heterozygote for the latter. This is the first case of dRTA with hyperammonemia in which the ATP6V0A4 mutations were identified. dRTA should be considered in the differential diagnosis of children presenting with hyperammonemia. Additionally, in a possible case of autosomal recessive dRTA with normal hearing, mutational analysis of ATP6V0A4 gene may be recommended first to confirm the diagnosis.

Successful pregnancy in a female patient with congenital chloride diarrhea (CLD) and renal impairment.

We report a successful case of pregnancy in a female patient with congenital chloride diarrhea (CLD) and reduced renal function due to interruption of treatment. CLD is an autosomal recessive disorder of intestinal electrolyte absorption caused by mutations in the solute carrier family 26, member 3 (SLC26A3) gene, and continuous production of watery diarrhea induces dehydration, metabolic alkalosis and many kinds of electrolyte disturbances in CLD patients. The patient in our case was a 24-year-old female CLD patient with moderate renal impairment; a renal biopsy specimen showed minimal glomerular changes, but tubulointerstitial damage by crystal formation, consistent with renal function data. One year after our initial examination and reinstitution of therapy, the patient got married and soon conceived. There were no major problems during the course of pregnancy, and the patient successfully delivered a healthy full-term infant vaginally. The symptoms and clinical course of the patient were particularly mild, and we discuss possible reasons for these observations from a perspective of genotype, phenotype and environmental conditions.

Longitudinal evaluation of patients with a homozygous R450H mutation of the TSH receptor gene.

BACKGROUND/AIM: The R450H mutation of the TSH receptor (TSHR) gene has been frequently observed in Japanese patients with resistance to TSH. The purpose of this study was to clarify the phenotype of patients with a homozygous R450H mutation of the TSHR gene; the mutant receptor has previously demonstrated moderately impaired function in vitro. METHODS: We performed a clinical investigation of 5 Japanese patients who had hyperthyrotropinemia as neonates, in whom a homozygous R450H mutation of the TSHR gene had been demonstrated by genetic sequencing analysis. RESULTS: The thyroid hormone levels of the patients were normal in early infancy, although their serum levels of TSH were mildly elevated. After supplemental treatment with levothyroxine sodium (L-T4) was started, we had to increase the dose to maintain the level of TSH within the normal range in all patients. Thyroid dysfunction became obvious in one patient at reexamination during adolescence when L-T4 treatment was stopped for 1 month. Four patients were examined for intelligence quotient and their scores were normal. CONCLUSIONS: Thyroid hormone replacement therapy should be considered based on biological data in patients with hyperthyrotropinemia who have a homozygous R450H mutation of the TSHR gene even if they do not exhibit obvious hypothyroidism in infancy.

Serum resistin concentrations in growth hormone-deficient children during growth hormone replacement therapy.

We performed this study to examine whether the serum resistin concentrations in growth hormone (GH)-deficient (GHD) children are influenced by administration of GH and to assess the relationship between serum resistin and free fatty acid levels during GH replacement therapy. The study included 20 prepubertal GHD children (16 boys and 4 girls) who were treated with recombinant human GH (hGH). The serum levels of resistin, insulin-like growth factor I, free fatty acid (FFA), triglyceride, cholesterol and glucose levels, leukocyte counts, and hemoglobin A(1c) were measured at baseline and after 1 month of hGH treatment. The serum resistin levels after hGH therapy were significantly higher than the basal resistin levels (median [range], 6.2 [4.9-11.8] vs 5.6 [4.4-8.3] ng/mL; P < .05), whereas the serum FFA levels were unchanged before and after treatment (0.51 [0.34-0.76] vs 0.37 [0.24-0.60] mEq/L). No significant relationship was found between serum resistin and FFA levels after hGH therapy. Body mass index, serum triglyceride, cholesterol and glucose levels, leukocyte counts, and hemoglobin A(1c) showed no significant differences before and after hGH treatment. Our results suggest that elevated serum resistin levels after 1-month hGH therapy in GHD children are not associated with the GH-induced lipolysis as found in GHD adults during short-time hGH therapy.

Cord blood insulin-like growth factor (IGF)-1, IGF-binding proteins and adiponectin, and birth size in offspring of women with mild gestational diabetes.

OBJECTIVE: To clarify the impact of a mild form of gestational diabetes mellitus (GDM) on neonatal birth size, and on insulin-related hormones and adiponectin (AdipoQ) in cord blood. METHODS: Two hundred and sixteen Japanese pregnant women diagnosed as having normal glucose tolerance according to the JSOG criteria were enrolled. Of the 216 women, 38 women were reclassified into a mild GDM (mGDM) group according to the IADPSG criteria. Of the remaining 178 women, 135 women with normal 50-g glucose challenge test were reclassified into a normal glucose tolerance (NGT) group. Cord blood insulin-like growth factor (IGF)-1, IGF-binding proteins (IGFBPs) and AdipoQ were measured in the offspring of the two groups. RESULTS: Birth weight and its SD scores were larger in the mGDM group than in the NGT group. The incidence of large-for-gestational age (LGA) newborns was higher in the mGDM than in the NGT group. No differences in cord blood free IGF-1, IGFBP-1, IGFBP-2 or AdipoQ levels were observed between the mGDM and NGT groups. CONCLUSIONS: Our study suggests that mild GDM reclassified according to the IADPSG criteria influences neonatal birth size, but neither the IGF-IGFBP axis nor AdipoQ can account for the changes of birth size in offspring of women with mild GDM.

Autosomal dominant distal renal tubular acidosis caused by a mutation in the anion exchanger 1 gene in a Japanese family.

Autosomal dominant distal renal tubular acidosis (dRTA) is a rare disorder caused by a mutation in the AE1 gene encoding the chloride-bicarbonate (Cl-/HCO3-) anion exchanger 1 (AE1). Most patients with this disorder present with clinical symptoms in adulthood and their phenotype is milder than that of those with autosomal recessive dRTA. In this report, we describe a Japanese family with autosomal dominant dRTA in which the mother and her daughter presented with severe symptoms caused by hypokalemia at 2 years of age. The heterozygous AE1 mutation G609R, which is a known causative mutation of dRTA, was identified in both patients. To our knowledge, this is the first report of a Japanese family with autosomal dominant type dRTA caused by an AE1 mutation. We, therefore, propose that alterations of AE1 should be considered causative of autosomal dominant dRTA even if typical symptoms appear during early childhood and the clinical features are severe.

Osteofibrous dysplasia in a Japanese boy with Costello syndrome.

We present the case of a boy with Costello syndrome who developed osteofibrous dysplasia during a phase of growth hormone therapy. The lesion and the accompanying pain disappeared after discontinuation of the therapy. Growth hormone is a known mitogen for some neoplasms and osteofibrous dysplasia has been reported to become aggressive. Thus, although osteofibrous dysplasia in Costello syndrome has not been reported before, growth hormone therapy should be used under close supervision in children with this syndrome.

Serum dipeptidyl peptidase 4 activity in children with type 1 diabetes mellitus.

BACKGROUND: It is poorly understood whether dipeptidyl peptidase 4 (DPP4) activity is altered and how DPP4 contributes to glycemic control in patients with type 1 diabetes mellitus (T1DM). AIM: The aim of this study was to measure serum DPP4 activity and to assess its relationships to metabolic variables in T1DM children. METHODS: Serum DPP4 activity was determined using a fluorometric assay in 43 T1DM and 26 control children. RESULTS: Serum DPP4 activity was significantly higher in T1DM children than in controls (3.57 ± 0.99 vs. 2.67 ± 0.77 U/mL, p<0.001). In the T1DM children, DPP4 activity was not correlated with HbA1c, blood glucose, or diabetes duration. A significant negative correlation was found between DPP4 activity and serum adiponectin levels in the T1DM group (r=-0.35, p<0.05). CONCLUSIONS: Serum DPP4 activity was increased in the T1DM children, whereas it was not associated with glycemic control. Given the negative correlation between serum DPP4 and adiponectin levels, further investigations are warranted to elucidate the role of DPP4 on insulin sensitivity in T1DM children.

Changes in serum adiponectin levels from birth to term-equivalent age are associated with postnatal weight gain in preterm infants.

BACKGROUND: Adiponectin, one of the adipocytokines, is postulated to play a key role in fetal growth, probably enhancing the growth-promoting effect of insulin through insulin-sensitizing action. OBJECTIVES AND METHODS: To examine how different intrauterine or postnatal growth patterns relate to adiponectin secretion, we measured serum adiponectin concentrations in 30 appropriate-for-gestational-age (AGA) and 19 small-for-gestational-age (SGA) preterm infants on the first day of life and at term-equivalent age. RESULTS: The serum levels of adiponectin increased significantly in all preterm infants from birth to term-equivalent age. The adiponectin levels at term-equivalent age were significantly higher in the AGA than in the SGA group [mean (SD) 40.4 (12.3) vs. 28.4 (10.4) µg/ml; p < 0.01] after adjustment for gestational age or term-equivalent body weight. The increase in adiponectin levels from birth to term-equivalent age was significantly higher in the AGA than in the SGA group, and was positively correlated with the weight gain rate (g/kg/day) in the combined groups (r = 0.37, p < 0.01). A multiple regression analysis with the adiponectin increase from birth to term-equivalent age as the dependent variable for all the subjects revealed that only weight gain rate was independently associated with the adiponectin increase. CONCLUSIONS: Our results suggest that the change in serum adiponectin levels may reflect postnatal growth from birth to term-equivalent age in preterm infants.

Serum levels of adiponectin and IGFBP-1 in short children born small for gestational age.

OBJECTIVE: The aim of this study was to quantify serum adiponectin concentrations in short children born small for gestational age (SGA) compared with those in children born appropriate for gestational age (AGA), and to assess the relationship between the serum levels of adiponectin and insulin-like growth factor binding protein-1 (IGFBP-1) known as a predictor of the development of type 2 diabetes mellitus and cardiovascular disease. SUBJECTS AND METHODS: Sixteen prepubertal short children born SGA and 20 short children born AGA, matched for age, body mass index, height, pubertal status, gestational age, bone age and midparental height, were included in the study. The serum levels of adiponectin, IGFBP-1, insulin and insulin-like growth factor-I (IGF-I) were measured in the fasting state. RESULTS: The levels of serum adiponectin were significantly lower in the SGA than in AGA children (10.5 +/- 4.2 vs. 13.9 +/- 5.1 micro g/ml, P < 0.05). The levels of serum IGFBP-1, insulin and IGF-I were all similar in both groups. Overall, there was a significant positive correlation between adiponectin and IGFBP-1 (r = 0.40, P < 0.05). CONCLUSIONS: Our results suggest that hypoadiponectinaemia in short SGA children without catch-up growth may reflect insulin resistance and imply a higher risk of developing type 2 diabetes mellitus. Additionally, adiponectin may be a more sensitive indicator for latent insulin resistance than IGFBP-1 in short SGA children.

A case of Moebius syndrome presenting with congenital bilateral vocal cord paralysis.

We describe a female infant with bilateral facial paralysis and abducens palsy. To the best of our knowledge, this is the first report of Moebius syndrome presenting with congenital bilateral vocal cord paralysis (CBVCP). Although CBVCP can be part of a recognizable syndrome, i.e. Down syndrome, 22q deletion syndrome, Robinow's syndrome and cerebro-oculo-facio-skeletal syndrome, no reports of Moebius syndrome with CBVCP were found in the literature. CBVCP is often associated with central nervous system abnormalities. However, our patient had no detectable brain abnormalities. The etiology of Moebius syndrome remains unknown. It is interesting that the clinical manifestations of Moebius syndrome can include CBVCP. However, the pathophysiology of CBVCP is unknown and further investigations into the etiology of Moebius syndrome are required.

Nevo syndrome with an NSD1 deletion: a variant of Sotos syndrome?

A 17-month-old girl with clinical manifestations of Nevo syndrome and NSD1 (nuclear receptor binding SET domain protein 1) deletion is described. Nevo syndrome is a rare overgrowth syndrome showing considerable phenotypic overlap with Sotos syndrome-another, more frequent overgrowth syndrome caused by NSD1 mutations or deletions. About a half of Japanese Sotos syndrome patients carry a 2.2-Mb common deletion encompassing NSD1 and present with frequent brain, cardiovascular, or urinary tract anomalies. The girl we described had the common deletion and showed patent ductus arteriosus, atrial septal defect, vesicoureteral reflux, and bilateral hydronephrosis. It was thus concluded that the clinical manifestations, including the Nevo syndrome phenotype, were caused by the microdeletion.