Association between timing of adiposity rebound and body weight gain during infancy.

OBJECTIVE: To investigate whether increments of weight gain in early infancy are related to the timing of adiposity rebound (AR). STUDY DESIGN: A total of 271 children (147 boys and 124 girls) in 1 community were enrolled in the study. Serial measurements of body mass index were carried out at the ages of 4, 8, and 12 months and 1.5, 2, 3, 4, 5, 6, 7, 8, 9, and 10 years, based on which the age of AR was determined. We also calculated body weight increments in 3 separate periods: birth to 4 months, 4-8 months, and 8-12 months. RESULTS: There was no significant relationship between weight gain in any period of infancy and the age of AR. Weight gain between birth and 4 months was positively correlated only with body mass index at 7 years of age. CONCLUSIONS: We could not find an association between body weight gain during infancy and the timing of AR. This suggests that infantile weight gain is not related to childhood obesity through AR.

Homozygous 6-bp deletion of IGFALS in a prepubertal boy with short stature.

Biallelic IGFALS variants lead to acid‒labile subunit (ALS) deficiency characterized by growth hormone resistance with or without delayed puberty. Here, we report a prepubertal boy with a homozygous 2-amino acid deletion within the fourth N-glycosylation motif (c.1103_1108del, p.N368_S370delinsT) associated with parental consanguinity. He showed short stature consistent with ALS deficiency. This case expands the mutation spectrum of IGFALS to include the elimination of only one N-glycosylation motif of ALS.

HLA-class II and class I genotypes among Japanese children with Type 1A diabetes and their families.

OBJECTIVE: To determine the HLA-DRB1, DQB1, DPB1, A, C, and B genotypes among Japanese children with autoimmune type 1 diabetes. METHODS: Four hundred and thirty patients who were GADAb and/or IA-2Ab-positive (Type 1A) were recruited from 37 medical centers as part of a nationwide multicenter collaborative study. DNA samples from 83 siblings of the children with Type 1A diabetes and 149 parent-child trios were also analyzed. A case-control study and a transmission disequilibrium test (TDT) were then performed. RESULTS: The susceptible and protective DRB1 and DQB1 alleles and haplotypes were confirmed. DPB1 alleles unique to the Japanese population and those common to multiple ethnic groups were also present. A linkage disequilibrium (LD) analysis showed both susceptible and protective haplotypes. The TDT did not reveal any alleles that were transmitted preferentially from the mother or father to children with Type 1A. Homozygosity for DRB1-09:01-DQB1-03:03 and heterozygosity for DRB1-04:05-DQB1-04:01 and DRB1-08:02-DQB1-03:02 were associated with an extremely high risk of Type 1A. A comparison of children with Type 1A and their parents and siblings suggested a dose effect of susceptible DRB1-DQB1 haplotypes and an effect of protective alleles on immunological pathogenesis. DRB1-09:01 appeared to be strongly associated with an early onset in preschool children with Type 1A diabetes. CONCLUSIONS: This study demonstrated the characteristic association of HLA-class II and class I genes with Type 1A diabetes among Japanese children. A TDT did not reveal the genomic imprinting of HLA-class II and class I genes in Type 1A diabetes.

Estimation of LDL Particle Size Using Lipid Indices: A Population-Based Study of 1578 Schoolchildren.

BACKGROUND: Low-density lipoprotein (LDL) is atherogenic and LDL particles are reduced in diameter in the presence of insulin resistance, forming small, dense LDL. This study was conducted to assess the relationship between commonly used lipid indices and LDL particle size and furthermore to clarify the best surrogate lipid markers that could conveniently be used to estimate LDL particle size in children. METHODS: We determined LDL particle diameter by gradient gel electrophoresis in 1578 children aged 10-12 years. At the fasting state, the relationships between measured LDL particle size and lipid variables [total cholesterol (TC), triglycerides (TG), LDL-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), atherogenic index [(TC-HDL-C)/HDL-C, TG/HDL-C, LDL-C/HDL-C, and LDL-C/apolipoprotein B (Apo B) and non-HDL-C (TC-HDL-C)] were analyzed. RESULTS: The LDL particle diameter was 26.64 (mean) ± 0.48 (SD) nm in boys (n = 820) and 26.66 ± 0.49 nm in girls (n = 758); there was not a statistically significant difference. There were statistically significant correlations between LDL particle size and TG or HDL-C concentrations (r = 0.28∼0.37), but the correlations with LDL-C and ApoB were very weak. The combined lipid measures, such as atherogenic index, TC/HDL-C, TG/HDL-C, and LDL-C/HDL-C showed moderate correlations (r = 0.33∼0.38) with LDL particle size; however, the correlation of non-HDL-C with LDL particle size was weak (r = 0.18∼0.19). Simple HDL-C measure appeared to be of comparable value to combined lipid measures. CONCLUSIONS: Our data indicate that various lipid indices are not superior to HDL-C levels alone as a clinical tool for estimating LDL particle size. Non-HDL-C was less valuable in this aspect.

Two de novo mutations in the AR gene cause the complete androgen insensitivity syndrome in a pair of monozygotic twins.

The androgen insensitivity syndrome (AIS) is the most common cause of male undermasculinization and is typically caused by mutations in the AR gene. Affected individuals may exhibit either complete external feminization (complete AIS) or a partial phenotype (partial AIS). Here we describe monozygotic twins diagnosed with complete AIS who each possess two substitutions (C-->G at position 2930 and T-->C at position 2955, both in exon 7), leading to Phe(856)Leu and Ser(865)Pro mutations, respectively. Neither parent was found to be a carrier for these mutations, indicating that the double mutation arose de novo. Both mutations were recreated by site-directed mutagenesis and compared functionally with the wild-type receptor. The Phe(856)Leu mutation did not affect androgen binding when expressed in COS-1 cells, nor did this mutation decrease androgen-dependent trans-activation in transfected HeLa cells. However, the Ser(865)Pro mutation completely ablated androgen binding and trans-activation. In this study we demonstrate that the replacement of serine by proline at position 865 is sufficient in itself to cause complete AIS in these twins. Analyses of nuclear receptor structures suggest that this mutation is likely to perturb the conformation of helix 10/11, which plays a role in ligand binding, dimerization, and receptor activation. To our knowledge this is the first confirmed instance of AIS (complete or partial) due to an AR mutation occurring in twins. Furthermore, the phenotype was associated with two mutations that were both novel in nature.

Relationship between the presence of small, dense low-density lipoprotein and plasma lipid phenotypes in Japanese children.

To clarify the relationship between the expression of atherogenic small, dense low-density lipoprotein (SDLDL) and underlying lipid metabolic abnormalities, the prevalence of SDLDL in relation to the serum lipid phenotype was analyzed in 229 children. The LDL particle size was measured using gradient gel electrophoresis, and a particle size of less than 25.5 nm was considered to represent SDLDL. The overall prevalence of SDLDL in the sample population was 8.2% (19/229; 11/117 for boys and 8/112 for girls). Hyperlipidemia phenotype IIb (elevated concentrations of both triglyceride [TG] and total cholesterol [TC]) was strongly associated with SDLDL in 83% (5/6) of the subjects. An elevated TG concentration (phenotype IV) was associated with SDLDL in 55% (10/18) of the subjects. The association between hyperlipidemia phenotype IIa (elevated TC but a normal TG concentration) and SDLDL was quite low (2%; 1/56), but SDLDL was detected in 5% (8/155) of the subjects who presented with normolipidemia. Therefore, these findings suggest that the expression of SDLDL is largely related to lipid abnormalities characterized by phenotype IIb or IV, the underlying metabolic abnormality of which is suspected to be insulin resistance; however, an additional mechanism for the formation of SDLDL that functions independently of plasma lipid abnormalities also seems to exist.

Formation of bis(2-pyridylcarbonyl)aminate by oxidation of ethylbis(2-pyridylmethyl)amine on the trichloridoruthenium(III) complex.

Oxidation of the facial-type trichloridoruthenium(III) complex bearing ethylbis(2-pyridyl-methyl)amine (ebpma), fac-[Ru(III)Cl3(ebpma)], with an equimolecular amount of (NH4)2[Ce(IV)(NO3)6] in acetonitrile afforded a ligand-based oxidation product of an acetonitriledichloridoruthenium(III) complex having bis(2-pyridylcarbonyl)aminato (bpca), [Ru(III)Cl2(NCCH3)(bpca)]. The complex changed into a trichloridoruthenium(III) complex by a reaction with hydrochloric acid and the triacetonitrileruthenium(II) complex by reduction with Zn in ethanol-acetonitrile. The bpca moiety showed interactions with cations such as protons.

Adiposity rebound and the development of metabolic syndrome.

OBJECTIVE: The age of adiposity rebound (AR) is defined as the time at which BMI starts to rise after infancy and is thought to be a marker of later obesity. To determine whether this age is related to future occurrence of metabolic syndrome, we investigated the relationship of the timing of AR with metabolic consequences at 12 years of age. METHODS: A total of 271 children (147 boys and 124 girls) born in 1995 and 1996 were enrolled in the study. Serial measurements of BMI were conducted at the ages of 4 and 8 months and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 years, based on which age of AR was calculated. Plasma lipids and blood pressure were measured at 12 years of age. RESULTS: An earlier AR (<4 years of age) was associated with a higher BMI (≥ 20) and a lipoprotein phenotype representative of insulin resistance. This phenotype consists of elevated triglycerides, apolipoprotein B, and atherogenic index and decreased high-density lipoprotein cholesterol in boys and elevated apolipoprotein B in girls at 12 years of age. The earlier AR was also related to elevated blood pressure in boys. CONCLUSIONS: This longitudinal population-based study indicates that children who exhibit AR at a younger age are predisposed to future development of metabolic syndrome. Therefore, monitoring of AR may be an effective method for the early identification of children at risk for metabolic syndrome.

Effect of excess estrogen on breast and external genitalia development in growth hormone deficiency.

BACKGROUND: The progress of sexual maturation and development in cases with growth hormone (GH) and insulin-like growth factor-I (IGF-I) deficiency is not well documented in females. CASE: We observed breast and genitalia development in a 2-year-old girl with GH deficiency following neonatal asphyxia; this girl later developed central precocious puberty. Markedly pigmented stimulated areolas and nipples without an apparent breast mound, and non-enlarged labia minora in the external genitalia were observed as features of sexual maturation in the patient. The hormonal condition was characterized by increased circulating estradiol levels and extremely low IGF-I levels. SUMMARY AND CONCLUSION: This case indicates that IGF-I is necessary for exerting the full effect of estrogen on the development of breasts and maturation of external genitalia.

Duration of isolation of children with influenza A treated with oseltamivir.

The duration of fervescence (24 hours in children or 30 hours in adults) was shorter in the oseltamivir group than in the placebo group. According to a Japanese law enacted before oseltamivir therapy became available, schoolchildren with influenza must be isolated 48 hours after defervescence. Our data suggest isolation should be at least 84 hours for children with influenza A treated with oseltamivir and 108 hours for preschool children.

Successfully treated acute lymphoblastic leukemia associated with craniopharyngioma.

The authors report a 2-year-old boy with acute lymphoblastic leukemia (ALL) associated with craniopharyngioma. To our knowledge, this is the first such report. Magnetic resonance imaging showed a suprasellar tumor, an apparent cystic lesion, whereas cerebral computed tomography confirmed that the tumor exhibited calcification. Without surgical intervention for the suprasellar tumor, we initiated chemotherapy for ALL. After 1 year of chemotherapy, complete remission was achieved, and partial resection and radiation therapy were performed on the suprasellar tumor. At 4 years after completing leukemia chemotherapy, the patient remains in complete ALL remission and has had no recurrence of craniopharyngioma.

Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency.

Carbamoylphosphate synthetase I deficiency (CPS1D) is a urea-cycle disorder characterized by episodes of life-threatening hyperammonemia. Correct diagnosis is crucial for patient management, but is difficult to make from clinical presentation and conventional laboratory tests alone. Enzymatic or genetic diagnoses have also been hampered by difficult access to the appropriate organ and the large size of the gene (38 exons). In this study, in order to address this diagnostic dilemma, we performed the largest mutational and clinical analyses of this disorder to date in Japan. Mutations in CPS1 were identified in 16 of 18 patients with a clinical diagnosis of CPS1D. In total, 25 different mutations were identified, of which 19 were novel. Interestingly, in contrast to previous reports suggesting an extremely diverse mutational spectrum, 31.8% of the mutations identified in Japanese were common to more than one family. We also identified two common polymorphisms that might be useful for simple linkage analysis in prenatal diagnosis. The accumulated clinical data will also help to reveal the clinical presentation of this rare disorder in Japan.

Discrepancies between Physician and Parent Perceptions of Psychosocial Problems of GHD Children Undergoing GH Therapy in Japan.

This study examined discrepancies between the perceptions of physicians treating short children with GH deficiency (GHD) using GH replacement therapy (GHRT) and the perceptions of the parents of these children and identified the major causes of parental anxiety. Three attending pediatric endocrinologists and the parents of 31 GHD children participated in this study. The physicians and parents completed a specially designed questionnaire to rate the types and degrees of psychosocial problems that GHD children might experience. For 6 of the first 11 questions, the physicians rated psychological problems differently than the parents did, tending to over- or underestimate parental concerns. This discrepancy did not disappear with treatment. However, the difference in the perception of anxiety between the physicians and parents changed for issues regularly discussed between them. Physicians and nurses were ranked as the most reliable providers of information. The parents of children who had previously undergone GHRT were a highly desired source of information. Psychosocial problems remain largely unaddressed by endocrinologists. Endocrinologists treating short stature are encouraged to be more involved in understanding parents' anxieties, evaluation of misperceptions concerning parents' expectations, and addressing these issues in future communication with parents. Support by experienced psychologists may help endocrinologists with this issue.

Hypocalcemia due to tubular dysfunction in a patient with holoprosencephaly.

This is the first report of a case of hypocalcemia in a female infant with holoprosencephaly. Hypocalcemia developed 60 days after birth, secondary to decreased serum 1,25-dihydroxyvitamin D, as a result of renal tubular dysfunction which may have been induced by prerenal acute renal failure, the administration of anticonvulsants, and hypothyroidism. However, there was no evidence of rickets, and her serum 25-hydroxyvitamin D value was normal. She was treated with high-dose (0.5 microg/kg) 1alpha-hydroxyvitamin D3 and calcium lactate, and her calcium and 1,25-dihydroxyvitamin D values were consequently, normalized. However, she died at 268 days after birth.