Keiko Nagahara

Cord serum adiponectin is positively related to postnatal body mass index gain.

Background:  The roles of adiponectin and leptin in the early stages of life are poorly understood. We previously studied longitudinal changes in these adipocytokines from birth to 12 months of age. The aim of this investigation was to evaluate the correlation between cord serum adipocytokine levels and postnatal growth by 3 years of age.

Feeding choice has a gender-associated effect on infant growth

Appropriate nutrition during childhood is important for preventing future development of lifestyle‐related diseases. The effect of feeding choice on infant growth in Japan is not known.

A novel de novo germline mutation Glu40Lys in AKT3 causes megalencephaly with growth hormone deficiency

Germline or somatic gain‐of‐function mutations in the v‐akt murine thymoma viral oncogene homolog 3 (AKT3) have been reported to cause syndromic megalencephaly. We describe a novel germline mutation, p.Glu40Lys, in AKT3. Phenotypically, the patient presented with megalencephaly with hypotonia, apparent connective tissue laxity, and growth hormone (GH) deficiency. To our knowledge, this is the first instance of a patient with megalencephaly with GH deficiency, harboring a germline de novo mutation in AKT3.

Evaluation of Hip/HeightP Ratio as an Index for Adiposity and Metabolic Complications in Obese Children: Comparison with Waist-related Indices

Aim: To investigate whether body adiposity index (BAI; hip/height1.5–18), pediatric BAI (BAIp; hip/height0.8–38), and other hip/heightP ratios are useful in obese children. Method: Ninety obese Japanese children, 55 boys and 35 girls, who visited our University Clinic, were enrolled. The age was 9.92 ± 2.6 (mean ± SD) years, and the percentage overweight (POW) was 51.6 ± 18.8%. We set the power value of the hip/heightP 0, 0.5, 0.8, 1, 1.5, and 2 and studied the association with overweight indices, biochemical data, and fat area measured by computed tomography. Waist, waist/height ratio, and waist/hip ratio were also evaluated. Results: Hip/height and hip/height0.8 (BAIp) were more closely correlated with POW, body mass index percentile, and percentage body fat than hip/height1.5 (BAI). The correlation coefficient of hip/height with POW (r = 0.855) was the highest among the studied hip/heightP indices. The approximate line to predict POW was 411 × hip/height−207. The waist/height was also highly correlated with POW (r = 0.879). Hip and hip/height0.5 were more closely correlated with visceral fat area than hip/height, BAIp, and hip/height1.5. Hip and hip/height0.5 were significantly correlated with insulin. Only hip was also significantly associated with dyslipidemia. All hip/heightP indices were not significantly correlated with alanine aminotransferase (ALT). Waist was significantly correlated with serum lipids, ALT, and insulin. Conclusion: Hip/height and BAIp are better markers for overweight (adiposity) in obese children than BAI. However, hip/height, BAIp, and BAI are not useful to predict metabolic complications. Waist appears to be the best index for obese children overall at this time.

A Japanese familial case of hypochondroplasia with a novel mutation in FGFR3

Gain-of-function mutations in the fibroblast growth factor receptor 3 gene (FGFR3) result in a group of skeletal dysplasias, such as prototypic achondroplasia (ACH: OMIM #100800) and lethal thanatophoric dysplasia (TD1: OMIM #187600). Hypochondroplasia (HCH: OMIM #146000) is the mildest of the FGFR3-associated skeletal dysplasias and is characterized by short stature with macrocephaly, brachydactyly, limited range of motion at the elbows, lumbar lordosis, and bowed legs. Radiological features of HCH are flared metaphyses, narrowed interpedicular distance, square ilia, and short femoral necks. These clinical and radiological signs are generally less pronounced than those seen with ACH and may not be noticeable until early or middle childhood. Because GH replacement is effective in some HCH patients (1, 2), genetic analysis to assist early diagnosis and intervention may improve the prognosis of these patients. Here, we present such an example and report the identification of a novel mutation in FGFR3 in a familial case of HCH and the effectiveness of GH treatment in the elder sister.

Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia

To define the ranges of biochemical markers during hypoglycemia for the diagnosis of congenital hyperinsulinism (CHI), using high sensitivity insulin assays.

A Japanese boy with fructose-1,6-bisphosphatase deficiency who had a novel FBP1 mutation (p.Phe90Val)

Fructose-1,6-bisphosphatase (FBPase) deficiency (OMIM 229700; FBPase; E.C.3.1.3.11) is a very rare autosomal recessive disorder of gluconeogenesis with a frequency of 1–9 per 100,000, which is characterized by recurrent episodes of hypoglycemia with metabolic and lactic acidosis, apnea, hyperventilation, and ketosis (1, 2). Fructose intake, fasting, and febrile infectious disease are known to trigger these symptoms. Once the diagnosis is established, the prognosis of this disorder is excellent if simple measures are followed such as the prevention of hypoglycemia (2) and avoidance of the consumption of foods with fructose (2) and glycerol (3). FBPase deficiency can be definitively diagnosed by confirming mutations in FBP1, which encodes fructose-1,6-bisphosphatase-1. FBP1 consists of 7 exons, which span more than 31 kb at chromosome 9q22.2-q22.3 and encodes a 362 amino acid protein that is mainly expressed in the liver and kidney. Since the first identified mutations in 1995, at least 36 additional mutations resulting in FBPase deficiency, including those from the Japanese population (4), have been described in the genomic region spanned by FBP1. Excretion of glycerol and glycerol-3-phosphate in the urine may help to distinguish this disease from other metabolic acidosis diseases (5). Here, we report a patient with FBPase deficiency caused by novel compound heterozygous mutations in FBP1, who had normal urine glycerol-3-phosphate during an oral fructose tolerance test. Received: November 21, 2016 Accepted: April 26, 2017 Corresponding author: Yukihiro Hasegawa, MD, PhD, Department of Endocrinology and Metabolism, Tokyo Metropolitan Children’s Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo 183-8561, Japan E-mail: yhaset@gmail.com

AICAR Attenuates TNFα-Induced Inappropriate Secretion of Monocyte Chemoattractant Protein-1 and Adiponectin in 3T3-L1 Adipocytes.

Aim: The increase in monocyte chemoattractant protein-1 (MCP-1) and the decrease in adiponectin production from hypertrophic adipocytes are associated with adipose tissue inflammation and its metabolic complications. The aim of this study was to determine whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an adenosine monophosphate-activated protein kinase (AMPK) activator, modulates these adipocytokine productions in tumor necrosis factor-α (TNFα)-treated adipocytes. Methods: AICAR and/or other reagents were added to the culture medium, and then, TNFα was added to fully differentiated 3T3-L1 adipocytes. The MCP-1 and adiponectin production in the culture supernatant was measured by ELISA. AMPK, phosphatidylinositol 3-kinase (PI3K), and nuclear factor-κB (NF-κB) activities were also assayed. Results: Treatment with TNFα increased MCP-1 and decreased adiponectin secretion dose-dependently in the 3T3-L1 adipocytes, and AICAR significantly inhibited these TNFα-mediated changes. Interestingly, metformin, another AMPK activator, did not have such effects on these adipocytokines. Both the AMPK and PI3K systems in the cells were significantly activated by the AICAR treatment, but the effects of AICAR on adipocytokines were not weakened by the addition of dorsomorphin, an AMPK inhibitor, or LY294002, a PI3K inhibitor. Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, showed protective effects similar to those as AICAR. AICAR, but not metformin, significantly inhibited the TNFα-stimulated activation of NF-κB, and dorsomorphin did not change AICARs effect. Conclusion: AICAR attenuates the TNFα-induced secretion of MCP-1 and adiponectin in 3T3-L1 adipocytes. The observed effects of AICAR seem to be mainly due to the inhibition of NF-κB activation rather than the activation of the AMPK pathway, at least in TNFα-treated adipocytes.

Evaluation of Phosphorylated Urinary Na-Cl Cotransporter Is Potentially Useful in a Patient With Pseudohypoaldosteronism Type II due to Mutation in CUL3.

Pseudohypoaldosteronism type II (PHA II), which is also known as Gordon syndrome, is a rare autosomal dominant disease characterized by hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and the absence of hyponatremia and hyperaldosteronemia.1 The pathophysiology of PHA II is explained by the constitutive activation of WNK (with no lysine) kinases–OSR1/SPAK kinases–sodium/chloride cotransporter (NCC) phosphorylation cascade. NCC is distributed on the apical plasma membranes of the distal convoluted tubules, and activation of NCC mediates increasing sodium chloride (NaCl) reabsorption in the kidney, leading to hypertension, hyperkalemia, and metabolic acidosis.2 Mutations of 4 genes, WNK1, WNK4, KLHL3 (Kelch-like 3), and CUL3 (Cullin 3), have been reported to be responsible to PHA II.3,4 Here, we present the case of a 6-year-old Japanese boy with PHA II. Our case is the third one with novel mutation in CUL3 gene. We also studied the excretion of urinary total NCC (tNCC) and phosphorylated NCC (pNCC) in his family members.

Persistent Leukocyturia Was a Clue to Diagnosis of Cystinuria in a Female Patient

Cystinuria (OMIM 220100) is characterized by the defective reabsorption of cysteine, lysine, ornithine, and arginine in the brush border membrane of proximal renal tubule and in the epithelial cells of the gastrointestinal tract. High cystine concentration causes the formation of recurring renal stones. Two genes, SLC3A1 (rBAT) and SLC7A9 (BAT1), are known to be responsible.1,2 Although leukocyturia is an important sign of urinary tract infection (UTI), we report the case of a female patient with cystinuria that was detected owing to continuous leukocyturia.