Vichit Supornsilchai

Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene

Objective  To describe clinical and genetic features of a Thai family with non‐autoimmune hyperthyroidism (NAH) caused by an activating germline mutation in the thyrotropin receptor (TSHR) gene.

Identification of two novel aquaporin-2 mutations in a Thai girl with congenital nephrogenic diabetes insipidus

Objective To describe a Thai girl with congenital nephrogenic diabetes insipidus (NDI) and perform mutation analysis of the AQP2 gene. Design: Case report. Patient A 6-year old girl with a history of failure to thrive, polydipsia and polyuria was studied. Polyuria and polydipsia were observed within the first few months of life. Despite normal serum osmolality and electrolyte, the result of water deprivation test was compatible with a diagnosis of NDI. Methods The entire coding regions of the AQP2 gene were assessed by polymerase chain reaction and sequencing analysis. The presence of mutations was also confirmed by restriction enzyme digestion analysis. Results Two heterozygous novel missense mutations were identified. Both were located in exon 1; a guanine-to-thymine substitution at nucleotide position 3 (c.3G→T) inherited from her mother and a guanine-to-adenine at position 85 (c.85G→A) inherited from her father, resulting in a methionine to isoleucine at codon 1 (p.M1I) and glycine to serine at codon 29 (p.G29S), respectively. These mutations have never been previously described and were not detected in 100 ethnic-matched unaffected control chromosomes. Conclusion We report two novel mutations of the AQP2 gene, p.M1I and p.G29S, associated with autosomal recessive congenital NDI. This study expands the genotypic spectrum of AQP2 mutations and emphasizes an important role of genetic testing for definite diagnosis and genetic counseling.

Splicing analysis of CYP11B1 mutation in a family affected with 11β-hydroxylase deficiency: case report

BackgroundCongenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency (11β-OHD) is a rare form of CAH associated with low renin hypertension, hypokalemia, hyperandrogenemia and ambiguous genitalia in affected females. Herein we describe the clinical, hormonal and molecular characteristics of two Uzbekistan siblings with 11β-OHD and analyze the effects of a splicing mutation.Case presentationA 46,XX girl presented with genital ambiguity and low renin hypertension; her 46,XY brother presented with precocious puberty. Hormonal studies suggested 11β-OHD. Mutation analysis was performed by PCR followed by Sanger sequencing of the entire coding regions and their flanking introns of the CYP11B1 gene. Mutation analysis showed that both patients were compound heterozygous for IVS7 + 1G > A, and c.421C > T. Although the identified mutations have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. A minigene assay was used to determine the effects of the splicing mutation. The constructs containing either the wild-type or the splice-site mutant CYP11B1 genomic DNA of exons-introns 6–9 were transfected into COS-7 cells; subsequently, RNA splicing was assessed by reversed transcribed-PCR of CYP11B1 complementary DNA. The minigene assay revealed that the IVS7 + 1G > A mutation resulted in two shorter incorrectly spliced products; one skipping the exon 7 and the other skipping the exons 7–8. The c.421C > T mutation leads to the introduction of a premature stop codon at residue 141 (p.R141X). These mutations are expected to code non-functional proteins.ConclusionCompound heterozygous mutations (IVS7 + 1G > A and p.R141X) in the CYP11B1 gene were found to cause 11β-OHD. The IVS7 + 1G > A mutation causes aberrant splicing of CYP11B1 leading to exon skipping. This finding could facilitate the future novel therapies targeted on splicing modulation to treat human disease.

DKA with Severe Hypertriglyceridemia and Cerebral Edema in an Adolescent Boy: A Case Study and Review of the Literature

A 13-year-old adolescent boy with type 1 diabetes mellitus (1b) presented with diabetic ketoacidosis (DKA) and cerebral edema. Grossly lipemic serum and lipemia retinals due to extremely high triglyceride (TG) level were observed without evidence of xanthoma or xanthelasma. Cerebral edema was treated by appropriate ventilation and mannitol administration. Normal saline was carefully given and regular insulin was titrated according to blood sugar levels. Triglyceride levels were reduced from 9,800 mg/dL to normal range within 9 days after conventional treatment was commenced without antilipid medication. Based on our review of the literature, this is the first reported case of confirmed pediatric DKA with severe hypertriglyceridemia and cerebral edema. In patients with DKA and hypertriglyceridemia, clinicians should be mindful of the possibility of associated acute pancreatitis and cerebral edema.

Original article. Trends and characteristics of childhood diabetes in a tertiary care center in Thailand

Abstract Background: Reports on characteristics of pediatric diabetes in children from Southeast Asian countries are limited. Objectives: To describe the clinical characteristics, prevalence, glycemic control, and current treatment regimens of diabetes in Thai children. Materials and Methods: Data from 132 patients seen at our pediatric diabetes clinic at Chulalongkorn University during 2001−2013 were retrospectively reviewed. Results: We found an increasing number of patients newly-diagnosed with type 1- (T1DM) or type 2- diabetes mellitus (T2DM). The overall proportion of T1DM was 69.7%, T2DM 23.4%, and other types 6.9%. Children with T1DM were younger at diagnosis, had higher initial glucose and glycated hemoglobin A1c (HbA1c), a lower body mass index z-score, lower C-peptide and insulin levels, and were more likely to have classic diabetes symptoms and ketoacidosis, compared with children with T2DM. Mixed diabetes phenotypes were found in about 12%−14% of these children. Glutamic acid decarboxylase and islet antigen-2 autoantibodies were found in 70% and 54% of T1DM patients, respectively, and not in T2DM patients. HbA1c in T1DM was 9.6 ± 2.2% total hemoglobin, and in T2DM was 7.9 ± 2.6%. There were no differences in HbA1c levels between different insulin regimens in the T1DM group. Conclusion: The number of children with T1DM or T2DM has been increasing and there are overlapping phenotypes in a significant proportion of these children. Correct diagnosis requires clinical evaluation and monitoring of the clinical course. Further research is needed to determine the risk factors for the poor glycemic control found in children with T1DM.

Insulin dynamics and biochemical markers for predicting impaired glucose tolerance in obese Thai youth.

Abstract Background: Subjects with impaired glucose tolerance (IGT) are at risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease. The predictors of IGT in obese youth are not well described. Methods: We studied 115 obese Thai children who underwent an oral glucose tolerance test (OGTT). Plasma glucose and insulin levels were calculated for assessment of β-cell function. Hemoglobin A1c (HbA1c), lipid profile, and clinical parameters were also used to determine predictors of IGT. Results: We found that three patients had T2DM and 30 subjects had IGT. IGT patients had significantly higher fasting glucose (FG), 1-h postload glucose, 2-h postload insulin, and lower whole-body insulin sensitivity indices than in normal glucose tolerance subjects whereas other indices were comparable. By ROC curve analyses, 1-h postload glucose was the best predictor of IGT, but FG or HbA1c represented a poor diagnostic tool for prediabetes screening. Subjects with 1-h OGTT glucose >155 mg/dL had significantly lower high-density lipoprotein levels, lower insulin sensitivity, and more insulin resistance than those with 1-h postload glucose of ≤155 mg/dL. Conclusions: Abnormal glucose tolerance is highly prevalent in obese Thai youth. Several fasting indices and HbA1c fail to predict IGT. An 1-h OGTT glucose of >155 mg/dL appears to be more associated with adverse insulin dynamics and metabolic profile than 2-h postload glucose.

Pubertal growth in normal Thai children: a longitudinal study

Abstract Background: Pubertal growth data in Thai children has been reported as cross-sectional studies. There is no longitudinal study in Thai children. Objective: Investigate the longitudinal growth data in normal Thai children including the relationship between age at pubertal onset and other growth parameters. Material and method: Eighty-eight normal children (44 boys, 44 girls) were longitudinally assessed for the growth and puberty until they reached their final adult height. Pubertal staging was assessed by the Tanner method. Results: Mean age of pubertal onset was 10.2 ± 1.2 years for girls and 12.2 ± 1.0 years for boys. Total pubertal height gain was 18.3 ± 4.0 cm for girls and 22.3 ± 4.4 cm for boys. Total pubertal height gain had a negative correlation with age at pubertal onset for girls, but not for boys. Conclusion: The onset of puberty was not much changed from previous studies. Girls with early puberty had a higher pubertal height gain. This might be due to a compensatory mechanism. These longitudinal growth data can be used as a reference in clinical practices for Thai children.

Adrenal insufficiency in non-transfusion-dependent α-thalassemia

Very few studies about adrenal insufficiency (AI) have been published with regard to non‐transfusion‐dependent (NTD) thalassemia, and none of those studies involved α‐thalassemia patients. The aim of this study was therefore to determine the prevalence of AI in patients with NTD α‐thalassemia, and to identify factors that predict the development of AI in this thalassemia subpopulation.

Phenytoin-induced dysglycemia in a child

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A girl with permanent neonatal diabetes due to KCNJ11 mutation presented with Mauriac syndrome after improper adjustment in sulfonylurea dosage over 6 years.

Abstract Mauriac syndrome is characterized by growth impairment, Cushingoid features, and hepatomegaly in patients with poorly controlled type 1 diabetes mellitus (T1DM). We report a novel presentation of Mauriac syndrome in a 9-year-old girl who was diagnosed with neonatal diabetes at 3 months of age due to the p.R201C mutation in KCNJ11. She was initially treated successfully with glipizide at a dose of 0.85 mg/kg/day but after being lost to follow-up and having improper adjustment in dose over many years, the recent dose of 0.6 mg/kg/day appears to have been insufficient for glycemic control but enough to maintain a low level of C-peptide and prevent diabetic ketoacidosis. With proper insulin administration, all presenting clinical characteristics were resolved within 1 month. A review of the literature relating to clinical manifestations of Mauriac syndrome in children with diabetes was performed and included in this report for comparison with our patient. While Mauriac syndrome has been traditionally associated with T1DM, the presence of Mauriac syndrome should not be excluded in other types of diabetes mellitus.