Jeerunda Santiprabhob

Etiologies of central diabetes insipidus in Thai children.

In order to determine the etiologies of central diabetes insipidus (DI) among Thai children, we retrospectively reviewed records of 67 patients (44 male and 23 female) between the age of 0.1 and 15.6 years (mean age 5.5 years) who were diagnosed with central DI at the Pediatric Endocrinology Unit, Siriraj Hospital, Bangkok, Thailand between 1996 and 2003. Etiologies were found to be central nervous system (CNS) malformations in 20 patients (29.8%), post resection of intracranial tumors and cysts in 17 patients (25.4%), intracranial tumors in 11 patients (16.4%), cerebral palsy of unknown cause in five patients (7.5%), infection in four patients (6%), and Langerhans cell histiocytosis in three patients (4.5%). In another seven patients (10.4%), the cause was considered to be idiopathic. This study revealed that CNS malformation was the most common etiology, followed by intracranial tumors and their treatment. A thorough investigation to rule out CNS lesions needs to be done before considering the diagnosis of idiopathic central DI.

Tamoxifen Improved Final Height Prediction in a Girl with McCune-Albright Syndrome: Patient Report and Literature Review

McCune-Albright syndrome (MAS) is characterized by gonadotropin-independent precocious puberty, café-au-lait spots on the skin and polyostotic fibrous dysplasia of bones. Treatment of precocious puberty (PP) in MAS should be considered in patients with poor predicted adult height (PAH). Treatment of gonadotropin-independent PP in MAS with ketoconazole, cyproterone acetate or testolactone, an aromatase inhibitor, does not appear to be always effective in slowing bon. maturation. We report here a Thai girl with MAS who received tamoxifen, one of the selective estrogen receptor modulators, for the management of advanced puberty and rapid bone maturation. Her pubertal progression, vaginal bleeding, growth rate and PAH improved during treatment with tamoxifen despite persistently elevated serum estradiol levels and an enlarged ovarian cyst.

Exome sequencing in Thai patients with familial obesity.

Obesity is a major worldwide health issue, with increasing prevalence in adults and children from developed and developing countries. Obesity causes several chronic diseases, including cardiovascular and respiratory diseases, osteoarthritis, hypertension, stroke, type II diabetes, obstructive sleep apnea, and several types of cancer. Previous genome-wide association studies have identified several genes associated with obesity, including LEP, LEPR, POMC, PCSK1, FTO, MC3R, MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B, SIM1, and TNKS/MSRA. However, most of these variants are found in the intronic or intergenic regions, making it difficult to elucidate the underlying mechanisms. Therefore, in this study, we performed a whole exome sequencing of the protein-coding regions in the total genome (exome) of two obese and one normal subject belonging to the same Thai family to identify the genes responsible for obesity. We identified 709 functional variants that were differentially expressed between obese and normal subjects; of these, 65 were predicted to be deleterious to protein structure or function. The minor allele frequency of 14 of these genes (ALOX5AP, COL9A2, DEFB126, GDPD4, HCRTR1, MLL3, OPLAH, OR4C45, PRIM2, RXFP2, TIGD6, TRPM8, USP49, and ZNF596) was low, indicating causal variants that could be associated with complex traits or diseases. Genotyping revealed HCRTR1, COL9A2, and TRPM8 to be associated with the regulation of feeding behavior and energy expenditure. These genes constituted a network of pathways, including lipid metabolism, signaling transduction, immune, membrane transport, and gene regulation pathways, and seemed to play important roles in obesity.

Genetic variant screening of MC3R and MC4R genes in early-onset obese children and their relatives among a Thai population: family- based study

MC3R (melanocortin-3 receptor) and MC4R (melanocortin-4 receptor) play important roles in energy homeostasis. Severe early-onset obesity, known as monogenic obesity when it is the consequence of a mutation in a single-gene product, may result when energy homeostasis is disrupted. The purpose of our study was to screen for variations of the MC3R and MC4R genes and observe the mode of inheritance of variations in affected families. We used polymerase chain reaction and direct sequencing to analyze the 11 early-onset obese children (probands) with their 71 family members, together with DNA from 100 healthy subjects used as controls. No novel mutations were found in the MC3R gene. Two previously described polymorphisms, rs3746619 and rs3827103, were detected in the MC3R gene. It was not associated with any obesity-related phenotypes. Three heterozygous variations of the MC4R gene were detected in 3 of 11 probands. The rs34114122 and rs61741819 variations have previously been reported, but rs182455344 was novel. Moreover, each MC4R variant was also found in a number of family members, indicating that this molecular analysis of a family-based study showed an autosomal dominant pattern. Our study indicated that MC4R variations in early-onset obese Thai children were found, and transmission of these variations in each family is in the dominant pattern. These variants could possibly contribute to a genetic influence of early-onset obesity in Thais. There is no evidence of any association between MC3R variations and obesity.

Association between rs155971 in the PCSK1 gene and the lipid profile of obese Thai children: a family-based study

Genetic variants of the POMC and PCSK1 genes cause severe obesity among patients in the early stages of childhood. This family-based study analyzed the links between single nucleotide polymorphisms (SNPs) in either the POMC or PCSK1 genes and obesity, as well as obesity-related traits among obese Thai children and their families. The variants rs1042571 and rs6713532 in the POMC gene in a sample of 83 obese children and their family members were investigated using polymerase chain reaction (PCR)-restriction fragment length polymorphism. In addition, the SNPs rs6232, rs155971, rs3762986, rs3811942, and rs371897784 of PCSK1 were analyzed in all samples using PCR and gene sequencing methods. Participants with the homozygous variant genotype in rs155971 had significantly elevated cholesterol and low-density lipoprotein cholesterol (LDL-C) levels (P = 0.011, OR = 1.025, 95%CI = 1.006-1.045; and P = 0.006, OR = 1.030, 95%CI = 1.009-1.053, respectively) after adjustment for age, gender, and body mass index (BMI). In addition, patients with the heterozygous variant genotype in rs371897784 of PCSK1 had a 1.249- fold higher risk (95%CI = 1.081-1.444, P = 0.027) of increased waist circumference than patients with the normal genotype, after adjustment for age, gender, and BMI. However, this analysis did not find any correlation between obesity and SNPs in PCSK1 and POMC. Therefore, these common variants in PCSK1 and POMC were not the major cause of obesity in the Thai subjects sampled. However, variants in PCSK1 did affect cholesterol level, LDL-C level, and waist circumference.

ANTERIOR PITUITARY HORMONE EFFECTS ON HEPATIC FUNCTIONS IN INFANTS WITH CONGENITAL HYPOPITUITARISM

BACKGROUND Congenital hypopituitarism is an uncommon cause of neonatal cholestasis. Little is known about the effect of anterior pituitary hormone on hepatic functions. METHODS A retrospective review of the medical charts of eight infants with congenital hypopituitarism and neonatal cholestasis was performed. The results of endocrinological investigations, eye examinations, and magnetic resonance imaging were used to classify these infants. RESULTS Eight infants (4 male and 4 female; mean age, 1.7 weeks) who presented with cholestatic jaundice subsequently (mean age, 7.6 weeks) developed isolated or multiple anterior pituitary hormone deficiencies. Persistent hypoglycemia, ocular abnormalities, and microphallus were often clinical signs prompting further endocrinological and radiological investigations. Septo-optic dysplasia was prevalent, occurring in five cases. Cholestasis and hepatosplenomegaly resolved within a mean of 9.7 and 10 weeks, respectively, in the majority of cases after replacement of glucocorticoid and thyroid hormones. However, transaminase levels remained high after hormone replacement. Cortisol deficiency and hypoglycemia were noted in all cases, often following stress. Hyperlipidemia persisted in one case after the resolution of cholestasis and after corticosteroid and thyroid hormone replacement therapy. Growth hormone deficiency was not corrected due to the absence of hypoglycemia after corticosteroid hormone, an infants age, and/or a lack of financial resources. CONCLUSIONS In our series, it appears that glucocorticoid and thyroid hormones play a significant role in the resolution of cholestasis and hepatosplenomegaly. A persistently elevated transaminase level and hyperlipidemia after corticosteroid and thyroid hormone replacement may indicate the need for long-term follow-up and/or growth hormone therapy.

Impact of a group-based treatment program on adipocytokines, oxidative status, inflammatory cytokines and arterial stiffness in obese children and adolescents

Abstract Background Dysregulation of adipocytokines, inflammatory cytokines and oxidative stress are associated with the pathogenesis of obesity-related complications. This study aimed to evaluate the effect of a group-based lifestyle modification program on adipocytokines, inflammatory cytokines, oxidative status and arterial stiffness in obese youth. Methods A 1-year weight-reduction program was conducted. The program consisted of initial hospitalization and five outpatient group-based sessions held at 1, 2, 3, 6 and 9 months. Pre- and post-intervention measurements included anthropometric data, blood tests, body composition and brachial-ankle pulse wave velocity (ba-PWV). Results A total of 126 obese youths were recruited, and 115 of those completed the study. Twenty-four participants had increased percentage weight for height at the end of the study (group A), 30 had minimal reduction (group B) and 61 had substantial reduction (group C). Lean mass significantly increased in all three groups (all p<0.001). A significant decrease in leptin (group A, p=0.021; group B, p=0.005; group C, p<0.001), interleukin-6 (IL-6) (group A, p=0.019; group B, p=0.004; group C, p<0.001) and ba-PWV (group A, p=0.031; group B, p=0.015; group C, p<0.001) was also observed. No significant change in the oxidative status was found among the groups. Reduction in ba-PWV was correlated with decreases in plasma malondialdehyde (pMDA) (r=0.233, p=0.036) and homeostasis model assessment of insulin resistance (HOMA-IR) (r=0.253, p=0.025). Conclusions A group-based healthy lifestyle program for obese youths had beneficial effects on adipocytokines, inflammatory cytokines and arterial stiffness. Participants without change in weight status also benefited. These improvements may reduce the risk of obese youths developing atherosclerosis.

Metabolic Disorders in HIV-Infected Adolescents Receiving Protease Inhibitors

Protease inhibitor (PI) may cause abnormal glucose metabolism, abnormal lipid metabolism, and metabolic syndrome in HIV-infected adults but less well studied in Asian adolescents. This cross-sectional study evaluated anthropometric factors, oral glucose tolerance test, and lipid profiles of perinatally HIV-infected Thai adolescents who had received PI-based antiretroviral therapy for at least 6 months. Eighty adolescents were enrolled [median (IQR) age 16.7 (14.6–18.0) years, 42 males]. Metabolic syndrome, prediabetes, and type 2 diabetes mellitus (T2DM) were found in 8 (10%), 17 (22.1%), and 3 (3.8%) adolescents, respectively. Dyslipidemia was found in 56 (70%) adolescents, with hypertriglyceridemia being the most common type. In multivariate analysis, presence of lipohypertrophy (OR: 25.7, 95% CI: 3.2–202.8; p = 0.002) and longer duration of PI use (OR: 1.04, 95% CI: 1.00–1.08; p = 0.023) were associated with metabolic syndrome. Obesity (OR: 7.71, 95% CI: 1.36–43.7; p = 0.021), presence of lipohypertrophy (OR: 62.9, 95% CI: 4.97–795.6; p = 0.001), and exposure to stavudine for ≥6 months (OR: 8.18, 95% CI: 1.37–48.7; p = 0.021) were associated with prediabetes/T2DM, while exposure to tenofovir for ≥6 months reduced the risk (OR: 0.17, 95% CI: 0.04–0.78; p = 0.022). Metabolic disorders were commonly found in adolescents receiving PI. Careful monitoring and early intervention to modify cardiovascular risk should be systematically implemented in this population particularly those with exposure to stavudine.