Genotypic spectrum of 21-hydroxylase deficiency in an endogamous population.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to autosomal recessive 21-hydroxylase deficiency (21-OHD) is caused by defects in the CYP21 (CYP21A2) gene. Several mutations have been identified in the CYP21 (CYP21A2) gene of patients with 21-OHD. We aimed at determining the frequency of these mutations among a group of Egyptian patients and studying the genotype-phenotype correlation. METHODS: Forty-seven patients with CAH due to 21-OHD from 42 different families diagnosed by clinical and hormonal evaluation and classified accordingly into salt wasting (SW) and simple virilizing (SV) phenotypes were enrolled. Their ages ranged between 1.78 and 18.99 years. Molecular analysis of the CYP21 (CYP21A2) gene was performed for the detection of eleven common mutations: P30L, I2 splice (I2 G), Del 8 bp E3 (G110del8nt), I172N, cluster E6 (I236N, V237E, M239K), V281L, L307 frameshift (F306 + T), Q318X, R356W, P453S, R483P by polymerase chain reaction (PCR) and reverse hybridization. RESULTS: Disease-causing mutations were identified in 47 patients, 55.31% of them were compound heterozygous. The most frequent mutations were I2 splice (25.43%), followed by cluster E6 (16.66%) and P30L (15.78%). Two point mutations (P453S, R483P) were not identified in any patient. In the SW patients, genotypes were more compatible with their phenotypes. CONCLUSION: Molecular characterization should be considered along with clinical and biochemical diagnosis of CAH since it could confirm the diagnosis, outline the treatment strategy and morbidity, and ensure proper genetic counseling.

Insulin resistance in patients on valproic acid: relation to adiponectin.

OBJECTIVES: To investigate the presence of insulin resistance in obese children with idiopathic epilepsy on valproic acid (VPA) monotherapy in comparison to obese otherwise healthy subjects. Secondary outcome was to explore the relation between adiponectin and insulin resistance among those patients. MATERIALS AND METHODS: Fifty obese children with generalized idiopathic epilepsy on VPA monotherapy and a control group of 49 obese clinically healthy age and sex-matched children with simple obesity were recruited in the study. Anthropometric assessment, fasting plasma insulin (FI), fasting glucose (FG) and fasting adiponectin levels were measured. Fasting glucose insulin ratio (FGIR) and homoeostasis model assessment for insulin resistance (HOMA-IR) were calculated for both patients and control subjects. Measurement of serum VPA trough level was also performed in patients. RESULTS: Patients had significantly higher fasting blood glucose, fasting insulin, lower FGIR and higher HOMA-IR values, compared to controls. Mean adiponectin level was significantly lower in patients compared to controls. The duration of treatment with valproic acid negatively correlated with adiponectin (r = -0.285, P = 0.045), but did not correlate with fasting glucose, insulin, FGIR or HOMA-IR. Total daily VPA dose significantly correlated with fasting insulin (r = 0.495, P < 0.001), FGIR (r = -0.525, P < 0.001) and HOMA-IR (r = 0.404, P = 0.004). CONCLUSION: This study ascertains the relationship between dose and duration of VPA therapy, insulin resistance and the adipocytokine axis. We are reporting the novel proposal that obese VPA-treated children are more insulin resistant and have lower adiponectin levels than obese and otherwise healthy children.

Carotid intima media thickness and other cardiovascular risk factors in children with congenital adrenal hyperplasia.

PURPOSE: Patients with congenital adrenal hyperplasia (CAH) are at increased risk for cardiovascular disease due to many factors. The aim of this study is to investigate the presence of dyslipidemia, insulin resistance, and subclinical atherosclerosis as indicated by carotid intima media thickness in children with congenital adrenal hyperplasia. METHODS: Thirty-two children with congenital adrenal hyperplasia (3-17 years) were compared with 32 healthy controls. All underwent anthropometric evaluation, measurement of fasting lipids, glucose, insulin, oral glucose tolerance test (OGTT), homeostasis model assessment for insulin resistance (HOMA-IR), and carotid intima media thickness (CIMT). RESULTS: Fasting glucose, glucose at 30, 60, 90, and 120 min during OGTT were significantly higher in patients. HOMA-IR was also significantly higher in patients (p = 0.036). Patients had significantly higher CIMT (p = 0.003), and higher systolic blood pressure. (p = 0.04). No significant difference existed in lipid profile. Both systolic and diastolic blood pressures correlated with treatment duration (p = 0.002, p = 0.043, respectively). CONCLUSION: Children with CAH are at increased risk of insulin resistance, glucose intolerance, early atherosclerosis, and cardiovascular disease. Screening of these patients at an early age is recommended.

Do children with type 1 diabetes have a relation between adiponectin level and vascular complications?

BACKGROUND: Adiponectin has anti-inflammatory, anti-atherogenic, insulin sensitizing, and cardioprotective roles. Adiponectin level is elevated in type 1 diabetes. Its low levels inversely predict the incidence of coronary artery disease. The purpose of this study is to assess the relation between adiponectin and microvascular complications, cardiovascular risk factors and carotid intima media thickness (CIMT) in children and adolescents with type 1 diabetes. METHODS: Serum adiponectin level was determined in forty diabetics and twelve healthy children. Patients were evaluated for the presence of microvascular complications and cardiovascular risk factors including body mass index, blood pressure, and fasting lipids. CIMT was measured as an indicator of subclinical atherosclerosis. RESULTS: The mean (SD) age of the patients was 13.35 (2.83) years, range (7 - 17.41 years). The mean (SD) diabetes duration was 6.14 (3.59) years. Adiponectin, triglycerides, and CIMT were higher in patients. Adiponectin correlated positively with microalbuminuria and was higher in patients with peripheral neuropathy. No correlation existed between adiponectin and CIMT or cardiovascular risk factors. Multivariate analysis showed that triglycerides was the strongest variable affecting CIMT followed by duration of diabetes, HbA1C, and the least effect was that of body mass index. CONCLUSION: High adiponectin correlate with the presence of microvascular disease but does not offer protection against cardiovascular disease in children with type 1 diabetes. The cardiovascular risk is more strongly related to cardiovascular risk factors and glycaemic control.

Association of polymorphisms in the mast cell chymase gene promoter region (-1903 g/A) and (TG)n(GA)m repeat downstream of the gene with bronchial asthma in children.

BACKGROUND: Mast cell chymase is a mediator of inflammation and remodeling in the asthmatic lung. Although various studies have examined the association between the -1903 G/A single nucleotide polymorphism (SNP)in the mast cell chymase gene (CMA1) and allergic phenotypes, the results have been inconsistent. A (TG)n(GA)m repeat polymorphism 254 base pairs downstream of CMA1 has been reported in adult asthmatics. We investigated the relationship between these CMA1 genetic variants and childhood asthma in Egyptian children. METHODS: A case-control study was undertaken in 15 children (6-10 years old) with bronchial asthma enrolled consecutively during exacerbation and 15 age-matched and sex-matched nonasthmatic control subjects. Genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism to search for polymorphisms in the CMA1 gene promoter region (-1903 G/A) and PCR amplification followed by sequencing to detect the (TG)n(GA)m repeat 254 base pairs downstream of the gene. RESULTS: Our data showed a positive association between the CMA1 -1903 G/A SNP and asthma in children. The G allele was detected in 70% of patients while the A allele was more frequent in the controls (83.3%). Concerning the (TG)n(GA)m repeat, allele 39 was only present in asthmatics while allele 37 was more common in controls. CONCLUSION: We report the association of the -1903 G/A CMA1 SNP and (TG)n(GA)m repeat polymorphism with bronchial asthma in a group of Egyptian children. These polymorphisms are possible determinants of asthma susceptibility and may be involved in regulating immunoglobulin E levels.