Sladjana Todorovic

Triple A syndrome: 32 years experience of a single centre (1977-2008)

Triple A syndrome is an autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and neurodegeneration. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Over the period 1977–2008 we evaluated ten subjects with the clinical diagnosis of triple A syndrome. Molecular analysis was performed in seven patients and revealed that all except one are compound heterozygotes for two mutations in the AAAS gene. Two novel mutations were detected: c.123+2T>C resulted in splice defect while c.1261_1262insG mutation resulted in a truncated protein (p.V421fs), which most probably is not functional. Genotype–phenotype correlation could not be established. In all our patients, except one sibling of previously diagnosed brother and sister, genetic analysis was performed when at least two symptoms were present, usually alacrima and achalasia. Based on our experience, we recommend that in case of the presence of alacrima and at least one more symptom of triple A syndrome, adrenal function testing and molecular analysis should be performed. In all children with mutation in AAAS gene, regular follow up of adrenal function is necessary to avoid adrenal crisis and start substitution therapy as soon as adrenal insufficiency is noted.

Metabolic syndrome in obese children and adolescents in Serbia: prevalence and risk factors.

Abstract Objective: To assess the prevalence of metabolic syndrome (MS) in obese children and adolescents in Serbia. Subjects and methods: The study group consisted of 254 subjects (148 female and 106 male), aged 4.6–18.9 years with diet-induced obesity (body mass index ≥95th percentile). Presence of MS using the International Diabetes Federation definition was assessed in all subjects, as well as oral glucose tolerance test and insulin resistance indices. Results: Overall prevalence of MS in all subjects aged ≥10 years was 31.2%, namely, 28.7% in children aged 10 to <16 years and 40.5% in adolescents ≥16 years. When adjusted for age, gender and pubertal development, higher degree of obesity was a strong predictor of MS. Multivariate analysis showed that taller subjects and those with higher degree of insulin resistance were at significantly higher risk of MS, independent of the degree of obesity. Conclusions: High prevalence of MS emphasizes the need for prevention and treatment of childhood obesity.

Effects of co-existing autoimmune diseases on serum lipids and lipoprotein subclasses profile in paediatric patients with type 1 diabetes mellitus

OBJECTIVE Paediatric patients with type 1 diabetes mellitus (T1DM) frequently develop other autoimmune disorders; most commonly autoimmune thyroiditis (ATD) and celiac disease (CD). In this study we evaluated whether co-existing autoimmune diseases had significant impact on lipid and lipoprotein subclasses, as known cardiovascular risk factors in T1DM. DESIGN AND METHODS Study included 201 subjects with T1DM (14.1 ± 2.9 years) and 141 age- and gender-matched controls. ATD was presented in 30 and CD in 15 T1DM patients. Serum lipid parameters were determined by routine laboratory methods and plasma low-density (LDL) and high-density lipoprotein (HDL) subclasses by gradient-gel electrophoresis method. RESULTS Both groups of T1DM patients with concomitant autoimmune disease had significantly lower HDL-C levels (P < 0.05) than the patients with T1DM only, but comparable to control group (P = 0.436). T1DM patients had significantly higher (P < 0.001) proportion of small HDL subclasses than controls. Mean value of atherosclerosis index in patients with T1DM + CD was the highest (1.75 ± 0.86) and it was significantly higher than the index in patients with T1DM only (1.33 ± 0.51; P < 0.05). LDL size did not differ between the groups of T1DM patients and control group (P = 0.619). The size of HDL particles was significantly reduced (P < 0.05) in the groups with associated autoimmune diseases. The patients with co-existing autoimmune diseases had higher risk of low HDL-C level (OR: 2.96; P < 0.05). CONCLUSIONS The results have shown significant impact of co-existing autoimmune diseases on lipid profile in patients with T1DM. The most prominent changes were found in HDL lipoprotein characteristics in T1DM + CD group.

Pediatric siMS score: A new, simple and accurate continuous metabolic syndrome score for everyday use in pediatrics

Background The dichotomous nature of the current definition of metabolic syndrome (MS) in youth results in loss of information. On the other hand, the calculation of continuous MS scores using standardized residuals in linear regression (Z scores) or factor scores of principal component analysis (PCA) is highly impractical for clinical use. Recently, a novel, easily calculated continuous MS score called siMS score was developed based on the IDF MS criteria for the adult population. Objective To develop a Pediatric siMS score (PsiMS), a modified continuous MS score for use in the obese youth, based on the original siMS score, while keeping the score as simple as possible and retaining high correlation with more complex scores. Subjects and methods The database consisted of clinical data on 153 obese (BMI ≥95th percentile) children and adolescents. Continuous MS scores were calculated using Z scores and PCA, as well as the original siMS score. Four variants of PsiMS score were developed in accordance with IDF criteria for MS in youth and correlation of these scores with PCA and Z score derived MS continuous scores was assessed. Results PsiMS score calculated using formula: (2xWaist/Height) + (Glucose(mmol/l)/5.6) + (triglycerides(mmol/l)/1.7) + (Systolic BP/130)—(HDL(mmol/l)/1.02) showed the highest correlation with most of the complex continuous scores (0.792–0.901). The original siMS score also showed high correlation with continuous MS scores. Conclusion PsiMS score represents a practical and accurate score for the evaluation of MS in the obese youth. The original siMS score should be used when evaluating large cohorts consisting of both adults and children.

Postprandial hyperinsulinemic hypoglycemia in a child as a late complication of esophageal reconstruction.

Abstract Background: Postprandial hyperinsulinemic hypoglycemia (PHH) is an increasingly recognized complication of gastric bypass surgery in obese adults, distinct from the “dumping syndrome”. Case presentation: Upon birth, primary repair of esophageal atresia was performed, and at the age of 14 months definite esophageal reconstruction was performed. At the age of 3 years, recurrent brief episodes of symptomatic hypoglycemia started. At the age of 5.7 years the girl was admitted to our clinic and investigations indicated hyperinsulinemic hypoglycemia. Oral glucose tolerance test (OGTT) and continuous glucose monitoring results revealed frequent postprandial hypoglycemic events, which were always preceded by early postprandial hyperglycemia. It was concluded that the patient had PHH caused by a delayed and hyperinsulinemic response to carbohydrate intake as a result of esophagogastric surgery. Treatment with acarbose was titrated using flash glucose monitoring, which resulted in satisfactory glucose regulation. Conclusions: This is the first described case of a child with PHH following esophageal reconstruction.

Recurrent Pheochromocytomas in a Child with Familial von Hippel-Lindau Syndrome

To the Editor: von Hippel-Lindau (VHL) syndrome is a rare hereditary disease characterized by the presence of benign or malignant tumors, such are CNS hemangioblastoma, pheochromocytoma, retinal angioma, Bclear cell^ renal carcinoma, renal and pancreatic cysts [1]. VHL syndrome is inherited in autosomal dominant pattern with high penetrance, but 20 % of cases are new mutations. Pheochromocytomas have been described in 10–50 % of patients with VHL syndrome [2]. We present a case of 12-y-old boy with type 2 VHL syndrome who had successive development of bilateral adrenal pheochromocytomas, as well as extraadrenal pheochromocytomas. Symptoms were first noted at 5 y of age and included arterial hypertension of 161/110, fatigueness, sweating and headache. The diagnosis was established very quickly, as family data revealed that the boy’s father had VHL syndrome: pheochromocytomas, cerebellar hemangioblastoma and retinal angiomas. High levels of the adrenaline (52,36 μg/24 h), and noradrenaline excretion (153,11 μg/24 h) were detected in the urine, and ultrasound, CT scan and MIBG scintigraphy imaging discovered a tumor in the left adrenal gland. The proposed PET-CT was not available [3]. Genetic analysis of the patient showed presence of a germline mutation in exon 3 of the VHL gene in codon 167 (Arg 167Gln; CGG→ CAG), which was proved to be the same as his father’s. In the previous 7 y the boy had 5 operations, a total of Bde novo^ 7 adrenal and extraadrenal benign pheochromocytomas were removed, and bilateral adrenalectomy was performed. The patient received preoperative two-week alpha blocker phenoxibenzamine premedication. Some authors prefer prazosin and doxazosin as alpha blockers in preoperative premedication [4]. Cortical-sparing adrenalectomy was not feasible, but it is a dominant alternative approach for bilateral pheochromocytomas [5]. After operations the patient remained symptom-free, with normal urinary excretion of catecholamines and ultrasound, CT/MRI and MIBG exams. The recurrence of the pheochromocytoma used to be diagnosed on regular screening based on the above mentioned diagnostic procedures. Presently, the boy is feeling well, with life-long substutional therapy. The early manifestation of VHL syndrome in the index patient, frequent recurrences of pheochromocytomas Bde novo^ at new locations and the hereditary nature of the syndrome are the highlights of this letter. * Aleksandar Vlahovic aleksandarvlahovic@yahoo.com