Dragan Zdravkovic

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.

Three siblings with triple A syndrome with a novel frameshift mutation in the AAAS gene and a review of 17 independent patients with the frequent p.Ser263Pro mutation

The triple A syndrome is an autosomal recessive disorder characterized by adrenal insufficiency, alacrima, achalasia, and impairment of the central, peripheral, and autonomic nervous system functions. The disease is caused by mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN. In the present study, we report three siblings with triple A syndrome caused by a compound heterozygous mutation consisting of a novel Val421 frameshift mutation in exon 14 and a previously described Ser236Pro (T>C transition) missense mutation in exon 8. The second mutation is one of the most frequent mutations in the AAAS gene, occurring in 17 independent patients from different countries. With haplotype analysis, we demonstrate a founder effect for at least 13 of the 17 patients. We conclude that, although very helpful in establishing the final diagnosis of triple A syndrome, DNA analysis is not useful for the prediction of the clinical expression and outcome of the disorder. Further investigations are necessary to evaluate the correlation between genotype and clinical phenotype in the triple A syndrome.

Pre-operative Differentiation of Pediatric Ovarian Tumors: Morphological Scoring System and Tumor Markers

OBJECTIVE To investigate the importance of morphological scoring systems in differentiation of ovarian tumors in childhood. METHODS Morphological assessment using DePriests index was performed for all patients with histopathological confirmation of ovarian tumor, with evaluation of tumor markers, from January 1997. RESULTS Fifty-three girls (age range 13 months to 19 years) were surgically treated for 59 ovarian tumors, including six bilateral. All lesions with cystic appearance on ultrasonography were benign, 23 of 35 semisolid, and four of ten solid tumors were also benign. Stage of malignant disease was as follows: stage I, ten; stage II, two; stage III, six. Sensitivity, positive predictive value and accuracy by DePriests and Uelands indexes for benign tumors (score <7) were: 0.88, 0.79; 0.89; and 0.94, 0.84; 0.93; respectively. Elevated levels of tumor markers were observed in 17 patients, including four patients with endocrine manifestations. In 24 patients ovaries were successfully preserved, including two patients with foci of immature teratoma in a dermoid cyst. CONCLUSION Ultrasonographic assessment with morphological analysis recommended by DePriest and Ueland is a very useful procedure for differentiating benign from malignant ovarian tumors in children. Tumor markers and endocrinological investigation are also useful for preoperative evaluation.

Transient neonatal diabetes mellitus in an infant with paternal uniparental disomy of chromosome 6 including heterodisomy for 6q24

We describe a female infant who developed transient neonatal diabetes mellitus (TNDM) (MIM 601410). At birth she presented with growth retardation and macroglossia. Diabetes was diagnosed on the fourth day of life and it resolved after two months of insulin therapy. Genetic testing revealed the presence of paternal uniparental disomy of chromosome 6 (UPD6) including heterodisomy of 6q24. This is the first documented case of uniparental heterodisomy for chromosome 6.

Adrenal crisis provoked by dental infection: case report and review of the literature.

Primary adrenal insufficiency is an endocrine disorder characterized by cortisol and aldosterone deficiency caused by destruction of the adrenal cortex. Adrenal crisis is a medical emergency with acute symptoms: nausea, vomiting, abdominal pain, fever, hypoglycemia, seizures, hypovolemic shock, and cardiovascular failure. It occurs in patients with chronic adrenal insufficiency who are exposed to additional stress, such as infection, trauma, or surgical procedures. Dental infection is a possible cause of adrenal crisis in patients with chronic adrenal insufficiency, so pediatric endocrinologists and pediatric dentists should be aware of this risk. The purpose of this report was to present a 6-year-old patient in whom Addison disease was diagnosed through adrenal crisis provoked by dental infection. The patient was treated with intravenous rehydration, intravenous hydrocortisone and antibiotics, and extraction of the infected primary tooth. Multidisciplinary approach and collaboration between the pediatric endocrinologist and the pediatric dentist are necessary to enable adequate medical and dental treatment in children with primary adrenal insufficiency.

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.

BLASTOCYSTIS HOMINIS: A MYSTERIOUS AND COMMONLY DISREGARDED PARASITE

Blastocystis hominis (B. hominis) is an anaerobic, single-cell protozoan, commonly present in human and animal stool samples. It can be found in healthy people as well and it still has not been elucidated whether it is a commensal organism or a pathogen. Blastocystosis is a disease caused by the protozoan in humans. The prevalence of the parasitosis varies both between the countries, and between certain population groups within individual countries. Due to poor hygienic conditions, common exposure to animals and intake of contaminated water and food, people in the developing countries have got a higher prevalence of blastocystosis, but economically developed countries have not been spared either. The taxonomy of B. hominis is still a matter of debates. For the reasons of genetic diversity, it has been suggested that the name B. hominis should be replaced with „Blastocystis species‟. Seventeen subtypes of the species have been so far identified, and a definitive characterization of Blastocystis spp. is possible at the molecular level only. The parasite is transferred by the fecal-oral route. A variety of hosts have been identified, and animal-to-human and vice versa transfers have been documented. The most common manifestations of the infection with the organism are diarrhea, abdominal pain, nausea, and bloating. This infection has also been associated with the irritable bowel syndrome (IBS), non-specific colitis, chronic inflammatory bowel disease (CIBD), and urticaria. The diagnosis can be made using the methods of conventional microscopy (CVM), phase-contrast and electron microscopy, cultivation, serodiagnosis, and by using molecular methods. The infection caused by the parasite does not always require treatment. In symptomatic patients, the first line medical treatment is metronidazole. Further studies are required to resolve all dilemmas regarding the parasite.

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The increasing incidence of obesity among children and adolescents has become a problem in Serbia as in the rest of the world. Obesity is defined as a BMI of 97 or more percentile specific for sex and age, calculated as an individuals weight divided by the square of their height. Overweight is defined as a BMI greater than 90. percentile. The differentiation between simple exogenous obesity and morbid obesity is based mostly on clinical findings. The investigation of obese adolescent includes the recognition of related comorbidities and complications. Given its detrimental affects on public health and the costs of its management, prevention of obesity and its treatment in childhood and adolescence has gained significance. Dietary and exercise advice remains the mainstay of the medical management of obesity. In these respects, the prescription of minimally one hour of daily physical activity for obese children and adolescents and the maintenance of this regimen has become one of the two most important measures. Physical exercise facilitates weight loss by increasing energy expenditure and increasing basal metabolic rate through an increase in muscle mass. The second most important measure is dietary control. Unfortunately, lifestyle interventions alone rarely result in long-term weight loss and the majority of obese patients return to baseline weight within 3-5 years. In the midst of obesity-related health crisis, the case for safe and efficacious pharmacotherapies is clear. Unfortunately, drugs currently available for long-term weight management are limited in number and efficacy. At present, the most effective means of significant and sustained weight loss for obese patients is bariatric surgery. An effective treatment of obesity at early ages has a greater success rate as compared to interventions in adulthood.