VARIATIONS IN MONOGENIC DIABETES AND DIABETES SUSCEPTIBILITY GENES IN PEDIATRIC CASES: SINGLE CENTER EXPERIENCE.

Context: Diabetes is a chronic disorder with a complex pathogenetic background including monogenic, polygenic, and environmental causes. Objective: The aim of the present paper is to share the information related to genetic and clinical data of large pediatric diabetes cohort. Design: The present study retrospectively analyzes genetic and clinical findings of subjects diagnosed with diabetes under the age of 18 year and are in follow-up in a pediatric diabetes referral center. Subjects and Methods: Out of 1205 children with diabetes (902 treated with insulin) 246 underwent genetic tests on the basis of clinical selection criteria since 2007. Results: One hundred and ten variants related to diabetes were found in 89 of them. Age at presentation was 9.5±4.02 years (F/M 44/45). In total 49 pathogenic and likely pathogenic, 11 "hot and warm" of unknown significance variants were found in fourteen MODY and fifteen non-MODY genes according to criteria developed by American College of Medical Genetics. Thirty novel mutations were found. GCK (26.6%) and ABCC8 (10%) were two most frequently affected genes. Antibody testing revealed negative results in 80% of cases. Conclusions: Genetic interpretation in selected cases is important to understand the nature of the disease better. Improvement in testing opportunity and awareness might increase the prevalence of genetically explained diabetes cases. The distribution of subtypes differs between countries and even regions of the same country.

Characteristics of Turkish children with Type 2 diabetes at onset: a multicentre, cross-sectional study.

AIMS: To describe the baseline clinical and laboratory findings and treatment modalities of 367 children and adolescents diagnosed with Type 2 diabetes in various paediatric endocrinology centres in Turkey. METHODS: A standard questionnaire regarding clinical and laboratory characteristics at onset was uploaded to an online national database system. Data for 367 children (aged 6-18 years) newly diagnosed with Type 2 diabetes at 37 different paediatric endocrinology centres were analysed. RESULTS: After exclusion of the children with a BMI Z-score < 1 SD, those with genetic syndromes associated with Type 2 diabetes, and those whose C-peptide and/or insulin levels were not available, 227 cases were included in the study. Mean age was 13.8 ± 2.2 (range 6.5-17.8) years, with female preponderance (68%). Family history of Type 2 diabetes was positive in 86% of the children. The mean BMI was 31.3 ± 6.5 kg/m2 (range 18.7-61) and BMI Z-score was 2.4 ± 0.8 (range 1-5). More than half (57%) of the children were identified by an opportunistic diabetes screening due to existing risk markers without typical symptoms of diabetes. Only 13% (n = 29) were treated solely by lifestyle modification, while 40.5% (n = 92) were treated with metformin, 13% (n = 30) were treated with insulin, and 33.5% (n = 76) were treated with a combination of insulin and metformin initially. Mean HbA1C levels of the insulin and combination of insulin and metformin groups were 98 (11.1%) and 102 mmol/mol (11.5%), respectively, and also were significantly higher than the lifestyle modification only and metformin groups mean HbA1C levels (70(8.6%) and 67 mmol/mol (8.3%), respectively). CONCLUSIONS: An opportunistic screening of children who are at high risk of Type 2 diabetes is essential, as our data showed that > 50% of the children were asymptomatic at diagnosis. The other important result of our study was the high rate of exclusion from the initial registration (38%), suggesting that accurate diagnosis of Type 2 diabetes in youth is still problematic, even for paediatric endocrinologists.

Response to growth hormone with respect to pubertal status on increased dose in idiopathic growth hormone deficiency: an analysis of Turkish children in the KIGS database (Pfizer International Growth Study).

AIM: To compare the growth response to growth hormone (GH) treatment in patients with idiopathic GH deficiency (IGHD) who were prepubertal with the response of those who were pubertal at the onset of GH therapy on an increased GH dose. PATIENTS AND METHODS: Among the Turkish patients enrolled in the Pfizer International Growth Study (KIGS) database with the diagnosis of IGHD, the growth data over 2 years of GH therapy were analyzed longitudinally of 113 (79 M) prepubertal (Group 1) and 44 (33 M) pubertal (Group 2) patients. Pubertal signs were reported to be present initially or to have appeared within 6 months of GH therapy in Group 2. Mean +/- SD age at onset of therapy was 8.7 +/- 3.5 and 13.5 +/- 1.8 years; height SDS -4.2 +/- 1.4 and -3.2 +/- 1.1 (p < 0.05) in Groups 1 and 2, respectively. Mid-parental height (MPH) SDS did not show a significant difference between the two groups (-1.5 +/- 1.1 vs -1.7 +/- 1.1). RESULTS: Delta height SDS over 2 years of therapy was significantly higher in Group 1 (1.1 +/- 1.0) than in Group 2 (0.7 +/- 0.6) (p <0.05) in spite of a significantly lower dose of GH (14.6 +/- 3.3 in Group 1 vs 17.0 +/- 3.1 IU/m2/week in Group 2, p < 0.05). Ht--MPH SDS showed an increase from -2.4 +/- 1.7 to -1.4 +/- 1.5 in Group 1 and from -1.5 +/- 1.5 to -0.8 +/- 1.3 in Group 2. Overall delta height SDS showed negative correlations with age (r = -0.32), height SDS (r = -0.41) and height--MPH SDS (r = -0.40) at onset of therapy (p < 0.001). CONCLUSIONS: These data show that in IGHD the slight increase (15-20%) in the dose of GH during puberty was not adequate to maintain height velocity at the same magnitude as in prepuberty, and thus was not cost effective.

A comparison of the use of premixed insulins in pen-injectors with conventional patient-mixed insulin treatment in children and adolescents with IDDM. Is there a decreased risk of night hypoglycemia?

Insulin injection is a problem in pediatric and adolescent age, and premixed insulin therapy given in pen-injectors (Novopen II) is expected to increase compliance. Compliance with treatment and safety of this kind of insulin substitution was investigated in 20 IDDM patients (8.2-19.6 years old). The study was of randomized cross-over design and its duration was 6 (2x3) months. Metabolic parameters were compared between premixed insulin therapy via pen-injector and patient-mixed insulin therapy via conventional syringe, and no differences were observed except for the postponing of night hypoglycemic attacks to 07.00 a.m. during premixed insulin therapy. No technical or medical problems occurred. Patients were more satisfied with the new therapy regimen as determined by questionnaire. We concluded that this kind of insulin substitution is safe in pediatric and adolescent IDDM patients.

Real-time sonography for screening of gallbladder dysfunction in children with type 1 diabetes mellitus.

The aim of this study was to evaluate the occurrence of gallbladder dysfunction in children with type 1 diabetes mellitus using real-time ultrasonography. The study population consisted of 20 diabetic children (11 male, 9 female; age 11.7+/-2.8 years; diabetes duration 0.5-7 years) with clinically negative neuropathy findings and 15 healthy controls (11 male, 4 female; age 10.5+/-3.7 years). Three-dimensional measurements of the gallbladder were made before and 15, 30, 45, 60 min after intake of diet chocolate. Gallbladder volumes were calculated by the ellipsoid formula. Fasting gallbladder volume of diabetic children (16.9+/-9.5 ml) was significantly greater than that of the controls (10.6+/-5.3 ml; p=0.017). Ejection fraction and maximal contraction showed no significant difference between the two groups. Diabetic patients with multiple microvascular complications had diminished gallbladder motility. There was a negative correlation between BMI and maximal contraction (p<0.05). Nerve conduction velocity was diminished in 45% of the diabetic patients. In conclusion, gallbladder function is preserved in pediatric type 1 diabetic patients with a disease duration less then 10 years, but dilated gallbladder at rest may be an early sign of gastrointestinal autonomic neuropathy and a risk factor for gallstone formation.

Diagnostic value of pituitary MRI in differentiation of children with normal growth hormone secretion, isolated growth hormone deficiency and multiple pituitary hormone deficiency.

Pituitary height, volume and morphology were investigated by MRI in patients aged 3.5-24.9 years with growth hormone deficiency (GHD) in relation to birth history and hormonal findings. Three groups with comparable age, sex and pubertal stage were studied: group I (n=42)--patients with isolated growth hormone deficiency (IGHD); group II (n=22)-- patients with multiple pituitary hormone deficiency (MPHD); and group III (n=30)--healthy controls. Pituitary height and volume differed significantly between the three groups, with the smallest in group II and largest in group III (p <0.001 for both). Both variables correlated significantly with peak GH value in the patient groups (p <0.001). The specificity of pituitary dysmorphology in the determination of GHD was 100% and its sensitivity in differentiation of IGHD and MPHD was 95%. Ectopic neurohypophysis was present in 75% of breech births and 27% of head-presenting patients (p <0.01). This study emphasizes the differential diagnostic value of pituitary MRI and its contribution to the understanding of the pathogenesis and prognosis in GHD.

Thyroxine hair content in congenital hypothyroidism and hyperthyroidism.

Using the determination of thyroxine (T4) hair content, we studied 16 hypothyroid newborns diagnosed by means of our regional screening program, and five hypothyroid infants, undetected at birth, at diagnosis and after 3 months of substitutive therapy (8-10 microg/kg/day L-thyroxine in newborns; 15 microg/kg/day in infants), and 13 hyperthyroid adults. Hair T4 content was similar at diagnosis in hypothyroid newborns (2.6 +/- 2.3 pg/mg hair) and in infants undetected at birth (2.4 +/- 1.7 microg/mg hair), but very high only in the latter after therapy (23.2 +/- 3.9 microg/mg hair). Untreated hyperthyroid adults surprisingly evidenced lower hair T4 (0.4 +/- 0.2 microg/mg hair) than controls (1.5 +/- 0.3 microg/mg hair). We suggest these findings are due to differential tissue storage of thyroid hormone, related to the different blood T4 concentration. Therefore, T4 hair assay could be a non-invasive method to further assess thyroid status.

Effects of growth hormone replacement therapy on lipids, lipoproteins and apolipoproteins: is the increased apolipoprotein A-1/B ratio the only benefit?

BACKGROUND: The aim of the present study was to investigate the controversial role of growth hormone (GH) therapy in lipid regulation. METHODS: We studied serum levels of cholesterol and subgroups, triglyceride and apolipoprotein A-1 and B in 41 GH-deficient children (with subgroups of untreated and short- and long-term treated subjects) and 20 healthy controls. RESULTS: Cholesterol and low-density lipoprotein cholesterol levels (in mmol/L) were found to be 4.92 +/- 1.34 and 3.02 +/- 1.58 in untreated, 4.15 +/- 0.72 and 2.46 +/- 0.65 in short-term (3 month) treated, 4.93 +/- 1.39 and 3.15 +/- 1.38 in long-term (> 1 year) treated and 4.11 +/- 0.5 and 2.0 +/- 0.74 in control subjects, respectively. The apolipoprotein A-1:B ratio was 1.98 +/- 0.5 in long-term treated and 1.6 +/- 0.6 in control subjects. CONCLUSIONS: The improvement of lipid composition with short-term GH therapy is temporary, but the increase in apo A-1:B is not and seems to be the particular benefit of this therapy.

Progressive white-matter disease with primary cerebellar involvement: a separate entity?

Abstract. Although its metabolic basis has not yet been clarified, we report a progressive white-matter disease in a Turkish girl, starting in the cerebellum and spreading to supratentorial white matter. The onset was at the age of 2.5 years with diabetes insipidus, followed by ataxia and pyramidal signs resulting in loss of walking. Aqueduct stenosis was first recognised at the age of 8 years. To our knowledge, this MRI and clinical pattern does not correspond to a recognised, well-defined white-matter disease and may indicate a separate entity.