Aims/hypothesis The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998) and second (1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008) halves of the period. Methods All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture-recapture methodology.Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied. Results Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase -012-2571-8 were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half. Conclusions/interpretation The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3-4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.Diabetologia (2012) 55:2142-2147 DOI 10.1007/s00125

Objective: Thyroid dyshormonogenesis is a genetically heterogeneous group of inherited disorders in the enzymatic cascade of thyroid hormone synthesis that result in congenital hypothyroidism (CH). Thyroid peroxidase gene (TPO) mutations are one of the most common causes of thyroid dyshormonogenesis. The aim of this study was to identify TPO gene defects in a cohort of patients with thyroid dyshormonogenesis from Slovenia, Bosnia, and Slovakia. Design and methods: Forty-three patients with permanent CH and orthoptic thyroid glands from 39 unrelated families participated in the study. Mutational analysis of the TPO gene and part of its promoter consisted of single-stranded conformation polymorphism analysis, sequencing, and restriction fragment length polymorphism (RFLP) analysis. Results: TPO gene mutations were identified in 46% of participants. Seven different mutations were identified, four mutations of these being novel, namely 613COT (R175X), 1519_1539del (A477_N483del), 2089GOA (G667S), and 2669GOA (G860R). Only a single allele mutation was identified in 65% of the TPO mutation carriers. Conclusions:The results showed a higher prevalence of TPO gene mutations in thyroid dyshormonogenesis when compared with published studies. The high percentage of single allele mutations implied possible intronic or regulatory TPO gene mutations or monoallelic expression.

A total of 1419 children with type 1 diabetes mellitus was investigated in order to assess the true frequency of Hashimoto's thyroiditis (HT), diagnosed by microsomal and/or thyroglobulin autoantibodies, by ultrasound and in many cases also by fine needle biopsy. According to these criteria, 55 cases (3.9%) of HT were identified, a number significantly higher (P < 0.0001) than the distribution reported in the normal paediatric population. No typical antibody pattern was seen prior to the onset of HT, nor was an antibody threshold level found which could have been diagnostic for this disease. Patients with subclinical hypothyroidism were treated with L-thyroxine and were investigated regarding the behaviour of anti-thyroid autoantibodies; however, no significant changes were seen. The data showed a high frequency of HT in diabetic children, and therefore we recommend that children with type 1 diabetes mellitus should be screened for thyroid autoantibodies and those positive should undergo periodic thyroid function testing.

Hereditary dwarfism was first recognized in inhabitants of the island of Krk in the Adriatic in 1864. Since then 24 related dwarfs have been recorded. Their pedigrees and heights are presented. Ten of these patients live in the villages Bascanska Draga and Jurandvor. Six have been studied by the authors. Clinical examination revealed dwarfism, obesity, dry wrinkled skin, and lack of sexual development. Hormonal investigations showed the absence of growth hormone (GH) unresponsive to growth hormone releasing hormone (GHRH), absence of luteinizing hormone (LH) and follicle stimulating hormone (FSH) unresponsive to gonadotropin releasing hormone (GnRH), and absence of thyrotropin stimulating hormone (TSH) unresponsive to TRH. Basal serum prolactin (PRL) was low but secretion of ACTH was normal as evidenced by normal Cortisol levels. Hypopituitarism in this isolate was not associated with a shortened life span or an increased incidence of diabetes. PROP-1 is a pituitary specific transcription factor that is required for the embryologic development of the pituitary cell types that ultimately produce GH, PRL, TSH and FSH/LH postnatally. Examination of genomic DNA from two of the patients revealed homozygosity for a one bp deletion in codon 50 of exon 2 of PROP-1. This mutation introduces a frame shift and

word count: 250 excluding headingsMain text word count: 2,564 including Table and Figure legends Tables and Figures: Tables (2) Methods Twenty-three population-based registers recorded date of diagnosis for new cases of type 1 diabetes among children under 15 years. Tests for seasonal variation in monthly counts aggregated over the 20 year period were conducted. Time series regression was used to investigate if sunshine hour and average temperature data were predictive of the 240 monthly diagnosis counts after taking account of seasonality and long term trends.Results Significant sinusoidal pattern was evident in all but two small centres with peaks in December to February and relative amplitudes ranging from 11% to 39% (median 18%). However, most centres showed significant departures from a sinusoidal pattern. Pooling results over centres, there was significant seasonal variation in each age-group at diagnosis, with least seasonal variation in those under 5 years. Boys showed greater seasonal variation than girls, particularly those aged 10-14 years. There were no differences in seasonal pattern between four five-year sub-periods. Departures from the sinusoidal trend in monthly diagnoses in the period were significantly associated with deviations from the norm in average temperature (0.8% reduction in diagnoses per 1 C excess) but not with sunshine hours.Conclusions/interpretation Seasonality was consistently apparent throughout the period in all age-groups and both sexes, but girls and the under 5s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.