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 (1989–1998) and second ...(1999–2008) 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 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.
Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and ...genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) - the most common chromosomal translocation observed in childhood ALL - which leads to an ETV6-RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, P(CMH)=8.94 × 10(-9), OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10(-11), OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10(-9), OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10(-7), OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6-RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis.
Aims/hypothesis The aim of this study was to investigate the evidence of an increased risk of childhood-onset type 1 diabetes in children born by Caesarean section by systematically reviewing the ...published literature and performing a meta-analysis with adjustment for recognised confounders. Methods After MEDLINE, Web of Science and EMBASE searches, crude ORs and 95% CIs for type 1 diabetes in children born by Caesarean section were calculated from the data reported in each study. Authors were contacted to facilitate adjustments for potential confounders, either by supplying raw data or calculating adjusted estimates. Meta-analysis techniques were then used to derive combined ORs and to investigate heterogeneity between studies. Results Twenty studies were identified. Overall, there was a significant increase in the risk of type 1 diabetes in children born by Caesarean section (OR 1.23, 95% CI 1.15-1.32, p < 0.001). There was little evidence of heterogeneity between studies (p = 0.54). Seventeen authors provided raw data or adjusted estimates to facilitate adjustments for potential confounders. In these studies, there was evidence of an increase in diabetes risk with greater birthweight, shorter gestation and greater maternal age. The increased risk of type 1 diabetes after Caesarean section was little altered after adjustment for gestational age, birth weight, maternal age, birth order, breast-feeding and maternal diabetes (adjusted OR 1.19, 95% CI 1.04-1.36, p = 0.01). Conclusions/interpretation This analysis demonstrates a 20% increase in the risk of childhood-onset type 1 diabetes after Caesarean section delivery that cannot be explained by known confounders.
Aims
Patients with maturity‐onset diabetes of the young (MODY) might be over‐represented in families with histories of Type 1 diabetes. Our aim was to re‐evaluate families participating in the Czech ...T1D Prediction Programme (PREDIA.CZ) with at least two members affected with diabetes to assess the proportion of MODY among these families and determine its most significant clinical predictors.
Methods
Of the 557 families followed up by the PREDIA.CZ, 53 (9.5%) had two or more family members with diabetes. One proband with diabetes from these families was chosen for direct sequencing of the GCK, HNF1A, HNF4A and INS genes. Non‐parametric tests and a linear logistic regression model were used to evaluate differences between MODY and non‐MODY families.
Results
MODY was genetically diagnosed in 24 of the 53 families with multiple occurrences of diabetes (45%). Mutations were detected most frequently in GCK (58%), followed by HNF1A (38%) and INS (4%). MODY families were more likely to have a parent with diabetes and had a higher proportion of females with diabetes than non‐MODY families. Higher age (P < 0.001), a lower level of HbA1c (P < 0.001) at clinical onset and at least two generations affected by diabetes were the variables most predictive for probands of MODY families already presenting with diabetes.
Conclusions
A prediction programme for Type 1 diabetes would provide a useful new source of patients with MODY most likely to benefit from an accurate diagnosis. This identification has implications for patient treatment and disease prognosis.
What's new?
Patients with maturity‐onset diabetes of the young (MODY) might be over‐represented among the relatives of children with Type 1 diabetes due to similar clinical outcomes.
To the best of our knowledge, this tiered investigation is the first to evaluate the prevalence of MODY in a Type 1 diabetes prediction project.
The results suggested that cases of MODY are hidden among multiplex families within Type 1 diabetes prediction projects and that the prevalence of these cases is not negligible.
Based on our results, a diagnosis of MODY should be considered and investigated within these programmes because patients clearly benefit from an accurate aetiological diagnosis that enables the optimization of therapy.
Aims
Specific patterns in incidence may reveal environmental explanations for type 1 diabetes incidence. We aimed to study type 1 diabetes incidence in European childhood populations to assess ...whether an increase could be attributed to either period or cohort effects.
Methods
Nineteen EURODIAB centres provided single year incidence data for ages 0–14 in the 25-year period 1989–2013. Case counts and person years were classified by age, period and cohort (APC) in 1-year classes. APC Poisson regression models of rates were fitted using restricted cubic splines for age, period and cohort per centre and sex. Joint models were fitted for all centres and sexes, to find a parsimonious model.
Results
A total of 57,487 cases were included. In ten and seven of the 19 centres the APC models showed evidence of nonlinear cohort effects or period effects, respectively, in one or both sexes and indications of sex-specific age effects. Models showed a positive linear increase ranging from approximately 0.6 to 6.6%/year. Centres with low incidence rates showed the highest overall increase. A final joint model showed incidence peak at age 11.6 and 12.6 for girls and boys, respectively, and the rate-ratio was according to sex below 1 in ages 5–12.
Conclusion
There was reasonable evidence for similar age-specific type 1 diabetes incidence rates across the EURODIAB population and peaks at a younger age for girls than boys. Cohort effects showed nonlinearity but varied between centres and the model did not contribute convincingly to identification of environmental causes of the increase.
Background
Seasonality at the clinical onset of type 1 diabetes (T1D) has been suggested by different studies, however, the results are conflicting. This study aimed to evaluate the presence of ...seasonality at clinical onset of T1D based on the SWEET database comprising data from 32 different countries.
Methods
The study cohort included 23 603 patients (52% males) recorded in the international multicenter SWEET database (48 centers), with T1D onset ≤20 years, year of onset between 1980 and 2015, gender, year and month of birth and T1D‐diagnosis documented. Data were stratified according to four age groups (<5, 5‐<10, 10‐<15, 15‐20 years) at T1D onset, the latitude of European center (Northern ≥50°N and Southern Europe <50°N) and the year of onset ≤ or >2009.
Results
Analysis by month revealed significant seasonality with January being the month with the highest and June with the lowest percentage of incident cases (P < .001). Winter, early spring and late autumn months had higher percentage of incident cases compared with late spring and summer months. Stratification by age showed similar seasonality patterns in all four age groups (P ≤ .003 each), but not in children <24 months of age. There was no gender or latitude effect on seasonality pattern, however, the pattern differed by the year of onset (P < .001). Seasonality of diagnosis conformed to a sinusoidal model for all cases, females and males, age groups, northern and southern European countries.
Conclusions
Seasonality at T1D clinical onset is documented by the large SWEET database with no gender or latitude (Europe only) effect except from the year of manifestation.
Background
The month of diagnosis in childhood type 1 diabetes shows seasonal variation.
Objective
We describe the pattern and investigate if year‐to‐year irregularities are associated with ...meteorological factors using data from 50 000 children diagnosed under the age of 15 yr in 23 population‐based European registries during 1989–2008.
Methods
Tests for seasonal variation in monthly counts aggregated over the 20 yr period were performed. 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 centers with peaks in November to February and relative amplitudes ranging from ±11 to ±38% (median ±17%). However, most centers showed significant departures from a sinusoidal pattern. Pooling results over centers, there was significant seasonal variation in each age‐group at diagnosis, with least seasonal variation in those under 5 yr. Boys showed greater seasonal variation than girls, particularly those aged 10–14 yr. There were no differences in seasonal pattern between four 5‐yr 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
Seasonality was consistently apparent throughout the period in all age‐groups and both sexes, but girls and the under 5 s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.
Aims/hypothesis
We investigated whether children who are heavier at birth have an increased risk of type 1 diabetes.
Methods
Relevant studies published before February 2009 were identified from ...literature searches using MEDLINE, Web of Science and EMBASE. Authors of all studies containing relevant data were contacted and asked to provide individual patient data or conduct pre-specified analyses. Risk estimates of type 1 diabetes by category of birthweight were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were then used to derive combined ORs and investigate heterogeneity between studies.
Results
Data were available for 29 predominantly European studies (five cohort, 24 case–control studies), including 12,807 cases of type 1 diabetes. Overall, studies consistently demonstrated that children with birthweight from 3.5 to 4 kg had an increased risk of diabetes of 6% (OR 1.06 95% CI 1.01–1.11;
p
= 0.02) and children with birthweight over 4 kg had an increased risk of 10% (OR 1.10 95% CI 1.04–1.19;
p
= 0.003), compared with children weighing 3.0 to 3.5 kg at birth. This corresponded to a linear increase in diabetes risk of 3% per 500 g increase in birthweight (OR 1.03 95% CI 1.00–1.06;
p
= 0.03). Adjustments for potential confounders such as gestational age, maternal age, birth order, Caesarean section, breastfeeding and maternal diabetes had little effect on these findings.
Conclusions/interpretation
Children who are heavier at birth have a significant and consistent, but relatively small increase in risk of type 1 diabetes.
Although a decreased areal bone mineral density (BMD) has been reported in patients with haemophilia, data are lacking that would reflect the three‐dimensional structure of the bone and the ...muscle‐bone relationship. We aimed to assess volumetric BMD, bone geometry and muscle‐bone phenotype in boys with haemophilia, and to describe the association between clinical characteristics of haemophilia and bone quality and structure. A cross‐sectional study was conducted in 41 boys with haemophilia (mean age 12.4, range 6.6–19.8 years) using peripheral quantitative CT (pQCT) at the nondominant forearm. Results were transformed into Z‐scores using previously published reference data. Significant differences were tested by one‐sample t‐test or sign test. Two‐sample t‐test and anova were used to compare results between subgroups of patients divided according to the severity of the disease, the fracture history and the number of joint and muscle bleedings. Boys with haemophilia had a decreased trabecular volumetric BMD (mean Z‐score −0.5, P < 0.01), while their cortical volumetric BMD was increased (mean Z‐score 0.4, P < 0.05). The volumetric bone mineral content and the bone geometry at the radial diaphysis were normal when adjusted for patients’ shorter body height. Muscle area was decreased (mean Z‐score −1.0, P < 0.001), irrespective of age. No association was observed of bone quality parameters and bone geometry with the disease severity, fracture history or number of bleedings. Bone strength measured at the diaphysis of the radius is not impaired in boys with haemophilia. The finding of the decreased trabecular bone density can be most likely attributed to their sarcopenia.
1 Department of Paediatric Haematology and Oncology, Motol University Hospital, Prague, The Czech Republic;
2 Institute of Haematology and Blood Transfusion, Prague, The Czech Republic;
3 Department ...of Paediatrics, Motol University Hospital, Prague, The Czech Republic
Correspondence: Petr Hubacek, M.D. Department of Paediatric Haematology and Oncology, Motol University Hospital, V Uvalu 84 CZ-150 06, Prague 5 – Motol, The Czech Republic. Phone: +420 224 432 026, Fax: +420 224 432 020. E-mail: Petr.Hubacek{at}Lfmotol.cuni.cz
We report a fifty-year-old woman presenting with severe aplastic anaemia (SAA) and prolonged high Human Herpesvirus 6 (HHV6) variant A DNAeamia detected by quantitative PCR. Multiple antiviral treatments failed to affect the HHV6 DNAemia and subsequent immunosuppressive treatment reached only partial improvement as judged by bone marrow examinations. The patient remained dependent on thrombocyte transfusions and G-CSF treatment. After one year of steady high HHV6 DNA load in blood, viral chromosomal integration was proved by demonstrating the viral DNA in hair follicles. This condition appeared to be unconnected with, and to have no effect, on the original SAA
Key words: human herpesvirus 6, severe aplastic anaemia, chromosomal integration.
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