Seasonal variation in month of diagnosis in children with type 1 diabetes registered in 23 European centers during 1989-2008: little short-term influence of sunshine hours or average temperature.

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.

Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase.

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.

Perinatal risk factors for childhood type 1 diabetes in Europe. The EURODIAB Substudy 2 Study Group.

OBJECTIVE: To explore whether perinatal factors are associated with the development of childhood type 1 diabetes. RESEARCH DESIGN AND METHODS: We studied hospital records from 892 cases of childhood type 1 diabetes compared with 2,291 population-based control subjects in seven study centers in Europe. RESULTS: In a pooled analysis incorporating stratification by center, we confirmed the previous findings that older maternal age, maternal preeclampsia, neonatal respiratory disease, and jaundice caused by blood group incompatibility are significant risk factors for type 1 diabetes, whereas being a firstborn child, having a low birth weight, or having a short birth length were protective. Cesarean section delivery and neonatal infectious diseases were not significantly associated with the risk of type 1 diabetes in this study. The strongest association was found for blood group incompatibility (AB0 and Rh factor) with an odds ratio (OR) of 2.96 (95% CI 1.88-4.65). AB0 incompatibility (OR = 3.92) was a more common and also a stronger risk factor than Rh incompatibility (OR = 1.62). The effect of AB0 blood group incompatibility was independent of treatment effects in logistical regression analysis. CONCLUSIONS: Different perinatal events are associated with an increased risk of type 1 diabetes. The effect of maternal-child blood group incompatibility is strong and indicates a true effect that must be further explored.

Blood glucose and plasma amino acid concentrations in infants of diabetic mothers.

Postnatal blood glucose and individual plasma free amino acid levels were measured in 14 newborn infants of diabetic mothers. All infants had a significantly lower blood glucose concentration than normal controls but no significant correlation was observed between the blood glucose values and any of the amino acids determined. As regards the quantitative and qualitative changes of the plasma aminogram, the total concentration of amino acids and the level of a few individual amino acids (glycine, alanine, taurine, and valine) were significantly elevated in full-term babies. However, no significant difference was found in the total plasma concentration of amino acids between premature infants of diabetic mothers and premature control infants, but the plasma alanine level was higher in the former. It is of interest that total plasma amino acid, alanine, and glycine levels were elevated in the asphyxiated babies. This suggests that the postnatal hyperaminoacidemia observed in infants of diabetic mothers was due to birth asphyxia rather than to impaired gluconeogenesis. The possible role of a defective gluconeogenesis in the etiology of postnatal hypoglycemia in infants of diabetic mothers is not supported by these data.

Transient but not permanent neonatal diabetes mellitus is associated with paternal uniparental isodisomy of chromosome 6.

OBJECTIVES: The factors determining the pathogenesis of transient and permanent neonatal diabetes mellitus are poorly characterized. The purpose of this study was to examine the role of chromosome 6 in the pathogenesis of neonatal diabetes mellitus and to detect differences between these 2 phenotypes. METHODS: Microsatellite markers (D6S334, D6S286, D6S310, D6S308, D6S292, D6S311, and D6S403) and human leukocyte antigen DQ alleles were examined using polymerase chain reaction and DNA fragment electrophoresis in 3 patients with transient and 3 patients with permanent neonatal diabetes mellitus. Humoral markers of islet cell autoimmunity and clinical characteristics were analyzed in the 2 groups. RESULTS: A patient with transient neonatal diabetes mellitus (TND) and macroglossia carrying paternal uniparental isodisomy (UPD) of chromosome 6 has been identified. The isodisomy affected the whole chromosome; no maternal chromosome 6 sequences were detected. The permanent neonatal diabetes mellitus cases and the other 2 cases with TND did not have UPD. None of the patients had high-risk type 1 diabetes human leukocyte antigen DQ alleles and most infants were negative for islet cell-specific autoantibodies indicating that none of the 2 forms of neonatal diabetes mellitus is likely to be of autoimmune origin. An association of TND and persistent granulocytopenia is described for the first time. CONCLUSIONS: We propose that transient and permanent forms of neonatal diabetes mellitus have different genetic background and represent different disease entities. TND is associated with UPD of chromosome 6 suggesting that an imprinted gene on chromosome 6 is responsible for this phenotype. It seems that 2 copies of the paternal allele are necessary for the development of TND; therefore, it is likely that overexpression of a putative gene located on chromosome 6 alters pancreatic beta-cell maturation and insulin secretion.

HLA alleles and IDDM in children in Hungary: a comparison with Finland.

It has been postulated that variation in the distribution of human leukocyte antigen (HLA)-encoded susceptibility alleles for insulin-dependent diabetes mellitus (IDDM) is the genetic basis for variation in the incidence of the disease between populations. The aim of this study was to characterize HLA-encoded susceptibility to IDDM in Hungary and to identify whether HLA-DRB1/DQ-encoded susceptibility could account for the five times lower incidence of disease in Hungary compared with Finland. The haplotypes DRB1*03-DQA1*05-DQB1*02 (DRB1*03-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DRB1*04-DQ8) were significantly associated with disease in both populations. Three genotypes incorporating either or both of these haplotypes accounted for over 70% of the diabetic population in both races. The combined background frequency and the degree of risk as measured by odds ratios of these HLA-DRB1-DQ genotypes were not significantly different in the two countries. Comparison of the DRB1*0401-DQ8 haplotype between the two races suggested a role for HLA-B alleles in susceptibility. These data indicate that the susceptibility associated with high risk DRB1-DQ genotypes alone is insufficient to account for the fivefold variation in incidence of IDDM between Hungary and Finland. Other genetic and/or environmental influences must be involved.

Isodicentric Y chromosome in an Ullrich-Turner patient without virilization.

We report on a 17-year-old young woman with Ullrich-Turner syndrome (UTS), who was found to have a karyotype 45,X/46,X,idic(Y)(q11). She had age-appropriate genitalia without virilization in spite of the presence of the Y-derived marker chromosome and SRY locus in 70% of her lymphocytes. Having reviewed the literature, we conclude that a possible explanation for the lack of virilization in these mosaic patients is most likely an uneven distribution of tissue mosaicism (gonadal mosaicism).

Fetal type lymphocytes in insulin dependent diabetes mellitus.

CD5+ B and gamma/delta T lymphocytes constituting a major population in the fetus and newborn infant, represent two small subsets of the B and T lymphocyte compartment in healthy adults. There is evidence for their potential involvement and relative expansion in autoimmune disorders. In insulin-dependent diabetes mellitus (IDDM) CD5+ B lymphocyte counts have been found to be increased or normal. The aim of our study was to determine the percentage of both "fetal type" lymphocyte subsets in peripheral blood of 22 recently diagnosed children with IDDM, in that of 13 high risk subjects (islet cell antibody (ICA) positive non-diabetic Ist degree relatives of diabetic children) and in 43 healthy controls. The percentage of gamma/delta TCR+ cells and of CD5+ B lymphocytes was found to be significantly (p < 0.0001 and p = 0.03, respectively) higher in the diabetic and prediabetic groups as compared to controls. Young children with IDDM associated antibodies carry a higher risk of developing clinical IDDM than older individuals. In our hands, the percentage of both CD5+ B and gamma/delta T lymphocytes was higher in the younger population. However, age-dependent decrease for both lymphocyte subpopulations in IDDM-prediabetic patients was less than in healthy controls. Since the above subpopulations are supposed to play a role in immune response to conserved structures, these observations would suggest a higher capacity of older individuals to 'natural autoimmunity" and would explain at least in part the increased risk of antibody positive young children to develop IDDM.

Correlation of blood-spot 17-hydroxyprogesterone daily profiles and urinary steroid profiles in congenital adrenal hyperplasia.

OBJECTIVE: To compare the value of blood-spot 17-hydroxyprogesterone (17-OHP) daily profiles and urinary steroid excretion in untreated and treated patients with congenital adrenal hyperplasia (CAH). PATIENTS: Ten patients with CAH were investigated during steroid replacement therapy (Group 1), and 11 patients were investigated without treatment (Group 2). METHODS: Capillary blood samples were collected for measurement of blood-spot 17-OHP values by non-chromatographic radioimmunoassay. Steroid profiles of 24-h urine samples were analyzed by gas chromatography. RESULTS: There was a close correlation between the individual daily means of blood-spot 17-OHP measurements and the pregnanetriol/ tetrahydrocortisone ratio in both groups of patients (Group 2: r=0.839, p<0.001; Group 1: r=0.686, p<0.001). Almost the same correlation was found between the blood-spot 17-OHP value and the sum of three 17-hydroxyprogesterone metabolites/the sum of three cortisol/cortisone metabolites ratio (Group 2: r=0.918, p<0.001; Group 1: r=0.741, p<0.001). CONCLUSIONS: Blood-spot 17-OHP measurements and 24-h urinary steroid profile have the same impact in identification and monitoring therapy of children with CAH.

The aminogram of the urine produced by the preserved kidney.

The function of autogenous canine kidneys may be considered even after successful preservation and reperfusion to be pathological for about 3 to 4 days, since a condition characterized by proteinuria and increased amino aciduria exists for a while.

[Pathogenesis and types of neonatal diabetes]. / A neonatalis diabetes formái és pathogenesise.

Studies on pathogenesis of neonatal diabetes may lead to better understanding of pancreatic beta-cell maturation and regulation of insulin secretion. The purpose of this study was to examine the clinical course, immunologic and genetic background of the transient and permanent form of neonatal diabetes. Clinical data (onset and duration of diabetes, C peptide levels, duration of insulin treatment, associated disorders) were collected, islet cell specific antibodies (islet cell antibody and glutamate decarboxylase antibody) were determined and genetic analyses (HLA DQA1-DQB1 typing and microsatellite mapping on chromosome 6) were performed in three patients with permanent and three patients with transient neonatal diabetes. None of the six patients had HLA DQ diabetes susceptibility alleles and most infants were negative for islet cell autoantibodies indicating that no pancreatic islet-cell specific autoimmunity exists in the two forms of neonatal diabetes mellitus. Complete paternal uniparental isodisomy of chromosome 6 has been identified in a transient neonatal diabetes case with macroglossia. The permanent neonatal diabetes cases and the other two cases with transient form did not possess this chromosome anomaly. It is concluded, that none of the two forms neonatal diabetes is of autoimmune origin. They have different genetic background and represent different disease entities. Transient neonatal diabetes is probably caused by alteration of expression of an imprinted gene on chromosome 6 which might play role in fetal growth and pancreatic beta-cell maturation and insulin secretion. Permanent neonatal diabetes is probably a more heterogenous phenotype, the cause of which remains to be clarified in the future.

[Clinical diagnosis of childhood insulin dependent diabetes mellitus. Hungarian Epidemiological Group for Childhood Diabetes]. / A gyermekkori inzulindependens diabetes mellitus klinikai diagnózisa. Magyar Gyermekdiabetes Epidemiológiai Munkacsoport.

The aim of this study was to describe the clinical presentation and severity of the disease at onset in childhood during 1994. Based on the prospective national incidence registry, data were collected (using a modified version of the EURODIAB ACE questionnaire) from all diabetic children diagnosed during a full calendar year (1994). The ascertainment was 91%. Polyuria, polydipsia and weight loss were the most frequent clinical symptoms, but fatigue, abdominal pain and personality changes were also often reported. Almost one quarter of the children presented with diabetic ketoacidosis. There was no correlation between age, duration of symptoms, blood glucose levels and the severity of disease. The unacceptably high incidence of presentation ketoacidosis called for an urgent improvement of the diagnostic acumen of the physicians dealing with children.

[Incidence of type 1 childhood diabetes in Hungary (1978-1997). Hungarian Committee on the Epidemiology of Childhood Diabetes]. / A gyermekkori 1-es típusú diabetes mellitus incidenciája Magyarországon (1978-1997). Magyar Gyermekdiabetes Epidemiológiai Munkacsoport.

The incidence of Type 1 diabetes in 2417 children aged 0-14 years was studied between 1978 and 1997. Statistical analysis of the data in the twenty-year period showed a steady increase in incidence of Type 1 diabetes with an average rate of 4.8% (95% CI 4.0-5.5) per annum. The incidence rate was lowest in children aged 0 to 4 years and the highest in the age group 10 to 14 years. This increase in incidence was similar for all age groups, but it was most pronounced in the 10 to 14 year-old age group. One hundred and twenty one of the 1239 families (9.7%), one of parents was also reported to have Type 1 diabetes and in 3 (0.2%) families both parents had Type 1 diabetes. Twenty two (2.3%) of the diabetic families had a sibling with Type 1 diabetes. The nearly three-fold increase in incidence during the last two decades (3.8 per 100,000 per year in 1978; 10.7 per 100,000 per year) was probably due to environmental factors, while the high degree of familial clustering emphasises the role of genetic factors in the etiology of Type 1 diabetes.

[Incidence of childhood diabetes in Hungary]. / A gyermekkori diabetes mellitus incidenciája Magyarországon.

A retrospective epidemiological study using primary data sources and external validation was made to assess the incidence of childhood diabetes (0-14 yr) over a ten-year period. The degree of ascertainment was 96.2 per cent. Age-specific incidence rates increased until puberty with peak incidence in girls at 10 year and in boys at 13 year. There was a seasonal variation of onset with peaks in autumn and winter. The yearly incidence rates showed an increasing trend, the incidence in 1987 (8.7/100,000) was 2.3 times higher than in 1978. The rise in incidence was not continuous, incidence rates were similar in the years 1978-79, 1980-84 and 1985-87, but relatively sharp increases could be observed in 1980 and in 1985 which were mainly due to increases in incidence of the age group 5 to 9 years. Dynamic changes have taken place in the incidence of childhood diabetes in Hungary between 1978 and 1987, but it is not known whether the increases can be regarded as epidemics or parts of a discontinuous trend.