Sten-A. Ivarsson

Thyroid dysfunction in Down’s syndrome: relation to age and thyroid autoimmunity

BACKGROUND The prevalence of thyroid disease is increased in Down’s syndrome. Most available data come from cross sectional studies. AIMS To study longitudinally thyroid function in patients with Down’s syndrome in Uppsala county (85 patients) up to the age of 25 years. METHODS Observational study based on yearly follow up in a children’s clinic. Thyroid function tests were performed at each visit to the clinic. RESULTS Hypothyroidism was found in 30 and hyperthyroidism was found in two of the 85 patients. No sex difference was seen. Half of the patients with hypothyroidism acquired the condition before the age of 8 years, but only one of them displayed thyroid autoantibodies at diagnosis. Most patients who developed hypothyroidism after this age had thyroid autoantibodies. In the prepubertal patients with hypothyroidism, growth velocity was lower during the year before the start of thyroxine treatment than during the year after treatment began; it was also lower than that of sex and age matched euthyroidic children with Down’s syndrome. CONCLUSION Thyroid dysfunction in patients with Down’s syndrome is common in childhood. Consequently, annual screening is important. Autoimmune thyroid disease is uncommon in young children with Down’s syndrome but is common after 8 years of age.

Prevalence of IgA-Antiendomysium and IgA-Antigliadin Autoantibodies at Diagnosis of Insulin-Dependent Diabetes Mellitus in Swedish Children and Adolescents

Objective. This study was conducted to investigate the prevalence of celiac disease (CD) in children and adolescents at diagnosis of insulin-dependent diabetes mellitus (IDDM) before insulin treatment was started. Material and Methods. At diagnosis of IDDM, and before treatment was started, 115 children and adolescents were screened for IgA- antiendomysium (EMA) and IgA-antigliadin antibodies (AGA). Those found to be EMA-positive and/or AGA-positive were investigated further with intestinal biopsy. Results. Of the 115 patients, 2 had known CD at diagnosis of IDDM; of the remainder of patients, 6% (7/113) were found to be EMA-positive and 9% (10/113) were found to have AGA levels above normal. Of the 6 patients who underwent biopsy, 5 manifested villous atrophy. In addition, 2 patients with high EMA and AGA antibody titers refused biopsy, and 4 patients with low EMA and/or AGA titers were found to have normal titers at control before biopsy decision. Conclusion. Because the prevalence of CD at diagnosis of IDDM would seem to be 6% to 8%, screening for CD seems to be justified among patients with newly diagnosed IDDM.

Revised Guidelines for Neonatal Screening Programmes for Primary Congenital Hypothyroidism

Since the first guidelines for neonatal screening for congenital hypothyroidism (CH) were issued by ESPE in 1993 [1], there have been considerable advances in our understanding of CH and our appreciation of the various geographical and logistic difficulties involved. Therefore, an updating of the guidelines is overdue. Experience from countries where screening began in the late 1970s and early 1980s has indicated that treatment should be started no later than the first 2 weeks of life using a ‘high’ dosage regime of L-thyroxine (10–15 Ìg/kg/day). It has also been shown that the quality of long-term outcome is closely related to the quality of follow-up. In Eastern Europe, screening programmes for CH have either been started or will start soon in almost all countries, and although many programmes are operating satisfactorily, it is important to standardise screening procedures and management of suspected cases as much as possible in order to optimise outcome. A degree of uniformity throughout Europe would not only facilitate early detection and treatment of individual patients but give insight into the economic and epidemiological aspects of the screening programmes as well as the epidemiological aspect of CH.

Genetic and perinatal factors as risk for childhood type 1 diabetes

The mechanisms by which gestational infections, blood incompatibility, birth weight, mothers age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population‐based prospective studies. The possibility of identifying children at type 1 diabetes risk among first‐degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first‐degree relative with the disease. Population‐based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skåne), which is examining a total of about 10 000 pregnancies expected every year in the Skåne (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high‐risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase–related IA‐2 antigen (IA‐2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high‐risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes. Copyright

Prevalence of celiac disease: before and after a national change in feeding recommendations.

Objective. A national change in infant feeding recommendations was proposed in 1996 in Sweden: a slow introduction to gluten during weaning was stressed, the recommendation being introduction at 4 instead of 6 months of age. The aim of the present study was to compare the prevalence of celiac disease in healthy young children born before and after the new feeding recommendations in 1996. Material and methods. Sera from 679 children at a median age of 2.9 years (range 2.5–4.2 years) born between January 1996 and November 1997 were investigated with IgA-antigliadin antibodies (AGA) and IgA-endomysial autoantibodies (EMA) and compared with 690 age-matched children born between July 1992 and June 1993. Children with a positive test for EMA and AGA or EMA only were re-tested, and if positive at follow up, investigated with intestinal biopsy. Results. At baseline, 2.2% (15/679) children were positive for EMA and another 0.6% (4/679) for both EMA and AGA. One child refused to be re-tested and eight children were still EMA positive at follow-up. Intestinal biopsy was performed in seven children (one declined biopsy), of whom three showed total villous atrophy. Two children with EMA titers 1:640, respectively, refused further participation in the study, but were strongly suspected to have celiac disease. In total, 0.7% (5/679) (95% confidence interval (CI) = 0.1–1.4%) were considered to have celiac disease compared with 1.3% (9/690) (95% CI = 0.4–2.2%) in the control group (p=0.4217). In addition, 0.3% of the children were diagnosed with symptomatic celiac disease compared with 0.7% in controls (p=0.0134). Conclusions. The prevalence of symptomatic celiac disease declined after the infant dietary recommendations were introduced in 1996, but we could not find any difference in undiagnosed celiac disease between the screened children born before and those born after 1996.

Type 1 diabetes patients born to immigrants to Sweden increase their native diabetes risk and differ from Swedish patients in HLA types and islet autoantibodies.

Delli AJ, Lindblad B, Carlsson A, Forsander G, Ivarsson S‐A, Ludvigsson J, Marcus C, Lernmark Å; for the Better Diabetes Diagnosis (BDD) Study Group. Type 1 diabetes patients born to immigrants to Sweden increase their native diabetes risk and differ from Swedish patients in HLA types and islet autoantibodies.

Management of Males with 45,X/46,XY Gonadal Dysgenesis

Males with the 45,X/46,XY karyotype and malformations of the external genitalia carry an increased risk of developing germ cell neoplasia of the gonads. We have studied gonadal tissue from 10 individuals, 0.3–17 years of age, with a male phenotype and either hypospadias and/or cryptorchidism. Four patients, 0.3–15 years of age, had carcinoma in situ, 1 boy had Sertoli-cell-only pattern and the remainder prepubertal histology. Gonadoblastoma or invasive carcinoma was not found. On the basis of our current knowledge we propose a strategy for management and follow-up of these boys in order to detect possible premalignant histological changes early and prevent development of a gonadal tumour.

Increased risk of Silver-Russell syndrome after in vitro fertilization?

opportunists—were pathogenic bacteria of meningitis in three cases. Pediococci meningitis frequently occurs in infant patients who have undergone gastrointestinal operation and had malnutrition and relatively lower immunity [2]. Another conditioned pathogen, Corynebacterium, was resistant to imipenem/cilastatin and only sensitive to vancomycin. With the advent of third-generation cephalosporins and their high level of activity against Gram-negative pathogens and their high degree of penetration into CSF, clinical outcomes have been remarkably improved [3]. At present, in our hospital, the susceptibility of E. coli to cefotaxime and ceftazidime is 72% and 78%, respectively. Ninety-four per cent of H. influenza isolates showed susceptibility to ceftazidime, 79% of coliform bacilli isolates susceptibility to ceftazidime, and 80% of Pseudomonas isolates susceptibility to ceftazidime. Ceftazidime has high sensitive to Pseudomonas aeruginosa. Clinical experience with ceftazidime in patients with P. aeruginosa meningitis has proved very effective (cure rate 70%) [4]. In our hospital, 10 of the isolates (three E. coli, one H. influenza, three coliform bacilli, two Pseudomonas and one Corynebacterium) were simultaneously resistant to ampicillin, amoxicillin-clavulanic, cefuroxime, cefotaxime, cetazidime and netilmicin. Six of the isolates (twoE. coli, two coliform bacilli, one Pseudomonas and one Corynebacterium) showed simultaneous resistance to imipenem/cilastatin. It was therefore noted that the emergence of multidrug-resistant Gramnegative bacillary strains and imipenem/cilastatinresistant strains further increased therapeutic dilemma in infants and children with bacterial meningitis. Our data were not in accordance with the reported view that Neisseria meningitidis is a frequent and predominant pathogen of meningitis [5]. Inability to recover bacteria from cultures may occur for the following two possible reasons: on the one hand, patients who were admitted to our hospital from county hospitals often received antibiotic treatment prior to lumbar puncture; on the other hand, the positive rate of meningcoccal culture was much lower than that of antigen detection of CSF or blood. Culture and microscopy established diagnosis in only 12 of 23 N. meningitidis cases, whereas latex-based assay did so in all 23. This suggests that the detection of bacterial antigens in the CSF or blood appeared to be a more efficient diagnostic approach in N. meningitidis cases, compared with culture and microscopy assay. In conclusion, CNS, as the predominant pathogen, ranks first among paediatric patients with bacterial meningitis. Vancomycin-resistant strains and imipenem/cilastatin-resistant strains are found among clinical isolates of infants and children with bacterial meningitis.

Selective screening of secretory vesicle-associated proteins for autoantigens in type 1 diabetes: VAMP2 and NPY are new minor autoantigens.

The four major autoantigens (IA-2, IA-2 beta, GAD65 and insulin) of type 1 diabetes are all associated with dense core or synaptic vesicles. This raised the possibility that other secretory vesicle-associated proteins might be targets of the autoimmune response in type 1 diabetes. To test this hypothesis 56 proteins, two-thirds of which are associated with secretory vesicles, were prepared by in vitro transcription/translation and screened for autoantibodies by liquid phase radioimmunoprecipitation. Two secretory vesicle-associated proteins, VAMP2 and NPY, were identified as new minor autoantigens with 21% and 9%, respectively, of 200 type 1 diabetes sera reacting positively. These findings add support to the hypothesis that secretory vesicle-associated proteins are particularly important, but not the exclusive, targets of the autoimmune response in type 1 diabetes. Selective screening of the human proteome offers a useful approach for identifying new autoantigens in autoimmune diseases.

Decline of C-peptide during the first year after diagnosis of Type 1 diabetes in children and adolescents

AIMS/HYPOTHESIS We studied the decline of C-peptide during the first year after diagnosis of Type 1 diabetes (T1D), and its relation to various factors. METHODS 3824/4017 newly diagnosed patients (95%) were classified as T1D in a national study. In a non-selected subgroup of 1669 T1D patients we determined non-fasting C-peptide both at diagnosis and after 1 year, and analyzed decline in relation to clinical symptoms and signs, initial C-peptide and occurrence of auto-antibodies. RESULTS Younger children lost more C-peptide (p<0.001) and the higher the C-peptide at diagnosis the larger the decline during the first year (p<0.0000). Patients with higher BMI had higher C-peptide at diagnosis but lost more (p<0.01), and those with lower HbA1c, without symptoms and signs at diagnosis, and with higher BMI, had higher C-peptide at diagnosis, but lost more during the first year (p<0.001). Finally, patients diagnosed during autumn had higher C-peptide at diagnosis, but lost more during the coming year (p<0.001). Occurrence of auto-antibodies did not correlate with C-peptide decline, except possibly for a more rapid loss in IAA-positive patients. CONCLUSIONS/INTERPRETATION Even in a restricted geographical area and narrow age range (<18 years), the natural course of Type 1 diabetes is heterogeneous. This should be considered in clinical trials.