Summary IA-2 has been identified as an autoantigen that is recognized by immunoglobulins from insulindependent diabetic (IDDM) patients. Using a liquid phase radiobinding assay, we performed an IA-2-autoantibody (IA-2-Ab) assay in 474 IDDM patients and 482 non-diabetic control subjects aged 0-39 years. IA-2-Ab were detected in 58 % of the patients and 0.8 % of control subjects. Their prevalence in patients was lower than that of islet cell autoantibodies (ICA; 73 %) or glutamic acid decarboxylase (M r 65 kDa)-autoantibodies (GAD 65 -Ab; 82 %) but higher than that of insulin autoantibodies (IAA; 42 %). IA-2-Ab were more frequent in patients under age 20 years (70 %) than between 20 and 40 years (45 %; p < 0.001). In the whole IDDM group, 92 % of patients were positive for at least one of the three molecular assays, which is higher than the positivity for the ICA assay (73 %). Only 1 % was negative in the molecular assays and positive in the ICA assay. IA-2-Ab levels were positively correlated with ICA titres (p < 0.001) and HLA DQ A1*0301 -DQ B1*0302 (p < 0.003) by multivariate analysis. In a group of 481 non-diabetic siblings (age 0-39 years) of IDDM patients only 7 were IA-2-Ab positive (1.5 %). All seven were under age 20 years and positive for at least two other autoantibodies and for DQ A1*0301 -DQB1*0302. Four of these seven developed IDDM during the 6-70-month follow-up period. The positive predictive value of IA-2-Ab (57 %) was higher than that of ICA, GAD 65 -Ab or IAA alone, or in combination (K 20 %) but these calculations are restricted by the relatively short observation period and the small number of cases. The only IA-2-Ab-negative case of pre-diabetes was also negative for IAA and GAD 65 -Ab, while it was strongly positive for ICA. In conclusion, IA-2-Ab show a high diagnostic specificity for IDDM and are predictive markers of impending diabetes in siblings of patients. In combination with other molecular antibody assays they may replace ICA testing in future. Our data also indicate that other autoantibodies than IA-2-Ab, GAD 65 -Ab and IAA contribute to ICA. [Diabetologia (1997) GAD 65 -Ab, autoantibodies against the 65 kDa isoform of glutamic acid decarboxylase; IAA, insulin autoantibodies; PTPase, protein tyrosine phosphatase; IA-2ic, intracellular domain of IA-2; CTLA-4, cytotoxic T-lymphocyte associated protein-4; 5′INS, 5′flanking region of the insulin gene; ROC, receiveroperating characteristics. * See AcknowledgementsDuring the past few years, molecular cloning has identified a family of intracellular and transmembrane proteins with protein tyrosine phosphatase (PTPase)-activity which are believed to play a role in intracellular and intercellular signal transduction [1]. Two structurally related transmembrane PTPases, IA-2 (homologous to ICA512) and IA-2b, have recently been characterized as autoantigens in insulin-dependent diabetes mellitus (IDDM) [1]; they represent the precursor forms of the previously described 37/40 kDa tryptic fragments of islet cell membrane proteins which are re...

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To evaluate the effect of combined exercise training on metabolic control, physical fitness and quality of life in adolescents with type 1 diabetes. Design: A double-blind randomized controlled trial with patients receiving combined aerobic and strength or no training. Setting: University Hospital Ghent (Belgium). Subjects: Sixteen children with type 1 diabetes were randomized into a control group (n ¼ 8) and an intervention group (n ¼ 8). Interventions: Patients participated twice a week for 20 weeks in the combined aerobic and strength group. The control group continued their normal daily activities. Main measures: Before and after the intervention anthropometric variables (weight, length, BMI, body composition), metabolic control (glycaemia, HbA1c, daily insulin injected), aerobic capacity (peak Vo 2 , peak power, peak heart rate, 6-minute walk distance), strength (1 repetition maximum of upper and lower limb, hand grip strength, muscle fatigue resistance, sit-to-stand) and quality of life (SF-36) were assessed. Results: At baseline, none of the measured parameters differed significantly between the two groups. There was no significant evolution in the groups concerning anthropometric indices, glycaemia and HbA1c. However, the daily doses of insulin injected were significantly lowered in the training group (0.96 IU/kg.day pre versus 0.90 IU/kg.day post; P50,05), while it was increased in the control group. Physical fitness increased significantly in the training group. General health, vitality and role emotional had a tendency to improve. Conclusion: Combined exercise training seemed to lower daily insulin requirement and improve physical fitness, together with better well-being.

Context: Noonan syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. Short-term effect of GH therapy in NS is beneficial, reports on the effect on adult height are scarce. Objective: To determine the effect of long-term GH therapy in children with NS. Design: Twenty-nine children with NS were treated with GH until final height was reached. Setting: Hospital endocrinology departments. Patients: Children with the clinical diagnosis of NS, with mean age at the start of therapy of 11.0 years, 22 out of 27 tested children had a mutation in the protein tyrosine phosphatase, non-receptor-type 11 gene (PTPN11 gene). Interventions: GH was administered subcutaneously at 0.05 mg/kg per day until growth velocity was 1 cm/6 months. Main outcome measure: Linear growth (height) was measured at 3-month intervals in the first year and at 6-month intervals thereafter until final height. Results: At the start of treatment, median height SDS (H-SDS) was K2.8 (K4.1 to K1.8) and 0.0 (K1.4 to C1.2), based on national and Noonan standards respectively. GH therapy lasted for 3.0-10.3 years (median, 6.4), producing mean gains in H-SDS of C1.3 (C0.2 to C2.7) and C1.3 (K0.6 to C2.4), based on national and Noonan standards respectively. In 22 children with a mutation in PTPN11 mean gain in H-SDS for National standards was C1.3, not different from the mean gain in the five children without a mutation in PTPN11C1.3 (PZ0.98). Conclusion: Long-term GH treatment in NS leads to attainment of adult height within the normal range in most patients.

X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the PHEX gene lead to elevated levels of the hormone fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and impaired skeletal and dental mineralization. Recently, international guidelines for the diagnosis and treatment of this condition have been published. However, more specific recommendations are needed to provide guidance at the national level, considering resource availability and health economic aspects. A national multidisciplinary group of Belgian experts convened to discuss translation of international best available evidence into locally feasible consensus recommendations. Patients with XLH may present to a wide array of primary, secondary and tertiary care physicians, among whom awareness of the disease should be raised. XLH has a very broad differential-diagnosis for which clinical features, biochemical and genetic testing in centers of expertise are recommended. Optimal care requires a multidisciplinary approach, guided by an expert in metabolic bone diseases and involving (according to the individual patient’s needs) pediatric and adult medical specialties and paramedical caregivers, including but not limited to general practitioners, dentists, radiologists and orthopedic surgeons. In children with severe or refractory symptoms, FGF23 inhibition using burosumab may provide superior outcomes compared to conventional medical therapy with phosphate supplements and active vitamin D analogues. Burosumab has also demonstrated promising results in adults on certain clinical outcomes such as pseudofractures. In summary, this work outlines recommendations for clinicians and policymakers, with a vision for improving the diagnostic and therapeutic landscape for XLH patients in Belgium.