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Aim Screening for coeliac disease in asymptomatic children with new-onset type 1 diabetes is controversial. The aim of this study was to analyse whether the confirmation of coeliac disease in children with new-onset type 1 diabetes and positive screening results can be postponed. Methods This was a multicentre population-based cohort study based on the German/Austrian/Swiss/Luxembourgian Prospective Diabetes Follow-up Registry (Diabetes Patienten Verlaufsdokumentation [DPV]). Participants aged ≤18 years diagnosed with type 1 diabetes between 1995 and June 2021 and with elevated IgA tissue transglutaminase antibodies (anti-tTGA) at diabetes onset on screening for coeliac disease were included. We compared outcomes of participants with a diabetes duration of more than 1 year between those in whom coeliac disease was confirmed histologically within the first 6 months and those in whom coeliac disease was confirmed between 6 and 36 months after diabetes diagnosis. Results Of 92,278 children and adolescents with a diagnosis of type 1 diabetes, 26,952 (29.2%) had documented anti-tTGA data at diabetes onset. Of these, 2340 (8.7%) had an elevated anti-tTGA level. Individuals who screened positive were younger (median age 9.0 vs 9.8 years, pp1c levels (62.8 mmol/mol vs 62.2 mmol/mol [7.9% vs 7.8%]), cardiovascular risk markers (lipids, rate of microalbuminuria, blood pressure), rates of acute diabetes complications (diabetic ketoacidosis, severe hypoglycaemia) and the proportions of participants reaching anti-tTGA levels within the normal range did not differ between groups. Participants with delayed histological confirmation of coeliac disease showed no negative effects on growth or weight gain during the observation period. Conclusions Our study suggests that the histological confirmation of coeliac disease in asymptomatic individuals with new-onset type 1 diabetes could be postponed. Graphical abstract

To study diabetic cataract in type 1 diabetes in a large pediatric cohort.The 92,633 patients aged 0.5-21 years from German/Austrian multicenter diabetes registry (DPV) were analyzed. The 235 patients (0.25%) with diabetic cataract were found, 200 could be categorized: 67 with early cataract (3 months before diabetes onset - 12 months afterwards), 133 with late cataract (12 months after diabetes onset). Regression models adjusted for age and gender were used to compare clinical parameters at diabetes onset. Regression models for patients with late cataract were implemented for the total documentation period and additionally adjusted for diabetes duration.Rate of cataract development shows a peak at diabetes onset and declines with longer diabetes duration. Patients with cataract showed strong female preponderance. Patients developing early cataract were older at diabetes onset (12.8 years [11.8/13.9] vs. 8.9 [8.9/9.0]; p 0.001) and showed higher HbA1c than patients without cataract (9.0% [8.55/9.38] vs. 7.6% [7.60/7.61]; p 0.001). They had lower height-SDS, (-0.22 [-0.48/0.04] vs. 0.25 [0.24/0.26]; p 0.001), lower weight-SDS (-0.31 [-0.55/-0.08] vs. 0.21 [0.20/0.21]; p 0.001) and lower BMI-SDS (-0.25 [-0.49/-0.02] vs. 0.12 [0.12/0.13); p = 0.002). Patients with late cataract showed higher HbA1c at diabetes onset (8.35% [8.08/8.62] vs. 8.04% [8.03/8.05]; p = 0.023) and higher mean HbA1c during total documentation period (8.00% [7.62/8.34] vs. 7.62% [7.61/7.63]; p = 0.048).Our data confirm known demographic and clinical characteristics of patients developing early cataract. Hyperglycemia-induced osmotic damage to lens fibers at diabetes onset might be the main pathomechanism. Long term glycemic control is associated with cataract development.

Context Autoimmune diseases affect ~8% of the population. Type 1 diabetes mellitus (T1DM) is linked to other autoimmune diseases (AIDs), such as autoimmune thyroid disease or Addison’s disease (AD), that may impact diabetes therapy and outcome. Objective To analyze demographic and clinical characteristics of other AIDs in T1DM from a large standardized registry, the Prospective Diabetes Follow-up Registry (DPV). Methods We searched the registry for T1DM with the additional diagnosis of Hashimoto’s thyroiditis (HT), Graves’ disease (GD), and/or AD. T1DM with other AIDs (n = 6166, 5.4%) were compared with isolated T1DM (n = 107 457). For group comparisons, we used multivariable regression models with age, sex, diabetes duration, migration background, and type of insulin regimen as basic adjustments (microvascular endpoints: additionally adjusted for glycated hemoglobin). Results Patients with additional AIDs were more often female (54.7 vs 32.0%, P Conclusion T1DM with additional AIDs show heterogeneous differences compared with isolated T1DM. T1DM plus AD or HT requires more insulin. Further, the rate of neuropathy is higher in HT or GD, whereas the rate of microalbuminuria is lower.

BACKGROUND Medullary thyroid carcinomas (MTC) account for 3% to 5% of all thyroid cancers. In most cases, MTC is hereditary and occurs as part of the multiple endocrine neoplasia (MEN) type 2A and 2B syndromes. There is a strong genotype-phenotype correlation associated with the respective RET mutations, making risk-adapted management possible. PROCEDURE We report the prospectively collected data on children and adolescents of the multicenter nonrandomized German GPOH-MET registry. Children and adolescents with MTC and C-cell hyperplasia (CCH) were included. RESULTS From 1997 to June 2019, a total of 57 patients with MTC and 17 with CCH were reported. In patients with MTC, median follow-up was five years (range, 0-19) and median age at diagnosis 10 years (range, 0-17). Overall survival and event-free survival (EFS) were 87% and 52%, respectively. In total 96.4% of patients were affected by MEN2 syndromes, which was in 37/42 MEN2A and 3/28 MEN2B (M918T mutation) inherited. EFS in MEN2A was 78%, and in MEN2B 38% (P

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely performed in children and adolescents with hematologic diseases, including very high-risk leukemia. With increasing success and survival rates, the long-term sequelae of HSCT have become important. Here, we provide guidance to the prevention and treatment of the most common bone morbidities—osteoporosis and osteonecrosis—emerging in the context of HSCT in children and adolescents. We give an overview on definitions, symptoms, and diagnostics and propose an algorithm for clinical practice based on discussions within the International Berlin Frankfurt Munster (BFM) Stem Cell Transplantation Committee and the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, our expert knowledge, and a literature review.

IMPORTANCE: Public health screening for type 1 diabetes in its presymptomatic stages may reduce disease severity and burden on a population level. OBJECTIVE: To determine the prevalence of presymptomatic type 1 diabetes in children participating in a public health screening program for islet autoantibodies and the risk for progression to clinical diabetes. DESIGN, SETTING, AND PARTICIPANTS: Screening for islet autoantibodies was offered to children aged 1.75 to 5.99 years in Bavaria, Germany, between 2015 and 2019 by primary care pediatricians during well-baby visits. Families of children with multiple islet autoantibodies (presymptomatic type 1 diabetes) were invited to participate in a program of diabetes education, metabolic staging, assessment of psychological stress associated with diagnosis, and prospective follow-up for progression to clinical diabetes until July 31, 2019. EXPOSURES: Measurement of islet autoantibodies. MAIN OUTCOMES AND MEASURES: The primary outcome was presymptomatic type 1 diabetes, defined by 2 or more islet autoantibodies, with categorization into stages 1 (normoglycemia), 2 (dysglycemia), or 3 (clinical) type 1 diabetes. Secondary outcomes were the frequency of diabetic ketoacidosis and parental psychological stress, assessed by the Patient Health Questionnaire-9 (range, 0-27; higher scores indicate worse depression; ≤4 indicates no to minimal depression; >20 indicates severe depression). RESULTS: Of 90 632 children screened (median [interquartile range {IQR}] age, 3.1 [2.1-4.2] years; 48.5% girls), 280 (0.31%; 95% CI, 0.27-0.35) had presymptomatic type 1 diabetes, including 196 (0.22%) with stage 1, 17 (0.02%) with stage 2, 26 (0.03%) with stage 3, and 41 who were not staged. After a median (IQR) follow-up of 2.4 (1.0-3.2) years, another 36 children developed stage 3 type 1 diabetes. The 3-year cumulative risk for stage 3 type 1 diabetes in the 280 children with presymptomatic type 1 diabetes was 24.9% ([95% CI, 18.5%-30.7%]; 54 cases; annualized rate, 9.0%). Two children had diabetic ketoacidosis. Median (IQR) psychological stress scores were significantly increased at the time of metabolic staging in mothers of children with presymptomatic type 1 diabetes (3 [1-7]) compared with mothers of children without islet autoantibodies (2 [1-4]) (P = .002), but declined after 12 months of follow-up (2 [0-4]) (P

Objective To analyze the interrelationship of metabolic control, age- and sex-adjusted body mass index, and daily insulin dose and to identify heterogeneous multivariate developmental curves from childhood to young adulthood in a large cohort of children with type 1 diabetes (T1D) Study design Data were extracted from the diabetes follow-up registry DPV. Longitudinal data from 9239 participants with T1D age 8-18 years with diabetes duration ≥2 years and ≥5 years of follow-up were analyzed. We applied group-based multitrajectory modeling to identify latent groups of subjects following similar developmental curves across outcomes (hemoglobin A1c [HbA1c], age/sex-standardized body mass index [BMI-SDS], daily insulin dose per kg). Group number was based on Bayes information criterion and group size (≥5%). Results The group-based multitrajectory approach revealed 5 heterogeneous 3-variate trajectories during puberty. Individuals with stable good metabolic control, high-normal increasing BMI-SDS, and rising insulin dose patterns were classified as group 1 (33%). Group 2 (20%) comprised youths with intermediate-increasing HbA1c, low BMI-SDS, and steeply increasing insulin dose trajectories. Group 3 (11%) followed intermediate-rising HbA1c and high-normal increasing BMI-SDS developmental curves, while insulin dose increased steeply. In group 4 (14%), both high-increasing HbA1c and insulin dose trajectories were observed, while BMI-SDS was stable-normal. Group 5 (22%) included subjects with intermediate-rising HbA1c patterns, high-increasing BMI-SDS, and increasing insulin dose patterns. Conclusions This study identified 5 distinct 3-variate curves of HbA1c, BMI-SDS, and insulin dose during puberty among youths with T1D. This approach demonstrates a considerable heterogeneity highlighting the importance of personalized medical care.

Aside from clinical endpoints like height gain, health-related quality of life has also become an important outcome indicator in the medical field. However, the data on short stature and health-related quality of life is inconsistent. Therefore, we examined changes in health-related quality of life in German children with idiopathic growth hormone deficiency or children born small for gestational age before and after 12 months of human growth hormone treatment. Children with idiopathic short stature without treatment served as a comparison group. At baseline, health-related quality of life data of 154 patients with idiopathic growth hormone deficiency (n = 65), born small for gestational age (n = 58), and idiopathic short stature (n = 31) and one parent each was collected. Of these, 130 completed health-related quality of life assessments after 1-year of human growth hormone treatment. Outcome measures included the Quality of Life in Short Stature Youth questionnaire, as well as clinical and sociodemographic data. Our results showed that the physical, social, and emotional health-related quality of life of children treated with human growth hormone significantly increased, while untreated patients with idiopathic short stature reported a decrease in these domains. Along with this, a statistically significant increase in height in the treated group can be observed, while the slight increase in the untreated group was not significant. In conclusion, the results showed that human growth hormone treatment may have a positive effect not only on height but also in improving patient-reported health-related quality of life of children with idiopathic growth hormone deficiency and children born small for gestational age.

Aim Type 1 diabetes is the most common chronic metabolic disease in childhood. Often diagnosis comes with acutely life-threatening ketoacidosis and requires hospitalization. To avoid this, early detection of children at a pre-symptomatic stage is worthwhile. This task is met by a population-based screening in Bavaria, Germany – the Fr1da study. Here, we aim to evaluate the study concept, feasibility and medical evidence of the Fr1da study. Methods 308 pediatricians, 16 diabetes care centers and participating families were asked to evaluate the Fr1da study by completing questionnaires assessing study concept and feasibility, educational program and study organization. The assessment was done anonymously. In order to evaluate the effectiveness of the training the parents had to answer questionnaires to assess their knowledge about diabetes. Results 48% of pediatricians and 56% of pediatric diabetes care centers filled out the questionnaire. The majority positively judged the collaboration with the Fr1da coordinating center and the feasibility to integrate the project into daily routine. Medical evidence of the screening was recognized and most of the respondents endorsed the screening to be permanently integrated into standard care-program. The majority of parents would recommend the study to other parents with young children since they were satisfied with the collaboration with pediatricians, diabetes care centers and the coordinating center. Quality control of the educational program revealed good understanding of the teaching content. Conclusion The Fr1da study received high acceptance and recognition by both, health care providers and participating families, and demonstrated sustainable success with the developed educational program. &nbsp

Background: Although detection of children at high risk of developing type 1 diabetes and diagnosis of early stages is possible, up to now there exists no approved therapy to delay or prevent type 1 diabetes. Thus it is vital to develop evidence-based interventions. For this a sufficient number of trial participants is crucial but difficult to obtain especially in asymptomatic children. Aim: Identifying family characteristics that lead to or impede trial participation and analyze reasons stated by families for non-participation. Methods: Participants for the Fr1da Insulin Intervention study are recruited from the Fr1da study, a population based screening for early stage type 1 diabetes in Bavaria. Families with eligible children were invited to enroll. We analyzed sex and age of the child, distance of the family to the study center in Munich and the existence of a first degree family member with type 1 as possible influential factors for study participation. We also analyzed reasons stated by families who declined study participation in a phone interview. Results: Of 146 eligible children 77 (53%) were enrolled into the trial. None of the tested family characteristics differed significantly between the enrolling and the families not participating, but in general enrolling families lived closer to the study site than families not participating. This is also reflected in the reasons given by non-participating families. The most frequent reason stated were time restrictions. The second most frequent reason was the venous blood draw. Conclusion: The factors for non-participation identified in this project need be taken into account for the design of future trials in young children to ensure proper recruitment and thus to generate valid results for medical treatment of children. More research on the reason of participation and non-participation in clinical trials is needed. Keywords: Type 1 diabetes, Trial recruitment, Trial enrollment, Infants, Children, Asymptomatic

Intrauterine and postnatal longitudinal growth is controlled by a strong genetic component that regulates a complex network of endocrine factors integrating them with cellular proliferation, differentiation and apoptotic processes in target tissues, particularly the growth centers of the long bones. Here we report on a patient born small for gestational age (SGA) with severe, proportionate postnatal growth retardation, discreet signs of skeletal dysplasia, microcephaly and moyamoya disease. Initial genetic evaluation revealed a novel heterozygous IGF1R p.Leu1361Arg mutation affecting a highly conserved residue with the insulin-like growth factor type 1 receptor suggestive for a disturbance within the somatotropic axis. However, because the mutation did not co-segregate with the phenotype and functional characterization did not reveal an obvious impairment of the ligand depending major IGF1R signaling capabilities a second-site mutation was assumed. Mutational screening of components of the somatotropic axis, constituents of the IGF signaling system and factors involved in cellular proliferation, which are described or suggested to provoke syndromic dwarfism phenotypes, was performed. Two compound heterozygous PCNT mutations (p.[Arg585X];[Glu1774X]) were identified leading to the specification of the diagnosis to MOPD II. These investigations underline the need for careful assessment of all available information to derive a firm diagnosis from a sequence aberration.

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune genetic disorder caused by mutation of the forkhead box protein 3 gene (FOXP3), a key regulator of immune tolerance. OBJECTIVE: We sought to provide clinical and molecular indicators that facilitate the understanding and diagnosis of IPEX syndrome. METHODS: In 14 unrelated affected male subjects who were given diagnoses of IPEX syndrome based on FOXP3 gene sequencing, we determined whether particular FOXP3 mutations affected FOXP3 protein expression and correlated the molecular and clinical data. RESULTS: Molecular analysis of FOXP3 in the 14 subjects revealed 13 missense and splice-site mutations, including 7 novel mutations. Enteropathy, generally associated with endocrinopathy and eczema, was reported in all patients, particularly in those carrying mutations within FOXP3 functional domains or mutations that altered protein expression. However, similar genotypes did not always result in similar phenotypes in terms of disease presentation and severity. In addition, FOXP3 protein expression did not correlate with disease severity. CONCLUSION: Severe autoimmune enteropathy, which is often associated with increased IgE levels and eosinophilia, is the most prominent early manifestation of IPEX syndrome. Nevertheless, the disease course is variable and somewhat unpredictable. Therefore genetic analysis of FOXP3 should always be performed to ensure an accurate diagnosis, and FOXP3 protein expression analysis should not be the only diagnostic tool for IPEX syndrome. OI RONCAROLO, Maria Grazia/0000-0002-2193-9186 ZS 1 ZR 2 ZB 47 Z8 7