Neutrophil Extracellular Trap Induced Dendritic Cell Activation Leads to Th1 Polarization in Type 1 Diabetes

Neutrophils releasing neutrophil extracellular traps (NETs) infiltrate the pancreas prior to type 1 diabetes (T1D) onset; however, the precise nature of their contribution to disease remains poorly defined. To examine how NETs affect immune functions in T1D, we investigated NET composition and their effect on dendritic cells (DCs) and T lymphocytes in T1D children. We showed that T1D patient NET composition differs substantially from that of healthy donors and that the presence of T1D-NETs in a mixed peripheral blood mononuclear cell culture caused a strong shift toward IFNγ-producing T lymphocytes, mediated through activation of innate immunity cells in T1D samples. Importantly, in a monocyte-derived DC (moDC) culture, NETs induced cytokine production, phenotypic change and IFNγ-producing T cells only in samples from T1D patients but not in those from healthy donors. RNA-seq analysis revealed that T1D-NETs presence causes TGFβ downregulation and IFNα upregulation and creates pro-T1D signature in healthy moDCs

Anophthalmia, hearing loss, abnormal pituitary development and response to growth hormone therapy in three children with microdeletions of 14q22q23

BACKGROUND: Microdeletions of 14q22q23 have been associated with eye abnormalities and pituitary defects. Other phenotypic features in deletion carriers including hearing loss and response to growth hormone therapy are less well recognized. We studied genotype and phenotype of three newly identified children with 14q22q23 deletions, two girls and one boy with bilateral anophthalmia, and compared them with previously published deletion patients and individuals with intragenic defects in genes residing in the region. RESULTS: The three deletions were de novo and ranged in size between 5.8 and 8.9 Mb. All three children lacked one copy of the OTX2 gene and in one of them the deletion involved also the BMP4 gene. All three patients presented partial conductive hearing loss which tended to improve with age. Analysis of endocrine and growth phenotypes showed undetectable anterior pituitary, growth hormone deficiency and progressive growth retardation in all three patients. Growth hormone therapy led to partial catch-up growth in two of the three patients but just prevented further height loss in the third. CONCLUSIONS: The pituitary hypoplasia, growth hormone deficiency and growth retardation associated with 14q22q23 microdeletions are very remarkable, and the latter appears to have an atypical response to growth hormone therapy in some of the cases

Clinical Heterogeneity in Patients With FOXP3 Mutations Presenting With Permanent Neonatal Diabetes

OBJECTIVE—Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM)

Analysis of children with familial short stature: who should be indicated for genetic testing?

Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤−2 SD in child and his/her shorter parent); secondary short stature and Turner/Prader–Willi syndrome were excluded criteria. Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by American College of Medical Genetics and Genomics (ACMG) guidelines. Nonparametric tests ev aluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) c hildren. Of these, 29 (81%) carried a causative genetic variant affecting the growth p late, 4 (11%) a variant affecting GH–insulin-like growth factor 1 (IGF1) axis and 3 (8%) a variant in miscellaneous genes. Lower shorter parent’s height (P = 0.015) and less delayed bone age (BA) before GH treatment (P = 0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent’s heights ≤−2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH , a monogenic etiology is frequent, and gene variants affecting the growth plate are th e most common. Shorter parent’s height and BA are clinical predictors of monogenic FSS

Temporal trends in diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes between 2006 and 2016: results from 13 countries in three continents

Aims/hypothesis The aim of this work was to evaluate geographical variability and trends in the prevalence of diabetic ketoacidosis (DKA), between 2006 and 2016, at the diagnosis of childhood-onset type 1 diabetes in 13 countries over three continents. Methods An international retrospective study on DKA at diagnosis of diabetes was conducted. Data on age, sex, date of diabetes diagnosis, ethnic minority status and presence of DKA at diabetes onset were obtained from Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA and the UK (Wales). Mean prevalence was estimated for the entire period, both overall and by country, adjusted for sex and age group. Temporal trends in annual prevalence of DKA were estimated using logistic regression analysis for each country, before and after adjustment for sex, age group and ethnic minority status. Results During the study period, new-onset type 1 diabetes was diagnosed in 59,000 children (median age [interquartile range], 9.0 years [5.5–11.7]; male sex, 52.9%). The overall adjusted DKA prevalence was 29.9%, with the lowest prevalence in Sweden and Denmark and the highest in Luxembourg and Italy. The adjusted DKA prevalence significantly increased over time in Australia, Germany and the USA while it decreased in Italy. Preschool children, adolescents and children from ethnic minority groups were at highest risk of DKA at diabetes diagnosis in most countries. A significantly higher risk was also found for females in Denmark, Germany and Slovenia. Conclusions/interpretation DKA prevalence at type 1 diabetes diagnosis varied considerably across countries, albeit it was generally high and showed a slight increase between 2006 and 2016. Increased awareness of symptoms to prevent delay in diagnosis is warranted, especially in preschool children, adolescents and children from ethnic minority groups

Bone geometry and volumetric bone mineral density in girls with Turner syndrome of different pubertal stages

Objective An increased rate of fractures has been reported in patients with Turner syndrome (TS). We aimed to assess bone geometry and volumetric bone mineral density (vBMD) at the radius in girls with TS and to evaluate the relationships between bone parameters and fracture history. Methods and design Sixty-seven girls with TS aged 6âÂÂ19 years treated currently or in the past with growth hormone (GH) and/or oestrogens were examined using peripheral quantitative computed tomography. Results were compared to reference data. Results Cortical area and cortical thickness were low in all age groups (all P < 0.001). Height-adjusted total bone area at the diaphysis was increased in prepubertal and postpubertal girls (mean Z-score 1.0, P < 0.05 for both) and normal in the pubertal group (mean Z-score 0.1). Cortical vBMD was decreased (mean age-specific Z-scores )2.0, )1ÃÂ6 and )1.0 for prepubertal, pubertal and postpubertal groups, respectively, P < 0.01 for all groups). Height- , age- and cortical thickness-adjusted cortical vBMD was positively correlated to the duration of GH therapy (P = 0.012) and to oestrogen administration (P = 0.047). Girls with a history of fractures had lower total vBMD at the metaphysis compared to nonfractured TS girls (mean Z-scores )1.7 vs )0.9, P = 0.04). Conclusions There is a cortical bone deficit in girls with TS characterized by low cortical area, thin cortex and probably decreased cortical vBMD. Early commencement of GH therapy, as well as oestrogen replacement, is associated with higher cortical vBMD. Further studies should investigate the potential causality of this relation

A 6-Year Follow-Up of Fracture Incidence and Volumetric Bone Mineral Density Development in Girls With Turner Syndrome

Context: Patients with Turner syndrome (TS) are at risk for osteoporotic fractures. Objective: The aims of this study were to assess the incidence of clinically important fractures in girls with TS and prospectively describe the development of volumetric bone mineral density (BMD). Design: Peripheral quantitative computerized tomography (pQCT) of the radius every other year over the 6 years of observation. Setting: Government-funded university referral center. Participants: Thirty-two girls with TS, aged 6 to 16 years, were included in the analyses. Fracture incidence was compared with the data in the general population. Bone density and strength were compared with data from 185 healthy girls. Outcomes: The main clinical outcome was the fracture occurrence. The secondary outcomes were the changes in Z-scores of the bone parameters. Results: Three girls with TS sustained four fractures during 6 years of observation. The fracture rate in TS was not substantially higher than the downward-biased fracture-rate estimate from age-matched, healthy controls (P = 0.48). Whereas the trabecular BMD Z-score decreased with age (beta estimate -0.21 +/- 0.04, P < 0.001), total bone cross-sectional area correspondingly increased (+ 0.16 +/- 0.04, P < 0.001), which led to normal bone strength. A positive history of incident fractures was not significantly associated with any of the pQCT-derived bone parameters. Conclusions: Current pediatric TS patients that are treated with growth hormone and estrogens are not at risk for osteoporotic fractures. Low BMD in TS may be counterweighted by enlarged bone radius, which leads to normal bone strength at the appendicular skeleton

Increase in lumbar spine but not distal radius bone mineral density in adults after pancreas kidney transplantation

Osteoporosis occurs in every third individual after simultaneous pancreas kidney transplantation (SPKT). Currently used bone measures insufficiently predict their fracture risk. Lumbar spine Trabecular bone score (TBS) and distal radius areal and volumetric bone mineral density (BMD) were monitored for the first time in patients with type 1 diabetes and chronic renal failure after SPKT with steroid-sparing protocol. In 33 subjects (mean age 43.4 ± 9.8 years), dual-energy X-ray absorptiometry and peripheral quantitative computed tomography were performed just after SPKT (baseline) and one and three years later. While TBS Z-scores increased (−1.1 ± 1.2 and −0.3 ± 1.0; p˂0.001, at baseline and year three, respectively), trabecular volumetric BMD Z-scores at distal radius metaphysis did not change during the study (−1.3 ± 1.3 and −1.3 ± 1.0; p = 0.38). Similarly, areal BMD Z-scores increased at lumbar spine, total hip and femoral neck (all p < 0.01), but not at the distal radius. SPKT induced bone measures' improvement at lumbar spine and hip but not at distal radius. Before suggesting changes in current clinical care, predictive value of individual bone measures or its combination for fracture risk assessment remains to be elucidated

Harmonize care to optimize outcome in children and adolescents with diabetes mellitus: treatment recommendations in Europe.

OBJECTIVE: Identify and evaluate current treatment recommendations in Europe for the care of children with diabetes in view of the European Union (EU) recommendations for Reference Centers. METHODS: A questionnaire was sent in 2008 to representatives of all EU countries and Norway, all known to be actively involved in pediatric diabetes care. Participants were asked whether specific guidelines were recommended and applied in their countries; when possible, they were invited to forward their national guidelines. As a second step, we evaluated the guideline mostly used in relationship to the recommendations of the EU. RESULTS: Information was obtained from all EU countries (including Scotland and Norway). National guidelines, as available, were forwarded for review. A 15/29 reported to use the International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines (CPCG), whereas 10 reported using national guidelines. These national guidelines were partly based on and/or compatible with ISPAD guidelines, but in most cases were far less detailed. The size and presentation differed (web based, booklet, page or chapter in adult guidelines). In four countries, no specific guidelines were used. As ISPAD CPCG were used most frequently, its content was evaluated within the EU Centres of Reference recommendations and minor changes were made in agreement with the ISPAD editor. DISCUSSION: Differences between guidelines may influence surveillance and quality of care in pediatric diabetes within Europe. Although a majority of countries is using or at least mentioning the ISPAD CPCG, their implementation as EU standard needs further endorsement. As language difficulties may hamper its implementation on a wider scale, further translation of the ISPAD guidelines should be endorsed to render it accessible to all healthcare professionals. With respect to the content, some changes were then made in agreement with the editors, adjusting them to the European context. For European Reference Centers, some further guidance on research may be included. Once implemented on an EU wide level, benchmarking of carefully defined robust quality of care and quality of life indicators will allow us to improve these guidelines on a regular basis ensuring an evidence-based care for all children with diabetes