Tilman Rohrer

Delayed pubertal onset and development in German children and adolescents with type 1 diabetes: cross-sectional analysis of recent data from the DPV diabetes documentation and quality management system

OBJECTIVEnTo investigate the effect of type 1 diabetes on pubertal onset and development, and to identify factors potentially affecting puberty, including glycemic control, relative diabetes duration, body mass index standard delta score (BMI SDS), insulin dose, and intensity of insulin therapy.nnnRESEARCH DESIGN AND METHODSnInitiated in 1990, the Diabetes-Patienten-Verlaufsdaten (DPV) is an ongoing, prospective longitudinal follow-up program to benchmark the quality of diabetes care provided to, predominantly, pediatric patients. Data collection for this non-interventional audit was carried out at 202 German diabetes treatment centers. Patient recruitment was done by referral, clinic/hospital ascertainment, or self-report. Data were analyzed for subcohorts of 1218-2409 boys and 579-2640 girls from a cohort of 24 385 pediatric type 1 diabetic patients. Selection was based on ethnicity and availability of data on Tanner stage 2, or higher, of genital and pubic hair development (boys) or breast and pubic hair development, and menarche (girls).nnnRESULTSnBoys showed significant (P<0.05) delay (years) in mean ages at onset of genital development (12.0 (+/-0.9) years) and pubarche (12.2 (+/-0.4) years). In girls, mean ages at thelarche (11.4 (+/-0.5) years), pubarche (11.5 (+/-0.1) years), and menarche (13.2 (+/-0.5) years) were significantly delayed compared with the general population. Sexual maturity (Tanner stage 5) was not delayed in either sex. Elevated glycohemoglobin and decreased BMI SDS were associated with significantly delayed pubertal onset, whereas relative diabetes duration and insulin dose were not.nnnCONCLUSIONSnPubertal onset, but not sexual maturity, is delayed in children with type 1 diabetes. Delay increases with higher glycohemoglobin and lower BMI SDS.

Influence of food intake, age, gender, HbA1c, and BMI levels on plasma cholesterol in 29,979 children and adolescents with type 1 diabetes--reference data from the German diabetes documentation and quality management system (DPV).

Objective:u2002 We investigated influences of a 12‐h fast, age, gender, body mass index (BMI), hemoglobin A1c (HbA1c) on total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C), and high‐density lipoprotein cholesterol (HDL‐C) to provide reference percentiles for TC, LDL‐C, and HDL‐C of patients with good diabetes control (HbA1cu2003<u20037.5%) and normal weight (BMIu2003<u200390th percentile).

Microvascular Complications in Childhood-Onset Type 1 Diabetes and Celiac Disease: A Multicenter Longitudinal Analysis of 56,514 Patients From the German-Austrian DPV Database

OBJECTIVE To investigate whether celiac disease (CD) associated with type 1 diabetes increases the risk of microvascular complications. RESEARCH DESIGN AND METHODS Patients (n = 56,514) aged >10 years with diabetes duration <20 years from 392 centers in Germany and Austria were assigned to one of three categories (n): no CD (50,933), biopsy-confirmed CD (812), or suspected CD (4,769; clinical diagnosis or positive antibodies). The confirmed and suspected groups were combined and analyzed for retinopathy or nephropathy. Cox proportional hazards regression was used to adjust for potential confounders (glycated hemoglobin [HbA1c], age at diabetes onset, sex, smoking, dyslipidemia, and hypertension). RESULTS Kaplan-Meier analysis revealed that retinopathy and nephropathy occurred earlier in the presence versus absence of CD: retinopathy at age 26.7 years (95% CI 23.7–30.2) in 25% of patients with CD vs. age 33.7 years (33.2–34.4) in 25% without CD and microalbuminuria at age 32.8 years (29.7–42.5) vs. 42.4 years (41.4–43.3). The adjusted risk for both retinopathy (hazard ratio 1.263 [95% CI 1.078–1.481]) and nephropathy (1.359 [1.228–1.504]) was higher in patients with diabetes and CD versus those without CD. Cox regression revealed CD as an independent risk factor for microvascular complications after adjustment for confounders. CONCLUSIONS CD is an independent risk factor for retinopathy and nephropathy in patients with type 1 diabetes. Our study therefore supports the recommendation for regular serologic testing for CD, even in the absence of clinical CD. Further prospective studies are required to investigate whether a gluten-free diet might reduce the risk of microvascular disorders in patients with diabetes and CD.

Growth in Children and Adolescents with Type 1 Diabetes

OBJECTIVEnTo investigate the effect of type 1 diabetes on growth and adult height.nnnSTUDY DESIGNnData from 22 651 children (10 494 females) with type 1 diabetes documented at onset of the disease from specialized centers in Germany and Austria were analyzed. Patients of non-German and non-Austrian origin and patients with celiac disease were excluded from the analysis. Near-adult height data were available in 1685 patients.nnnRESULTSnAt the time of diagnosis of type 1 diabetes, the mean age of the 22 651 children was 8.8 ± 4.2 years, with a mean height SDS of 0.22 ± 1.0. The 1685 patients with diabetes onset before age 11 years reached a mean adult height of -0.16 ± 1.0 SDS. Mean adult height was was 167.1 ± 6.2 cm (-0.16 ± 0.97 SDS) in females (n = 846) and 179.6 ± 7.1 cm (-0.17 ± 1.0 SDS) in males (n = 839). Mean duration of diabetes was 9.1 ± 2.6 years, and mean Hemoglobin A1c concentration was 7.9% ± 1.2% (63 ± 10 mmol/mol). In a multivariate regression model, adult height was positively correlated with height at onset of diabetes (P < .0001) and negatively with mean Hemoglobin A1c (P < .0001) and duration of diabetes (P = .0015).nnnCONCLUSIONnHeight at the time of diagnosis of type 1 diabetes is above average. Even with intensive insulin therapy, growth and adult height remain indicators of metabolic diabetes control in the 21st century.

Differential diagnosis in patients with suspected bile acid synthesis defects

AIMnTo investigate the clinical presentations associated with bile acid synthesis defects and to describe identification of individual disorders and diagnostic pitfalls.nnnMETHODSnAuthors describe semiquantitative determination of 16 urinary bile acid metabolites by electrospray ionization-tandem mass spectrometry. Sample preparation was performed by solid-phase extraction. The total analysis time was 2 min per sample. Authors determined bile acid metabolites in 363 patients with suspected defects in bile acid metabolism.nnnRESULTSnAbnormal bile acid metabolites were found in 36 patients. Two patients had bile acid synthesis defects but presented with atypical presentations. In 2 other patients who were later shown to be affected by biliary atresia and cystic fibrosis the profile of bile acid metabolites was initially suggestive of a bile acid synthesis defect. Three adult patients suffered from cerebrotendinous xanthomatosis. Nineteen patients had peroxisomal disorders, and 10 patients had cholestatic hepatopathy of other cause.nnnCONCLUSIONnScreening for urinary cholanoids should be done in every infant with cholestatic hepatopathy as well as in children with progressive neurological disease to provide specific therapy.

Altered Phenotype and Functionality of Varicella Zoster Virus–Specific Cellular Immunity in Individuals With Active Infection

BACKGROUNDnVaricella zoster virus (VZV) establishes lifelong persistence and may reactivate in individuals with impaired immune function. To investigate immunologic correlates of protection and VZV reactivation, we characterized specific immunity in 207 nonsymptomatic immunocompetent and 132 immunocompromised individuals in comparison with patients with acute herpes zoster.nnnMETHODSnVZV-specific CD4 T cells were quantified flow cytometrically after stimulation and characterized for expression of interferon-γ, interleukin 2, and tumor necrosis factor α and surface markers for differentiation (CD127) and anergy (cytotoxic T lymphocyte antigen 4 [CTLA-4] and programmed death [PD]-1). Immunoglobulin G and A levels were quantified using an enzyme-linked immunosorbent assay.nnnRESULTSnIn healthy individuals, VZV-specific antibody and T-cell levels were age dependent, with the highest median VZV-specific CD4 T-cell frequencies of 0.108% (interquartile range, 0.121%) during adolescence. VZV-specific T-cell profiles were multifunctional with predominant expression of all 3 cytokines, CD127 positivity, and low expression of CTLA-4 and PD-1. Nonsymptomatic immunocompromised patients had similar VZV-specific immunologic properties except for lower T-cell frequencies (P<.001) and restricted cytokine expression. In contrast, significantly elevated antibody- and VZV-specific CD4 T-cell levels were found in patients with zoster. Their specific T cells showed a shift in cytokine expression toward interferon γ single positivity, an increase in CTLA-4 and PD-1, and a decrease in CD127 expression (all P<.001). This phenotype normalized after resolution of symptoms.nnnCONCLUSIONSnVZV-specific CD4-T cells in patients with zoster bear typical features of anergy. This phenotype is reversible and may serve as adjunct tool for monitoring VZV reactivations in high-risk patients.

Intuitiveness, ease of use, and preference of a prefilled growth hormone injection pen: a noninterventional, randomized, open-label, crossover, comparative usability study of three delivery devices in growth hormone-treated pediatric patients.

BACKGROUNDnGrowth hormone (GH) is used to treat pediatric and adult GH deficiency (GHD) and growth failure in, among others, patients with Turner syndrome or children born small for gestational age. To improve treatment adherence, self-injection devices should be easy to learn, easy to use, and well accepted, especially in pediatric patients. Several GH pen devices are available, each with distinct features designed for specific patient needs.nnnOBJECTIVESnThis study compared injection time and intuitiveness of a prefilled test injection device (Norditropin FlexPro, Novo Nordisk A/S, Bagsværd, Denmark) with those of 2 commercially available durable injection devices (easypod, Merck Serono SA, Geneva, Switzerland; and Genotropin, Pfizer Inc, New York, New York) in GH-treated pediatric patients. Dose accuracy, application errors, intuitiveness, usability, device features, ease of learning, ease of use, and overall preference were also assessed.nnnMETHODSnThis noninterventional, randomized, open-label, crossover study enrolled patients aged ≥10 to <18 years who were diagnosed with GHD or Turner syndrome or were born small for gestational age. Patients were allocated to an intuitiveness group (without instruction) or an instruction group and assigned to 1 of 3 sequences of device testing. For each device, time taken to deliver a mock injection of test medium (FlexPro) or GH (easypod and Genotropin) into an Eppendorf tube and the delivered dose were measured. Dose accuracy and application errors were assessed by a health care professional. Patients assessed the intuitiveness (intuitiveness group only), device features, ease of learning, ease of use, and overall preference of the devices using questionnaires.nnnRESULTSnIncluded in the study were 56 patients (mean [SD] age, 13.6 [2.1] years; 63% male; GHD, 44 patients; Turner syndrome, 3; born small for gestational age, 9): 30 in the intuitiveness group and 26 in the instruction group. In the intuitiveness group, the mean (SD) mock injection time was significantly shorter with FlexPro (47.0 [49.0] seconds) than with the easypod (219.2 [72.6] seconds; P < 0.001) or the Genotropin pen (95.1 [78.4] seconds; P < 0.01). In the instruction group, injection time was also shortest with FlexPro (30.7 [10.8] seconds vs 59.6 [13.1] with easypod and 40.7 [18.6] with the Genotropin pen; both, P < 0.001). Most patients (70%) ranked FlexPro as the most intuitive device (easypod, 0%; Genotropin, 30%). In both the intuitiveness and instruction groups, a significantly greater proportion of patients considered FlexPro easiest to learn compared with the easypod and Genotropin devices (both, P < 0.001), although more patients preferred the easypod or Genotropin devices than FlexPro with regard to appearance (intuitiveness group: FlexPro, 8 patients; easypod, 9; and Genotropin, 13; instruction group: FlexPro, 4; easypod, 10; and Genotropin, 12) and quality (intuitiveness group: FlexPro, 6 patients; easypod, 10; and Genotropin, 14; instruction group: FlexPro, 8; easypod, 12; and Genotropin, 6), and easy- pods delivery feedback feature was preferred by more patients (intuitiveness group: FlexPro, 8 patients; easypod, 14; Genotropin, 8; instruction group: FlexPro, 8; easypod, 14; and Genotropin, 4). Dose accuracies (as assessed by weighing the delivered dose and calculating variation in the delivered dose by device) were 4.6% with FlexPro, 14.6% with easypod, and 20.6% with the Genotropin pen in the intuitiveness group, and 2.7% with FlexPro, 5.8% with easypod, and 24.4% with the Genotropin pen in the instruction group.nnnCONCLUSIONnIn this study, Norditropin FlexPro was associated with shorter injection times, higher dose accuracy, and greater intuitiveness, and was rated as easier to learn compared with the easypod and Genotropin devices.

Down’s syndrome in diabetic patients aged <20 years: an analysis of metabolic status, glycaemic control and autoimmunity in comparison with type 1 diabetes

Aims/hypothesisIntellectual impairment in individuals with Down’s syndrome and diabetes mellitus potentially limits the quality of diabetic control. In addition, these patients are at risk of having immunological abnormalities. The present study compared metabolic status and concomitant diseases in young (<20xa0years old) Down’s syndrome patients with diabetes vs young type 1 diabetic patients.MethodsThe Diabetes-Patienten-Verlaufsdaten is a longitudinal follow-up database, which collects data from 298 German and Austrian diabetes centres. Data available on diabetic patients aged <20xa0years were analysed statistically.ResultsWe compared data for 159 Down’s syndrome patients with diabetes and 41,983 type 1 diabetic patients. The former used less insulin, but showed better glycaemic control (HbA1c). Diabetes onset during the first 3xa0years of life occurred in 18.9% of Down’s syndrome patients with diabetes and in 6.4% of type 1 diabetic patients. Antibody titres indicative of coeliac disease and thyroid peroxidase antibodies were more frequent in Down’s syndrome patients with diabetes. No significant differences were found regarding the beta cell autoantibodies studied.Conclusions/interpretationThe age-of-onset distribution showed a shift towards younger ages and was bimodal in the Down’s syndrome group. The better metabolic control found, despite intellectual impairment, in young Down’s syndrome patients with diabetes cannot be conclusively explained by our data, but is likely to be due to a less complex lifestyle. Our data provide further confirmation that coeliac and thyroid antibodies are more prevalent in Down’s syndrome. The presence of beta cell autoantibodies supports an autoimmune cause of diabetes in some children with Down’s syndrome.

Growth hormone therapy and the risk of tumor recurrence after brain tumor treatment in children.

ABSTRACT To assess the effect of human growth hormone (hGH) therapy and other factors on tumor recurrence after treatment of pediatric brain tumors (BTs), we retrospectively analyzed data from 108 craniopharyngioma, medulloblastoma, and ependymoma patients. Risk factors were identified using multifactorial univariate regression analysis. Recurrences occurred in 41 and second malignant neoplasms in 4 patients. There were significant correlations for completeness of tumor removal and recurrence-free survival (RFS). 13/44 hGH-treated and 28/59 non-hGH-treated children relapsed. This difference was found only for medulloblastomas and accounted for by higher rates of incomplete tumor removal in non-hGH patients. Craniopharyngioma recurrence correlated only with RFS. Malignant BT recurrence correlated with completeness of tumor removal, chemotherapy, and RFS. 4 children developed SMNs, 3/4 after hGH therapy. Our regression model yielded accurate within-sample prediction of recurrence for 90% of the study population. We conclude that hGH therapy after treatment of pediatric BTs does not increase tumor recurrence risk.

Delayed menarche in young German women with type 1 diabetes mellitus: recent results from the DPV diabetes documentation and quality management system

BackgroundFindings have been inconsistent regarding the effect of T1DM (type 1 diabetes) on age at menarche.ObjectiveThe purpose was to investigate in young German women with T1DM menarcheal age and factors potentially affecting menarche, including glycemic control, BMI (body mass index), relative T1DM duration (proportion of life with diabetes), insulin dose, and insulin therapy intensity. Initiated in 1990, the DPV program is an ongoing, prospective long-term longitudinal follow-up study to benchmark the quality of care provided to pediatric and, more recently, adult diabetes patients. Two hundered two German diabetes centers participated in nationwide data collection. Based on ethnicity and the availability of menarche and T1DM onset data as the main inclusion criteria, 643 young German women were selected from 11,629 female T1DM patients aged <20xa0years, recruited by referral, clinic or hospital ascertainment, or self report. Mean age at menarche (±SD) was 13.22u2009±u20091.31xa0years, representing a delay of 0.52xa0years (pu2009<u20090.001) relative to the general population. Significant delay (pu2009<u20090.05) was also found for relative T1DM duration, BMI SD score, insulin dose, and HbA1c level, with a 1% increase in HbA1c resulting in a delay in menarche by 0.07xa0years.ConclusionsAge at menarche is delayed in type 1 diabetes mellitus. The delay increases with relative T1DM duration and poor quality of glycemic control.