Spectrum of diabetes mellitus in patients with Shwachman-Diamond syndrome: case report and review of the literature.

BACKGROUND: Shwachman-Diamond syndrome (SDS) is a rare congenital disorder caused by mutations in the SBDS gene and characterized by exocrine pancreatic deficiency, hematologic dysfunction, and skeletal growth failure. Although the hematologic features and characteristics of the somatic disorders commonly associated with SDS are well known, emerging data from case reports and patient registries suggest that SDS may also be associated with an increased risk of diabetes mellitus. However, currently available data on SDS-associated diabetes are limited and do not allow conclusions regarding prevalence and incidence rates, clinical course, and outcomes. CASE PRESENTATION: Here we report the case of a 5-year-old girl with SDS who underwent bone marrow transplantation at the age of 3 months and developed autoantibody-positive type 1 diabetes mellitus at the age of 1.8 years. The manifestation and course of diabetes development were mild, complicated by concurrent spontaneous episodes of hypoglycemia even before the onset of antidiabetic treatment. Currently, adequate metabolic control can be achieved by dietary intervention. CONCLUSIONS: Considering that the SBDS protein regulates mitosis and ribosomal biosynthesis and that its suppression may cause immunologic instability and chronic inflammation, this case provides insight into the phenotype of rare Shwachman-Diamond syndrome-associated diabetes mellitus, which may be characterized by significant age-dependent differences in clinical course.

Is COVID-19 to Blame? Trends of Incidence and Sex Ratio in Youth-Onset Type 2 Diabetes in Germany.

OBJECTIVE: We investigated the incidence of pediatric type 2 diabetes (T2D) in Germany during 2 years of the coronavirus disease 2019 (COVID-19) pandemic (2020-2021) compared with the control period 2011-2019. RESEARCH DESIGN AND METHODS: Data on T2D in children (aged 6 to <18 years) were obtained from the DPV (German Diabetes Prospective Follow-up) Registry. Poisson regression was used to estimate incidences for 2020 and 2021 based on data from 2011 to 2019, and these were compared with observed incidences in 2020 and 2021 by estimating incidence rate ratios (IRRs) with 95% CIs. RESULTS: Incidence of youth-onset T2D increased from 0.75 per 100,000 patient-years (PYs) in 2011 (95% CI 0.58, 0.93) to 1.25 per 100,000 PYs in 2019 (95% CI 1.02, 1.48), an annual increase of 6.8% (95% CI 4.1, 9.6). In 2020, T2D incidence increased to 1.49 per 100,000 PYs (95% CI 1.23, 1.81), which was not significantly higher than predicted (IRR 1.15; 95% CI 0.90, 1.48). In 2021, the observed incidence was significantly higher than expected (1.95; 95% CI 1.65, 2.31 vs. 1.38; 95% CI 1.13, 1.69 per 100,000 PYs; IRR 1.41; 95% CI 1.12, 1.77). Although there was no significant increase in incidence in girls in 2021, the observed incidence in boys (2.16; 95% CI 1.73, 2.70 per 100,000 PYs) significantly exceeded the predicted rate (IRR 1.55; 95% CI 1.14, 2.12), leading to a reversal of the sex ratio of pediatric T2D incidence. CONCLUSIONS: In Germany, incidence of pediatric T2D increased significantly in 2021. Adolescent boys were more affected by this increase, resulting in a reversal of the sex ratio of youth-onset T2D.

Could setmelanotide be the game-changer for acquired hypothalamic obesity?

Children with acquired hypothalamic obesity, e.g. following treatment for pediatric craniopharyngioma are at great risk for metabolic syndrome, cardiovascular health problems and premature mortality. Treatment for acquired hypothalamic obesity has thus far been disappointing. Several interventions were reported to be partially successful, including dextro-amphetamine and GLP-1R agonists, although results in acquired hypothalamic obesity are conflicting. Disruption of signaling through the melanocortin-4 receptor (MC4R) pathway results in hyperphagia and severe early-onset hypothalamic obesity. Recently, the MC4R agonist setmelanotide has shown promising results in children with genetic forms of hypothalamic obesity; POMC, PCSK1 and LEPR. Patient quotes such as "we have our family life back" illustrate the magnitude of the effect. Targeted hormone replacement therapy with a MC4R agonist for acquired hypothalamic obesity could be a game-changer. Preliminary results of setmelanotide treatment in 14, mostly pediatric, patients with acquired hypothalamic obesity are promising. The FDA has recommended that a prospective, randomized, blinded trial be conducted over a 12 months treatment period, comparable to pivotal trials for other obesity drugs. It may be discussed whether setmelanotide should be regarded as an obesity drug or whether it may be envisioned as an agent for hypothalamic substitution therapy. In this commentary we discuss the trial that is currently recruiting patients with acquired hypothalamic obesity.

Lower Circulating Leptin Levels Are Related to Non-Alcoholic Fatty Liver Disease in Children With Obesity.

Background: While for individuals with obesity an association between hyperleptinemia and an increased risk of non-alcoholic fatty liver disease (NAFLD) is assumed, a leptin deficiency is also related to the development of NAFLD early in life in ob/ob mice, in patients with leptin deficiency due to biallelic likely pathogenic variants in the leptin gene, and in patients with lipodystrophy. Objectives: To investigate the association of circulating leptin levels in pre-pubertal children with obesity and steatosis hepatis. Methods: The cross-sectional study consisted data of n=97 (nmale=76) pre-pubertal children (11.8 ± 1.5 years) with obesity (BMIz: 2.4 ± 0.4). Fasting concentrations of cardiometabolic parameters were measured: insulin, c-peptide, glucose, triglyceride, cholesterol, HDL, LDL, AST, ALT, GGT, leptin. Steatosis hepatis was diagnosed by an ultrasound examination (mild, moderate or severe). Patients were categorized into two groups: low z-score of circulating leptin levels (≤25th percentile) vs. normal z-score of circulating leptin levels. Results: One-third of the children with obesity were diagnosed with steatosis hepatis (I°: 63.6%, II°/III°: 36.4%). Children with steatosis hepatis had significantly lower z-scores of circulating leptin levels compared to children with an unremarkable liver ultrasonography (-2.1 ± 0.8 vs. -0.7 ± 0.6). Z-scores of circulating leptin levels correlate negatively with degree of steatosis hepatis. Children with low z-scores of circulating leptin levels had significantly higher triglyceride, fasting insulin and c-peptide levels compared to children with normal z-scores of circulating leptin levels. Conclusion: Prepubertal children with NAFLD and obesity and partial leptin deficiency might be defined as a clinical subgroup.

Genetic Obesity in Children: Overview of Possible Diagnoses with a Focus on SH2B1 Deletion.

INTRODUCTION: Genetic obesity is rare and quite challenging for pediatricians in terms of early identification. Src-homology-2 (SH2) B adapter protein 1 (SH2B1) is an important component in the leptin-melanocortin pathway and is found to play an important role in leptin and insulin signaling and therefore in the pathogenesis of obesity and diabetes. Microdeletions in chromosome 16p11.2, encompassing the SH2B1 gene, are known to be associated with obesity, insulin resistance, hyperphagia, and developmental delay. The aim of our study is to report on a case series of young individuals with 16p11.2 microdeletions, including the SH2B1 gene, and provide detailed information on body mass index (BMI) development and obesity-associated comorbidities. In this way, we want to raise awareness of this syndromic form of obesity as a differential diagnosis of genetic obesity. METHODS: We describe the phenotype of 7 children (3 male; age range: 2.8-18.0 years) with 16p11.2 microdeletions, encompassing the SH2B1 gene, and present their BMI trajectories from birth onward. Screening for obesity-associated comorbidities was performed at the time of genetic diagnosis. RESULTS: All children presented with severe, early-onset obesity already at the age of 5 years combined with variable developmental delay. Five patients presented with elevated fasting insulin levels, 1 patient developed diabetes mellitus type 2, 4 patients had dyslipidemia, and 4 developed nonalcoholic fatty-liver disease. DISCUSSION/CONCLUSION: Chromosomal microdeletions in 16p11.2, including the SH2B1 gene, in children are associated with severe, early-onset obesity and comorbidities associated with insulin resistance. Early genetic testing in suspicious patients and early screening for comorbidities are recommended.

Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors.

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Frequency of Autoantibody-Negative Type 1 Diabetes in Children, Adolescents, and Young Adults During the First Wave of the COVID-19 Pandemic in Germany.

OBJECTIVE: The aim of this study was to investigate the frequency of newly diagnosed type 1 diabetes without evidence of autoimmunity and the respective frequencies of ketoacidosis in children, adolescents, and young adults during the coronavirus disease 2019 (COVID-19) pandemic in Germany compared with the previous decade. RESEARCH DESIGN AND METHODS: Based on data from the German Diabetes Prospective Follow-up Registry (DPV), we compared data from 715 children, adolescents, and young adults, newly diagnosed with type 1 diabetes during the COVID-19 pandemic in Germany between 1 March and 30 June 2020, with data from 5,428 children, adolescents, and young adults of the same periods from 2011 to 2019. Adjusted differences and relative risks (RRs) of negative ß-cell autoantibody test results and diabetic ketoacidosis were estimated using multivariable log-binomial regression analysis. An upper noninferiority test (margin 1%) was applied to evaluate whether the autoantibody-negativity rate in 2020 was not higher than that in 2011 to 2019. RESULTS: The estimated frequencies of autoantibody negativity in 2020 and 2011-2019 were 6.6% (95% CI 5.1-8.4) and 7.2% (95% CI 6.5-8.0), respectively, with an absolute difference of -0.68% (90% CI -2.07 to 0.71; P upper noninferiority = 0.023). The increase of the estimated frequency of diabetic ketoacidosis during the COVID-19 pandemic was similar between autoantibody-negative and -positive type 1 diabetes (adjusted RRs 1.28 [95% CI 0.80-2.05] and 1.57 [1.41-1.75], respectively). CONCLUSIONS: This study found no evidence that the COVID-19 pandemic leads to a significantly increased number of new cases with autoantibody-negative type 1 diabetes in children, adolescents, and young adults. In addition, autoantibody-negative type 1 diabetes showed no particular susceptibility to ketoacidosis, neither before nor during the pandemic.

Serum IGF1 and linear growth in children with congenital leptin deficiency before and after leptin substitution.

BACKGROUND: Evidence from in vitro and rodent studies suggests that leptin, a key signal of long-term energy reserves, promotes IGF1 synthesis and linear growth. This effect of leptin has not been fully investigated in humans. The aim of our study was to investigate the effect of leptin substitution on growth factors and linear growth in children with congenital leptin deficiency (CLD). METHODS: In this cohort study we included eight pediatric patients (six males), age 0.9-14.8 years, who were diagnosed with CLD and received leptin substitution at our University Medical Center. We calculated standard deviation scores (SDS) for serum levels of IGF1 and IGFBP3, IGF1/IGFBP3 molar ratio, and height at baseline (T0) and 12 months (T12) after the initiation of substitution with metreleptin. RESULTS: All patients had severe obesity (BMI-SDS mean ± SD: 4.14 ± 1.51) at T0 and significant BMI-SDS reduction to 2.47 ± 1.05 at T12. At T0, all patients were taller than the mid-parental median, yet had low IGF1 and IGF1/IGFBP3 molar ratios (IGF1-SDS[Formula: see text]T0: -1.58 ± 0.92, IGF1/IGFBP3 molar ratio-SDS[Formula: see text]T0: -1.58 ± 0.88). At T12, IGF1-SDS increased significantly (∆T0-12: 1.63 ± 1.40, p = 0.01), and IGFBP3-SDS and IGF1/IGFBP3 molar ratio-SDS showed a trend toward an increase. In the three children within the childhood growth period (post-infancy, pre-puberty) height-SDS increased (∆height-SDST0-12: 0.57 ± 0.06, p = 0.003) despite substantial weight loss. CONCLUSIONS: These results in CLD patients are contrary to observations in children with idiopathic obesity who typically have above-mean IGF1 levels that decrease with weight loss, and therefore suggest that leptin increases IGF1 levels and promotes linear growth.

Comparison of cardiovascular risk factors between children and adolescents with classes III and IV obesity: findings from the APV cohort.

OBJECTIVE: Obesity is associated with many cardiovascular risk factors (CVRF) in childhood. There is an ongoing discussion whether there is a linear relationship between degree of overweight and deterioration of CVRFs justifying body mass index (BMI) cut-offs for treatment decisions. METHODS: We studied the impact of BMI-SDS on blood pressure, lipids, and glucose metabolism in 76,660 children (aged 5-25 years) subdivided in five groups: overweight (BMI-SDS 1.3 to <1.8), obesity class I (BMI-SDS 1.8 to <2.3), class II (BMI-SDS 2.3-2.8), class III (BMI-SDS > 2.8-3.3), and class IV (BMI-SDS > 3.3). Analyses were stratified by age and sex. RESULTS: We found a relationship between BMI-SDS and blood pressure, triglycerides, HDL cholesterol, liver enzymes, and the triglycerides-HDL-cholesterol ratio at any age and sex. Many of these associations lost significance when comparing children with obesity classes III and IV: In females < 14 years and males < 12 years triglycerides and glucose parameters did not differ significantly between classes IV and III obesity. Prevalence of dyslipidemia was significantly higher in class IV compared to class III obesity only in females ≥ 14 years and males ≥ 12 years but not in younger children. In girls < 14 years and in boys of any age, the prevalences of type 2 diabetes mellitus did not differ between classes III and IV obesity. CONCLUSIONS: Since a BMI above the highest BMI cut-off was not associated consistently with dyslipidemia and disturbed glucose metabolism in every age group both in boys and girls, measurements of CVRFs instead of BMI cut-off seem preferable to guide different treatment approaches in obesity such as medications or bariatric surgery.

Lipodystrophy as a Late Effect after Stem Cell Transplantation.

Survivors of childhood cancer are at high risk of developing metabolic diseases in adulthood. Recently, several patients developing partial lipodystrophy following hematopoietic stem cell transplantation (HSCT) have been described. In this review, we summarize the cases described so far and discuss potential underlying mechanisms of the disease. The findings suggest that HSCT-associated lipodystrophies may be seen as a novel form of acquired lipodystrophy.

Fertility preservation for female patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration.

Applicability of Magnetic Resonance Imaging for Bone Age Estimation in the Context of Medical Issues. / Einsatz der MRT zur Knochenalterbestimmung im Rahmen medizinischer Fragestellungen.

OBJECTIVE: The determination of bone age is a method for analyzing biological age and structural maturity. Bone age estimation is predominantly used in the context of medical issues, for example in endocrine diseases or growth disturbance. As a rule, conventional X-ray images of the left wrist and hand are used for this purpose. The aim of the present study is to investigate the extent to which MRI can be used as a radiation-free alternative for bone age assessment. METHODS: In 50 patients, 19 females and 31 males, in addition to conventional left wrist and hand radiographs, MRI was performed with T1-VIBE (n = 50) and T1-TSE (n = 34). The average age was 11.87 years (5.08 to 17.50 years). Bone age assessment was performed by two experienced investigators blinded for chronological age according to the most widely used standard of Greulich and Pyle. This method relies on a subjective comparison of hand radiographs with gender-specific reference images from Caucasian children and adolescents. In addition to interobserver and intraobserver variability, the correlation between conventional radiographs and MRI was determined using the Pearson correlation coefficient. RESULTS: Between the bone age determined from the MRI data and the results of the conventional X-ray images, a very good correlation was found for both T1-VIBE with r = 0.986 and T1-TSE with r = 0.982. Gender differences did not arise. The match for the interobserver variability was very good: r = 0.985 (CR), 0.966 (T1-VIBE) and 0.971 (T1-TSE) as well as the match for the intraobserver variability for investigator A (CR = 0.994, T1-VIBE = 0.995, T1-TSE = 0.998) and for investigator B (CR = 0.994, T1-VIBE = 0.993, T1-TSE = 0.994). CONCLUSION: The present study shows that MRI of the left wrist and hand can be used as a possible radiation-free alternative to conventional X-ray imaging for bone age estimation in the context of medical issues. KEY POINTS: · MRI and X-ray show a very good correlation for bone age determination in medical issues.. · With short examination times, T1 VIBE shows slight advantages over T1 TSE.. · Both investigators show high intra- and interobserver variability.. CITATION FORMAT: · Diete V, Wabitsch M, Denzer C et al. Applicability of Magnetic Resonance Imaging for Bone Age Estimation in the Context of Medical Issues. Fortschr Röntgenstr 2021; 193: 692 - 700.

Transient neonatal diabetes due to a disease causing novel variant in the ATP-binding cassette subfamily C member 8 (ABCC8) gene unmasks maturity-onset diabetes of the young (MODY) diabetes cases within a family.

OBJECTIVES: Neonatal diabetes mellitus (NDM) is a rare monogenic diabetes form, occurring mainly from ATP-binding cassette subfamily C member 8 (ABCC8) and KCNJ11 mutations. ABCC8 mutations have also been found to cause adult-onset diabetes. What is new?: •Novel ABCC8 mutation in an NDM case •Heterogeneous clinical presentation of diabetes and response to sulfonylurea therapy among family members with the same ABCC8 mutation. CASE PRESENTATION: We report the case of a newborn with NDM and a heterozygous ABCC8 novel variant (c.3835G>A), successfully treated with sulfonylurea. The same ABCC8 variant was found in two other family members, already treated for type 2 diabetes. CONCLUSIONS: This case demonstrates the variable phenotypic presentation of diabetes due to a novel ABCC8 mutation (c.3835G>A), ranging from transient NDM to adult-onset, insulin-demanding diabetes, among family members. Genetic testing in young individuals with a strong family history of diabetes, presenting with non-autoimmune diabetes is recommended as it can determine prognosis and treatment of affected family members.

Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency.

BACKGROUND: Rare genetic variations in the leptin-melanocortin signalling pathway can severely impair appetite regulation and cause extreme obesity in early childhood. CASE PRESENTATION: Our case reports describe the diagnostic and therapeutic procedures in a girl as well as in a non-related boy of non-consanguineous, German parents with severe early-onset obesity, pronounced hyperphagia, and permanent food-seeking behaviour. Excessive weight gain within the first year of life initiated extensive diagnostics without finding a causal diagnosis. Furthermore, a wide range of intensive, interdisciplinary, and behavioural therapies for weight control were unsuccessful. Prior to bariatric surgery, the 18-year-old girl and the 14-year-old boy reached a BMI of 67.7 kg/m2 and 55.2 kg/m2, respectively. However, even surgical outcomes were unsatisfactory. A subsequently initiated genetic analysis including sequencing of the leptin receptor gene revealed compound heterozygous variants as a cause of the severe early-onset obesity in both patients (c.2598-3_2607delTAGAATGAAAAAG and c.2227 T>C; c.1874G>A and c.2051A>C). Both patients were enrolled in the clinical study RM-493-015 and treated with melanocortin receptor agonist setmelanotide. Currently, they are still on setmelanotide treatment in the extension trial RM-493-022. CONCLUSION: Our case report illustrates the urgent necessity of early genetic diagnostics in children with severe early-onset obesity to avoid frustrating and potentially damaging therapies. Thus, genetic examination should precede bariatric surgery. In the future, several pharmacological therapies will be available for some forms of monogenetic obesity.

Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by mutations in the active 21-hydroxylase gene (CYP21A2). The clinical symptoms can vary greatly. To date, no systematic studies have been undertaken in Germany. AIMS: Description of the phenotype, evaluation of the diagnostics and genotype-phenotype correlation PATIENTS AND METHODOLOGY: Retrospective analysis of the data of 134 patients (age range 0.1-18.6 years) in a multicentre study covering 10 paediatric endocrinology centres in Bavaria and Baden-Württemberg. The data was gathered on site from the medical records. Two hundred and thirty-three alleles with a mutation of the CYP21A2 gene were identified in 126 patients. A genotype-phenotype correlation of the mutation findings was undertaken (C1, severe/mild; C2, mild/mild). Individuals with a heterozygous mutation of the CYP21A2 were also included (C3). The data was collected with the approval of the ethics committee of the University Hospital of Erlangen during the period of 2014 and 2015. RESULTS (MW ± SD): One hundred and seventeen out of 134 patients (115 f, 29 m) were symptomatic. The chronological age (CA) at diagnosis was 7.1 ± 4.4 years. The most frequent symptom (73.5%) was premature pubarche. The height-SDS on diagnosis was 0.8 ± 1.3 and the BMI-SDS was 0.8 ± 1.2. Bone age (BA) was ascertained in 82.9% of the symptomatic patients. The difference between BA and CA was 1.9 ± 1.4 years. Basal 17OHP concentrations were 14.5 ± 19.1 ng/ml (18 patients < 2 ng/ml). In total, 58.1% mild and 34.7% severe mutations were found. The most common mutation was p.Val281Leu (39.1%); 65.8% of the patients could be allocated to group C1. No phenotypical differences were found between the 3 mutation groups. The 17OHP levels (basal and after ACTH) in the standard ACTH stimulation test were highest in group C1 and also significantly higher in group C2 as in C3, the ACTH-stimulated cortisol levels (ng/ml) were significantly lower in groups C1 (192.1 ± 62.5) and C2 (218 ± 50) than in C3 (297.3 ± 98.7). CONCLUSION: Most of the patients have symptoms of mild androgenisation. Male patients are underdiagnosed. Diagnostics are not standardised. Differences between the types of mutations are found in the hormone concentrations but not in phenotype. We speculate that further, as yet not clearly defined, factors are responsible for the development of the respective phenotypes.

Estimated Glomerular Filtration Rates Calculated by New and Old Equations in Children and Adolescents With Type 1 Diabetes-What to Do With the Results?

Background: To apply and evaluate various equations for estimated glomerular filtration rates (eGFR) in a large paediatric type 1 diabetes population and compare the eGFR values with urinary creatinine clearances (UCC) in a subset of patients. Methods: Six eGFR formulae applicable for children and adolescents were used for calculation of eGFR values in 36,782 children/adolescents with type 1 diabetes. Via regression models, factors influencing eGFR values were identified. eGFR values were compared with measured UCC in 549 patients. Spearman correlation coefficients were given to assess the relation of eGFR and UCC values. Bland-Altman-Plots with corresponding linear regression were drawn to evaluate the agreement between eGFR and UCC. Results: eGFR values differed widely depending on the formula used, resulting in a percentage of pathological values <60 mL/min/1.73 m2 up to 8%. Regression models showed age, sex, and duration of diabetes as influencing factors. Microalbuminuria was associated with significantly higher eGFR values for all formulae. In comparison of eGFR with UCC, the highest correlation coefficient was 0.33, the lowest 0.01. Bland-Altman-Plots demonstrated graphically a poor agreement between eGFR and UCC, regardless of the formula used. Conclusions: The broad range of eGFR values indicate that an ideal eGFR formula for children and adolescence with T1D is yet missing. The minimal agreement between measured UCC and eGFR values urges us to be careful in application and interpretation of eGFR values regardless of the formula used.

Methylphenidate in children with monogenic obesity due to LEPR or MC4R deficiency improves feeling of satiety and reduces BMI-SDS-A case series.

BACKGROUND: The clinical phenotype of patients with monogenic obesity due to mutations in the leptin receptor (LEPR) or melanocortin 4 receptor (MC4R) gene is characterized by impaired satiety and hyperphagia, leading to extreme, sometimes life-threatening weight gain. SUBJECTS/METHODS: In a case series, we analysed the effect of an off-label methylphenidate (MPH) use for 1 year as an individual treatment approach on eating behaviour (Child Eating Behaviour Questionnaire [CEBQ]), appetite (visual analogue scales) and body mass index (BMI) trajectories in five patients with severe obesity due to mutations in the LEPR (n = 3) or MC4R (n = 2) gene. RESULTS: After 1 year use of MPH (20 mg/day divided in two to three doses), BMI (Δ BMIT0-T1x¯ : -0.7 ± 0.9 kg/m2 ), BMI standard deviation score (SDS) (Δ BMI-SDST0-T1x¯ : -0.32 ± 0.20), and %BMIP95 (Δ %BMIP95T0-T1x¯ : -6.6 ± 7.8%) decreased. BMI-SDS velocity decreased from +0.17 ± 0.22 to -0.30 ± 0.20. Appetite and CEBQ subscale scores for "food responsiveness" and "enjoyment of food" decreased. We observed adverse effects with increase in self-reported frequency of disordered sleep, nervousness, hyperactivity, and tics. CONCLUSIONS: The observed decrease in BMI trajectories with MPH use for one year is clinically meaningful in this group of patients, since the natural course would have been associated with a pronounced increase in BMI, leading to comorbidities and complications over time.

Treatment of Hypothalamic Obesity with Dextroamphetamine: A Case Series.

BACKGROUND: A limited number of published case reports suggest a positive effect of dextroamphetamine, an adrenergic agonist affecting both the central nervous system (CNS) and peripheral nervous system, on physical activity and weight in patients with hypothalamic obesity (intractable obesity following CNS insult). Here, we present our clinical experience with dextroamphetamine treatment for hypothalamic obesity. METHODS: The clinical course of all patients started on dextroamphetamine treatment for severe hypothalamic obesity at our institution between 2010 and 2013 is reported. Dextroamphetamine administration was initiated at a single dose of 5 mg per day and titrated to effect up to a dose of 20 mg/day. BMI z-score velocity was calculated as change in BMI z-score over standardized intervals of 12 months. Parameters of treatment success and adverse events were assessed in a standardized fashion. RESULTS: Seven patients (2 males; mean age 17.6 years [range 12.9-24.5]) underwent individual treatment attempts with dextroamphetamine between 2010 and 2013. The primary diagnoses were craniopharyngioma (n = 4), ganglioglioma WHO I (n = 1), astrocytoma (n = 1), and neonatal meningitis (n = 1). Time from initial CNS insult to initiation of dextroamphetamine treatment averaged 5.2 years (range 2.4 months to 16.5 years). All patients demonstrated a steady increase in BMI z-score from the time of initial diagnosis until initiation of dextroamphetamine treatment. Mean baseline BMI z-score was +3.17 ± 0.93 (+1.9 to +4.4). Mean BMI z-score velocity decelerated to -0.18 ± 0.12 per year during the first year of treatment and stabilized at +0.05 ± 0.32 per year during the second year of treatment. No significant adverse events were reported. CONCLUSION: Dextroamphetamine treatment led to stabilization or reduction of BMI z-score in a cohort of 7 patients with hypothalamic obesity, with no adverse effects. Considering the projected increase in BMI z-score according to the natural course of the disease, these findings are promising and warrant further study.

Screening for coeliac disease in 1624 mainly asymptomatic children with type 1 diabetes: is genotyping for coeliac-specific human leucocyte antigen the right approach?

OBJECTIVES: To investigate the frequency of coeliac disease (CD)-specific human leucocyte antigen (HLA) genotypes in paediatric patients with type 1 diabetes (T1D), who are known to have a higher prevalence of CD than the general population, and to evaluate whether HLA genotyping is a suitable first-line screening method for CD. STUDY DESIGN: The study was a multicentre observational analysis of patients with T1D aged <20 years of whom a subgroup had undergone HLA genotyping. Patient data were retrieved from the Diabetes Prospective Follow-up database, a large diabetes follow-up registry. The present analysis included data from 439 centres throughout Germany, Austria, Switzerland and Luxembourg. RESULTS: In March 2017, the database contained 75 202 patients with T1D (53% male, mean age (SD) 14.6 (4.1) years, mean age at diagnosis 8.8 (4.3) years and mean diabetes duration 5.8 (4.3) years). 1624 patients had undergone coeliac-specific HLA genotyping, of whom 1344 (82.8%) were positive for HLA-DQ2, HLA-DQ8 or both, while 17.2% had no coeliac-specific HLA-markers. 26.6% of at-risk patients had a clinical suspected diagnosis of CD, and 3.6% had biopsy-proven CD. CONCLUSIONS: Genotyping for HLA-DQ2, HLA-DQ8 or both is positive in the vast majority (>80%) of patients with T1D. Therefore, screening for coeliac-specific HLA genotypes as a first-line test is not a suitable method to exclude CD in T1D. Regular screening for coeliac-specific antibodies in T1D is still recommended.