We recently showed that a 3-year growth hormone (GH) treatment improves linear growth in severely short children with X-linked hypophosphatemic rickets (XLH). It is unknown if GH therapy increases adult height in XLH patients.

Background: Congenital hyperinsulinism (CHI) is a rare disease with an estimated incidence of 1: 40,000 live births. Here, we characterize 11 patients treated at Munich Children's Hospital Schwabing.Methods: We analyzed data on birth, treatment and laboratory results including genetic testing and evaluated the long-term course with a follow-up visit.Results: All patients had severe, diazoxide-(DZX)-resistant hypoglycemia, beginning immediately after birth. Two patients were treated by medical therapy, eight underwent subtotal pancreatectomy and one had a partial resection. Both patients who had medical therapy still suffer from occasional hypoglycemia. Six patients with subtotal pancreatectomy were affected by mild hypoglycemia. Seventy-five percent of patients who had surgical treatment developed diabetes mellitus (DM) at a median age of 10.5 (8-13) years. In 89% of patients with available genetic testing, mutations of the ABCC8 gene were detected.Conclusions: The majority of CHI-patients not responding to DZX underwent surgery. After subtotal pancreatectomy, patients typically developed diabetes around early puberty.

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that includeGPR101. We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold forGPR101that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

BACKGROUNDSeveral genetic syndromes are associated with diabetes mellitus (DM). This study aimed to analyse data from the DPV database with regard to frequency, treatment strategies and long-term complications in paediatric DM patients with genetic syndromes, including Turner syndrome (TS), Prader-Willi syndrome (PWS), Friedreich ataxia (FA), Alström syndrome (AS), Klinefelter syndrome (KS), Bardet-Biedl syndrome (BBS), Berardinelli-Seip syndrome (BSS) and Down syndrome (DS).METHODSLongitudinal data for 43 521 patients with DM onset at age < 20 years were collected from 309 treatment centres in Germany and Austria using the DPV software. Data included anthropometric parameters, type of diabetes, mean age, age at diabetes onset, daily insulin dose, HbA 1c , micro- and macroalbuminuria, retinopathy and dyslipidaemia. Descriptive statistics and standard statistical tests were used for data analysis.RESULTSIn total, 205 DM patients had one of the following syndromes: DS (141 patients), TS (24), PWS (23), FA (5), AS (5), KS (4), BBS (2) and BSS (1). Diabetes-specific antibodies were positive in the majority of patients with DS, TS and FA.CONCLUSIONDespite the well-known association between DM and certain syndromic disorders, the number of affected patients in the German and Austrian paediatric diabetic population is very low. Nevertheless, physicians should be aware of syndromic forms of diabetes. Joint multicentre analyses are needed to draw relevant conclusions.

CONTEXT:Only occasionally, endocrine-active tumors develop directly from hepatic tissue, and may lead to paraneoplastic syndromes (PNS). PNS mostly accompany malignancy of adulthood and are exceedingly rare in children.PATIENT:A girl aged 6 years and 9 months presented with a 2-month history of rapidly progressive weight gain, abdominal distension, and polyuria/pollakiuria accompanied by short episodes of abdominal pain. She showed the typical clinical features of Cushing's syndrome and a huge hepatic mass. An abdominal computed tomography (CT) scan revealed a large liver tumor. Blood glucose and serum calcium were greatly elevated.DESIGN AND OBJECTIVE:Case report describing the causative relationship of the clinical findings.METHODS:Physical examination; ultrasound of the abdomen; CT scan of the abdomen and the chest; conventional X-rays; routine hematology; blood chemistry and multiple parameters of calcium and phosphorus metabolism; multisteroid analysis in serum and urine; adrenocortical stimulation and suppression tests; histopathological assessment of the resected tumor; immunohistochemistry for ACTH, beta-endorphin, corticotrophin-releasing hormone (CRH), and PTH-related peptide (PTHrP); electron microscopy of tumor cells; ACTH and CRH extraction from the tumor tissue; and clinical follow-up for more than 20 years.RESULTS:Giant hepatoblastoma (HB; approximately 1000 ml volume) of the right lobe of the liver with combined ectopic ACTH syndrome and PTHrP-induced tumor-associated hypercalcemia. Wide local excision and polychemotherapy led to complete reversal of the paraneoplastic phenotype.CONCLUSIONS:This is the first report of an endocrine-active HB causing both Cushing's syndrome and PTHrP-related 'humoral hypercalcemia of malignancy'. This information should be added to the well-known beta-human chorionic gonadotropin-related paraneoplastic effects of HB in children.

Fragestellungen: Nur wenige prospektive Verlaufsdaten zur Stoffwechselkontrolle über viele Jahre der Diabeteserkrankung liegen bisher vor. Die Frage des langfristigen HbA1c-„Trackings“ ist bei Kindern mit Diabetesbeginn im Kindergarten- und Grundschulalter aufgrund entwicklungsspezifischer Besonderheiten in der Pubertät (physiologische Insulinresistenz, Non-Compliance) besonders relevant.

Der congenitale Hyperinsulinismus (CHI) führt meist bereits im Neugeborenenalter infolge inadäquat hoher Insulinsekretion zu schweren Hypoglykämien. Bei etwa einem Drittel der Betroffenen liegt ursächlich ein kleiner Fokus (<5mm Durchmesser) vor, der durch L-DOPA-PET/CT lokalisiert und durch eine begrenzte Pankreasoperation geheilt werden kann. Bei diffuser Form des CHI wird eine konservative Therapie mittels Diazoxid bzw. Octreotid und adäquater Diät eingeleitet. Um irreversiblen Hirnschäden vorzubeugen, ist im Einzelfall eine subtotale Pankreatektomie indiziert. Mutationen in ABCC8, KCNJ11, Glukokinase, GLUD und UCP2 wurden ursächlich für die inadäquate Insulinsekretion nachgewiesen. Hypoglykämieepisoden im Kindesalter werden unter konservativer Therapie seltener, insbesondere bei milderen Verläufen. Leibowitz et al. berichteten bei >50% der Kinder nach subtotaler Pankreatektomie nach zuvor jahrelanger Euglykämie über eine Diabetesmanifestation (JCEM 80: 386–92, 1995). Um die Entwicklung des Diabetes bei CHI zu untersuchen, analysierten wir die prospektive Langzeitdokumentation aus dem Diabetes-Patienten-Verlaufsdaten (DPV) Register. Zum Zeitpunkt der Datenanalyse (non-interventional audit) waren aus 20 Betreuungszentren im DPV-Register 25 Kinder und Jugendliche (12männlich) mit Diabetes bei CHI im mittleren Alter von 14,9 Jahren (4,67–20,9) erfasst. Im Vergleich wurden 50 645 Patienten (52% männlich) mit Diabetes mellitus Typ 1 (T1DM) im Alter bis 20 Jahre aus 269 Betreuungszentren aus Deutschland und Österreich dokumentiert. Zwischen den Gruppen mit Diabetes mellitus bei CHI und bei T1DM wurden signifikante Unterschiede (nicht parametrischer Kruskal-Wallis-Test) für folgende Parameter nachgewiesen: Alter bei Diabetesmanifestation im Mittel 7,3 (0–17,7) vs. 9,8 Jahre, Diabetesdauer zum Zeitpunkt der Analyse 7,6 (0,92–17,4) vs. 5,5 Jahre, BMI-SDS 0,84 (-1,05/3,5) vs. 0,49 SDS, Körperhöhen-SDS -0,62 (-2,2/1,1) vs. -0,02 SDS. Die mittlere tägliche Insulindosis liegt bei 0,7 (0,1/1,2) vs. 0,79 U/kg Körpergewicht, der HbA1c 7,6 (5,4/12) vs. 7,9%.

Fragestellung: Eine standardisierte Dokumentation über längere Zeiträume ist die Basis, um Veränderungen der Prozess- und Ergebnisqualität chronischer Krankheiten zu objektivieren. Die vorliegende Auswertung zeigt Änderungen der pädiatrisch-diabetologischen Versorgung in Deutschland und Österreich über die letzten 13 Jahre.

Death occurring in an avalanche is caused by different mechanisms. The cause of death differs depending on the type of the avalanche, depth and time of burying and whether the person has an air pocket or not. Based on the systematics of avalanche awareness various safety measures and possible causes of death following avalanche accidents are described.

DESIGN:The purpose of this study was to generate insulin dose (ID) percentiles for children and adolescents with type 1 diabetes mellitus (DM1) having the opportunity to assess this important parameter in relation to age and sex.METHODS:Daily IDs per weight (ID/kg) were recorded in 22,177 patients with DM1 (3-25 years of age, DM1 duration of more than 2 years, 48% female) and ID percentiles (ID-Perc) were created statistically. The ID-Perc were compared between male and female, and between multiple insulin injection therapy (MIT) and continuous s.c. insulin infusion (CSII). A multivariate regression analysis was performed for ID in the third year of DM1 with ID/kg, body weight, age, gender, and insulin delivery regimen as variables.RESULTS:The 50th ID-Perc (P50) varied among 0.67 IU/kg (age 3 years), 0.93 IU/kg (13 years), and 0.70 IU/kg (23 years) increasing from early childhood to adolescence and decreasing toward adulthood. Highest P50 ID was found at 12 years in females (0.94 IU/kg) and at 14 years in males (0.92 IU/kg). Using ICT, the ID was significantly higher compared with CSII (P50: 0.94 IU/kg versus 0.79 IU/kg at 13 years). In multivariate regression analysis, ID was significantly (P>0.001) associated with age, gender, and insulin delivery regime.CONCLUSION:The ID-Perc were significantly different during various periods of childhood and were influenced by gender, body weight, and insulin injection regimes. Therefore, the presented data 1) provide evidence to interpret individual ID in children and adolescents with DM1 and 2) more specifically identify children with unusually high (insulin resistance and non-compliance) or low (MODY and persistent remission) insulin requirement.

Fragestellung: Aktuell existieren im deutschsprachigen Raum keine epidemiologischen Daten des Diabetes mellitus bei „syndromalen Erkrankungen“. In der vorliegenden Arbeit sind die syndromalen Erkrankungen, wie das Alström-Hallgren-, das Prader-Willi- (PWS), das Beradinelli-Seip, das Noonan-, das Ullrich-Turner-(UTS), das Klinefelter-Syndrom und die Friedrich-Ataxie, von besonderem Interesse.

Introduction: Chest X-rays have been shown to be poor at detecting rib and sternal fractures after CPR when compared with autopsy findings; the use of CT has never been reported. As females have been shown to at higher risk than males of such fractures, we performed a prospective, blinded study comparing CT and autopsy findings in fresh, female corpses following one minute of CPR given by a mechanical device.

INTRODUCTION:While the central role of HbA1c levels for the prediction of micro- and macrovascular complications in patients with type 1 diabetes is generally accepted; recommendations in current guidelines and the level of metabolic control actually achieved during routine care differ widely. Limited information is available on factors that influence metabolic control in the pediatric age group and during the transition from pediatric to adult diabetes care. In a large prospective multicenter database (DPV-Wiss), 338,330 individual HbA1c measurements from 27,035 patients with type-1 diabetes (94,074 observation years) were recorded between 1995 and 2005. Data were anonymously transmitted from 207 institutions. HbA1c values were mathematically standardized to the DCCT normal range (4.05-6.05%). The SAS 9.1 software was used for statistical analysis using nonparametric statistics. Median HbA1c for all measurements was 7.8%, with a strong effect of diabetes duration: median HbA1c at onset was 9.1%, during the first 2 years of diabetes 7.1% with a subsequent increase to 7.9% in patients beyond the remission phase (>2 years, 20,314 patients); a strong age dependency was present. HbA1c above the recommended guidelines was found in 23%. For all age groups, girls/women had higher HbA1c values compared to boys (mean difference 0.1%, p<0.0001). Seasonal variation was remarkably small with the lowest HbA1c values in September (mean: 7.86%) and highest values in January (8.08%; p<0.0001). Some improvement in HbA1c was observed comparing three periods: 1995-1997, 1998-2000 and 2001-2005; after remission the median HbA1c decreases from 8.5% to 7.6%. In a multivariate model, a significant influence on HbA1c was detected for age (p<0001), duration of diabetes (p<0.0001), gender (p<0.02), minority status (p<0.0001), season (p<0.0001), treatment period (p<0.0001), insulin therapy (p<0.0001) and center effect (p<0.0001).CONCLUSIONS:Both patient-related and treatment-related variables have a strong influence on metabolic control achieved in pediatric and young adult patients with T1DM. In contrast to wide-spread belief, metabolic control is only marginally better in summer compared to winter. Some improvement in metabolic control was observed during the last 10 years.

Idiopathic dilated cardiomyopathy (IDCM) is a primary myocardial disease of unknown cause characterized by ventricular chamber enlargement with impaired contractile function. In familial forms of IDCM, mutations of genes coding for cytoskeletal proteins related to force transmission, such as dystrophin, cardiac actin, desmin, and δ‐sarcoglycan, have been identified. Here, we report the data of a retrospective investigation carried out to evaluate the expression of atrial natriuretic peptide (ANP), CD34, troponin T and nestin in the myocardium of patients affected with IDCM. Formalin‐fixed and paraffin‐embedded consecutive tissue sections from the ventricular wall of 10 human normal hearts (NH) following forensic autopsy and 22 IDCM (living explanted hearts) were studied using primary monoclonal antibodies against ANP, CD34, troponin T and nestin by immunohistochemistry. Myocardial fibers were counted independently by three pathologists. Statistics included analysis of variance, log‐rank test for Kaplan‐Meier analysis, and kappa assessment for intra‐ and inter‐observer variability. ANP and CD34 were significantly overexpressed in IDCM compared to NH (p<0.05). Conversely, troponin T and nestin expression levels did not show significant variation. Inter‐observer kappa statistics showed a value of 0.87 and intra‐observer kappa statistics a value of 0.98. Evaluation of the marker distribution in the myocardium of patients with IDCM CD34 expression curve was similar to that of troponin T (p<0.0001), although two groups could be identified. Patients with a difference of more than 20 myocardial fibers in expression of CD34 and troponin T had a somewhat less favorable survival although the difference was not significant. The analysis of cells positive for troponin T resulted in a similar number of cardiac fibers between NH and IDCM. This is in agreement with cardiac enlargement present in IDCM, which is due to ventricular dilatation rather than increased number of myocytes. Moreover, the expression of nestin, a marker of activation of myocardial precursors, did not change either, and this may confirm that there are no hyperplastic phenomena in the IDCM pathogenesis. The increase in ANP‐positive cells in IDCM could be a consequence of neurohormonal activation due to a decline in the impaired myocyte contractility. Furthermore, since it was already shown that ANP could be important in the control of vascular remodeling, we postulated that the increase in CD34‐positive cells might be functionally correlated with the increase in ANP production. Differential expression of CD34 and troponin T might be used in future studies to evaluate their prognostic value.