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Aim Intraosseous (IO)-access plays an alternative route during resuscitation. Our study in preterm and term stillborns was performed to find alternative IO puncture sites beside the recommended proximal tibia. Methods The cadavers used were legal donations. 20 stillborns (mean: 29.2weeks, IQR 27.1–39.6) were investigated. Spectral-CT were analysed to calculate the diameter and circumferences of: i) proximal humerus ii) distal femur iii) proximal tibia iv) diaphyseal tibial. Contrast medium was applied under video documentation to investigate the drainage into the vascular system. Results In term newborns, diameter of the cortex of the proximal humeral head is 12.1 ± 1.8 mm, distal end of the femur 11.9 ± 3.4 mm and the proximal tibial bone 12.0 ± 2.4 mm with cross-sectional diameter of 113.5 ± 19.7 mm2, 120.6 ± 28.2 mm2 and 111.6 ± 29.5 mm2, respectively. Regarding the preterm groups, there is a strong age-related growth in diameter and cross -sectional size. The diaphyseal area is the smallest in all measured bones with an age-dependent increase and is about half of that of metaphyseal diameters (proximal and distal) and about one third of that of metaphyseal cross sectional areas. The proximal femoral head region has the largest diameter of all measured bones with an egg-shaped formation with an extensive joint capsula. All investigated metaphyseal areas lack a clearly enclosed bone marrow cavity. Infusion of contrast medium into the distal femoral end and the proximal humerus head demonstrate the drainage of contrast medium into the central venous system within seconds. Conclusion Proximal humeral head and distal femoral end might be alternative IO areas which may lead to further IO puncture sites in neonates.

Das Spektrum solider Tumore bei Kindern und Jugendlichen unterscheidet sich ebenso wie bestimmte Therapieformen (z. B. Knochenmarktransplantationen) von denen des Erwachsenen. Daruber hinaus werden fast alle Patienten in Studien nationaler und internationaler onkologischer Gesellschaften eingeschlossen und in kinderonkologischen Zentren behandelt. Die padiatrische Radiologie ubernimmt hierbei essenzielle Aufgaben, insbesondere bei der therapeutischen Risikostratifizierung und der Therapiekontrolle. Auf der Basis selektiver Literaturrecherche in der Datenbank PubMed, der Leitlinien und Studienprotokollen der nationalen und internationalen Fachgesellschaften wurden die bildgebenden Standards sowie die neuesten Entwicklungen fur ausgewahlte solide Tumorentitaten beschrieben. Im Einzelnen werden von den in kinderonkologischen Zentren tatigen Autoren embryonale Tumoren, Lymphome. Hirntumoren sowie Tumorpradispositionssyndrome erortert. In der Bildgebung solider Tumore sind sowohl die Durchfuhrung als auch die Beurteilung der Bilddaten bereits relativ standardisiert. Erfahrene Untersucher in zertifizierten Zentren sollten in erster Linie hieran beteiligt sein. Insbesondere die weiteren Innovationen in funktioneller Bildgebung lassen hoffen, dass zukunftig bildgebende Biomarker als Zielparameter in Therapiestudien verwendet werden konnen.

Background Aicardi-Goutieres syndrome (AGS) is a clinically and genetically heterogenous autoinflammatory disorder caused by constitutive activation of the type I interferon axis. It has been associated with the genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1. The clinical diagnosis of AGS is usually made in the context of early-onset encephalopathy in combination with basal ganglia calcification or white matter abnormalities on cranial MRI and laboratory prove of interferon I activation. Case presentation We report a patient with early-onset encephalopathy, severe neurodevelopmental regression, progressive secondary microcephaly, epilepsy, movement disorder, and white matter hyperintensities on T2 weighted MRI images. Via whole-exome sequencing, we identified a novel homozygous missense variant (c.1399C > T, p.Pro467Ser) in PNPT1 (NM_033109). Longitudinal assessment of the interferon signature showed a massively elevated interferon score and chronic type I interferon-mediated autoinflammation. Conclusion Bi-allelic mutations in PNPT1 have been reported in early-onset encephalopathy. Insufficient nuclear RNA import into mitochondria with consecutive disruption of the respiratory chain was proposed as the main underlying pathomechanism. Recent studies have shown that PNPT1 deficiency causes an accumulation of double-stranded mtRNAs in the cytoplasm, leading to aberrant type I interferon activation, however, longitudinal assessment has been lacking. Here, we present a case of AGS with continuously elevated type I interferon signature with a novel likely-pathogenic homozygous PNTP1 variant. We highlight the clinical value of assessing the interferon signature in children with encephalopathy of unknown origin and suggest all patients presenting with a phenotype of AGS should be screened for mutations in PNPT1.

Das Strategiepapier der GPR zeigt Entwicklungsmöglichkeiten der Kinder- und Jugendradiologie als Querschnittsfach zwischen der Radiologie und der konservativen und operativen Kinder- und Jugendmedizin auf. Zitierweise

Good training is the basis for high job satisfaction and high-quality patient care in radiology. The aim of this survey was to record the current state of working conditions for residents in radiology training in Germany and to focus on the aspects of training and psychosocial workload. The description of the actual state should help to identify possible problem areas and to develop improvement approaches. At the beginning of 2018, we sent an electronic questionnaire to the German Roentgen Society (DRG), the German Association of Chairmen in Academic Radiology (KLR), the Chief Physician Forum of the DRG (CAFRAD) and the Forum of Registered Radiologists (FUNRAD) with the request to forward it to radiology residents. With 63 questions, the questionnaire covered seven essential areas of medical working and training conditions. In order to ensure interdisciplinary comparability, most questions were identical to previous surveys among residents of other disciplines. 643 residents started the survey. 501 (78 %) questionnaires were fully processed and included in the final analysis. 65 % of respondents were satisfied with their current job situation. At the same time, shortcomings, especially with regard to the reconciliation of family and work as well as scientific and clinical work, became clear. Only 36 % of participants with children were satisfied with the compatibility of family and work at their workplace. Only 31 % of the researchers were satisfied with their research conditions. In addition, residents experienced a high psychosocial workload. Job satisfaction is high among radiology residents in direct comparison to other disciplines. However, based on this survey, adjustments to working conditions and training in radiology seem necessary to maintain the health of the physicians concerned, to encourage motivation for scientific work and to enhance development opportunities, especially for women, through a better compatibility of work and family life. The present survey identifies strategies and leadership tools that can help to achieve this. Residents in radiology training ... · have a relatively high job satisfaction.. · experience a high psychosocial workload.. · evaluate the compatibility of family and work as in need of improvement.. · are interested in research, but evaluate research conditions as insufficient.· Oechtering TH, Panagiotopoulos N, Völker M et al. Work and Training Conditions of German Residents in Radiology - Results from a Nationwide Survey Conducted by the Young Radiology Forum in the German Roentgen Society. Fortschr Röntgenstr 2020; 192: 458 - 469.ZIEL: Eine qualitativ hochwertige Weiterbildung ist Grundlage für eine hohe Arbeitszufriedenheit und eine exzellente Patientenversorgung in der Radiologie. Ziel dieser Umfrage war es, den aktuellen Stand der Arbeitsbedingungen von Ärzten in der Weiterbildung Radiologie in Deutschland zu erfassen und einen Fokus auf die Teilaspekte Weiterbildung sowie psychosoziale Arbeitsbelastung zu legen. Die Beschreibung des Ist-Zustandes soll helfen, mögliche Problemfelder zu identifizieren und Verbesserungsansätze zu entwickeln. Anfang 2018 wurde ein elektronischer Fragebogen über die Deutsche Röntgengesellschaft (DRG) e. V., die Konferenz der Lehrstuhlinhaber für Radiologie (KLR), das Chefarztforum der DRG (CAFRAD) und das Forum Niedergelassener Radiologen (FUNRAD) an radiologische Weiterbildungsassistenten verschickt. Der Fragebogen deckte mit 63 Fragen 7 wesentliche Themenfelder ärztlicher Arbeits- und Weiterbildungsbedingungen ab. Um eine fächerübergreifende Vergleichbarkeit zu sichern, wurden Fragen von bisherigen Erhebungen unter Ärzten in Weiterbildung anderer Fachrichtungen übernommen. 643 Ärzte haben die Umfrage begonnen. 501 (78 %) Fragebögen wurden vollständig bearbeitet und in die endgültige Analyse einbezogen. 65 % der Befragten waren mit ihrer derzeitigen beruflichen Situation zufrieden. Gleichzeitig wurden Defizite besonders in Bezug auf die Vereinbarkeit von Familie und Beruf sowie die Möglichkeit zu wissenschaftlichem Arbeiten deutlich. Nur 36 % der Teilnehmer mit Kindern waren zufrieden mit der Vereinbarkeit von Familie und Beruf an ihrem Arbeitsplatz. Nur 31 % der wissenschaftlich Tätigen waren zufrieden mit ihren Forschungsbedingungen. Zudem war die psychosoziale Arbeitsbelastung unter den befragten Ärzten stark ausgeprägt. Die Arbeitszufriedenheit ist unter radiologischen Assistenzärzten im Vergleich zu anderen Fachrichtungen hoch. Dennoch scheinen auf Basis dieser Erhebung Anpassungen der Arbeits- und Weiterbildungsbedingungen in der Radiologie erforderlich, um die Gesundheit der betroffenen Ärzte zu erhalten, die Motivation für wissenschaftliches Arbeiten zu fördern und die Entwicklungsmöglichkeiten insbesondere von Frauen durch eine bessere Vereinbarkeit von Familie und Beruf aufzuwerten. Die vorliegende Umfrage zeigt Strategien und Führungsinstrumente auf, mit denen dies erreicht werden kann. Ärzte in radiologischer Weiterbildung ... · sind zufrieden mit ihrer beruflichen Situation.. · stehen unter hoher psychosozialer Arbeitsbelastung.. · bewerten die Vereinbarkeit von Familie und Beruf als verbesserungsbedürftig.. · sind an Forschung interessiert, bewerten die Forschungsbedingungen aber als unzureichend..· Oechtering TH, Panagiotopoulos N, Völker M et al. Work and Training Conditions of German Residents in Radiology – Results from a Nationwide Survey Conducted by the Young Radiology Forum in the German Roentgen Society. Fortschr Röntgenstr 2020; 192: 458 – 470.

ZusammenfassungFrakturen im Kindesalter können nicht nur Folge eines Unfalls, sondern auch einer Kindesmisshandlung sein. Diese Differenzierung ist gerade im Kleinkindalter häufig schwierig, für das weitere Vorgehen und die Zukunft der Patientin oder des Patienten aber von größter Bedeutung. Nach Anamneseerhebung und klinischer Untersuchung dienen Röntgenaufnahmen, Laborwerte und weitere Untersuchungen zur Frakturdiagnose und zum Ausschluss anderer Erkrankungen.

Objective Radiotherapy (RT) is an integral part of the interdisciplinary treatment of patients with high-risk neuroblastoma (NB). With the continuous improvements of outcome, the interest in local treatment strategies that reduce treatment-related side effects while achieving optimal oncological results is growing. Proton beam therapy (PBT) represents a promising alternative to conventional photon irradiation with regard to the reduction of treatment burden. Method Retrospective analysis of children with high or intermediate risk NB receiving PBT of the primary tumor site during first-line therapy between 2015 and 2020 was performed. Data from the prospective in-house registry Standard Protonentherapie WPE – Kinder- (KiProReg) with respect to tumor control and treatment toxicity were analyzed. Adverse events were classified according to CTCAE Version 4 (V4.0) before, during, and after PBT. Results In total, 44 patients (24 male, 20 female) with high (n = 39) or intermediate risk NB (n = 5) were included in the analysis. Median age was 3.4 years (range, 1.4–9.9 years). PBT doses ranged from 21.0 to 39.6 Gray (Gy) (median 36.0 Gy). Five patients received PBT to the MIBG-avid residual at the primary tumor site at time of PBT according to the NB-2004 protocol. In 39 patients radiation was given to the pre-operative tumor bed with or without an additional boost in case of residual tumor. After a median follow-up (FU) of 27.6 months, eight patients developed progression, either local recurrence (n = 1) or distant metastases (n = 7). Four patients died due to tumor progression. At three years, the estimated local control, distant metastatic free survival, progression free survival, and overall survival was 97.7, 84.1, 81.8, and 90.9%, respectively. During radiation, seven patients experienced higher-grade (CTCAE ≥ °3) hematologic toxicity. No other higher grade acute toxicity occurred. After PBT, one patient developed transient myelitis while receiving immunotherapy. No higher grade long-term toxicity was observed up to date. Conclusion PBT was a well tolerated and effective local treatment in children with high and intermediate risk NB. The role of RT in an intensive multidisciplinary treatment regimen remains to be studied in the future in order to better define timing, doses, target volumes, and general need for RT in a particularly sensitive cohort of patients.

Das Strategiepapier der GPR zeigt Entwicklungsmöglichkeiten der Kinder- und Jugendradiologie als Querschnittsfach zwischen der Radiologie und der konservativen und operativen Kinder- und Jugendmedizin auf. ZITIERWEISE: · Mentzel H, von Kalle T, Antoch G et al. Challenges in Pediatric Radiology – Strategies of the board of the German speaking Society of Pediatric Radiology. Fortschr Röntgenstr 2020; 192: 531 – 536.

Introduction Recently recessive mutations in sphingosine-1-phosphate lyase (SGPL1) have been published as a cause of syndromic congenital nephrotic syndrome with adrenal insufficiency. We have identified a case with fetal hydrops and brain malformations due to a mutation in SGPL1. Case report We report a patient presenting with severe fetal hydrops, congenital nephrotic syndrome and adrenal calcifications. MRI imaging showed generalized cortical atrophy with simplified gyral pattern and hypoplastic temporal lobes as well as cerebellar hypoplasia and hyperintensity in the pons. The boy deceased at 6 weeks of age. Via whole exome sequencing, we identified a novel homozygous frameshift mutation c.1233delC (p.Phe411Leufs∗56) in SGPL1. Conclusion In our patient, we describe a novel mutation in sphingosine-1-phosphate lyase (SGPL1) leading to severe brain malformation. Neurodevelopmental phenotypes have been reported earlier, but not described in detail. To this end, we present a review on all published SGPL1-mutations and genotype-phenotype correlations focusing on neurodevelopmental outcomes. We hypothesized on the severe neurological phenotypes, which might be due to disruption of neuronal autophagy. Mutations in SGPL1 shall be considered in the differential diagnosis of fetal hydrops as well as congenital brain malformations and neuropathies.

Umbilical cord catheters (UCC) are important for the primary care of critically ill newborns. To analyze anatomical variations of the umbilical vein (UV) and its further course, we performed abdominal spiral-CT examinations on stillborns. The aim of the study was to explore the high incidence of mal-positioned UCCs and to improve their positioning. Eighteen stillborns were investigated (29.2 weeks ± 6.7 weeks (IQR)). CTs were performed using either air or contrast medium injection into the UV. We measured the diameter at the narrowest points of (i) the umbilical vein, (ii) the segmental portal vein, (iii) the left portal vein, (iv) the umbilical recess, and (v) the ductus venosus. The branching angles between (a) the umbilical vein and intrahepatic veins and (b) the ductus venosus and umbilical recess were measured. The diameter of the UV increases from 3.4 to 11 mm (median [IQR]:4.6 mm [4.2-6.9]: r2 = 0.64). The left portal vein has a larger diameter (3.6 mm [2.6-4.55]; r2 = 0.43) than the left segmental portal vein (2.3 mm [1.8-2.75]; r2 = 0.23). The diameter of the ductus venosus (2.5 mm [1.6-3.4]; r2 = 0.59) is half that of the umbilical recess (5.1 mm [3.3-6.2]; r2 = 0.43). The most obtuse angle is formed by the junction between the umbilical recess and ductus venosus (151° [133-159]; r2 = 0.001). The branch angle from the outgoing UV into the left portal vein is more obtuse (128° [123-144]; r2 = 0.0001) than that of the segmental portal vein (115° [105-119]; r2 = 0.0001). To avoid mal-positioning, our data suggest the use of a soft catheter. The UV and its extensions are wide enough to admit a 4 Fr. catheter without complete obstruction. Clin. Anat. 31:269-274, 2018. © 2017 Wiley Periodicals, Inc.

Central venous cannulation is widely used in neonatal critical care. Pericardial tamponade caused by vessel wall perforation can occur if the catheter tip induces extravasation at the level of the pericardium. To investigate the level of the superior pericardial reflection in stillborn babies. We dissected 20 bodies (11 female, mean gestational age 33 6/7 weeks, range 25–43 weeks), with careful opening of the thoracic area. After injecting contrast medium into the pericardial sac, we introduced a catheter through the right internal jugular vein. We then took radiographs to analyse the relationship between visual osseous landmarks and the pericardium. Mean distance between the pericardial reflection at its upper end and the first thoracic vertebra was 1.3 cm (standard deviation [SD]: 0.3 cm) and did not extend over the 3rd intercostal space. The mean distance from the entry of the superior vena cava into the pericardial sac and the 1st thoracic vertebra was 2.3 cm (SD: 0.5). The upper end of the pericardial reflection in neonates at autopsy lies below the middle of the 3rd thoracic vertebra. The tip of an upper inserted catheter should not extend below the level of the 3rd intercostal space.

Conventional lateral spine and hand radiographs are the standard tools to evaluate vertebral morphometry and bone age in children. Beside bone mineral density analyses, dual-energy X-ray absorptiometry (DXA) measurements with lower radiation exposure provide high-resolution scans which are not approved for diagnostic purposes. Data about the comparability of conventional radiographs and DXA in children are missing yet. The purpose of the trial was to evaluate whether conventional hand and spine radiographs can be replaced by DXA scans to diminish radiation exposure. Thirty-eight children with osteogenesis imperfecta or secondary osteoporosis or short stature (male, n=20; age, 5.0-17.0 yr) were included and assessed once by additional DXA (GE iDXA) of the spine or the left hand. Intraclass correlation coefficients (ICCs) were used to express agreement between X-ray and iDXA assessment. Evaluation of the spine morphometry showed reasonable agreement between iDXA and radiography (ICC for fish-shape, 0.75; for wedge-shape, 0.65; and for compression fractures, 0.70). Bone age determination showed excellent agreement between iDXA and radiography (ICC, 0.97). IDXA-scans of the spine in a pediatric population should be used not only to assess bone mineral density but also to evaluate anatomic structures and vertebral morphometry. Therefore, iDXA can replace some radiographs in children with skeletal diseases.

Aim Intraosseous (IO)-access plays an alternative route during resuscitation. Our study was performed to investigate the successful rate of IO-access in preterm and term stillborns using different devices and techniques. Methods The cadavers used were legal donations. 16 stillborns, median: 29.2 weeks (IQR 27.2–38.4) were investigated. Two different needles (a: Butterfly needle, 21G, Venofix® Fa.Braun; b: Arrow®EZ-IO®15G, Teleflex, Dublin, Ireland) were used. Needles were inserted i: manually, using a Butterfly needle; ii: manually, using EZ-IO® needle or iii: using a battery-powered semi-automatic drill (Arrow®EZ-IO®). Spectral-CT's were performed. The diameter of the corticalis was determined from the CT-images. Successful hit rates with 95% confidence intervals (CI) and odds ratios between the three methods were estimated using a generalised linear mixed model (GLMM). Results Estimated success rate was 61.1% (95%CI:39.7%–78.9%) for the Butterfly needle, 43.0% (95%CI:23.4%–65.0%) for hand-twisted EZ-IO® screwing and 39.7% (95%CI:24.1–57.7%) for the semi-automatic drill (Arrow®EZ-IO®), all referring to an average diameter of the corticalis of 1.2 mm. The odds of a correct position were 2.4 times higher (95%CI:0.8–7.6) when using the Butterfly needle than with the drill. In contrast, the odds of correct positioning when inserting the needle by hand were not significantly different from using the drill (odds ratio 1.1, 95%CI: 0.4–3.3). Neither of these effects nor the diameter of the corticalis with an odds ratio near one were significant in the model. Median diameter of the bone marrow cavity was 4.0 mm [IQR 3.3–4.7]. Conclusion Intraosseous access for premature and neonatal infants could be best achieved by using a manually twisted Butterfly needle.

Polycystic kidney disease (PKD) is among the leading causes of end-stage renal disease. Increasing evidence exists that molecular therapeutic strategies targeted to cyst formation and growth might be more efficacious in early disease stages, highlighting the growing need for sensitive biomarkers. Here we apply quantitative magnetic resonance imaging techniques of T2 mapping and diffusion-weighted imaging in the jck mouse model for PKD using a clinical 3.0 T scanner. We tested whether kidney T2 values and the apparent diffusion coefficient (ADC) are superior to anatomical imaging parameters in the detection of early cystogenesis, as shown on macro- and histopathology. We also tested whether kidney T2 values and ADC have the potential to monitor early treatment effects of therapy with the V2 receptor antagonist Mozavaptane. Kidney T2 values and to a lesser degree ADC were found to be highly sensitive markers of early cystogenesis and superior to anatomical-based imaging parameters. Furthermore, kidney T2 values exhibited a nearly perfect correlation to the histological cystic index, allowing a clear separation of the two mouse genotypes. Additionally, kidney T2 values and ADC were able to monitor early treatment effects in the jck mouse model in a proof-of-principle experiment. Thus, given the superiority of kidney T2 values and ADC over anatomical-based imaging in mice, further studies are needed to evaluate the translational impact of these techniques in patients with PKD.

Autosomal recessive polycystic kidney disease (ARPKD) constitutes an important cause of pediatric end stage renal disease and is characterized by a broad phenotypic variability. The disease is caused by mutations in a single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1), which encodes a large transmembrane protein of poorly understood function called fibrocystin. Based on current knowledge of genotype–phenotype correlations in ARPKD, two truncating mutations are considered to result in a severe phenotype with peri- or neonatal mortality. Infants surviving the neonatal period are expected to carry at least one missense mutation. We report on a female patient with two truncating PKHD1 mutations who survived the first 30 months of life without renal replacement therapy. Our patient carries not only a known stop mutation, c.8011C>T (p.Arg2671*), but also the previously reported c.51A>G PKHD1 sequence variant of unknown significance in exon 2. Using functional in vitro studies we have confirmed the pathogenic nature of c.51A>G, demonstrating activation of a new donor splice site in intron 2 that results in a frameshift mutation and generation of a premature stop codon. This case illustrates the importance of functional mutation analyses and also raises questions regarding the current belief that the presence of at least one missense mutation is necessary for perinatal survival in ARPKD.

We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next-generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole-exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with nonsyndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD.

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder associated with bone fragility and susceptibility to fractures after minimal trauma. OI type V has an autosomal-dominant pattern of inheritance and is not caused by mutations in the type I collagen genes COL1A1 and COL1A2. The most remarkable and pathognomonic feature, observed in ∼65% of affected individuals, is a predisposition to develop hyperplastic callus after fractures or surgical interventions. To identify the molecular cause of OI type V, we performed whole-exome sequencing in a female with OI type V and her unaffected parents and searched for de novo mutations. We found a heterozygous de novo mutation in the 5′-untranslated region of IFITM5 (the gene encoding Interferon induced transmembrane protein 5), 14 bp upstream of the annotated translation initiation codon (c.−14C>T). Subsequently, we identified an identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing, thereby confirming that this is the causal mutation for the phenotype. IFITM5 is a protein that is highly enriched in osteoblasts and has a putative function in bone formation and osteoblast maturation. The mutation c.−14C>T introduces an upstream start codon that is in frame with the reference open-reading frame of IFITM5 and is embedded into a stronger Kozak consensus sequence for translation initiation than the annotated start codon. In vitro, eukaryotic cells were able to recognize this start codon, and they used it instead of the reference translation initiation signal. This suggests that five amino acids (Met-Ala-Leu-Glu-Pro) are added to the N terminus and alter IFITM5 function in individuals with the mutation.

Purpose: Osteogenesis imperfecta (OI) is a rare hereditary disease leading to multiple bone deformities and fractures. In the absence of causal therapy, a symptomatic approach is based on treatment with bisphosphonates and physiotherapy. The clinical and radiological manifestations vary. Therefore, standardization and quantification for an objective comparison, especially during therapy, are required. In this paper, radiological changes of the spine are quantified according to their clinical relevance to define a scoring system that transfers the morphological changes into a single value representing the severity of the disease. Materials and Methods: 268 lateral spine X-rays of 95 patients with OI (median age 5.6 years) were assessed. The findings were classified based on their clinical relevance. Results: The three criteria, vertebral compression, thoracolumbar kyphosis and deformity type, were quantified in a new grading system. Based on this, a “severity classification” (1 to 5) was defined with implications for diagnostics and treatment. A mathematical formula that takes into account the three criteria and their correlations to clinical relevance, resulting in a “severity score”, was developed. Conclusion: “Severity classification” and “severity score” introduce a new concept for a standardized evaluation of spine X-rays in patients with OI. For both scientific and routine purposes, it provides the user with a simple and easy-to-handle tool for assessing and comparing different stages of severity prior to and during therapy with detailed accuracy.

Background. The infantile form of primary hyperoxaluria type I (PHI) is the most devastating PH subtype leading to early end-stage renal failure and severe systemic oxalosis. Combined or sequential liver–kidney transplantation (LKTx) is the only curative option but it involves substantial risks, especially in critically ill infants. The procedure also requires resources that are simply not available to many children suffering from PHI worldwide. Less invasive and less complex therapeutic interventions allowing a better timing are clearly needed. Liver cell transplantation (LCT) may expand the narrow spectrum of auxiliary measures to buy time until LKTx for infants can be performed more safely. Methods. We performed LCT (male neonate donor) in a 15-month-old female in reduced general condition suffering from systemic oxalosis. Renal replacement therapy, initiated at the age of 3 months, was complicated by continuous haemodialysis access problems. Living donor liver transplantation was not available for this patient. Plasma oxalate (Pox) was used as the primary outcome measure. Results. Pox decreased from 104.3 6 8.4 prior to 70.0 6 15.0lmol/L from Day 14 to Day 56 after LCT. A significant persistent Pox reduction (P < 0.001) comparing mean levels prior to (103.8 lmol/L) and after Day 14 of LCT until LKTx (77.3 lmol/L) was seen, although a secondary increase and wider range of Pox was also observed. In parallel, the patient’s clinical situation markedly improved and the girl received a cadaveric LKTx 12 months after LCT. However, biopsy specimens taken from the explanted liver did not show male donor cells by amelogenin polymerase chain reaction. Conclusions. With due caution, our pilot data indicate that LCT in infantile oxalosis warrants further investigation. Improvement of protocol and methodology is clearly needed in order to develop a procedure that could assist in the cure of PHI.

Joubert syndrome (JBTS) is characterized by a specific brain malformation with various additional pathologies. It results from mutations in any one of at least 10 different genes, including NPHP1, which encodes nephrocystin-1. JBTS has been linked to dysfunction of primary cilia, since the gene products known to be associated with the disorder localize to this evolutionarily ancient organelle. Here we report the identification of a disease locus, JBTS12, with mutations in the KIF7 gene, an ortholog of the Drosophila kinesin Costal2, in a consanguineous JBTS family and subsequently in other JBTS patients. Interestingly, KIF7 is a known regulator of Hedgehog signaling and a putative ciliary motor protein. We found that KIF7 co-precipitated with nephrocystin-1. Further, knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and microtubular dynamics. Thus, we suggest that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to JBTS.

Ziel: Ziel der vorgestellten Untersuchungen ist die Definition eines Befundungsstandards fur die seitlichen Rontgenaufnahmen der Wirbelsaule bei Patienten mit Osteogenesis imperfecta (OI), der objektivierbar die anatomische Situation vor und unter Bisphosphonattherapie widerspiegelt. Material und Methode: In die retrospektive Studie wurden 48 Patienten (31 wbl., 17 ml, Alter 1,5 Monate bis 19 Jahre, im Mittel 9 Jahre), eingeschlossen. Rontgenaufnahmen der Wirbelsaule im seitlichen Strahlengang vor und unter Therapie wurden im Konsensverfahren von zwei Radiologen ausgewertet. Die Definition des Befundungsstandards ergibt sich aus den Kriterien von Sinterungen einzelner Wirbelkorper, des thorakolumbalen Kyphosewinkels, des vorherrschenden Deformierungstyps der Wirbelkorper und dem Ausmas der Wirbelkorpersinterungen (Grad 1 – 5). Ergebnisse: Die Entwicklung der Einzelsinterungen erwies sich als uneinheitlich. Wirbelkorper mit ventral betonten Hohenminderungen wiesen tendenziell eine Harmonisierung auf, ansonsten blieb der vorherrschende Deformierungstyp weitgehend identisch. Bei 26 Patienten besserte sich die Kyphose, bei 36 Patienten die Hohenminderung der BWK und bei 30 Patienten die der LWK. Eine Verschlechterung war bei zwei Patienten zu verzeichnen. Durchschnittlich kam es zu einer Abnahme des Kyphosewinkels um etwa 10° und der Hohenminderungen in BWS und LWS um eine Gradeinteilung. Schlussfolgerung: Zur reprasentativen Beschreibung der Wirbelsaulenbefunde bei OI-Patienten wird ein Befundungsstandard eingefuhrt, der Einzelkorpersinterungen, thorakolumbale Kyphosewinkel, Wirbelkorperformen und die Graduierung der Wirbelkorpersinterungen in BWS und LWS umfasst. Die Wirbelkorpermorphometrie wird im Verlauf wiedergegeben und die thorakolumbale Kyphose als wichtiges Element mit einbezogen. Purpose: In this study we present a standard for radiological reports in patients with osteogenesis imperfecta (OI). The parameters can be used to describe X-rays of the lateral spine and give an impartial description of anatomical structures during a treatment with bisphosphonates. Material and Methods: In this retrospective analysis we included 48 patients with OI (31 female, 17 male [1.5 months – 19 years, mean age 9.0 years]). Lateral spine X-rays were analyzed by 2 radiologists before and during treatment. The parameters of the standardized report are degree of kyphoscoliosis, compression of single vertebrae, predominant type of vertebral deformities and extent of vertebral compression (score 1 – 5). Results: There was no clear trend in the change of compression of single vertebrae. Some vertebrae with ventral compression showed an upgrowth to vertebrae with harmonic compression. Other deformities showed only marginal changes. In 26 patients the kyphoscoliosis improved (mean 10 degrees), in 36 patients the thoracic vertebrae compression increased and in 30 patients the vertebral height in the lumbar spine increased. The improvement of vertebral height was 1 point in the thoracic and lumbar spine. Conclusion: We propose a standardized report of X-rays of the lateral spine in patients with OI with quantitative and semiquantitative parameters using morphological criteria. These include compression of single vertebrae, degree of kyphoscoliosis, vertebral deformities and the severity of vertebral compression in the thoracic and lumbar spine.

Background Osteogenesis imperfecta (OI) is a hereditary disease causing reduced bone mass, increased fracture rate, long bone deformities and vertebral compressions. Additional non skeletal findings are caused by impaired collagen function and include hyperlaxity of joints and blue sclera. Most OI cases are caused by dominant mutations in COL1A1/2 affecting bone formation. During the last years, recessive forms of OI have been identified, mostly affecting posttranslational modification of collagen. In 2011, mutations in SERPINF1 were identified as the molecular cause of OI type VI, and thereby a novel pathophysiology of the disease was elucidated. The subgroup of patients with OI type VI are affected by an increased bone resorption, leading to the same symptoms as observed in patients with an impaired bone formation. Severely affected children are currently treated with intravenous bisphosphonates regardless of the underlying mutation and pathophysiology. Patients with OI type VI are known to have a poor response to such a bisphosphonate treatment. Method Deciphering the genetic cause of OI type VI in our 4 patients (three children and one adolescent) led to an immediate translational approach in the form of a treatment with the monoclonal RANKL antibody Denosumab (1 mg/kg body weight every 12 weeks). Results Short-term biochemical response to this treatment was reported previously. We now present the results after 2 years of treatment and demonstrate a long term benefit as well as an increase of bone mineral density, a normalization of vertebral shape, an increase of mobility, and a reduced fracture rate. Conclusion This report presents the first two-year data of denosumab treatment in patients with Osteogenesis imperfecta type VI and in Osteogenesis imperfecta in general as an effective and apparently safe treatment option.

Purpose Resection is generally considered the gold standard for treatment of low-grade (WHO grades I and II) gliomas (LGGs) in childhood. However, approximately 30% to 50% of these tumors are inoperable because of their localization in highly eloquent brain areas. A few reports have suggested stereotactic brachytherapy (SBT) with implantation of iodine-125 (125I) seeds as a safe and effective local treatment alternative. This single-center study provides a summary of the long-term outcome after SBT in one of the largest reported patient series. Patients and Methods All pediatric patients treated with SBT (125I seeds; cumulative therapeutic dose 50-65 Gy within 9 months) by our group for LGG with follow-up of more than 6 months were included. Clinical and radiologic outcome, time to progression, and overall survival were evaluated. Prognostic factors (age, sex, Karnofsky performance score, tumor volume, and histology) for survival and disease progression were investigated. Results In all, 147 of 160 pediatric patients treated with SBT (from 1982 through 2009) were analyzed in detail. Procedure-related mortality was zero, and the 30-day morbidity was transient and low (5.4%). Survival rates at 5 and 10 years were 93%, and 82%, respectively, with no significant difference between WHO grades I and II tumors (median follow-up, 67.1 ± 57.7 months). Twenty-one (14.8%) of 147 patients presented with tumor relapse. The remaining 126 patients revealed complete response in 24.6%, partial response in 31.0%, and stable disease in 29.6%. Neurologic status improved (57.8%) or remained stable (23.0%). None of the evaluated factors had significant impact on the study's end points except tumor volume more than 15 mL, which caused significantly higher rates of tumor recurrence (P < .05). Conclusion We demonstrate that SBT represents a safe, minimally invasive, and highly effective local treatment option for pediatric patients with inoperable LGG WHO grades I and II.

Cleft palates are among the most common birth defects. Serious complications in perioperative airway management after palatoplasty are rare and mostly described in children with preexisting compromise of airway due to craniofacial anomalies. A very uncommon but typical and frightening complication is postoperative extreme, very rapid emergence, and life-threatening macroglossia. While macroglossia usually has its peak within 24–48 h after palatoplasty and resolves spontaneously, we report a patient with massive lingual swelling with complete obstruction of the upper airway on the fifth postoperative day requiring tracheotomy. Swelling only resolved after removing the endotracheal tube after tracheotomy. Next to the description of our case, we discuss standard care procedure in perioperative management of patients with cleft palate to prevent this life-threatening complication after palatoplasty. Conclusion: Macroglossia can occur even 3–5 days after surgery and can be maintained by the pressure of the endotracheal tube to the tongue ground. Knowledge and avoidance of these risk factors are as important as early treatment of respiratory compromise.

Item does not contain fulltext Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis.

Background/Aims: Osteogenesis imperfecta (OI) is a hereditary disease causing increased bone fragility. Pamidronate (PAM), which has to be administered as a 3-day course according to the original protocol by Glorieux, is the most frequently used therapy. Other bisphosphonates like neridronate (NER), which can be infused during an outpatient visit, have also proven to be effective. This is the first analysis comparing the effect of PAM and NER using vertebral morphometry. Methods: 28 patients with OI type III and IV were retrospectively analyzed by matched pairs. Results: No differences were detected between patients treated with PAM or NER at the start of therapy: mean age 4.4 years (p = 0.730), mean height 86.8 cm/85.3 cm (p = 0.854), lumbar vertebral area 208.9 mm2/206.0 mm2 (p = 0.555), and in all vertebral indices. After 1 year of treatment (mean 1.16 years; p = 0.854) both groups showed a significant increase in the vertebral area and improved vertebral indices. Again there were no differences between the groups in the vertebral area (p = 0.590). Conclusion: In this study there was no difference between patients treated with PAM or NER regarding vertebral morphometry during the first year of therapy. Because of the possibility of an outpatient setting, NER is convenient for these children.

Hyperphosphatemic Familial Tumoral Calcinosis (HFTC; MIM211900) is a rare autosomal recessive disorder characterized by the progressive deposition of calcified masses in cutaneous and subcutaneous tissues, associated with elevated circulating levels of phosphate. The disease was initially found to result from mutations in GALNT3 encoding a glycosyltransferase. However, more recently, the S71G missense mutation in FGF23, encoding a potent phosphaturic protein, was identified in two families. In the present report, we describe a second mutation in FGF23 underlying a severe case displaying calcifications of cutaneous and numerous extracutaneous tissues. The mutation (M96T) was found to affect a highly conserved methionine residue at position 96 of the protein. These observations illustrate the extent of genetic and phenotypic heterogeneity in HFTC.

et al., We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated β-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis., This work was supported by German Federal Ministry of Education and Research grants 01GM1211A (E-RARE network CRANIRARE-2), 01GM1109C (national rare disease network Forschungsverbund Ausgewählter Craniofacialer Entwicklungsstörungen) to B.W., and 01EC1006A (Molecular Pathogenesis of Osteoporosis) to U.K. and S.M., by TÜBITAK grant 112S398 (E-RARE network CRANIRARE-2) to H.K., and by National Institute of Child Health and Human Development (National Institutes of Health) Intramural Research Program funding to S.L. and J.C.M. M.S. holds a Doc female forte scholarship from Austria and is a member of the Berlin-Brandenburg School for Regenerative Therapies.