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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.

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.

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.

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.

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.