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BackgroundFetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We aimed to further define the set of genes involved.MethodsWe performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature.ResultsWe identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in the kinesin family member 21A gene (KIF21A) was found.ConclusionOur study underlines the broad locus heterogeneity of FA with well-established and atypical genotype–phenotype associations. We describe KIF21A as a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets., publishedVersion

This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).

Fetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We aimed to further define the set of genes involved.We performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature.We identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in theOur study underlines the broad locus heterogeneity of FA with well-established and atypical genotype-phenotype associations. We describe

Objective The objective of this report of a fatal propofol-related infusion syndrome in a young adult was to present-to our knowledge for the first time-direct ultrastructural evidence for the central role of mitochondrial damage in the pathogenesis of this syndrome. Data sources Histological and electron microscopical analysis of liver, skeletal, and heart muscle obtained by autopsy and blood obtained from patient. Study selection Case report. Data extraction In addition to conventional macroscopical and histological investigations, electron-microscopical analysis of myocardial- and skeletal muscle and liver tissue obtained at autopsy from a young man was performed in order to search for ultrastructural changes of mitochondria. Acylcarnitine concentrations of his blood were determined by ultra-high performance liquid chromatography mass spectrometry. Data synthesis A 19-year-old male was admitted with acute left-side hemiparesis. The patient was intubated, then propofol infusion started, and a craniotomy was performed to remove an intracerebral hematoma. In the postoperative period, the patient presented with elevated intracranial pressure and brain edema. After repeat surgery, the patient showed impaired systolic left ventricular function, increasing fever, anuria, hyperkalemia, and metabolic acidosis, and he finally expired. Electron microscopy revealed dark, electron dense amorphous structures associated with mitochondria in heart muscle and liver tissue obtained at autopsy. Peripheral blood analysis revealed increased levels of acetyl-, propionyl-, butyryl-, malonyl-, and valeryl-carnitine as an indicator for propofol-related infusion syndrome, as well as for propofol-mediated inhibition of free fatty acid uptake into mitochondria, affecting beta-oxidation. Conclusions Electron dense bodies found in association with mitochondria in muscle and liver cells probably correspond to accumulation of free fatty acid provide direct morphological evidence for the mitochondrial damage in propofol-related infusion syndrome.

Human Cytomegalovirus (CMV) infection during pregnancy is the most frequent viral cause of intrauterine infection and responsible for various cerebral and other ultrasound abnormalities of the fetus. It is the leading infectious cause of mental retardation and sensorineural deafness in affected newborns and infants. We present three cases of primary cytomegalovirus infection in pregnancy and demonstrate three different scenarios of the disease with regard to clinical outcome and therapy options. We first report on CMV related phospho- and glycoprotein-specific antibody reactivities in amnion fluid that have not been reported earlier in literature.Case 1: A 33-year-old Gravida II Para I was referred for primary CMV infection at 15 weeks gestation presenting with a history of fever. HIG therapy was performed resulting in good neonatal outcome. Case 2: A 23-year-old Gravida I was referred for targeted ultrasound at 23 weeks of gestation presenting with intrauterine growth retardation, multiple fetal hepatic echodensities and thickened placenta. Termination of pregnancy was initiated. Case 3: A 29-year-old Gravida II Para I was referred for primary CMV infection at 16 weeks gestation presenting with no clinical symptoms of CMV. HIG therapy was performed, resulting in good neonatal outcome.We want to stress the potential benefit of an off label use of CMV-specific hyperimmune globulin (HIG) therapy, present an algorithm for the management of affected pregnancies and review current literature on this issue.

A 55-year old man suffers from progressive, distinctive dyspnoea and physical weakness since 5 days. Due to ST-segment changes in the ECG and a positive troponin-test, the primary care physician initiates an hospitalization.After admission, the laboratory tests confirm the elevated troponin-values, and show additionally elevated pro-brain-natriuric-peptide-values. The coronary angiography presents a highly reduced left ventricular function, an aortic insufficiency III° and a coronary heart disease.After clinical deterioration and fever up to 42°C with consecutive tachycardia, the patient is taken over to the intensive care unit. Blood cultures are taken and an empirical antibiotic treatment is started. The patient dies within a few hours in catecholamine refractory circulatory failure. In the autopsy we find signs of an acute recurrent bacterial aortic valve endocarditis with a paravalvular abscess in the myocardium and a septic abscess in the left kidney. The patient died on acute left ventricular failure.The manifestation of an endocarditis can be presented very variable and can thus be a challenge in clinical practice. For one thing, the disease presents as an acute, rapidly progressive infection, on the other hand it acts as subacute or chronic disease with just little fever and nonspecific symptoms. To initiate an adequate therapy without loss of time, endocarditis should be included in the differential diagnosis where the risk profile is evident. There are risk factors (poor dental status, intravenous drug use, artificial valve or cardiological devices) for endocarditis. These risk factors with additional symptoms should always be given to a further diagnostics to detect an endocarditis. In addition to a multiple cultivation and laboratory analysis additional diagnostics such as ECG, echocardiography (transthoracic, transthoracic) and chest X-ray should be performed. Further stratification of patients is then performed using the modified Duke criteria. The anti-infective therapy is carried out using the new ESC Guidelines (2015). If a surgical procedure is indicated, this should be done in close consultation with the colleagues of Thoracic and Cardiovascular Surgery.

We report on a 48-year-old man presenting with progressive hepatopathy and encephalopathy for two weeks based on a chronic hepatitis C. He takes ledipasvir and sofosbuvir (Harvoni) and ribavirin for almost 24 weeks. After admission to hospital his state deteriorated rapidly. He is directly transferred to the medical intensive care unit, where he died on day 3.During the physical examination, a pronounced jaundice and significant peripheral edema were found. Laboratory tests showed anemia, an increased C-reactive proteine and bilirubin, a limited coagulation and renal insufficiency with elevated creatinine. Quantitative HCV-PCR was negative. Echocardiographically a severe tricuspid- and mitral-valve regurgitation was found in a massively increased pulmonary artery pressure and pulmonary heart disease. The gastroscopy revealed a Forrest IIb situation with corresponding clip supply.In the autopsy we find signs of portal hypertension in presence of progressive liver cirrhosis. In addition, portopulmonary hypertension is diagnosed. The patient died on right ventricular failure resulting from a massively increased pulmonary pressure Conclusion: Advanced liver disease and an increased pulmonary pressure are often associated. Therefore, an early as possible diagnosis and classification are essential for adequate therapy in these patients.

Tolerance induction toward the semiallogeneic fetus is crucial to enable a successful pregnancy; its failure is associated with abortion or preterm delivery. Skewing T cell differentiation toward a Th2-dominated phenotype seems to be pivotal in maternal immune adaption, yet underlying mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that mediate T cell suppression and are increased in cord blood of healthy newborns and in peripheral blood of pregnant women. In this study, we demonstrate that granulocytic MDSCs (GR-MDSCs) accumulate in human placenta of healthy pregnancies but are diminished in patients with spontaneous abortions. Placental GR-MDSCs effectively suppressed T cell responses by expression of arginase I and production of reactive oxygen species and were activated at the maternal–fetal interface through interaction with trophoblast cells. Furthermore, GR-MDSCs isolated from placenta polarized CD4+ T cells toward a Th2 cytokine response. These results highlight a potential role of GR-MDSCs in inducing and maintaining maternal–fetal tolerance and suggest them as a promising target for therapeutic manipulation of pregnancy complications.

Myxoma in neonatal life are extremely rare. We report a case of a neonate with a pedunculated cardiac tumour arising from the anterolateral left ventricular wall protruding across the left ventricular outflow tract and continuously extending into the distal aortic arch. Surgical removal at 14 days of age via combined transaortic approach and apical ventriculotomy was indicated because of the risk of further compromise of aortic valve function and aortic arch obstruction. Histopathologic examination was consistent with a myxoma.

Anamnese und klinischer Befund: Ein 55-jahriger Mann klagt seit 5 Tagen uber zunehmende, ausgepragte Dyspnoe und Leistungsminderung. Beim Hausarzt zeigten sich im EKG ST-Strecken-Veranderungen, ein Troponin-Schnelltest war positiv. Bei der stationaren Aufnahme finden sich erneut erhohte Troponin- und „pro-brain-natriuric“-Peptid-Werte. Untersuchungen: Die Koronarangiografie ergibt eine hochgradig reduzierte linksventrikulare Funktion bei Aortenklappeninsuffizienz III° und koronarer 1-Gefas-Erkrankung. Diagnose, Therapie und Verlauf: Bei klinischer Verschlechterung und Fieber bis 42°C mit konsekutiver Tachykardie wird der Patient auf die Intensivstation ubernommen, Kulturen abgenommen und eine empirische Antibiose begonnen. Am Folgetag kommt es zu einem generalisierten Krampfanfall mit 20-minutiger Reanimation. Der Patient stirbt innerhalb weniger Stunden an einem Katecholamin-refraktaren Kreislaufversagen. Bei der Obduktion finden sich eine akut rezidivierende bakterielle Aortenklappenendokarditis mit paravalvularer Abszessbildung im Myokard und einem septischen Abszess im Bereich der linken Niere. Todesursache war ein akutes Linksherzversagen. Diskussion: Eine Endokarditis kann sich sehr variabel manifestieren und kann damit eine Herausforderung im klinischen Alltag sein: Zum einen prasentiert sich das Krankheitsbild als akute, rasch progrediente Infektion, zum anderen tritt sie als subakute oder chronische Erkrankung mit nur geringem Fieber und einer unspezifischen Symptomatik in Erscheinung. Bei entsprechendem Risikoprofil sollte eine infektiose Endokarditis in die Differenzialdiagnosen einbezogen werden, um ohne grosen Zeitverlust eine adaquate Therapie einleiten zu konnen. Es gibt Risikofaktoren (schlechter Zahnstatus, iv Drogenkonsum, Kunstklappe oder ein kardiologisches Device), die bei zusatzlicher Symptomatik immer eine weiterfuhrende Diagnostik nach sich ziehen sollten (mehrfache Kultivierung, EKG, Echokardiografie [transthorakal, transosophageal] und Rontgen-Thorax). Die weitere Stratifizierung der Patienten erfolgt anschliesend anhand der modifizierten Duke-Kriterien. Die antiinfektive Therapie wird anhand der neuen europaischen Richtlinien von 2015 durchgefuhrt. Ist bei entsprechender Indikation ein chirurgisches Vorgehen indiziert, sollte dies in enger Absprache mit den Kollegen der Thorax-, Herz- und Gefaschirurgie erfolgen.

Anamnese und klinischer Verlauf: Der 55-jahriger Patient litt seit 6 Monaten an einer progredienten Hepatopathie und seit 12 Monaten unter rezidivierenden thorakalen Beschwerden. Er stellte sich mit Verschlechterung des Allgemeinzustands und einem progredienten Ikterus seit einer Woche vor. Untersuchungen: Der Stuhl war entfarbt, der Urin hingegen dunkel. Der Troponinwert war erhoht. In der Untersuchung des Spontanurins fand sich eine ausgepragte unselektierte Proteinurie, in der Serumprotein-Elektrophorese zeigte sich eine Hypogammaglobulinamie. Im Rontgen-Thorax zeigte sich ein Pleuraerguss links, die Echokardiographie zeigte eine hypertrophe nicht obstruktive Kardiomyopathie. Die Leber war vergrosert. Im weiteren Verlauf verschlechterte sich der Allgemeinzustand des Patienten rasch und es entwickelte sich eine progrediente Niereninsuffizienz, sodass 8 Tage nach Aufnahme eine Hamodialyse begonnen wurde. 13 Tage nach Aufnahme wurde der Patient auf die internistische Intensivsation verlegt, wo er starb. Obduktion und Diagnose: Bei der Obduktion fanden sich kongophile Ablagerungen in allen Organen mit Nachweis von Amyloid-p-Komponente und kappa-Leichtketten. Im Knochenmark zeigte sich keine Plasmazellvermehrung, so dass die Diagnose einer primaren systemischen AL-Amyloidose gestellt wurde. Folgerung: Da die Prognose der Erkrankung vom Amyloidtyp und der individuellen Ausbreitung abhangt, sind Fruherkennung und Klassifikation des Amyloidose essentiell zur Steuerung der Therapie.