Publications by authors named "Elisabeth Bruder"

59 Publications

Lack of Mucosal Cholinergic Innervation Is Associated With Increased Risk of Enterocolitis in Hirschsprung's Disease.

Cell Mol Gastroenterol Hepatol 2021 Mar 16. Epub 2021 Mar 16.

Department of Pediatric Surgery, University Children's Hospital Basel (UKBB) and University of Basel, Basel, Switzerland.

Background & Aims: Hirschsprung's disease (HSCR) is a congenital intestinal motility disorder defined by the absence of enteric neuronal cells (ganglia) in the distal gut. The development of HSCR-associated enterocolitis remains a life-threatening complication. Absence of enteric ganglia implicates innervation of acetylcholine-secreting (cholinergic) nerve fibers. Cholinergic signals have been reported to control excessive inflammation, but the impact on HSCR-associated enterocolitis is unknown.

Methods: We enrolled 44 HSCR patients in a prospective multicenter study and grouped them according to their degree of colonic mucosal acetylcholinesterase-positive innervation into low-fiber and high-fiber patient groups. The fiber phenotype was correlated with the tissue cytokine profile as well as immune cell frequencies using Luminex analysis and fluorescence-activated cell sorting analysis of colonic tissue and immune cells. Using confocal immunofluorescence microscopy, macrophages were identified in close proximity to nerve fibers and characterized by RNA-seq analysis. Microbial dysbiosis was analyzed in colonic tissue using 16S-rDNA gene sequencing. Finally, the fiber phenotype was correlated with postoperative enterocolitis manifestation.

Results: The presence of mucosal nerve fiber innervation correlated with reduced T-helper 17 cytokines and cell frequencies. In high-fiber tissue, macrophages co-localized with nerve fibers and expressed significantly less interleukin 23 than macrophages from low-fiber tissue. HSCR patients lacking mucosal nerve fibers showed microbial dysbiosis and had a higher incidence of postoperative enterocolitis.

Conclusions: The mucosal fiber phenotype might serve as a prognostic marker for enterocolitis development in HSCR patients and may offer an approach to personalized patient care and new therapeutic options.
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http://dx.doi.org/10.1016/j.jcmgh.2021.03.004DOI Listing
March 2021

Placental Pathology Findings during and after SARS-CoV-2 Infection: Features of Villitis and Malperfusion.

Pathobiology 2021 18;88(1):69-77. Epub 2020 Sep 18.

Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.

Since the outbreak of coronavirus disease 2019 (COVID-19), there has been a debate whether pregnant women are at a specific risk for COVID-19 and whether it might be vertically transmittable through the placenta. We present a series of five placentas of SARS coronavirus 2 (SARS-CoV-2)-positive women who had been diagnosed with mild symptoms of COVID-19 or had been asymptomatic before birth. We provide a detailed histopathologic description of morphological changes accompanied by an analysis of presence of SARS-CoV-2 in the placental tissue. All placentas were term deliveries (40th and 41st gestational weeks). One SARS-CoV-2-positive patient presented with cough and dyspnoea. This placenta showed prominent lymphohistiocytic villitis and intervillositis and signs of maternal and foetal malperfusion. Viral RNA was present in both placenta tissue and the umbilical cord and could be visualized by in situ hybridization in the decidua. SARS-CoV-2 tests were negative at the time of delivery of 3/5 women, and their placentas did not show increased inflammatory infiltrates. Signs of maternal and/or foetal malperfusion were present in 100% and 40% of cases, respectively. There was no transplacental transmission to the infants. In our cohort, we can document different time points regarding SARS-CoV-2 infection. In acute COVID-19, prominent lymphohistiocytic villitis may occur and might potentially be attributable to SARS-CoV-2 infection of the placenta. Furthermore, there are histopathological signs of maternal and foetal malperfusion, which might have a relationship to an altered coagulative or microangiopathic state induced by SARS-CoV-2, yet this cannot be proven considering a plethora of confounding factors.
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http://dx.doi.org/10.1159/000511324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573905PMC
February 2021

Dual independent genetic etiologies in a lethal complex malformation phenotype.

Ultraschall Med 2020 04 7;41(2):112-114. Epub 2020 Apr 7.

Center for Prenatal Ultrasound, Freie Strasse, Basel and University of Basel, Switzerland.

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http://dx.doi.org/10.1055/a-1104-3625DOI Listing
April 2020

Expanding the spectrum of SMAD3-related phenotypes to agnathia-otocephaly.

Mol Genet Genomic Med 2020 04 26;8(4):e1178. Epub 2020 Feb 26.

Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Agnathia-otocephaly is a rare and lethal anomaly affecting craniofacial structures derived from the first pharyngeal arch. It is characterized by agnathia, microstomia, aglossia, and abnormally positioned auricles with or without associated anomalies. Variants affecting function of OTX2 and PRRX1, which together regulate the neural crest cells and the patterning of the first pharyngeal arch as well as skeletal and limb development, were identified to be causal for the anomaly in a few patients.

Methods: Family-based exome sequencing (ES) on a fetus with severe agnathia-otocephaly, cheilognathopalatoschisis, laryngeal hypoplasia, fused lung lobes and other organ abnormalities and mRNA expression analysis were performed.

Results: Exome sequencing detected a de novo SMAD3 missense variant in exon 6 (c.860G>A) associated with decreased mRNA expression. Variants in SMAD3 cause Loeys-Dietz syndrome 3 presenting with craniofacial anomalies such as mandibular hypoplasia, micro- or retro-gnathia, bifid uvula and cleft palate as well as skeletal anomalies and arterial tortuosity. The SMAD3 protein acts as a transcriptional regulator in the transforming growth factor β (TGFB) and bone morphogenetic (BMP) signaling pathways, which play a key role in the development of craniofacial structures originating from the pharyngeal arches.

Conclusion: Agnathia-otocephaly with or without associated anomalies may represent the severe end of a phenotypic spectrum related to variants in genes in the interacting SMAD/TGFB/BMP/SHH/FGF developmental pathways.
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http://dx.doi.org/10.1002/mgg3.1178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196462PMC
April 2020

Hectd1 is essential for embryogenesis in mice.

Gene Expr Patterns 2019 12 10;34:119064. Epub 2019 Jul 10.

Department of Biomedicine, University Hospital, University of Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland. Electronic address:

Many aspects of the functional role of the E3 ubiquitin ligase Hectd1 in embryogenesis and in cell biology still remain to be elucidated. In order to contribute to this task we now report the generation of a new transgenic mouse model for Hectd1 using the gene trap strategy. The HECT domain deletion mutant mouse was created by inserting a β-geo cassette into the Hectd1 locus. Mice homozygous for Hectd1-mutant showed early embryonic lethality with abnormal placental development and defective of neural tube closure resulting in exencephaly. The thickness of the placenta of both Hectd1-mutant homozygous and heterozygous mice was distinctly thinner than that of wildtype mice, the difference being most pronounced in the labyrinth layer of the placenta. We also addressed the temporal and spatial expression profiles of Hectd1 in adult tissues by X-gal staining. Hectd1 expression was detected in specific cell populations of most but not all tissues of the adult organism. Furthermore, the expression of Hectd1 was regulated by insulin and by both heat and hypoxia. Thus, our studies reveal that Hectd1 is indispensable for normal embryogenesis and fetal survival. The generation of this new Hectd1 mutant mouse model provides ample opportunities to study the function of Hectd1 in mammalian cells in detail.
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http://dx.doi.org/10.1016/j.gep.2019.119064DOI Listing
December 2019

Sialoblastoma of the submandibular gland: a distinct entity?

Eur J Pediatr 2019 Aug 1;178(8):1301-1304. Epub 2019 Jul 1.

Department of Otolaryngology, University Hospital Basel, University of Basel, 4031, Basel, Switzerland.

Sialoblastoma is a rare congenital malignant tumor of the salivary glands. A case of a submandibular sialoblastoma in a 1.5-year-old child is presented. A comparative analysis on 79 pediatric cases reported in the literature suggests a less aggressive behavior for submandibular sialoblastoma in comparison with other sites. Classically, diagnosis is confirmed by open biopsy, but fine-needle aspiration may offer an alternative with reduced morbidity. Expression of AFP and high levels of Ki-67 have been associated with poor prognosis. Whilst early surgical resection with negative margins is widely accepted as first-line treatment, there is no consensus on therapy of recurrence and follow-up. MRI and sonography represent valid tools for the follow-up, which is usually restricted to 3-5 years.Conclusion: Submandibular sialoblastomas may have a different biological profile in comparison with parotid tumors with the absence of metastasis and much lower rate of recurrence. Comprehensive diagnostics should include additional options such as fine-needle aspiration and markers to assess cell proliferation and AFP. Literature suggests that surgery alone is sufficient for the treatment of tumors with low malignancy. Follow-up should be tailored according to the tumor site and might be limited to 3-5 years. What is Known: • Sialoblastoma is a rare congenital malignant tumor with an unpredictable clinical outcome. What is New: • Sialoblastoma of submandibular origin seems to have a less aggressive behavior in comparison with other sites. • Fine-needle aspiration and markers to assess proliferation index (i.e., suggestive of potential more aggressive course/malignancy) should be strongly considered in the diagnostic work-up. • Radical surgery as first-line therapy and a 3-5-year follow-up are acceptable for tumors with a low malignancy.
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http://dx.doi.org/10.1007/s00431-019-03411-xDOI Listing
August 2019

Exome sequencing of fetal anomaly syndromes: novel phenotype-genotype discoveries.

Eur J Hum Genet 2019 05 24;27(5):730-737. Epub 2019 Jan 24.

Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.

The monogenic etiology of most severe fetal anomaly syndromes is poorly understood. Our objective was to use exome sequencing (ES) to increase our knowledge on causal variants and novel candidate genes associated with specific fetal phenotypes. We employed ES in a cohort of 19 families with one or more fetuses presenting with a distinctive anomaly pattern and/or phenotype recurrence at increased risk for lethal outcomes. Candidate variants were identified in 12 families (63%); in 6 of them a definite diagnosis was achieved including known or novel variants in recognized disease genes (MKS1, OTX2, FGFR2, and RYR1) and variants in novel disease genes describing new fetal phenotypes (CENPF, KIF14). We identified variants likely causal after clinical and functional review (SMAD3, KIF4A, and PIGW) and propose novel candidate genes (PTK7, DNHD1, and TTC28) for early human developmental disease supported by functional and cross-species phenotyping evidence. We describe rare and novel fetal anomaly syndromes and highlight the diagnostic utility of ES, but also its contribution to discovery. The diagnostic yield of the future application of prenatal ES will depend on our ability to increase our knowledge on the specific phenotype-genotype correlations during fetal development.
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http://dx.doi.org/10.1038/s41431-018-0324-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461982PMC
May 2019

Juvenile xanthogranuloma involving concurrent iris and skin: Clinical, pathological and molecular pathological evaluations.

Am J Ophthalmol Case Rep 2018 Mar 23;9:10-13. Epub 2017 Sep 23.

Department of Pathology, University Basel, Schönbeinstrasse 40, 4003 Basel, Switzerland.

Purpose: To report a case of juvenile xanthogranuloma involving the iris and skin that clincally was diagnosed with an obvious cutaneous lesion.

Observations: A four month-old girl with hyphema and increased intraocular pressure of the left eye persisting for 2 weeks. A suspicious yellow-brown mass with nodular surface and traversed by irregular vascularization was noted on the inferior iris surface. Ultrasound biomicroscopy (UBM; 35 MHz) of the mass revealed multiple nodular irregular hyperreflective lesions in the peripheral iris. Using a biopsy of an obvious cutaneous abdominal skin lesion a diagnosis was made based on histopathological analyses. The biopsy showed dense dermal infiltrate consisting of foamy histiocytes. Additional stains revealed CD68 positivity and CD1a and S100 negativity. This mass revealed histopathologic features identical to juvenile xanthogranuloma and was concurrent with the iris lesion. Next-generation sequencing using Ion AmpliSeqTM Cancer Hotspot Panel revealed a missense mutation of (p.F386L).

Conclusion And Importance: The diagnosis of a xanthogranuloma of the iris with hyphema can be made easier in patients with obvious cutaneous lesions as described in our case. The significance of mutation in association with JXG is unknown and should be further investigated.
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http://dx.doi.org/10.1016/j.ajoc.2017.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787822PMC
March 2018

Diagnostic Criteria of Pediatric Intestinal Myopathies.

J Pediatr Gastroenterol Nutr 2018 03;66(3):383-386

DiNOGMI, University of Genova.

The authors aim to identify criteria for the diagnosis of intestinal visceral myopathy (IVM); results were compared with ultrastructural studies. Six IVM patients and 7 pediatric control cases (without gastrointestinal diseases) were studied. One case was a typical megacystis-microcolon-intestinal hypoperistalsis syndrome. The diagnostic path included: rectal suction biopsy, one-trocar transumbilical laparoscopic intestinal full-thickness biopsy technique. Pathological analysis included anti-alpha smooth muscle actin staining, and US study of intestinal biopsies. IVM histological examination demonstrated thinning of longitudinal muscle layer. The ratio of circular/longitudinal thickness was evaluated in all samples; in cases, this ratio presented as a mean value of 2.91, and in controls, a mean value of 1.472 (P = 0.0002). Ultrastructural diagnosis revealed variable myofibrils density in smooth muscle cells, irregularity of sarcolemma membranes, interstitial fibrosis, and myofiber disarray. The authors concluded that in IVM, circular/longitudinal thickness ratio and alpha smooth muscle actin staining can be used as significant tools to address the diagnosis.
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http://dx.doi.org/10.1097/MPG.0000000000001727DOI Listing
March 2018

A novel homozygous splice-site mutation in RYR1 causes fetal hydrops and affects skeletal and smooth muscle development.

Prenat Diagn 2017 07 13;37(7):720-724. Epub 2017 Jun 13.

Medical Genetics, University Hospital Basel, Basel, Switzerland.

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http://dx.doi.org/10.1002/pd.5073DOI Listing
July 2017

HECTD1 controls the protein level of IQGAP1 to regulate the dynamics of adhesive structures.

Cell Commun Signal 2017 01 5;15(1). Epub 2017 Jan 5.

Department of Biomedicine, University Hospital, University of Basel, Basel, Switzerland.

Background: Cell migration including collective cell movement and individual cell migration are crucial factors in embryogenesis. During the spreading/migration of cells, several types of adhesive structures physically interacting with the extracellular matrix (ECM) or with another cell have been described and the formation and maturation of adhesion structures are coordinated, however the molecular pathways involved are still not fully understood.

Results: We generated a mouse embryonic fibroblast line (MEF) from homozygous mutant (Hectd1 , Hectd1 ) mouse of the E3 ubiquitin ligase for inhibin B receptor (Hectd1). Detailed examination of cell motion on MEF cells demonstrated that loss of Hectd1 resulted in accelerated cell spreading and migration but impaired directionality of migration. In Hectd1 cells paxillin and zyxin were largely mis-localized, whereas their expression levels were unchanged. In addition the formation of focal adhesions (FAs) was impaired and the focal complexes (FXs) were increased. We further identified HECTD1 as a key regulator of IQGAP1. IQGAP1 co-localized together with HECTD1 in the leading edge of cells. HECTD1 interacted with IQGAP1 and regulated its degradation through ubiquitination. Over-expression of IQGAP1 in control MEF phenocopied the spreading and migration defects of Hectd1 cells. In contrast, siRNA-mediated knockdown of IQGAP1 rescued the defects in cellular movement of Hectd1 cells.

Conclusions: The E3 ligase activity of Hectd1 regulates the protein level of IQGAP1 through ubiquitination and therefore mediates the dynamics of FXs including the recruitment of paxillin and actinin. IQGAP1 is one of the effectors of HECTD1.
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http://dx.doi.org/10.1186/s12964-016-0156-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225595PMC
January 2017

Renal Cell Carcinoma in a Young Adult - Do We Need Further Investigations?

Urol Case Rep 2016 May 12;6:27-9. Epub 2016 Mar 12.

Department of Urology, Cantonal Hospital Aarau, Aarau, Switzerland.

Renal cell carcinomas (RCC), mostly occurring in adults aged 60-70 years, can result from well-known factors like cigarette smoking, obesity and hypertension. However, they have been associated with genetic alterations in children and young adults. A 28 year-old male patient with a confirmed RCC underwent biomolecular and immunohistochemical analyses due to his young age. A point mutation of the von Hippel-Lindau tumor suppressor gene was identified. Young patients under 40 years with diagnosed RCC should undergo additional diagnostic investigation, hence the discovery of an underlying cause. This could be important for further treatment and counseling of these young patients.
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http://dx.doi.org/10.1016/j.eucr.2016.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855903PMC
May 2016

Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF.

Hum Mutat 2016 Apr 9;37(4):359-63. Epub 2016 Feb 9.

Section for Clinical Neurosciences, Department of Pediatrics, Oslo University Hospital and University of Oslo, Oslo, Norway.

Strømme syndrome was first described by Strømme et al. (1993) in siblings presenting with "apple peel" type intestinal atresia, ocular anomalies and microcephaly. The etiology remains unknown to date. We describe the long-term clinical follow-up data for the original pair of siblings as well as two previously unreported siblings with a severe phenotype overlapping that of the Strømme syndrome including fetal autopsy results. Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs. Compound heterozygous inheritance was confirmed in both families. Recently, mutations in this gene were shown to cause a fetal lethal phenotype, the phenotype and functional data being compatible with a human ciliopathy [Waters et al., 2015]. We show for the first time that Strømme syndrome is an autosomal-recessive disease caused by mutations in CENPF that can result in a wide phenotypic spectrum.
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http://dx.doi.org/10.1002/humu.22960DOI Listing
April 2016

Actinomyces neuii Isolated From a 20-Month-Old Girl With Cervical Lymphadenitis.

J Pediatric Infect Dis Soc 2015 Sep 14;4(3):e32-7. Epub 2014 Oct 14.

Paediatric Infectious Diseases Unit Paediatric Infectious Diseases Unit, Royal Children's Hospital Melbourne, Australia.

Actinomycetes are Gram-positive bacteria that can be part of the normal human flora of the gastrointestinal, pulmonary, and genital tract. Infections are rare, slowly progressing and most commonly affect the cervicofacial region. Actinomyces israelii is the most frequently isolated species but a number of other species may cause infection. We report the first postnatally acquired case of an actinomycosis caused by A. neuii in a child. We also provide a systematic review of all published cases of A. neuii infections. In children, there is one case report of a premature infant with perinatally acquired A. neuii sepsis. In adults 21 cases have currently been reported and A. neuii infection was associated with endophthalmitis after eye surgery, foreign material-associated infection and abscess formation in the inguinal, axillary, and mammary area. Our case highlights that a A. neuii infection is also a potential differential diagnosis in children with chronic lymphadenitis.
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http://dx.doi.org/10.1093/jpids/piu096DOI Listing
September 2015

Gene expression profiles of similarly derived human embryonic stem cell lines correlate with their distinct propensity to exit stemness and their different differentiation behavior in culture.

Cell Reprogram 2014 Jun 8;16(3):185-95. Epub 2014 May 8.

1 Clinic of Gynecological Endocrinology and Reproductive Medicine, University of Basel , CH-4031, Basel, Switzerland .

Four normal-karyotype human embryonic stem cell (hESC) lines were generated using the same protocol and maintained under identical conditions. Despite these precautions, gene expression patterns were found to be dissimilar among the four lines. The observed differences were typical of each cell line, correlated with their distinct propensity to exit stemness, created heterogeneity among the cells during cell line maintenance, and correlated with their altered capacity as a source of differentiated cells. The capacity of some cell lines to give rise to more, and more mature, neurons within comparable time frames of directed differentiation reflected the distinct proportions of cells already predifferentiated at the onset. These findings demonstrate that the subsequent stages of neural differentiation were altered both in a quantitative and timely fashion. As a consequence, cell lines with apparent better and quicker ability to produce neurons were actually the less capable of reproducing proper differentiation. Previous data suggested that cell lines able to generate more neurons faster would be more suitable to clinical application. Our analysis of the differentiation process strongly suggests the opposite. The spontaneous tendency to predifferentiate of any particular hESC line should be known because it clearly impacts further experimental results.
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http://dx.doi.org/10.1089/cell.2013.0089DOI Listing
June 2014

Morphologic and GATA1 sequencing analysis of hematopoiesis in fetuses with trisomy 21.

Hum Pathol 2014 May 17;45(5):1003-9. Epub 2014 Jan 17.

Department of Pathology, Hospital of the University of Basel, Basel, Switzerland.

Trisomy 21 alters fetal liver hematopoiesis and, in combination with somatic globin transcription factor 1 (GATA1) mutations, leads to development of transient myeloproliferative disease in newborns. However, little is known about the morphological hematopoietic changes caused by trisomy 21 in the fetus, and to date, the exact onset of GATA1 mutations remains uncertain. Therefore, we analyzed fetal liver hematopoiesis from second trimester pregnancies in trisomy 21 and screened for GATA1 mutations. We examined 57 formalin-fixed and paraffin-embedded fetal liver specimens (49 harboring trisomy 21 and 8 controls) by immunohistochemistry for CD34, CD61, factor VIII, and glycophorin A. GATA1 exon 2 was sequenced in fetal livers and corresponding nonhematologic tissue. Cell counts of megakaryocytes (P = .022), megakaryocytic precursors (P = .021), and erythroid precursors were higher in trisomy 21 cases. CD34-positive hematopoietic blasts showed no statistically significant differences. No mutation was detected by GATA1 exon 2 sequencing in fetal livers from 12 to 25 weeks of gestation. Our results suggest that GATA1 exon 2 mutations occur late in trisomy 21 fetal hematopoiesis. However, trisomy 21 alone provides a proliferative stimulus of fetal megakaryopoiesis and erythropoiesis. CD34-positive precursor cells are not increased in trisomy 21 fetal livers.
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http://dx.doi.org/10.1016/j.humpath.2013.12.014DOI Listing
May 2014

Minimally invasive, imaging guided virtual autopsy compared to conventional autopsy in foetal, newborn and infant cases: study protocol for the paediatric virtual autopsy trial.

BMC Pediatr 2014 Jan 20;14:15. Epub 2014 Jan 20.

Department of Neonatology, University Hospital Zurich, Zurich, Switzerland.

Background: In light of declining autopsy rates around the world, post-mortem MR imaging is a promising alternative to conventional autopsy in the investigation of infant death. A major drawback of this non-invasive autopsy approach is the fact that histopathological and microbiological examination of the tissue is not possible. The objective of this prospective study is to compare the performance of minimally invasive, virtual autopsy, including CT-guided biopsy, with conventional autopsy procedures in a paediatric population.

Methods/design: Foetuses, newborns and infants that are referred for autopsy at three different institutions associated with the University of Zurich will be eligible for recruitment. All bodies will be examined with a commercial CT and a 3 Tesla MRI scanner, masked to the results of conventional autopsy. After cross-sectional imaging, CT-guided tissue sampling will be performed by a multifunctional robotic system (Virtobot) allowing for automated post-mortem biopsies. Virtual autopsy results will be classified with regards to the likely final diagnosis and major pathological findings and compared to the results of conventional autopsy, which remains the diagnostic gold standard.

Discussion: There is an urgent need for the development of alternative post-mortem examination methods, not only as a counselling tool for families and as a quality control measure for clinical diagnosis and treatment but also as an instrument to advance medical knowledge and clinical practice. This interdisciplinary study will determine whether virtual autopsy will narrow the gap in information between non-invasive and traditional autopsy procedures.

Trial Registration: ClinicalTrials.gov: NCT01888380.
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http://dx.doi.org/10.1186/1471-2431-14-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897955PMC
January 2014

Identification of molecular tumor markers in renal cell carcinomas with TFE3 protein expression by RNA sequencing.

Neoplasia 2013 Nov;15(11):1231-40

Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland ; Life Science Zurich PhD Program on Molecular and Translational Biomedicine, Zurich, Switzerland ; Competence Center for Systems Physiology and Metabolic Diseases, Zurich, Switzerland.

TFE3 translocation renal cell carcinoma (tRCC) is defined by chromosomal translocations involving the TFE3 transcription factor at chromosome Xp11.2. Genetically proven TFE3 tRCCs have a broad histologic spectrum with overlapping features to other renal tumor subtypes. In this study, we aimed for characterizing RCC with TFE3 protein expression. Using next-generation whole transcriptome sequencing (RNA-Seq) as a discovery tool, we analyzed fusion transcripts, gene expression profile, and somatic mutations in frozen tissue of one TFE3 tRCC. By applying a computational analysis developed to call chimeric RNA molecules from paired-end RNA-Seq data, we confirmed the known TFE3 translocation. Its fusion partner SFPQ has already been described as fusion partner in tRCCs. In addition, an RNA read-through chimera between TMED6 and COG8 as well as MET and KDR (VEGFR2) point mutations were identified. An EGFR mutation, but no chromosomal rearrangements, was identified in a control group of five clear cell RCCs (ccRCCs). The TFE3 tRCC could be clearly distinguished from the ccRCCs by RNA-Seq gene expression measurements using a previously reported tRCC gene signature. In validation experiments using reverse transcription-PCR, TMED6-COG8 chimera expression was significantly higher in nine TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in 24 ccRCCs (P < .001) and 22 papillary RCCs (P < .05-.07). Immunohistochemical analysis of selected genes from the tRCC gene signature showed significantly higher eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) and Contactin 3 (CNTN3) expression in 16 TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in over 200 ccRCCs (P < .0001, both).
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859447PMC
http://dx.doi.org/10.1593/neo.131544DOI Listing
November 2013

Thyroid hemorrhage causing airway obstruction after intravenous thrombolysis for acute ischemic stroke.

Neurocrit Care 2013 Dec;19(3):381-4

Clinic of Intensive Care Medicine, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.

Background: There are several life-threatening complications associated with intravenous thrombolysis after acute ischemic stroke such as symptomatic intracerebral hemorrhage, orolingual angioedema, or less frequent, bleedings of the mucosa or ecchymosis. Aside from these known critical incidents, rare and unfamiliar complications may be even more challenging, as they are unexpected and may mimic events that appear more frequently. We report a rare and unusual acute complication of intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) (0.9 mg/kg) administered for acute ischemic stroke.

Methods: Medical records, radiologic imaging, and pathologic specimens were reviewed.

Results: A 86-year-old woman developed acute respiratory failure 20 h after thrombolysis with suspected angioedema triggered by intravenous rt-PA. The inspiratory stridor and dyspnea were unresponsive to bronchodilators, corticosteroids, and inhaled adrenaline. After endotracheal intubation, laryngoscopy showed no significant supraglottic narrowing. Thyroidal sonography and cervical computed tomography revealed a thyroidal mass causing a tracheal and vascular compression compatible with thyroidal hemorrhage. Sonography showed a nodular goiter of the right thyroid gland. A total thyroidectomy was performed and histologic analysis confirmed a hemorrhage of the right thyroidal lobe.

Conclusions: Acute airway obstruction with respiratory failure due to thyroidal hemorrhage after intravenous thrombolysis is an important life-threatening complication, mimicking an anaphylactic reaction or a more frequent orolingual angioedema.
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http://dx.doi.org/10.1007/s12028-013-9889-zDOI Listing
December 2013

Abnormalities in "low" anorectal malformations (ARMs) and functional results resecting the distal 3 cm.

J Pediatr Surg 2013 Jun;48(6):1294-300

Pediatric Surgery, Maggiore University Hospital of Parma, Parma, Italy.

Purpose: "Low" anorectal malformations (ARMs) are considered minor anomalies of the distal rectum and anal-canal development. Nonetheless, the prognosis of affected patients is far from excellent, as some degree of constipation is a frequent complaint in the long-term follow-up. Constipation in "low" ARM has been reported in 42%-70% of cases. Vestibular fistulas seem to have the highest rate of constipation (not less than 61.4%). The aim of this study was to evaluate all the histological wall abnormalities of ARM with recto-perineal and recto-vestibular fistulas in order to identify features that could explain the bowel dysfunctions. Moreover, the resection of distal perineal and vestibular fistulas (last 3 cm) allowed evaluating functional results in "low" ARM series with extensive fistula resection.

Methods: One hundred four specimens were collected from 52 patients (32 recto-perineal and 20 recto-vestibular fistulas) during the posterior sagittal anorectoplasty (PSARP). The distal 3 cm of aberrant anorectal canals (fistulas) was systematically resected and divided longitudinally. One portion was fixed for immuno-histochemical stainings (PGP 9.5, S-100, NSE), H&E, and tricromic stainings. The frozen sections of the second portion were incubated for enzyme histochemical stainings (AChE, etc.). The follow-up of 42 of 52 ARM was postoperatively evaluated at 3-8 years of age, and the assessment of the outcome after PSARP repair was in line with Krickenbeck's 2005 meeting parameters.

Results: Muscle coat was abnormal in all cases (100%), showing aspect and absence of organization into the circular and longitudinal layers. The connective tissue was found to be irregular and abnormally represented in 100% of cases. Abnormal vascularization was detected in 5 cases (9.6%). All vestibular (100%) and 71.8% of perineal fistulas showed different degrees of enteric nervous system (ENS) anomalies. In the series of 42 patients followed up at least after 3 years of age, 40 cases (95.2%) showed postoperative good continence without use of laxatives (according to Krickenbeck's 2005 criteria).

Conclusion: Every wall component of the distal rectum can be affected by different structural abnormalities in "low" ARMs. Pediatric surgeons should take into consideration the implications of these structural abnormalities during radical treatment. The resection of a significant portion of the distal fistula seems to permit better functional results.
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http://dx.doi.org/10.1016/j.jpedsurg.2013.03.026DOI Listing
June 2013

Neuroblastoma tumorigenesis is regulated through the Nm23-H1/h-Prune C-terminal interaction.

Sci Rep 2013 ;3:1351

Centro di Ingegneria Genetica e Biotecnologie Avanzate-CEINGE, Naples, Italy.

Nm23-H1 is one of the most interesting candidate genes for a relevant role in Neuroblastoma pathogenesis. H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers. Our study focuses on the role of the Nm23-H1/h-Prune protein complex in Neuroblastoma. Using NMR spectroscopy, we performed a conformational analysis of the h-Prune C-terminal to identify the amino acids involved in the interaction with Nm23-H1. We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation. Meta-analysis performed on three Neuroblastoma cohorts showed Nm23-H1 as the gene highly associated to Neuroblastoma aggressiveness. We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP. These data suggest a new avenue for potential clinical application of CPP in Neuroblastoma treatment.
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http://dx.doi.org/10.1038/srep01351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584926PMC
August 2013

Neurogenic appendicopathy: clinical, macroscopic, and histopathological presentation in pediatric patients.

Eur J Pediatr Surg 2013 Jun 26;23(3):238-42. Epub 2013 Feb 26.

Department of Pediatric Surgery, University Children's Hospital Basel, Basel, Switzerland.

Background: The proliferation of nerve fibers in the appendix, in association with an increase of the neuropeptides such as vasoactive intestinal peptide and substance P characterizes neurogenic appendicopathy (NA), which may mimic the symptoms of acute appendicitis (AA). It may be difficult to differentiate this little known distinct pathological entity clinically from AA. The aim of this study is to describe the epidemiology, clinical signs, and histological description of NA in pediatric patients.

Patients And Methods: After institutional review board approval, all appendiceal specimens from children who underwent appendectomy between February 2006 and December 2008 were analyzed. Analysis included age, gender, clinical symptoms, blood tests, intraoperative macroscopic assessment of the appendix, and the histopathological type of NA. NA was diagnosed by hematoxylin-eosin staining and /or S-100 immunochemistry and then classified into different histopathological groups.

Results: Of the 385 appendix specimens examined, 29 (7.5%) met the histopathological criteria of NA. The median duration of abdominal pain was 2 days (range, 1 to 7). The surgeon characterized the appendix as follows: not inflamed in 5 (17.2%), acute in 17 (58.6%), phlegmonous in 4 (13.8%), and perforated in 3 patients (10.4%). Histopathological diagnosis of NA classified the specimen as axial neuroma in 2 (7%), mucosal in 12 (41%), and submucosal in 15 cases (52%).

Conclusion: NA is a relatively common diagnosis in children. NA must be considered in patients with recurrent right lower quadrant pain or signs of AA, even if intraoperative findings are normal. For these patients, we recommend appendectomy and consideration of a subsequent histopathological workup.
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http://dx.doi.org/10.1055/s-0032-1333119DOI Listing
June 2013

Connective tissue in gut development: a key player in motility and in intestinal desmosis.

Eur J Pediatr Surg 2012 Dec 17;22(6):445-59. Epub 2012 Aug 17.

Department of Pediatric Surgery, Lucerne Hospital, Lucerne, Switzerland.

Introduction: Efficient intestinal peristalsis is a function of intact enteric nervous system, muscle, and connective muscularis propria tissue. Malfunction of any component results in impaired peristalsis. Hirschsprung disease (HD) as prototypic enteric neural migration disorder is increasingly well characterized. More recently, intestinal myopathies and particularly defects of myenteric collagenization have entered the focus of attention. However, detailed development of muscularis propria connective tissue is not well known. The aim of this study was to morphologically characterize intestinal connective tissue in fetal and postnatal development and intestinal pseudo-obstruction.

Materials And Methods: In this study, 130 archival specimens of fetal autopsies, intestinal resections, and biopsies were analyzed. Patients' age was 10th gestational week (gw) to 70 years. Muscularis mucosae, muscle layers, collagen tissue, and enteric plexus were analyzed. Picrosirius red stains, enzyme histochemistry, and immunohistochemistry for collagens I, III, and IV were performed.

Results: Total 89 normal intestinal specimens were from fetal autopsies or intestinal resections; 41 patients showed a primary structural colon wall defect (HD, desmosis). Our results showed a constant increase in tunica muscularis propria thickness with age. Separation into circular and longitudinal muscle layer first occurred in the 11th gw. A tendinous collagen plexus layer first arose in the 10th gw and showed a steady caliber increase. Muscularis mucosae first appeared in the 10th gw and grew independent of any primary gastrointestinal disease. In the 11th gw, enteric ganglia were fully developed. In desmosis, a collagen plexus layer was absent. In contrast, in HD, muscularis mucosae showed hypertrophy, but the collagen plexus layer was intact in the aganglionic segment. In intestinal neuronal dysplasia and hypoganglionosis, nerve cell development was disturbed; connective tissue and muscle layers were well developed.

Conclusion: Our comprehensive study of intestinal connective tissue development in comparison to neural intestinal wall components in normal and pathological conditions showed that tendinous tissue develops parallel to muscularis propria and arises early in embryogenesis. In enteric nervous system disorders, ganglionic lesions develop independently of impaired collagen network, whereas mucosal biopsies serve for diagnosis of HD, seromuscular biopsies are required to prove desmosis in gastrointestinal dysmotility disorders.
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http://dx.doi.org/10.1055/s-0032-1322544DOI Listing
December 2012

Vascular and perivascular lesions of skin and soft tissues in children and adolescents.

Pediatr Dev Pathol 2012 ;15(1 Suppl):26-61

Institute for Pathology, Hospital of the University of Basel, Basel, Switzerland.

Vascular anomalies in children and adolescents are the most common soft tissue lesions and include reactive, malformative, and neoplastic tumefactions, with a full spectrum of benign, intermediate, and malignant neoplasms. These lesions are diagnostically challenging because of morphologic complexity and recent changes in classification systems, some of which are based on clinical features and others on pathologic findings. In recent decades, there have been significant advances in clinical diagnosis, development of new therapies, and a better understanding of the genetic aspects of vascular biology and syndromes that include unusual vascular proliferations. Most vascular lesions in children and adolescents are benign, although the intermediate locally aggressive and intermediate rarely metastasizing neoplasms are important to distinguish from benign and malignant mimics. Morphologic recognition of a vasoproliferative lesion is straightforward in most instances, and conventional morphology remains the cornerstone for a specific diagnosis. However, pathologic examination is enhanced by adjunctive techniques, especially immunohistochemistry to characterize the type of vessels involved. Multifocality may cause some uncertainty regarding the assignment of "benign" or "malignant." However, increased interest in vascular anomalies, clinical expertise, and imaging technology have contributed greatly to our understanding of these disorders to the extent that in most vascular malformations and in many tumors, a diagnosis is made clinically and biopsy is not required for diagnosis. The importance of close collaboration between the clinical team and the pathologist cannot be overemphasized. For some lesions, a diagnosis is not possible from evaluation of histopathology alone, and in a subset of these, a specific diagnosis may not be possible even after all assembled data have been reviewed. In such instances, a consensus diagnosis in conjunction with clinical colleagues guides therapy. The purpose of this review is to delineate the clinicopathologic features of vascular lesions in children and adolescents with an emphasis on their unique aspects, use of diagnostic adjuncts, and differential diagnosis.
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http://dx.doi.org/10.2350/11-11-1119-PB.1DOI Listing
June 2012

Surgical decision criteria: Bednar tumour of the foot in a child.

J Plast Reconstr Aesthet Surg 2011 Dec 29;64(12):1697-701. Epub 2011 Jun 29.

Department of Paediatric Surgery, University Children's Hospital (UKBB), Basel, Switzerland.

An 8-year-old boy was admitted for excision of a putative 'blue nevus' on the left foot. Histological examination and immunohistochemistry revealed a Bednar tumour, the pigmented variant of dermatofibrosarcoma protuberans. Surgical options considered by a multidisciplinary team included wide local excision, Mohs micrographic surgery or a staged excision with examination of several histological sections. The third alternative procedure was chosen after consideration of tumour and patient factors to achieve the best possible clinical, cosmetic and functional outcome. After the final surgical procedure with resection of the third metatarsal bone, all peripheral margins were free of tumour, and the interdigital space was reconstructed with a pedicled pulpa flap. Three years after surgery, there was no tumour recurrence, and further long-term follow-up for this patient will be provided.
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http://dx.doi.org/10.1016/j.bjps.2011.05.030DOI Listing
December 2011

Fetal polydactyly: a study of 24 cases ascertained by prenatal sonography.

J Ultrasound Med 2011 Jul;30(7):1021-9

Division of Medical Genetics and Department of Biomedicine, University Children's Hospital, Burgfelderstrasse 101, Building J, 4005 Basel, Switzerland.

Records of 24 pregnancies with fetal polydactyly were reviewed for the type of polydactyly, family history, associated sonographic findings, genetic testing, and postnatal/postmortem examination findings. The importance of fetal polydactyly can be mainly elucidated by the family history and absent or associated anomalies on a specialized malformation scan. Fetal karyotyping diagnoses frequent chromosomal anomalies in about half of cases with additional malformations, and array comparative genomic hybridization may be a future means of detecting cryptic chromosomal aberrations. Syndromic disorders of monogenic origin demand a careful interdisciplinary clinical assessment for establishing a clinical diagnosis and prognosis for the outcome of the child.
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http://dx.doi.org/10.7863/jum.2011.30.7.1021DOI Listing
July 2011

Odontogenic myxoma: diagnostic and therapeutic challenges in paediatric and adult patients--a case series and review of the literature.

J Craniomaxillofac Surg 2012 Apr 31;40(3):271-6. Epub 2011 May 31.

Department of Cranio-Maxillofacial Surgery (Head: Prof. Hans-Florian Zeilhofer), University Hospital Basel, Spitalstrasse 21, Basel, Switzerland.

Introduction: Odontogenic myxomas are benign but locally invasive tumours originating from primordial mesenchymal tooth forming tissues which do not metastasise. We present a series of two paediatric and two adult cases and focus on differences in diagnostic and therapeutic approaches between children and adults based on our own experience and a critical review of the literature.
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http://dx.doi.org/10.1016/j.jcms.2011.04.009DOI Listing
April 2012

The London Classification of gastrointestinal neuromuscular pathology: report on behalf of the Gastro 2009 International Working Group.

Gut 2010 Jul;59(7):882-7

Centre for Academic Surgery, Royal London Hospital, London, UK.

Objective: Guidelines on histopathological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology have been produced recently by an international working group (IWG). These addressed the important but relatively neglected areas of histopathological practice of the general pathologist, including suction rectal biopsy and full-thickness intestinal tissue. Recommendations were presented for the indications, safe acquisition of tissue, histological techniques, reporting and referral of such histological material.

Design: Consensual processes undertaken by the IWG and following established guideline decision group methodologies.

Results And Conclusion: This report presents a contemporary and structured classification of gastrointestinal neuromuscular pathology based on defined histopathological criteria derived from the existing guidelines. In recognition of its origins and first presentation in London at the World Congress of Gastroenterology 2009, this has been named 'The London Classification'. The implementation of this classification should allow some diagnostic standardisation, but should necessarily be viewed as a starting point for future modification as new data become available.
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http://dx.doi.org/10.1136/gut.2009.200444DOI Listing
July 2010