RESUMEN
OBJECTIVES: The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) discourages invasive procedures to determine the histology of paediatric renal neoplasms at diagnosis. Therefore, the histological subtype of Wilms' tumours (WT) is unknown at the start of neoadjuvant chemotherapy. MR-DWI shows potential value as a non-invasive biomarker through apparent diffusion coefficients (ADCs). This study aimed to describe MR characteristics and ADC values of paediatric renal tumours to differentiate subtypes. MATERIALS AND METHODS: Children with a renal tumour undergoing surgery within the SIOP-RTSG 2016-UMBRELLA protocol were prospectively included between May 2021 and 2023. In the case of a total nephrectomy, a patient-specific cutting guide based on the neoadjuvant MR was 3D-printed, allowing a correlation between imaging and histopathology. Whole-tumour volumes and ADC values were statistically compared with the Mann-Whitney U-test. Direct correlation on the microscopic slide level was analysed through mixed model analysis. RESULTS: Fifty-nine lesions of 54 patients (58% male, median age 3.0 years (range 0-17.7 years)) were included. Forty-four lesions involved a WT. Stromal type WT showed the lowest median decrease in volume after neoadjuvant chemotherapy (48.1 cm3, range 561.5-(+)332.7 cm3, p = 0.035). On a microscopic slide level (n = 240 slides) after direct correlation through the cutting guide, stromal areas showed a significantly higher median ADC value compared to epithelial and blastemal foci (p < 0.001). With a cut-off value of 1.195 * 10-3 mm2/s, sensitivity, and specificity were 95.2% (95% confidence interval 87.6-98.4%) and 90.5% (95% confidence interval 68.2-98.3%), respectively. CONCLUSION: Correlation between histopathology and MR-DWI through a patient-specific 3D-printed cutting guide resulted in significant discrimination of stromal type WT from epithelial and blastemal subtypes. CLINICAL RELEVANCE STATEMENT: Stromal Wilms' tumours could be discriminated from epithelial- and blastemal lesions based on high apparent diffusion coefficient values and limited decrease in volume after neoadjuvant chemotherapy. This may aid in future decision-making, especially concerning discrimination between low- and high-risk neoplasms. KEY POINTS: MR-DWI shows potential value as a non-invasive biomarker in paediatric renal tumours. The patient-specific cutting guide leads to a correlation between apparent diffusion coefficient values and Wilms' tumour subtype. Stromal areas could be discriminated from epithelial and blastemal foci in Wilms' tumours based on apparent diffusion coefficient values.
RESUMEN
Mutations in ARCN1 give rise to a syndromic disorder with rhizomelic short stature with microretrognathia and developmental delay. ARCN1 encodes the delta subunit of the coat protein I complex, which is required for intracellular trafficking of collagen 1 and which may also be involved in the endoplasmic reticulum (ER) stress response. In this paper we describe for the first time the skeletal histological abnormalities in an 18-week-old fetus with an ARCN1 mutation, and we suggest that the skeletal phenotype in ARCN1-related syndrome has more resemblance with ER stress than with a defect in collagen 1 metabolism.
Asunto(s)
Colágeno , Feto , Humanos , Mutación , Síndrome , Feto/metabolismo , Colágeno/metabolismo , FenotipoRESUMEN
Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.
Asunto(s)
Huesos/metabolismo , Colágeno Tipo I/metabolismo , Proteínas del Choque Térmico HSP47/metabolismo , Osteogénesis Imperfecta/genética , Proteínas de Transporte Vesicular/metabolismo , Adulto , Alelos , Secuencia de Aminoácidos , Animales , Sitios de Unión , Huesos/patología , Pollos , Preescolar , Colágeno Tipo I/química , Colágeno Tipo I/genética , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Expresión Génica , Aparato de Golgi/metabolismo , Aparato de Golgi/patología , Proteínas del Choque Térmico HSP47/química , Proteínas del Choque Térmico HSP47/genética , Humanos , Lactante , Masculino , Osteogénesis Imperfecta/diagnóstico , Osteogénesis Imperfecta/metabolismo , Osteogénesis Imperfecta/patología , Linaje , Cultivo Primario de Células , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Estructura Secundaria de Proteína , Transporte de Proteínas , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/genéticaRESUMEN
The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders. TMX2 encodes one of the five TMX proteins of the protein disulfide isomerase family, hitherto not linked to human developmental brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER mitochondria-associated membranes (MAMs), is involved in posttranslational modification and protein folding, and undergoes physical interaction with the MAM-associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as a signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with an in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking an increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox signaling pathway and identify it as a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.
Asunto(s)
Encefalopatías/patología , Encéfalo/anomalías , Discapacidades del Desarrollo/patología , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Tiorredoxinas/metabolismo , Adolescente , Adulto , Encefalopatías/genética , Encefalopatías/metabolismo , Niño , Preescolar , Estudios de Cohortes , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Proteínas de la Membrana/genética , Mitocondrias/patología , Oxidación-Reducción , Pronóstico , Piel/metabolismo , Piel/patología , Tiorredoxinas/genética , TranscriptomaRESUMEN
Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.
Asunto(s)
Anemia de Diamond-Blackfan/genética , Procesamiento Postranscripcional del ARN/genética , Proteínas Ribosómicas/genética , Ribosomas/genética , Regiones no Traducidas 5'/genética , Adolescente , Adulto , Anemia de Diamond-Blackfan/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Niño , Células Eritroides , Femenino , Humanos , Masculino , Mutación/genética , Precursores del ARN/genética , ARN Mensajero/genética , Secuenciación del ExomaRESUMEN
BACKGROUND: Postmortem examinations frequently show cerebellar injury in infants with severe hypoxic-ischemic encephalopathy (HIE), while it is less well visible on MRI. The primary aim was to investigate the correlation between cerebellar apparent diffusion coefficient (ADC) values and histopathology in infants with HIE. The secondary aim was to compare ADC values in the cerebellum of infants with HIE and infants without brain injury. METHODS: ADC values in the cerebellar vermis, hemispheres and dentate nucleus (DN) of (near-)term infants with HIE (n = 33) within the first week after birth were compared with neonates with congenital non-cardiac anomalies, normal postoperative MRIs and normal outcome (n = 22). Microglia/macrophage activation was assessed using CD68 and/or HLA-DR staining and Purkinje cell (PC) injury using H&E-stained slices. The correlation between ADC values and the histopathological measures was analyzed. RESULTS: ADC values in the vermis (p = 0.021) and DN (p < 0.001) were significantly lower in infants with HIE compared to controls. ADC values in the cerebellar hemispheres were comparable. ADC values in the vermis were correlated with the number and percentage of normal PCs; otherwise ADC values and histology were not correlated. CONCLUSION: Histopathological injury in the cerebellum is common in infants with HIE. ADC values underestimate histopathological injury. IMPACT: ADC values might underestimate cerebellar injury in neonates with HIE. ADC values in the vermis and dentate nucleus of infants with HIE are lower compared to controls, but not in the cerebellar hemispheres. Abnormal ADC values are only found when cytotoxic edema is very severe. ADC values in the vermis are correlated with Purkinje cell injury in the vermis; furthermore, there were no correlations between ADC values and histopathological measures.
Asunto(s)
Cerebelo/patología , Hipoxia-Isquemia Encefálica/patología , Enfermedades del Recién Nacido/patología , Femenino , Humanos , Hipoxia-Isquemia Encefálica/diagnóstico por imagen , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: Chorioamnionitis, an intrauterine infection of the placenta and fetal membranes, is a common risk factor for adverse pulmonary outcomes in premature infants including BPD, which is characterized by an arrest in alveolar development. As endogenous epithelial stem/progenitor cells are crucial for organogenesis and tissue repair, we examined whether intrauterine inflammation negatively affects these essential progenitor pools. METHODS: In an ovine chorioamnionitis model, fetuses were intra-amniotically exposed to LPS, 2d or 7d (acute inflammation) before preterm delivery at 125d of gestation, or to intra-amniotic Ureaplasma parvum for 42d (chronic inflammation). Lung function, pulmonary endogenous epithelial stem/progenitor pools, and downstream functional markers were studied. RESULTS: Lung function was improved in the 7d LPS and 42d Ureaplasma groups. However, intrauterine inflammation caused a loss of P63+ basal cells in proximal airways and reduced SOX-9 expression and TTF-1+ Club cells in distal airways. Attenuated type-2 cell numbers were associated with lower proliferation and reduced type-1 cell marker Aqp5 expression, indicative for impaired progenitor function. Chronic Ureaplasma infection only affected distal airways, whereas acute inflammation affected stem/progenitor populations throughout the lungs. CONCLUSIONS: Acute and chronic prenatal inflammation improve lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes. IMPACT: In this study, prenatal inflammation improved lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes. Importantly, we demonstrate that these essential alterations can already be initiated before birth. So far, stem/progenitor dysfunction has only been shown postnatally. This study indicates that clinical protocols to target the consequences of perinatal inflammatory stress for the immature lungs should be initiated as early as possible and ideally in utero. Within this context, our data suggest that interventions, which promote function or repair of endogenous stem cells in the lungs, hold great promise.
Asunto(s)
Corioamnionitis/patología , Pulmón/patología , Células Madre/patología , Animales , Células Epiteliales/patología , Femenino , Embarazo , Nacimiento Prematuro , OvinosRESUMEN
BACKGROUND: Idiopathic dilated cardiomyopathy (DCM) is recognised to be a heritable disorder, yet clinical genetic testing does not produce a diagnosis in >50% of paediatric patients. Identifying a genetic cause is crucial because this knowledge can affect management options, cardiac surveillance in relatives and reproductive decision-making. In this study, we sought to identify the underlying genetic defect in a patient born to consanguineous parents with rapidly progressive DCM that led to death in early infancy. METHODS AND RESULTS: Exome sequencing revealed a potentially pathogenic, homozygous missense variant, c.542G>T, p.(Gly181Val), in SOD2. This gene encodes superoxide dismutase 2 (SOD2) or manganese-superoxide dismutase, a mitochondrial matrix protein that scavenges oxygen radicals produced by oxidation-reduction and electron transport reactions occurring in mitochondria via conversion of superoxide anion (O2-·) into H2O2. Measurement of hydroethidine oxidation showed a significant increase in O2-· levels in the patient's skin fibroblasts, as compared with controls, and this was paralleled by reduced catalytic activity of SOD2 in patient fibroblasts and muscle. Lentiviral complementation experiments demonstrated that mitochondrial SOD2 activity could be completely restored on transduction with wild type SOD2. CONCLUSION: Our results provide evidence that defective SOD2 may lead to toxic increases in the levels of damaging oxygen radicals in the neonatal heart, which can result in rapidly developing heart failure and death. We propose SOD2 as a novel nuclear-encoded mitochondrial protein involved in severe human neonatal cardiomyopathy, thus expanding the wide range of genetic factors involved in paediatric cardiomyopathies.
Asunto(s)
Cardiomiopatía Dilatada/genética , Mutación Missense , Miocardio/patología , Superóxido Dismutasa/genética , Secuencia de Aminoácidos , Cardiomiopatía Dilatada/enzimología , Cardiomiopatía Dilatada/metabolismo , Secuencia Conservada , Análisis Mutacional de ADN , Femenino , Homocigoto , Humanos , Lactante , Recién Nacido , Mitocondrias/metabolismo , Miocardio/metabolismo , Estrés Oxidativo , Linaje , Superóxido Dismutasa/química , Superóxido Dismutasa/metabolismo , Superóxidos/metabolismoRESUMEN
Chronic intervillositis of unknown etiology (CIUE) is a rare, poorly understood, histopathological diagnosis of the placenta that is frequently accompanied by adverse pregnancy outcomes including miscarriage, fetal growth restriction, and intrauterine fetal death. CIUE is thought to have an immunologically driven pathophysiology and may be related to human leukocyte antigen mismatches between the mother and the fetus. Dizygotic twins with one-sided CIUE provide an interesting context to study the influence of immunogenetic differences in such cases. The main immune-cell subsets were investigated using immunohistochemistry. We identified three dizygotic twin pregnancies in which CIUE was present in only one of the two placentas. Two of the pregnancies ended in term delivery and one ended in preterm delivery. Presence of CIUE was correlated with lower placental weight and lower birthweight. Relative number of CD68, CD56, CD20, and CD3 positive cells were comparable between co-twins. The presence of one-sided CIUE in dizygotic twin pregnancy was associated with selective growth restriction in the affected twin. This suggests a unique fetal immunogenetic contribution to the pathogenesis of CIUE. Further study of dizygotic and monozygotic placentas affected by CIUE could identify new insights into its pathophysiology and into the field of reproductive immunology.
Asunto(s)
Enfermedades Placentarias/patología , Placenta/patología , Gemelos Dicigóticos , Antígenos CD/análisis , Vellosidades Coriónicas/patología , Femenino , Humanos , Recién Nacido , Masculino , Enfermedades Placentarias/etiología , Embarazo , Resultado del Embarazo , Nacimiento Prematuro/etiologíaRESUMEN
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease that causes thrombocytopenia and a risk of bleeding in the (unborn) child that result from maternal alloantibodies directed against fetal, paternally inherited, human platelet antigens (HPA). It is hypothesized that these alloantibodies can also bind to the placenta, causing placental damage. This study aims to explore signs of antibody-mediated placental damage in FNAIT. We performed a retrospective study that included pregnant women, their newborns, and placentas. It comprised 23 FNAIT cases, of which nine were newly diagnosed (14 samples) and 14 were antenatally treated with intravenous immune globulins (IVIg) (21 samples), and 20 controls, of which 10 had anti-HLA-class I antibodies. Clinical information was collected from medical records. Placental samples were stained for complement activation markers (C1q, C4d, SC5b-9, and mannose-binding lectin) using immunohistochemistry. Histopathology was examined according to the Amsterdam criteria. A higher degree of C4d deposition was present in the newly diagnosed FNAIT cases (10/14 samples), as compared to the IVIg-treated FNAIT cases (2/21 samples, p = 0.002) and anti-HLA-negative controls (3/20 samples, p = 0.006). A histopathological examination showed delayed maturation in four (44%) placentas in the newly diagnosed FNAIT cases, five (36%) in the IVIg-treated FNAIT cases, and one in the controls (NS). C4d deposition at the syncytiotrophoblast was present in combination with low-grade villitis of unknown etiology in three newly diagnosed FNAIT cases that were born SGA. We conclude that a higher degree of classical pathway-induced complement activation is present in placentas from pregnancies with untreated FNAIT. This may affect placental function and fetal growth.
Asunto(s)
Activación de Complemento/inmunología , Feto/patología , Antígenos de Histocompatibilidad Clase I/inmunología , Inmunoglobulinas Intravenosas/inmunología , Placenta/patología , Trombocitopenia Neonatal Aloinmune/patología , Adulto , Anticuerpos/inmunología , Estudios de Casos y Controles , Femenino , Feto/inmunología , Humanos , Recién Nacido , Masculino , Placenta/inmunología , Embarazo , Estudios Retrospectivos , Trombocitopenia Neonatal Aloinmune/inmunologíaRESUMEN
BACKGROUND & AIMS: Congenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids. METHODS: We collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7. RESULTS: In the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids. CONCLUSIONS: We identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/genética , Duodeno/metabolismo , Fibroblastos/metabolismo , Hipoalbuminemia/genética , Trastornos del Metabolismo de los Lípidos/genética , Organoides/metabolismo , Enteropatías Perdedoras de Proteínas/genética , Células CACO-2 , Estudios de Casos y Controles , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Niño , Preescolar , Consanguinidad , Dermis/citología , Diacilglicerol O-Acetiltransferasa/deficiencia , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Países Bajos , Forboles , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADN , TurquíaRESUMEN
PURPOSE: Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care. METHODS: Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital. RESULTS: In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy. CONCLUSION: We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.
Asunto(s)
Aminoacil-ARNt Sintetasas/deficiencia , Enfermedades Genéticas Congénitas/enzimología , Enfermedades Genéticas Congénitas/genética , Aminoacil-ARNt Sintetasas/genética , Enfermedades del Sistema Nervioso Central/enzimología , Enfermedades del Sistema Nervioso Central/genética , Niño , Insuficiencia de Crecimiento/enzimología , Insuficiencia de Crecimiento/genética , Trastornos de Alimentación y de la Ingestión de Alimentos/enzimología , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Femenino , Genes Recesivos , Trastornos del Crecimiento/enzimología , Trastornos del Crecimiento/genética , Humanos , Hepatopatías/enzimología , Hepatopatías/genética , Masculino , FenotipoRESUMEN
Patients with a Zellweger spectrum disorder (ZSD) have a defect in the assembly or maintenance of peroxisomes, leading to a multisystem disease with variable outcome. Liver disease is an important feature in patients with severe and milder phenotypes and a frequent cause of death. However, the course and histology of liver disease in ZSD patients are ill-defined. We reviewed the hepatic symptoms and histological findings of 13 patients with a ZSD in which one or several liver biopsies have been performed (patient age 0.2-39 years). All patients had at least some histological liver abnormalities, ranging from minor fibrosis to cirrhosis. Five patients demonstrated significant disease progression with liver failure and early death. In others, liver-related symptoms were absent, although some still silently developed cirrhosis. Patients with peroxisomal mosaicism had a better prognosis. In addition, we show that patients are at risk to develop a hepatocellular carcinoma (HCC), as one patient developed a HCC at the age of 36 years and one patient a precancerous lesion at the age of 18 years. Thus, regular examination to detect fibrosis or cirrhosis should be included in the standard care of ZSD patients. In case of advanced fibrosis/cirrhosis expert consultation and HCC screening should be initiated. This study further delineates the spectrum and significance of liver involvement in ZSDs.
Asunto(s)
Carcinoma Hepatocelular/etiología , Cirrosis Hepática/etiología , Neoplasias Hepáticas/etiología , Hígado/patología , Síndrome de Zellweger/complicaciones , Adolescente , Adulto , Carcinoma Hepatocelular/patología , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Países Bajos , Peroxisomas/genética , Síndrome de Zellweger/genéticaRESUMEN
When first published, this article inadvertently listed the Dutch NODO group individually within the author list without specifying the names of the collaborators. The collaborators have been listed within the Acknowledgements section only. The corrected author list is presented in this Correction.
RESUMEN
BACKGROUND: Postmortem CT is a relatively new field of interest within paediatric radiology. This paper focusses on its value in cases of unexpected natural death. OBJECTIVE: We report on an observational Dutch study regarding the value of postmortem CT in children with an assumed natural unexpected death because postmortem CT is part of the Dutch NODO (additional investigations of cause of death) procedure. MATERIALS AND METHODS: We included consecutive children who fulfilled criteria for the NODO procedure and were therefore referred to one of the centres for the procedure. Postmortem CT was performed in all cases and skeletal survey was performed in all children ages <5 years. The cause of death was defined in a consensus meeting. RESULTS: We included a total of 54 children (30 boys, median age 1.1 years, and 24 girls, median age 0.8 years). A definitive cause of death was established in 38 cases. In 7 cases the cause of death could be identified on postmortem CT. In 7 cases imaging findings were clinically relevant but did not lead to a cause of death. In the remaining 40 cases postmortem CT did not add to the diagnostic workup. CONCLUSION: Our study shows that in a group of children who unexpectedly died of an assumed natural cause of death and in whom a cause of death was found at autopsy, postmortem CT detected the cause of death in a minority of cases (12.9%). In the majority of cases (74.1%) postmortem CT did not add value in diagnosing the cause of death.
Asunto(s)
Autopsia , Causas de Muerte , Tomografía Computarizada por Rayos X/métodos , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Países BajosRESUMEN
BACKGROUND: Congenital cytomegalovirus (cCMV) infections are the most prevalent intrauterine infections worldwide and are the result of maternal primary or non-primary infections. Early maternal primary infections are thought to carry the highest risk of fetal developmental abnormalities as seen by ultrasound; however, non-primary infections may prove equally detrimental. METHODS/RESULTS: This case series presents 5 cases with fetal abnormalities detected in the second and third trimester, in which cCMV infection was ruled out due to negative maternal CMV-IgM. DISCUSSION: This series highlights the possible pitfalls in serology interpretation and fetal diagnosis necessary for appropriate parental counseling. Once fetal abnormalities have been confirmed and cCMV is suspected, maternal CMV serostatus and fetal infection should be determined. Maternal CMV serology may be ambiguous; therefore, caution should be exercised when interpreting the results.
Asunto(s)
Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/diagnóstico por imagen , Citomegalovirus/inmunología , Inmunoglobulina M/inmunología , Complicaciones Infecciosas del Embarazo/diagnóstico por imagen , Infecciones por Citomegalovirus/inmunología , Femenino , Edad Gestacional , Humanos , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Diagnóstico Prenatal , Ultrasonografía PrenatalRESUMEN
BACKGROUND: We recently published pump/acardiac umbilical venous diameter (UVD) ratios, representing the pump twin's excess cardiac output fraction, of 27 acardiac twin pregnancies. There was a clear separation between the 17 pump twins that had life-threatening complications and the 10 that did not. The hypothesis of this study is that placental chorangioma and sacrococcygeal teratoma (SCT), tumors whose perfusion also causes high-output complications, have the same fetal outcome as pump twins when perfusion of the tumor requires the same excess cardiac output fraction. METHODS: We compared the three fetoplacental circulations. Fetuses with a placental chorangioma and acardiac twin pregnancies both have their feeding artery and draining vein located at the placental cord insertion. In contrast, SCT lacks a prescribed feeding artery and draining vein. We, therefore, had to modify our model to assume that the diameter of the hypothetical draining vein is related to the flow difference between inferior vena cava and superior vena cava. The latter flow has been estimated sonographically and is the same as the inferior vena cava flow in the absence of an SCT. Furthermore, a simple modification accounts for the different location of the tumor with respect to the placental cord insertion. RESULTS: We propose to apply the clinical pump/acardiac UVD ratios to pregnancies complicated by placental chorangiomas and the modified pump/acardiac UVD ratios for SCT. CONCLUSION: Risk prediction of these rare fetal tumors may be possible based on application of data on excess cardiac output fractions from pump/acardiac UVD ratios and will require future clinical validation. Birth Defects Research (Part A) 106:733-738, 2016. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Enfermedades Fetales , Hemangioma , Embarazo Gemelar , Teratoma , Venas Umbilicales/patología , Femenino , Enfermedades Fetales/patología , Enfermedades Fetales/fisiopatología , Hemangioma/patología , Hemangioma/fisiopatología , Humanos , Tamaño de los Órganos , Embarazo , Región Sacrococcígea , Teratoma/patología , Teratoma/fisiopatologíaRESUMEN
BACKGROUND: Acardiac monochorionic twins lack cardiac function but grow by passive perfusion of the pump twin's deoxygenated arterial blood through placental arterioarterial (AA) and venovenous (VV) anastomoses and by hypoxia-mediated neovascularization. Pump twins therefore must continuously increase their cardiac output which may cause heart failure. Our aims were: to adapt our twin-twin transfusion syndrome model for acardiac twin pregnancies, to simulate pump and acardiac twin development, and to examine the model for early prognostic markers of pump twin survival. METHODS: We used an infinite acardiac placental resistance, based on placental dye injection studies and simulations, suggesting the AA-Acardiac-VV series resistance determines the pump twin's excess cardiac output. Pump and acardiac development were expressed by the pump's excess cardiac output versus its normal value, represented by pump/acardiac umbilical venous diameter (UVD) ratios. RESULTS: UVD ratios distinguish between AA-VV anastomoses that do and do not cause hydropic pump twins. Pump twins can handle relative larger acardiac perfusion at later than earlier gestation. Both VV and acardiac resistances are significantly smaller than the AA resistance, based on respectively clinical data and acardiac blood volumetric growth. CONCLUSION: Our simulations support clinical results which show that UVD ratios aid in the prediction of pump twin risk. The AA anastomosis controls the future of both the pump and the acardiac. Correlation between acardiac size and pump twin risk is secondary to the AA size but remains clinically usable. These factors may aid in the development of methods for pump twin prognosis and the promotion of selective clinical interventions.Birth Defects Research (Part A), 2016.© 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1008-1015, 2016. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Enfermedades en Gemelos/fisiopatología , Cardiopatías Congénitas/fisiopatología , Modelos Cardiovasculares , Neovascularización Patológica/fisiopatología , Placenta/irrigación sanguínea , Gemelos Monocigóticos , Gasto Cardíaco , Simulación por Computador , Enfermedades en Gemelos/patología , Femenino , Feto , Cardiopatías Congénitas/patología , Humanos , Neovascularización Patológica/patología , Placenta/anomalías , Circulación Placentaria , Embarazo , Embarazo Gemelar , Venas Umbilicales/patología , Venas Umbilicales/fisiopatologíaRESUMEN
BACKGROUND: Acardiac twinning is a rare anomaly of monochorionic twin pregnancies. Acardiac fetuses lack a functional heart but are passively perfused by arterial blood from their pump co-twin. Although four acardiac morphological types have been classified, the various paths of anatomical and circulatory acardiac twin development, and the potential influence of acardiac size and perfusion flow as possible predictors of pump twin morbidity and mortality are poorly understood. This report presents the first high resolution three-dimensional reconstruction of the vasculature of an acardiac twin by cryomicrotome imaging. CASE: A small, approximately 7.5-cm-diameter ball-shaped acardius amorphous of 30 5/7 weeks had caused pump twin cardiac decompensation that necessitated an emergency cesarian section. The pump twin survived well. The acardiac body had a partially intact vascular system with large diameter arteries and veins and multiple zones that appeared devoid of perfusion. The three-dimensional reconstruction showed neither recognizable organ structures nor identifiable blood vessels except for the umbilical artery and vein. CONCLUSION: Our case showed a small acardiac mass with large diameter vessels and consequential low outflow resistance that caused pump twin complications. This indicates that the development of a method that allows pump twin prognosis is likely more successful if based on the use of acardiac versus pump twin perfusion flows than on body volume ratios.