RESUMEN
Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection in vitro; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of the African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance.
Asunto(s)
Anemia Hemolítica Congénita/patología , Población Negra/genética , Hidropesía Fetal/patología , Canales Iónicos/genética , Malaria/patología , Alelos , Anemia Hemolítica Congénita/genética , Animales , Deshidratación , Modelos Animales de Enfermedad , Eritrocitos/citología , Eritrocitos/metabolismo , Eliminación de Gen , Genotipo , Humanos , Hidropesía Fetal/genética , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/deficiencia , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/genética , Canales Iónicos/química , Malaria/genética , Malaria/parasitología , Malaria/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Plasmodium berghei/crecimiento & desarrollo , Plasmodium berghei/patogenicidad , Linfocitos T/citología , Linfocitos T/metabolismoRESUMEN
Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom de novo heterozygous missense variants in the planar cell polarity gene CELSR1 were detected using exome sequencing. Using several in vitro assays, we show that the CELSR1 p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rare CELSR1 variants could be a possible cause of fetal hydrops.
Asunto(s)
Heterocigoto , Hidropesía Fetal , Mutación Missense , Humanos , Femenino , Mutación Missense/genética , Hidropesía Fetal/genética , Hidropesía Fetal/patología , Embarazo , Derrame Pleural/genética , Derrame Pleural/patología , Cadherinas/genética , Secuenciación del Exoma , Polaridad Celular/genéticaRESUMEN
Several factors associated with poor outcome in patients with prenatally diagnosed sacrococcygeal teratoma (SCT) have been found. However, the prognostic accuracy of these factors has not been well established. Therefore, we aimed to systematically review the prognostic accuracy of factors associated with poor outcome in these patients. We queried Search Premier, COCHRANE Library, EMCARE, EMBASE, PubMed, ScienceDirect, and Web of Science databases to identify studies regarding patients with prenatally diagnosed SCT. Poor outcome was defined as termination of pregnancy (TOP), intrauterine fetal death (IUFD), or perinatal death. We estimated the odds ratio of factors associated with poor outcome. Eleven studies (447 patients) were included. Overall mortality, including TOP, was 34.9%. Factors associated with poor outcome in fetuses with prenatally diagnosed SCT were cardiomegaly, hypervascular tumor, solid tumor morphology, fetal hydrops, and placentomegaly. A tumor volume to fetal weight ratio (TFR) of >0.12 before a gestational age of 24 weeks is predictive of poor outcome. The prognostic accuracy of factors associated with poor outcome in fetuses prenatally diagnosed with SCT seems promising. Factors associated with cardiac failure such as cardiomegaly, hypervascular tumor, solid tumor morphology, fetal hydrops, placentomegaly, and TFR >0.12 were found to be predictive of poor outcome.
Asunto(s)
Hidropesía Fetal , Teratoma , Embarazo , Femenino , Humanos , Lactante , Pronóstico , Hidropesía Fetal/patología , Ultrasonografía Prenatal , Teratoma/diagnóstico por imagen , Teratoma/complicaciones , Cardiomegalia/complicaciones , Cardiomegalia/patología , Región Sacrococcígea/diagnóstico por imagenAsunto(s)
Anemia Hemolítica Congénita , Hidropesía Fetal , Canales Iónicos , Policitemia , Humanos , Policitemia/genética , Anemia Hemolítica Congénita/genética , Anemia Hemolítica Congénita/patología , Canales Iónicos/genética , Hidropesía Fetal/genética , Hidropesía Fetal/diagnóstico , Hidropesía Fetal/patología , Masculino , Femenino , MutaciónRESUMEN
Homozygous variants of the thrombospondin type-1 domain-containing 1 (THSD1) gene have recently been associated with nonimmune hydrops fetalis (NIHF; OMIM 236750) in infants, as well as with congenital heart disease, hemangiomas, prematurity, and embryonic lethality. Here, we report the first case of a biallelic variant of THSD1 in an extremely premature infant (25 weeks) who suffered from NIHF (eventually resolved) and other manifestations of the THSD1 variant, such as congenital heart disease and hemangiomas. Her prematurity was complicated by pulmonary hypertension and chronic lung disease. This case indicates that biallelic homozygous variants of THSD1 are among the likely causes of NIHF. Information from this case report will aid in determining the prognosis of NIHF caused by such variants in premature infants.
Asunto(s)
Predisposición Genética a la Enfermedad , Hidropesía Fetal/genética , Recien Nacido Extremadamente Prematuro , Trombospondinas/genética , Femenino , Homocigoto , Humanos , Hidropesía Fetal/patología , Lactante , Recién NacidoRESUMEN
Lymphedema distichiasis syndrome (LDS) is a rare autosomal dominant condition characterized by lower limb lymphedema, distichiasis, and variable additional features. LDS is usually caused by heterozygous sequence variants in the FOXC2 gene located at 16q24, but in one previous instance LDS has resulted from a balanced reciprocal translocation with a breakpoint at 16q24, 120 kb distal to the FOXC2 gene suggesting a position effect. Here, we describe a second family with LDS caused by a translocation involving 16q24. The family were ascertained after detection of a paternally inherited balanced reciprocal translocation t(16;22)(q24;q13.1) in a pregnancy complicated by severe fetal hydrops. There was a past history of multiple miscarriages in the father's family, and a personal and family history of lymphedema and distichiasis, consistent with the diagnosis of LDS. Using whole genome amplified DNA from single sperm of the male proband, bead array analysis demonstrated that the FOXC2 gene was intact and the chromosome 16 breakpoint mapped to the same region 120Kb distal to the FOXC2 gene. This case highlights the clinical consequences that can arise from a translocation of genomic material without dosage imbalance, and that it is increasingly feasible to predict and characterize possible effects with improved access to molecular techniques.
Asunto(s)
Pestañas/anomalías , Factores de Transcripción Forkhead/genética , Predisposición Genética a la Enfermedad , Hidropesía Fetal/genética , Linfedema/genética , Elementos de Facilitación Genéticos/genética , Pestañas/patología , Femenino , Heterocigoto , Humanos , Hidropesía Fetal/patología , Extremidad Inferior/patología , Linfedema/patología , Masculino , Linaje , Regiones Promotoras Genéticas/genética , Secuencias Reguladoras de Ácidos Nucleicos/genéticaRESUMEN
BACKGROUND: Mirror syndrome (MS) is a rare obstetric disorder complicated with high maternal morbidity and fetal mortality. MS is often misdiagnosed or underdiagnosed due to the low incidence and lack of awareness of its diverse features. This study aimed to summarise the etiology, clinical characteristics, and risk factors of MS among mothers with fetal hydrops. METHODS: This retrospective case-control study included 37 pregnant women with fetal hydrops in the second and third trimesters from 58,428 deliveries performed at the Third Affiliated Hospital of Sun Yat-Sen University between January 2012 and December 2020. Cases were categorized as MS and non-MS according to the presence or absence of maternal mirroring symptoms. Binary logistic regression was performed for analysis. RESULTS: Fourteen women developed MS with an overall incidence of 0.024% (14/58,428) and 37.8% (14/37) in the fetal hydrops cases. Among the 11 MS cases with known associated etiologies, seven had alpha thalassemia major. Onset of fetal hydrops was later (27.8 vs. 23.0 weeks) and the rate of placental thickening was higher (85.7% vs. 34.8%) in the MS group than in the non-MS group (P < 0.05). Regarding maternal characteristics, the MS group had higher maternal morbidity (85.7% vs. 8.7%), more weight gain (9.0 vs. 5.5 kg), higher rates of hypertension (35.7 vs. 0%) and proteinuria (64.3% vs. 4.3%), and lower levels of hemoglobin (88 vs. 105 g/L) and serum albumin (25.8 vs. 35.0 g/L) than the non-MS group (P < 0.05). Logistic regression analysis showed that onset of fetal hydrops at ≥24 weeks and placental thickening were associated with the risk of MS among fetal hydrops cases (OR 15.83, 95% CI 1.56-160.10 and OR 8.63, 95% CI 1.29-57.72, respectively). CONCLUSIONS: MS is relatively common among fetal hydrops cases in the late second and third trimesters, and alpha thalassemia major is the main etiology for fetal hydrops and also MS in this population. Complicated with high maternal morbidity, the key maternal features of MS include more weight gain, hemodilution, and hypertension. Among those with fetal hydrops, the onset time of ≥24 weeks and placental thickening are risk factors for MS.
Asunto(s)
Edema/patología , Hemodilución , Hidropesía Fetal/patología , Hipertensión , Enfermedades Placentarias/patología , Complicaciones del Embarazo/patología , Aumento de Peso , Estudios de Casos y Controles , China/epidemiología , Edema/diagnóstico , Edema/etiología , Femenino , Humanos , Hidropesía Fetal/diagnóstico , Hidropesía Fetal/etiología , Enfermedades Placentarias/diagnóstico , Enfermedades Placentarias/etiología , Embarazo , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/etiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Síndrome , Talasemia alfa/complicacionesRESUMEN
The exact prevalence of mirror syndrome remains unclear, and the precise clinical features need to be disclosed. We retrospectively reviewed 85 cases of foetal hydrops from a total of 98,484 deliveries. Of these 16 showed mirror syndrome, while 69 did not. The incidence of mirror syndrome among all deliveries was 0.0162%, while that among patients with foetal hydrops was 23.2%. Maternal symptoms of mirror syndrome included anaemia (n = 15), hypertension (n = 7), proteinuria (n = 8), pulmonary oedema (n = 3), cardiac failure (n = 2) and HELLP syndrome (n = 2). Placental thickness, placental weight and amniotic fluid index were significantly different between the groups. In the mirror syndrome group, uric acid, lactate dehydrogenase, creatinine and D-dimer levels were significantly higher (p < .05), whereas haemoglobin, serum albumin levels, haematocrit value and platelet count were significantly lower (p < .05). Elevated uric acid, lactate dehydrogenase and D-dimer levels may be useful as predictors of mirror syndrome.Impact statementWhat is already known on this subject? As mirror syndrome is uncommon and under-diagnosed, its exact incidence is not yet clear, and most publications are case reports or reviews of case reports.What the results of this study add? The incidence of mirror syndrome among all deliveries was 0.0162%, while that among patients with foetal hydrops was 23.2%. Pregnant women who develop mirror syndrome may show severe complications of pregnancy. Attention should be paid to the further progress of the condition. Placental thickness, placental weight and amniotic fluid index were significantly different between those with mirror syndrome and those without. In the mirror syndrome group, the uric acid, lactate dehydrogenase, creatinine and D-dimer levels were significantly higher (p < .05), whereas haemoglobin level, haematocrit value, platelet count and serum albumin level were significantly lower (p < .05).What the implications are of these findings for clinical practice and/or further research? Mirror syndrome is not rare among patients with foetal hydrops. Elevated uric acid, lactate dehydrogenase and D-dimer levels may be useful as predictors of mirror syndrome.
Asunto(s)
Edema/patología , Hidropesía Fetal/patología , Complicaciones del Embarazo/patología , Adulto , Edema/sangre , Edema/complicaciones , Femenino , Humanos , Placenta/patología , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/etiología , Estudios Retrospectivos , SíndromeRESUMEN
The etiology of nonimmune hydrops fetalis is extensive and includes genetic disorders. We describe a term-born female neonate with late onset extensive nonimmune hydrops, that is, polyhydramnios, edema, and congenital bilateral chylothorax. This newborn was successfully treated with repetitive thoracocentesis, total parenteral feeding, octreotide intravenously and finally surgical pleurodesis and corticosteroids. A genetic cause seemed plausible as the maternal history revealed a fatal nonimmune hydrops fetalis. A homozygous truncating variant in GDF2 (c.451C>T, p.(Arg151*)) was detected with exome sequencing. Genetic analysis of tissue obtained from the deceased fetal sibling revealed the same homozygous variant. The parents and two healthy siblings were heterozygous for the GDF2 variant. Skin and lung biopsies in the index patient, as well as the revised lung biopsy of the deceased fetal sibling, showed lymphatic dysplasia and lymphangiectasia. To the best of our knowledge, this is the first report of an association between a homozygous variant in GDF2 with lymphatic dysplasia, hydrothorax and nonimmune hydrops fetalis.
Asunto(s)
Anomalías Craneofaciales/genética , Factor 2 de Diferenciación de Crecimiento/genética , Hidropesía Fetal/genética , Linfangiectasia Intestinal/genética , Linfedema/genética , Polihidramnios/genética , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/patología , Femenino , Homocigoto , Humanos , Hidropesía Fetal/diagnóstico , Hidropesía Fetal/patología , Recién Nacido , Linfangiectasia Intestinal/diagnóstico , Linfangiectasia Intestinal/patología , Linfedema/diagnóstico , Linfedema/patología , Polihidramnios/diagnóstico , Polihidramnios/patología , Embarazo , Toracocentesis , Ultrasonografía Prenatal , Secuenciación del ExomaRESUMEN
Dehydrated hereditary stomatocytosis (DHS), or xerocytosis, is an autosomal dominant hemolytic anemia. Most patients with DHS carry mutations in the PIEZO1 gene encoding a mechanosensitive cation channel. We here demonstrate that patients with DHS have low levels of hepcidin and only a slight increase of ERFE, the erythroid negative regulator of hepcidin. We demonstrated that at the physiological level, PIEZO1 activation induced Ca2+ influx and suppression of HAMP expression in primary hepatocytes. In two hepatic cellular models expressing PIEZO1 WT and two PIEZO1 gain-of-function mutants (R2456H and R2488Q), we highlight altered expression of a few genes/proteins involved in iron metabolism. Mutant cells showed increased intracellular Ca2+ compared to WT, which was correlated to increased phosphorylation of ERK1/2, inhibition of the BMP-SMADs pathway, and suppression of HAMP transcription. Moreover, the HuH7 cells, treated with PD0325901, a potent inhibitor of ERK1/2 phosphorylation, reduced the phosphorylation of ERK1/2 with the consequent increased phosphorylation of SMAD1/5/8, confirming the link between the two pathways. Another "proof of concept" for the mechanism that links PIEZO1 to HAMP regulation was obtained by mimicking PIEZO1 activation by cell Ca2+ overload, by the Ca2+ ionophore A23187. There was strong down-regulation of HAMP gene expression after this Ca2+ overload. Finally, the inhibition of PIEZO1 by GsMTx4 leads to phenotype rescue. This is the first demonstration of a direct link between PIEZO1 and iron metabolism, which defines the channel as a new hepatic iron metabolism regulator and as a possible therapeutic target of iron overload in DHS and other iron-loading anemias.
Asunto(s)
Anemia Hemolítica Congénita , Proteínas Morfogenéticas Óseas/metabolismo , Mutación con Ganancia de Función , Hepcidinas/biosíntesis , Hidropesía Fetal , Canales Iónicos , Hierro/metabolismo , Hígado/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas Smad/metabolismo , Sustitución de Aminoácidos , Anemia Hemolítica Congénita/genética , Anemia Hemolítica Congénita/metabolismo , Anemia Hemolítica Congénita/patología , Benzamidas/farmacología , Proteínas Morfogenéticas Óseas/genética , Difenilamina/análogos & derivados , Difenilamina/farmacología , Regulación de la Expresión Génica , Células Hep G2 , Hepcidinas/genética , Humanos , Hidropesía Fetal/genética , Hidropesía Fetal/metabolismo , Hidropesía Fetal/patología , Canales Iónicos/genética , Canales Iónicos/metabolismo , Hígado/patología , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas Smad/genéticaRESUMEN
We report a rare case of severe congenital dyserythropoietic anemia type 1 with fetal onset. Our patient presented with fetal hydrops from 19 weeks of gestation, requiring multiple intrauterine transfusions. At birth, she had severe hemolytic anemia with severe jaundice, and was subsequently transfusion dependent. She eventually developed severe iron overload and fulminant liver failure before her demise at 5 months of age. Genetic testing revealed a novel mutation in CDAN1.
Asunto(s)
Anemia Diseritropoyética Congénita , Colestasis Intrahepática , Glicoproteínas/genética , Hidropesía Fetal , Sobrecarga de Hierro , Mutación , Índice de Severidad de la Enfermedad , Anemia Diseritropoyética Congénita/genética , Anemia Diseritropoyética Congénita/patología , Colestasis Intrahepática/genética , Colestasis Intrahepática/patología , Femenino , Humanos , Hidropesía Fetal/genética , Hidropesía Fetal/patología , Lactante , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/patología , Proteínas NuclearesRESUMEN
We identified a child with KLF1-E325K congenital dyserythropoietic anemia type IV who experienced a severe clinical course, fetal anemia, hydrops fetalis, and postnatal transfusion dependence only partially responsive to splenectomy. The child also had complete sex reversal, the cause which remains undetermined. To gain insights into our patient's severe hematologic phenotype, detailed analyses were performed. Erythrocytes from the patient and parents demonstrated functional abnormalities of the erythrocyte membrane, attributed to variants in the α-spectrin gene. Hypomorphic alleles in SEC23B and YARS2 were also identified. We hypothesize that coinheritance of variants in relevant erythrocyte genes contribute to the clinical course in our patient and other E325K-linked congenital dyserythropoietic anemia IV patients with severe clinical phenotypes.
Asunto(s)
Anemia Diseritropoyética Congénita/genética , Trastornos del Desarrollo Sexual/genética , Hidropesía Fetal/genética , Factores de Transcripción de Tipo Kruppel/genética , Mutación Missense , Sustitución de Aminoácidos , Anemia Diseritropoyética Congénita/patología , Anemia Diseritropoyética Congénita/terapia , Trastornos del Desarrollo Sexual/patología , Trastornos del Desarrollo Sexual/terapia , Humanos , Hidropesía Fetal/patología , Hidropesía Fetal/terapia , Recién Nacido , Masculino , Índice de Severidad de la Enfermedad , Proteínas de Transporte Vesicular/genéticaRESUMEN
PURPOSE: The aim of the present study was to report experiences with invasive prenatal diagnosis of α-thalassemia for the prevention of Hb Bart's hydrops fetalis syndrome in the Guangxi Zhuang Autonomous Region, China. METHODS: Pregnant women and their partners who tested positive for α0-thalassemia or were diagnosed with HbH diseases were counseled and suggested to undergo a prenatal diagnostic procedure for α-thalassemia. Fetal material was obtained by chorionic villus sampling (CVS) between 9 and 13 weeks of gestation, by amniocentesis between 16 and 24 weeks of gestation and by cordocentesis after 24 weeks of gestation. The α0-thalassemia gene types were detected by gap polymerase chain reaction (Gap-PCR). All results were finally confirmed by DNA analysis after delivery or termination of pregnancy. RESULTS: An invasive prenatal α-thalassemia diagnosis was performed in 3155 cases at risk for Hb Bart's hydrops fetalis syndrome at our hospital from 2002 to 2016. CVS was performed in 1559 cases (49.4%), amniocentesis in 1240 cases (39.3%) and cordocentesis in 356 cases (11.3%). In total, 786 fetuses were diagnosed as Hb Bart's hydrops fetalis syndrome. Among these cases, the α-thalassemia genotype was --SEA/--SEA in 784 cases and --SEA/--THAI in 2 cases. All affected pregnancies were terminated in time. CONCLUSIONS: This extensive experience suggests that carrier screening, molecular diagnostics, genetic counselling, and prenatal diagnosis are effective measures to prevent Hb Bart's hydrops fetalis syndrome.
Asunto(s)
Hemoglobinas Anormales/efectos adversos , Hidropesía Fetal/diagnóstico , Diagnóstico Prenatal/métodos , Talasemia alfa/diagnóstico , Femenino , Humanos , Hidropesía Fetal/patología , Embarazo , Estudios Retrospectivos , Factores de Tiempo , Talasemia alfa/patologíaRESUMEN
We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis.
Asunto(s)
Anemia Neonatal/genética , Anemia Neonatal/patología , Eliminación de Gen , Hidropesía Fetal/genética , Hidropesía Fetal/patología , Factores de Transcripción de Tipo Kruppel/genética , Transcriptoma , Anemia Neonatal/sangre , Anemia Neonatal/complicaciones , Autofagia , Eritroblastos/metabolismo , Eritroblastos/patología , Eritropoyesis , Femenino , Regulación de la Expresión Génica , Humanos , Hidropesía Fetal/sangre , Recién Nacido , Factores de Transcripción de Tipo Kruppel/metabolismo , MasculinoRESUMEN
The autopsy of a fetus at 23 weeks gestational age revealed a partial pericardial defect with subsequent herniation of parts of the left ventricle. The myocard was impinged by the fibrous rim of the residual pericardium. Microscopic examination showed signs of recurrent myocardial infarctions with necrosis, calcification, fibrosis and prominent deposition of iron.Partial pericardial defects result from incomplete fusion of the pleuropericardial membrane and may lead to myocardial infarction via compression of the coronary arteries.
Asunto(s)
Divertículo/patología , Cardiopatías Congénitas/patología , Infarto del Miocardio/congénito , Infarto del Miocardio/patología , Pericardio/anomalías , Pericardio/patología , Diagnóstico Prenatal , Aborto Eugénico , Adulto , Femenino , Humanos , Hidropesía Fetal/patología , Miocardio/patología , Embarazo , Segundo Trimestre del EmbarazoRESUMEN
Familial xerocytosis (HX) in humans is an autosomal disease that causes dehydration of red blood cells resulting in hemolytic anemia which has been traced to two individual mutations in the mechanosensitive ion channel, PIEZO1. Each mutation alters channel kinetics in ways that can explain the clinical presentation. Both mutations slowed inactivation and introduced a pronounced latency for activation. A conservative substitution of lysine for arginine (R2456K) eliminated inactivation and also slowed deactivation, indicating that this mutant's loss of charge is not responsible for HX. Fitting the current vs. pressure data to Boltzmann distributions showed that the half-activation pressure, P1/2, for M2225R was similar to that of WT, whereas mutations at position 2456 were left shifted. The absolute stress sensitivity was calibrated by cotransfection and comparison with MscL, a well-characterized mechanosensitive channel from bacteria that is driven by bilayer tension. The slope sensitivity of WT and mutant human PIEZO1 (hPIEZO1) was similar to that of MscL implying that the in-plane area increased markedly, by â¼6-20 nm(2) during opening. In addition to the behavior of individual channels, groups of hPIEZO1 channels could undergo simultaneous changes in kinetics including a loss of inactivation and a long (â¼200 ms), silent latency for activation. These observations suggest that hPIEZO1 exists in spatial domains whose global properties can modify channel gating. The mutations that create HX affect cation fluxes in two ways: slow inactivation increases the cation flux, and the latency decreases it. These data provide a direct link between pathology and mechanosensitive channel dysfunction in nonsensory cells.
Asunto(s)
Anemia Hemolítica Congénita/metabolismo , Hidropesía Fetal/metabolismo , Canales Iónicos/metabolismo , Mecanotransducción Celular , Mutación Missense , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Anemia Hemolítica Congénita/genética , Anemia Hemolítica Congénita/patología , Anemia Hemolítica Congénita/fisiopatología , Escherichia coli , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Células HEK293 , Humanos , Hidropesía Fetal/genética , Hidropesía Fetal/patología , Hidropesía Fetal/fisiopatología , Canales Iónicos/genética , Cinética , Datos de Secuencia Molecular , Estructura Terciaria de ProteínaRESUMEN
As the information obtained from previable fetal and stillbirth autopsies is used not only to explain the loss to the parents, but for future pregnancy planning, general pathologists need to be comfortable in dealing with these autopsies. The importance of an adequate fetal examination has been emphasized in a recent policy on the subject by the American Board of Pathology http://www.abpath.org/FetalAutopsyPoli'cy.pdf. This second review paper covers the approach to hydrops fetalis. The approach to the nonanomalous and anomalous fetus was covered in the first part of this series.
Asunto(s)
Autopsia , Feto/patología , Hidropesía Fetal/patología , Recién Nacido , Mortinato , Humanos , Hidropesía Fetal/etiologíaRESUMEN
RASA1 mutations have been shown to cause capillary malformation-arteriovenous malformation (CM-AVM). We describe a patient with CM-AVM and a fetus who presented with non-immune hydrops fetalis during the pregnancy. Sequencing revealed a novel RASA1 mutation in the RASGAP domain that results in a loss of function of p120-RasGap. This report expands our current genetic and clinical understanding of CM-AVM in pregnancy.
Asunto(s)
Malformaciones Arteriovenosas/genética , Capilares/anomalías , Hidropesía Fetal/genética , Mutación , Mancha Vino de Oporto/genética , Proteína Activadora de GTPasa p120/genética , Adulto , Malformaciones Arteriovenosas/patología , Capilares/patología , Análisis Mutacional de ADN , Femenino , Feto , Expresión Génica , Humanos , Hidropesía Fetal/patología , Recién Nacido , Masculino , Mancha Vino de Oporto/patología , Embarazo , Estructura Terciaria de ProteínaRESUMEN
OBJECTIVE: Nonimmune hydrops fetalis (NIHF) is one of the most difficult problems related to pregnancy. The aim of this study was to evaluate the etiological analysis as well as the fetal and neonatal outcomes of NIHF. METHODS: We reviewed the prenatal sonographic data and postnatal medical records of pregnant women diagnosed as NIHF in our hospital between January 2001 and May 2013. All cases were categorized using 12 etiological classification groups. Demographic data, diagnostic laboratory parameters, karyotyping results, sonographic and autopsy findings, postnatal final diagnoses, and perinatal mortality rates were also recorded. RESULTS: This study included 147 cases. The mean gestational age at the time of the initial diagnosis was 23.84±6.30 weeks. Cardiovascular causes were the most common (21.7%), followed by structural abnormalities (17.0%), chromosomal abnormalities (6.8%), and skeletal dysplasias (5.4%). Chromosomal abnormalities were detected in 12.8% of these cases. The most common karyotype abnormality was monosomy X. Postmortem autopsy was performed in 50 (34%) cases, and at least one finding was detected in 40 (80%) of these cases. The overall mortality rate was 78.2%. The gestational week at delivery, birth weight, and Apgar score (1st and 5th min) showed a statistically significant difference between exitus and surviving fetuses (P<0.05). CONCLUSION: NIHF can lead to high perinatal morbidity and mortality, yet its etiopathology remains poorly understood. Early diagnosis of NIHF gives parents an opportunity to make an informed choice about the possible complications of a pregnancy.
Asunto(s)
Hidropesía Fetal/etiología , Adulto , Femenino , Humanos , Hidropesía Fetal/mortalidad , Hidropesía Fetal/patología , Recién Nacido , Embarazo , Diagnóstico Prenatal , Estudios Retrospectivos , Turquía/epidemiología , Adulto JovenRESUMEN
Fetoplacental hydrops is the final stage of several pathological conditions in which the placenta and umbilical cord become edematous and the fetus develops an anasarcatic state characterized by an excessive accumulation of extravascular fluids in at least two serous cavities of the body. It is a common histological finding of stillbirth, characterized by the appearance of markedly edematous villi, suggesting an increased interstitial fluid accumulation. The recent improved knowledge of lymphangiogenesis and the availability of monoclonal antibodies selectively labeling lymphatic endothelium lead to the hypothesis that villous edema is essentially a lymphedema from defective lymphatic function following inadequate villous blood circulation. Lymphedema is a morphologic phenotype found by our research group in a 24-case series of stillbirths from different morbid conditions such as chromosomal aberrations, congenital malformations, inherited hemoglobinopathies, and prolonged perinatal severe anoxia. Unlike long-lived organs, the placenta is devoid of innervation by the autonomic nervous system; therefore, the vascular tone regulation and the peripheral perfusion are modulated by the expression of the angiotensin converting enzyme (ACE) in the vascular endothelia. This finding may suggest to the clinician to search for a more suitable therapy in case of mother's hypertension during pregnancy.