RESUMEN
In normal cardiovascular development in birds and mammals, the outflow tract of the heart is divided into two distinct channels to separate the oxygenated systemic blood flow from the deoxygenated pulmonary circulation. When the process of outflow tract septation fails, a single common outflow vessel persists resulting in a serious clinical condition known as persistent truncus arteriosus or common arterial trunk. In this chapter, we will review molecular pathways and the cells that are known to play a role in the formation and development of the outflow tract and how genetic manipulation of these pathways in animal models can result in common arterial trunk.
Asunto(s)
Modelos Animales de Enfermedad , Tronco Arterial Persistente , Animales , Humanos , Transducción de Señal , Tronco Arterial/metabolismo , Tronco Arterial/fisiopatología , Tronco Arterial/patología , Tronco Arterial Persistente/genética , Tronco Arterial Persistente/fisiopatología , Tronco Arterial Persistente/patologíaRESUMEN
Truncus Arteriosus (TA) is a congenital heart disease characterized by a single common blood vessel emerging from the right and left ventricles instead of the main pulmonary artery and aorta. TA accounts for 4% of all critical congenital heart diseases. The most common cause of TA is 22q11.2 deletion syndrome, accounting for 12-35% of all TA cases. However, no major causes of TA other than 22q11.2 deletion have been reported. We performed whole-genome sequencing of 11 Japanese patients having TA without 22q11.2 deletion. Among five patients, we identified pathogenic variants in TMEM260; the biallelic loss-of-function variants of which have recently been associated with structural heart defects and renal anomalies syndrome (SHDRA). In one patient, we identified a de novo pathogenic variant in GATA6, and in another patient, we identified a de novo probably pathogenic variant in NOTCH1. Notably, we identified a prevalent variant in TMEM260 (ENST00000261556.6), c.1617del (p.Trp539Cysfs*9), in 8/22 alleles among the 11 patients. The c.1617del variant was estimated to occur approximately 23 kiloyears ago. Based on the allele frequency of the c.1617del variant in the Japanese population (0.36%), approximately 26% of Japanese patients afflicted with TA could harbor homozygous c.1617del variants. This study highlights TMEM260, especially c.1617del, as a major genetic cause of TA in the Japanese population.
Asunto(s)
Síndrome de DiGeorge , Proteínas de la Membrana , Femenino , Humanos , Masculino , Alelos , Síndrome de DiGeorge/genética , Pueblos del Este de Asia/genética , Japón/epidemiología , Proteínas de la Membrana/genética , Receptor Notch1/genética , Tronco Arterial/patología , Secuenciación Completa del GenomaRESUMEN
The 22q11.2 deletion syndrome has an estimated prevalence of 1 in 4-6,000 livebirths. The phenotype varies widely; the most common features include: facial dysmorphia, hypocalcemia, palate and speech disorders, feeding and gastrointestinal disorders, immunodeficiency, recurrent infections, neurodevelopmental and psychiatric disorders, and congenital heart disease. Approximately 60-80% of patients have a cardiac malformation most commonly including a subset of conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B), conoventricular and/or atrial septal defects, and aortic arch anomalies. Cardiac patients with a 22q11.2 deletion do not generally experience higher mortality upon surgical intervention but suffer more peri-operative complications than their non-syndromic counterparts. New guidelines suggest screening for a 22q11.2 deletion in the patient with tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, conoventricular septal defects as well as those with an isolated aortic arch anomaly. Early identification of a 22q11.2 deletion in the neonate or infant when other syndromic features may not be apparent allows for timely parental screening for reproductive counseling and anticipatory evaluation of cardiac and noncardiac features. Screening the at-risk child or adult allows for important age-specific clinical, neurodevelopmental, psychiatric, and reproductive issues to be addressed.
Asunto(s)
Aorta Torácica/anomalías , Aracnodactilia/epidemiología , Craneosinostosis/epidemiología , Síndrome de DiGeorge/epidemiología , Cardiopatías Congénitas/epidemiología , Síndrome de Marfan/epidemiología , Aorta Torácica/patología , Aracnodactilia/complicaciones , Aracnodactilia/genética , Deleción Cromosómica , Craneosinostosis/complicaciones , Craneosinostosis/genética , Síndrome de DiGeorge/complicaciones , Síndrome de DiGeorge/genética , Guías como Asunto , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/genética , Humanos , Hibridación Fluorescente in Situ , Síndrome de Marfan/complicaciones , Síndrome de Marfan/genética , Tetralogía de Fallot/complicaciones , Tetralogía de Fallot/epidemiología , Tetralogía de Fallot/genética , Tronco Arterial/patologíaRESUMEN
Plexin D1 belongs to a family of transmembrane proteins called plexins. It was characterized as a receptor for semaphorins and is known to be essential for axonal guidance and vascular patterning. Mutations in Plexin D1 have been implicated in pathologic conditions such as truncus arteriosus and Möbius syndrome. Emerging data show that expression of Plexin D1 is deregulated in several cancers; it can support tumor development by aiding in tumor metastasis and EMT; and conversely, it can act as a dependence receptor and stimulate cell death in the absence of its canonical ligand, semaphorin 3E. The role of Plexin D1 in tumor development and progression is thereby garnering research interest for its potential as a biomarker and as a therapeutic target. In this review, we describe its discovery, structure, mutations, role(s) in cancer, and therapeutic potential.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Síndrome de Mobius/genética , Metástasis de la Neoplasia/genética , Neoplasias/genética , Biomarcadores de Tumor/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular , Glicoproteínas de Membrana , Síndrome de Mobius/complicaciones , Síndrome de Mobius/terapia , Terapia Molecular Dirigida , Metástasis de la Neoplasia/patología , Neoplasias/complicaciones , Neoplasias/terapia , Transducción de Señal/genética , Tronco Arterial/patologíaRESUMEN
OBJECTIVE: We sought to describe characteristics and operative outcomes of children who underwent repair of truncus arteriosus and identify risk factors for the occurrence of major adverse cardiac events (MACE) in the immediate postoperative period in a contemporary multicenter cohort. METHODS: We conducted a retrospective review of children who underwent repair of truncus arteriosus between 2009 and 2016 at 15 centers within the United States. Patients with associated interrupted or obstructed aortic arch were excluded. MACE was defined as the need for postoperative extracorporeal membrane oxygenation, cardiopulmonary resuscitation, or operative mortality. Risk factors for MACE were identified using multivariable logistic regression analysis and reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: We reviewed 216 patients. MACE occurred in 44 patients (20%) and did not vary significantly over time. Twenty-two patients (10%) received postoperative extracorporeal membrane oxygenation, 26 (12%) received cardiopulmonary resuscitation, and 15 (7%) suffered operative mortality. With multivariable logistic regression analysis (which included adjustment for center effect), factors independently associated with MACE were failure to diagnose truncus arteriosus before discharge from the nursery (OR, 3.1; 95% CI, 1.3-7.4), cardiopulmonary bypass duration >150 minutes (OR, 3.5; 95% CI, 1.5-8.5), and right ventricle-to-pulmonary artery conduit diameter >50 mm/m2 (OR, 4.7; 95% CI, 2.0-11.1). CONCLUSIONS: In a contemporary multicenter analysis, 20% of children who underwent repair of truncus arteriosus experienced MACE. Early diagnosis, shorter duration of cardiopulmonary bypass, and use of smaller diameter right ventricle-to-pulmonary artery conduits represent potentially modifiable factors that could decrease morbidity and mortality in this fragile patient population.
Asunto(s)
Tronco Arterial/cirugía , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/métodos , Humanos , Recién Nacido , Masculino , Diagnóstico Prenatal , Estudios Retrospectivos , Resultado del Tratamiento , Tronco Arterial/patología , Estados UnidosAsunto(s)
Aorta/patología , Arteria Pulmonar/patología , Tronco Arterial/patología , Anastomosis Quirúrgica , Aorta/anomalías , Aorta/diagnóstico por imagen , Angiografía por Tomografía Computarizada/métodos , Vasos Coronarios/anatomía & histología , Vasos Coronarios/diagnóstico por imagen , Ecocardiografía/métodos , Ventrículos Cardíacos/cirugía , Humanos , Recién Nacido , Masculino , Arteria Pulmonar/anomalías , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/cirugía , Tronco Arterial/diagnóstico por imagen , Tronco Arterial/cirugíaRESUMEN
An intramural coronary artery in the setting of truncus arteriosus (common arterial trunk) is an uncommon association. Following an uneventful surgical repair, a neonate developed a low cardiac output state deteriorating into cardiac arrest shortly after arrival into the intensive care unit, requiring extracorporeal membrane oxygenation support. Echocardiography and angiography showed occlusion of the left coronary artery, prompting emergency surgical reexploration. A "slit-like" orifice with an intramural left coronary artery was successfully unroofed, allowing full recovery. Full definition of the proximal coronary anatomy beyond the orifices should be investigated preoperatively in truncus arteriosus, as a missed intramural segment could lead to significant morbidity or mortality.
Asunto(s)
Tronco Arterial Persistente/diagnóstico , Gasto Cardíaco Bajo/diagnóstico , Gasto Cardíaco Bajo/cirugía , Vasos Coronarios/cirugía , Oxigenación por Membrana Extracorpórea , Femenino , Humanos , Recién Nacido , Resultado del Tratamiento , Tronco Arterial/anomalías , Tronco Arterial/patología , Tronco Arterial/cirugía , Tronco Arterial Persistente/cirugíaRESUMEN
BACKGROUND: Neonatal diabetes is a rare form of monogenic diabetes with onset in the first six months of life occurring in 1/100,000 to 1/400,000 births. Both permanent and transient forms have been described. Permanent neonatal diabetes results predominantly from mutations in the KCNJ11 and ABCC8 genes. Less frequently, mutations of the GATA6 gene, located on chromosome 18 cause a form of permanent neonatal diabetes resulting from pancreatic hypoplasia or agenesis. Other anomalies associated with mutations of this gene have also been reported, most commonly congenital heart disease. CASE PRESENTATION: We report the case of a Caucasian male infant diagnosed shortly after birth with neonatal diabetes, truncus arteriosus type III, ventricular septal defect, atrial septal defect, an absent gallbladder and a right inguinal hernia. His diabetes resulted from a de novo mutation of the GATA6 gene resulting in pancreatic hypoplasia. At 20 months of age he developed protein losing enteropathy. This has not previously been associated with GATA6 mutations and it is not known if this association is causal. CONCLUSION: The combination of neonatal diabetes and pancreatic agenesis/hypoplasia should alert the clinician to the possibility of a GATA6 gene abnormality. The association of protein losing enteropathy is unique to the reported case.
Asunto(s)
Diabetes Mellitus/genética , Enteropatías Perdedoras de Proteínas/genética , Cromosomas Humanos Par 18/genética , Diabetes Mellitus/diagnóstico , Factor de Transcripción GATA6/genética , Defectos del Tabique Interatrial/diagnóstico , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interventricular/diagnóstico , Defectos del Tabique Interventricular/genética , Humanos , Lactante , Masculino , Páncreas/patología , Canales de Potasio de Rectificación Interna/genética , Enteropatías Perdedoras de Proteínas/diagnóstico , Receptores de Sulfonilureas/genética , Tronco Arterial/patología , Población Blanca/genéticaRESUMEN
The association of 46,XY disorder of sex development (DSD) with congenital diaphragmatic hernia (CDH) is rare, but has been previously described with and without other congenital anomalies. Literature review identified five cases of 46,XY DSD associated with CDH and other congenital anomalies. These five cases share characteristics including CDH, 46,XY karyotype with external female appearing or ambiguous genitalia, cardiac anomalies, and decreased life span. The present case had novel features including truncus arteriosus, bifid thymus, gut malrotation, and limb anomalies consisting of rhizomelia and adactyly. With this case report, we present a review of the literature of cases of 46,XY DSD and CDH in association with multiple congenital abnormalities. This case may represent a unique syndrome of 46,XY DSD and diaphragmatic hernia or a more severe presentation of a syndrome represented in the previously reported cases.
Asunto(s)
Anomalías Múltiples/genética , Anomalías del Sistema Digestivo/genética , Trastorno del Desarrollo Sexual 46,XY/genética , Deformidades Congénitas de la Mano/genética , Cardiopatías Congénitas/genética , Hernias Diafragmáticas Congénitas/genética , Vólvulo Intestinal/genética , Anomalías Múltiples/patología , Anomalías del Sistema Digestivo/patología , Trastorno del Desarrollo Sexual 46,XY/patología , Facies , Resultado Fatal , Femenino , Deformidades Congénitas de la Mano/patología , Cardiopatías Congénitas/patología , Hernias Diafragmáticas Congénitas/patología , Humanos , Lactante , Recién Nacido , Vólvulo Intestinal/patología , Masculino , Timo/metabolismo , Timo/patología , Tronco Arterial/metabolismo , Tronco Arterial/patologíaRESUMEN
During embryological development the heart develops from a simple tube into a complex fully developed heart with four chambers. Hence all congenital heart defects develop before the ninth week of gestation. Currently a steadily increasing number of genetic mutations have been found to be responsible for congenital heart defects. Nevertheless, up to now it has been impossible to diagnose a heart defect just on the basis of molecular pathology. Despite the current excellent prenatal and postnatal ultrasound diagnostics, the post-mortem examination is still the gold standard for the diagnosis of complex heart malformations. However, this requires knowledge of the pathomorphology of the heart malformation in question. Therefore, characteristic and distinguishing features of septal defects including atrioventricular septal defects are presented, especially as the latter are part of complex heart defects, such as conotruncal heart malformations.
Asunto(s)
Defectos de la Almohadilla Endocárdica/patología , Cardiopatías Congénitas/patología , Defectos de los Tabiques Cardíacos/patología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Ecocardiografía , Defectos de la Almohadilla Endocárdica/genética , Femenino , Edad Gestacional , Atrios Cardíacos/patología , Cardiopatías Congénitas/genética , Tabiques Cardíacos/patología , Ventrículos Cardíacos/patología , Humanos , Recién Nacido , Embarazo , Arteria Pulmonar/patología , Síndrome , Transposición de los Grandes Vasos/patología , Tronco Arterial/patología , Ultrasonografía PrenatalRESUMEN
OBJECTIVE: A dilated aortic root is a common finding in children and adults with some forms of congenital heart defects. No data exist on root dilation in truncus arteriosus. We sought to delineate root dimensions across a population of patients with truncus arteriosus. DESIGN: We performed a single-center retrospective review of all patients with truncus arteriosus. Demographic information, clinical history, and most recent echocardiographic data were evaluated. RESULTS: We identified 76 patients whose most recent study was at a median age of 5.4 years (range 0--32.7 years). Mean truncal root z-score was 5.1 ± 2.3. All but three patients had truncal root z-scores greater than or equal to 2. Truncal root z-scores remained stable with increasing body surface area and age. There were no cases of dissection or rupture. Six patients underwent truncal root surgery, typically for indications of root dilation with significant truncal valve insufficiency and left ventricular dilation. CONCLUSIONS: In conclusion, mean truncal root z-score was 5, and all but three patients had truncal root z-scores greater than or equal to 2. Although repeat surgical intervention was rare and major complications related to root dilation did not occur in our cohort, further studies with longitudinal follow-up into adulthood are needed.
Asunto(s)
Tronco Arterial Persistente/patología , Tronco Arterial/patología , Adolescente , Adulto , Factores de Edad , Superficie Corporal , Distribución de Chi-Cuadrado , Niño , Preescolar , Dilatación Patológica , Humanos , Lactante , Pronóstico , Análisis de Regresión , Estudios Retrospectivos , Texas , Tronco Arterial/anomalías , Tronco Arterial Persistente/terapia , Adulto JovenRESUMEN
Two rare patients are reported with tetralogy of Fallot and congenital aortic valvar stenosis. The anatomic and developmental interrelationship between tetralogy of Fallot and truncus arteriosus is summarized. A study of 100 randomly selected postmortem cases of tetralogy revealed aortic valve pathology in 8%, myxomatous aortic valve leaflets without stenosis in 4%, bicuspid aortic valves without stenosis in 3%, and congenital aortic valvar stenosis in 1%. The frequency of systemic semilunar valve pathology in truncus was much higher (66%): moderate to marked myxomatous change in 44%, mild myxomatous change in 22%, truncal valvar stenosis in 11%, and truncal valvar regurgitation in 15%. Being aware of the tetralogy-truncus interrelationship and knowing that myxomatous aortic valves are prone to premature calcific aortic stenosis and/or regurgitation, physicians should follow the aortic valves of surgically repaired patients with tetralogy of Fallot and truncus arteriosus long term with great care. Timely aortic valvuloplasty or replacement may well prove life-saving in such patients.
Asunto(s)
Estenosis de la Válvula Aórtica/epidemiología , Tetralogía de Fallot/epidemiología , Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/congénito , Resultado Fatal , Femenino , Humanos , Recién Nacido , Tronco Arterial/patologíaAsunto(s)
Cardiopatías Congénitas/patología , Anestesia , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/fisiopatología , Tabiques Cardíacos/fisiopatología , Humanos , Venas Pulmonares/anomalías , Venas Pulmonares/fisiopatología , Tetralogía de Fallot/diagnóstico , Tetralogía de Fallot/patología , Tetralogía de Fallot/fisiopatología , Transposición de los Grandes Vasos/diagnóstico , Transposición de los Grandes Vasos/patología , Transposición de los Grandes Vasos/fisiopatología , Atresia Tricúspide/diagnóstico , Atresia Tricúspide/patología , Atresia Tricúspide/fisiopatología , Tronco Arterial/patología , Tronco Arterial/fisiopatologíaAsunto(s)
Pared Abdominal/anomalías , Anomalías Múltiples/patología , Defectos del Tabique Interventricular/patología , Deformidades Congénitas de las Extremidades/patología , Tronco Arterial/patología , Anomalías Múltiples/genética , Aborto Espontáneo , Adulto , Autopsia , Femenino , Humanos , EmbarazoRESUMEN
El estudio y tratamiento de las cardiopatías congénitas ha mostrado en los últimos 50 años un progreso acelerado. El ecocardiograma permite observar casi todas las características de las cardiopatías y el cateterismo tiene un carácter primordialmente terapéutico. La cirugía cardiaca es cada vez más temprana y con intenciones correctivas. Hoy en día hay una mayor sobrevida de estos pacientes que llegan a la vida adulta y por razones naturales procrean. Un aspecto que no había tenido este desarrollo es el conocimiento de la etiología de algunas cardiopatías. Con las técnicas de estudio molecular de los cromosomas se encontró la deleción de la región 11.2 en el brazo largo del cromosoma 22, en pacientes que comparten cardiopatía troncoconal y características fenotípicas como facies con puente de la nariz ancho, punta nasal recortada, anomalía en la forma e implantación de los pabellones auriculares y paladar alto, entre otros. Con la finalidad de saber cuales de nuestros pacientes tienen tal deleción, reunimos a aquellos con aspectos fenotípicos asociados a cardiopatías troncoconales. En los primeros dos pacientes a los cuales se les realizó estudio cromosómico de inmunofluorescencia in situ se comprobó deleción en la región 11.2 en el cromosoma 22. La importancia de estos resultados reside en que un porcentaje significativo de los pacientes que acuden a nuestra Institución tienen alteraciones troncoconales, el comprobar en algunos de ellos su etiología permite establecer la indicación del asesoramiento genético y el tratamiento adecuado a nivel cardiológico y del desarrollo psicológico.
Asunto(s)
Humanos , Masculino , Preescolar , Niño , Cardiopatías Congénitas/genética , Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Tetralogía de Fallot/etiología , Aberraciones Cromosómicas/genética , Atresia Pulmonar/etiología , Tronco Arterial/patologíaRESUMEN
Experimental studies in chick embryos have demonstrated that truncus arteriosus (TA), a form of conotruncal cardiac defect, is due to abnormalities in the cranial neural crest. However, no data are available to support this hypothesis in humans with isolated TA. In the present study, the assessment of calcitonin immunoreactive cells (C-cells) has been employed to evaluate whether or not the proportion of thyroid cells derived from the cranial neural crest is normal in patients with isolated TA. Thyroid sections from 15 such patients in which no other extracardiac malformations were neither clinically nor pathologically found, and from 11 control age-matched patients were studied immunohistochemically at autopsy in order to determine the number and distribution of calcitonin-containing cells. The volume density of C-cells (0.888%) and the number of C-cells per follicle (0.991) was significantly lower in patients with TA than in control patients (3.475%, and 2.367, respectively). The decrease of neural crest-derived cells in the thyroid of patients with "isolated" TA documents more extent abnormalities than clinically suspected and supports the hypothesis of neural crest disturbance as the pathogenetic factor responsible for this heart malformation.
Asunto(s)
Calcitonina/metabolismo , Tronco Arterial/metabolismo , Femenino , Humanos , Inmunohistoquímica , Lactante , Recién Nacido , Masculino , Cresta Neural/citología , Cresta Neural/embriología , Cresta Neural/metabolismo , Tronco Arterial/embriología , Tronco Arterial/patologíaRESUMEN
This is the second review in a three-part series concerned with the description and categorization of ventricular septal defects. By viewing the defects from the right ventricular aspect, they can be placed into one of three classes: perimembranous, muscular, or doubly committed and juxta-arterial. According to the posteroinferior margin of the third group, these could extend to become perimembranous or muscular. In this review, the complications produced by malalignment of the septal structures associated with overriding of an arterial or atrioventricular valve are described in detail. It shows that although there are problems in defining the extent of any interventricular communication, these ventricular septal defects can be classified with the same categorization as developed for those not associated with overriding. The nosology developed is able to serve as a guide to the surgeon to the site of the specialized axis for atrioventricular conduction.
Asunto(s)
Defectos del Tabique Interventricular/patología , Tabiques Cardíacos/patología , Válvulas Cardíacas/patología , Nodo Atrioventricular/patología , Defectos del Tabique Interventricular/cirugía , Tabiques Cardíacos/cirugía , Humanos , Válvula Mitral/patología , Válvula Pulmonar/patología , Válvula Tricúspide/patología , Tronco Arterial/patologíaRESUMEN
Autopsy of a baby suspicious to SIDS. Most interesting postmortem finding was a congenital malformation of the great vessels, a truncus arteriosus communis typus van Praagh A I. That one is very rare with a clinically frequency of only 1.7%. The malformation was not cause of death and was statistically survived for 2 months. The baby died of aspiration resultant from an incarcerated inguinal hernia.
Asunto(s)
Muerte Súbita del Lactante/patología , Tronco Arterial Persistente/patología , Asfixia/patología , Causas de Muerte , Humanos , Lactante , Masculino , Neumonía por Aspiración/patología , Tronco Arterial/patologíaRESUMEN
A new corrective operation for truncus arteriosus without the use of an extracardiac conduit was performed in seven patients with truncus type I (six patients) or type II (one patient) aged from 2 to 9 months. The common truncus arteriosus was septated with a patch into aortic and pulmonary segments and the ventricular septal defect was closed through a ventriculotomy. A direct anastomosis between the pulmonary arteries and the right ventricle was performed, the anterior wall being constructed with a patch with a monocusp valve. There was one death in the immediate postoperative period. In the surviving six patients the postoperative right ventricular/left ventricular peak systolic pressure ratio was less than 0.51 in five and 0.60 in one with a residual ventricular septal defect. All are in functional class I between 1 and 14 months after the operation. On the basis of these results, we propose this technique for patients with truncus type I or II in the first year of life.