Identificación de factores asociados a alteraciones del desarrollo psicomotor en pacientes con cardiopatía congénita grave

Las cardiopatías congénitas son lesiones anatómicas de una o varias de las cuatro cámaras cardiacas, de los tabiques que las separan, o de las válvulas o tractos de salida (zonas ventriculares por donde sale la sangre del corazón) que están presentes, aunque puedan serlo de manera latente, en el momento del nacimiento. Alrededor del 25% de las cardiopatías congénitas pueden presentarse en el contexto de síndromes polimalformativos o asociados a cromosomopatías, lo que aumenta la morbimortalidad en estos pacientes. Los defectos cardiacos constituyen el grupo de malformaciones congénitas más frecuentes. De forma general se estima una incidencia entre 8 y 12 cardiopatías por cada 1.000 recién nacidos vivos, lo que supone que en España nacen al año unos 5.000 niños con algún tipo de cardiopatía. Aunque la mayoría son cardiopatías leves, que evolucionan favorablemente y pueden llegar incluso a desaparecer espontáneamente con el tiempo, constituyen la causa principal de mortalidad por anomalías congénitas en los pacientes menores de un año. Suponen algo más de un tercio de las muertes por anomalías congénitas y alrededor de una de cada 10 del total de muertes en este periodo de la vida. Sin embargo, la mortalidad por esta causa ha caído considerablemente con el paso de los años debido a los avances en el diagnóstico, en el tratamiento, tanto del intervencionismo percutáneo como de los avances en el manejo quirúrgico, y en los cuidados postoperatorios, por lo que ha aumentado el interés en la morbilidad asociada y las consecuencias a largo plazo en las distintas esferas de la vida del paciente, con especial atención a las alteraciones en el neurodesarrollo. Por ello, esta tesis tiene como objetivo identificar los factores asociados a alteraciones del desarrollo psicomotor en pacientes con cardiopatía congénita graveDepartamento de Pediatría e Inmunología, Obstetricia y Ginecología, Nutrición y Bromatología, Psiquiatría e Historia de la CienciaDoctorado en Investigación en Ciencias de la Salu

Patient with Cri-du-chat and Beckwith-Wiedemann Syndromes originating from a paternal translocation

Citogenética y Genética molecularCri-du-Chat syndrome (CdCS) is one of the most common deletion syndromes (1/15,000-1/50,000 live births) caused by the loss of material from the short arm of chromosome 5 (5p). Although the breakpoints are variable, the CdCS critical region has been shown to be located at 5p15.2 as microdeletions of this region as well as larger deletions of varying sizes, produce the phenotype associated with this syndrome. Patients born with CdCS usually present with microcephaly, round face, hypertelorism, epicanthic folds, micrognathia, large nasal bridge, growth delay, and severe psychomotor retardation. However, the main distinguishing feature of this syndrome is the characteristic cry: a high-pitched, monotonous, cat-like cry. Approximately 80% of patients with CdCS have “de novo” deletions, 10% present with a derivative chromosome from a parental translocation that results in monosomy 5p with trisomy of the other chromosome involved in the rearrangement, and 10% are caused by rarer chromosome alterations, such as inversions. The second disorder of interest, Beckwith-Wiedemann syndrome (BWS), has a frequency of 1 in 13,700 live born children and is the most common of the overgrowth syndromes. It is characterised by macrosomia, hemihyperplasia, macroglossia, abdominal wall defects (omphalocele, umbilical hernia, diastasis recti), earlobe creases, visceromegaly, neonatal hypoglycemia, and a predisposition to embryonal malignancies such as hepatoblastoma, neuroblastoma, rabdomyosarcoma, and Wilms tumour. The etiology of BWS is very complex, involving genetic and epigenetic processes within the p15 region in the short arm of chromosome 11. Up to 60 % of patients with BWS have an epigenetic error in one of the imprinting centers in 11p15 (caused by loss or gain of methylation), approximately 20% have uniparental disomy (UPD), 10% have mutations of the CDKN1C gene, and only 2% of cases have chromosome rearrangements affecting 11p. The majority of these alterations result from the unbalanced segregation of a parental translocation or inversion, and when the disorder is caused by the inheritance of a balanced rearrangement, the alteration is always maternallyderived. To assess the recurrence risk, it is very important to identify the type of mechanism causing the syndrome, although in 10-15% patients the etiology for BWS remains unidentified. In this article, we present a newborn female with a derivative chromosome 5, resulting from a paternal translocation involving chromosomes 5 and 11. This has resulted in the proband having partial monosomy for 5p and partial trisomy for 11p, producing a clinical picture in which the features of both CdCS and BWS are observed. The baby presented with a strange cry, dysmorphics features, (including epicanthic folds, long palpebral fissures, broad nasal bridge with small nose, and microretrognathia), macroglossia, short neck, bell-shaped thorax with widely-spaced, asymmetrical nipples, single-palmar crease on both hands, long feet with malposition of the toes, and interiorly displaced anus. She also showed generalized hypotonia and neonatal persistent hypoglycemia. Although high-resolution G-banded chromosome studies showed an apparently normal, female karyotype, a FISH screening of the subtelomeric regions of all chromosomes showed monosomy for 5p and trisomy for 11p. Further FISH investigation with a probe specific for the CdCS critical region confirmed this locus to be deleted. Parental studies detected the presence of an apparently balanced translocation between chromosomes 5 and 11 in the father. Molecular analysis using microsatelites was carried out showing a deletion of 15.93 Megabases (Mb) on chromosome 5 and a deletion of 10.87 Mb on chromosome 11, both of paternal origin. Although there are six previous published cases that originated from similar paternal translocations, the altered chromosome regions are of different sizes, and the current infant seems to be the first in which the clinical characteristics of both CdCS and BWS are recognized.N

Recomendaciones de la Sociedad Española de Cardiología Pediátrica y Cardiopatías Congénitas en relación con el uso de medicamentos en el trastorno por déficit de atención e hiperactividad en niños y adolescentes con cardiopatías conocidas y en la población pediátrica general, posicionamiento de la Asociación Española de Pediatría.

Approved drugs for attention deficit hyperactivity disorder (ADHD) in Spain are methylphenidate, lisdexamphetamine, atomoxetine and guanfacine. Due to adverse cardiovascular effects, mainly increased blood pressure and heart rate, its use in patients with known or undiagnosed heart disease may be controversial. To obtain a consensus document from the Spanish Society of Paediatric Cardiology and Congenital Heart Diseases (SECPCC) and experts from other Agencies and Societies as a guide for the paediatric cardiologist and physicians who treat children and adolescents with ADHD. An analysis was performed on the bibliography and Clinical Practice Guidelines, technical data sheets approved by the Spanish Agency of Medicines and Health Devices, and the Spanish Ministry of Health Guidelines. A Working Group was formed, with a Coordinator, as well as members of the Clinical Cardiology Working Group and Arrhythmia Group of the SECPCC. This Group produced a preliminary document that was reviewed by a group of external experts and a group of internal experts of the SECPCC with a consensus being reached on the final document. The recommendations of the SECPCC and the group of experts are presented on cardiovascular evaluation prior to treatment in children and adolescents with no known cardiovascular disease and with known cardiovascular disease. The recommendations of the SECPCC and the group of experts are also presented on the use of medications for ADHD in children and adolescents with cardiological symptoms with no evidence of heart disease, congenital heart disease, cardiomyopathy, Marfan syndrome and other aortic diseases, hypertension, and arrhythmias

Nutrition in congenital heart disease: consensus document

Introduction: The prevalence of malnutrition among infants with congenital heart disease (CHD) is high. Early nutritional assessment and intervention contribute significantly to its treatment and improve outcomes. Our objective was to develop a consensus document for the nutritional assessment and management of infants with CHD. Material and methods: We employed a modified Delphi technique. Based on the literature and clinical experience, a scientific committee prepared a list of statements that addressed the referral to paediatric nutrition units (PNUs), assessment, and nutritional management of infants with CHD. Specialists in paediatric cardiology and paediatric gastroenterology and nutrition evaluated the questionnaire in 2 rounds. Results: Thirty-two specialists participated. After two evaluation rounds, a consensus was reached for 150 out of 185 items (81%). Cardiac pathologies associated with a low and high nutritional risk and associated cardiac or extracardiac factors that carry a high nutritional risk were identified. The committee developed recommendations for assessment and follow-up by nutrition units and for the calculation of nutritional requirements, the type of nutrition and the route of administration. Particular attention was devoted to the need for intensive nutrition therapy in the preoperative period, the follow-up by the PNU during the postoperative period of patients who required preoperative nutritional care, and reassessment by the cardiologist in the case nutrition goals are not achieved. Conclusions: These recommendations can be helpful for the early detection and referral of vulnerable patients, their evaluation and nutritional management and improving the prognosis of their CHD. Resumen: Introducción: La tasa de desnutrición entre los lactantes con cardiopatías congénitas (CC) es elevada. Una evaluación e intervención nutricional tempranas ayudan a su tratamiento y mejoran el pronóstico. El objetivo fue elaborar un documento de consenso para la evaluación y el tratamiento nutricional del lactante con CC. Material y Métodos: Se utilizó una técnica Delphi modificada. En base a la literatura y a su experiencia clínica, un comité científico elaboró un listado de afirmaciones que abordaban la derivación a Unidades de Nutrición Pediátrica (UNP), la evaluación y el manejo nutricional de los lactantes con CC. Especialistas en cardiología pediátrica, y gastroenterología y nutrición pediátrica evaluaron el cuestionario en 2 rondas. Resultados: Participaron 32 especialistas. Tras dos rondas de evaluación, se consensuaron 150 de 185 ítems (81%). Se determinaron patologías cardiacas de bajo y alto riesgo nutricional y factores asociados cardíacos o extracardíacos que confieren riesgo nutricional alto. Se elaboraron recomendaciones para la evaluación y seguimiento en unidades de nutrición y sobre el cálculo de los requerimientos nutricionales, el tipo de nutrición y la vía de administración. Se enfatiza la necesidad de un tratamiento nutricional intensivo en el preoperatorio, del seguimiento por la UNP en el postoperatorio cuando se haya necesitado intervención preoperatoria, y de la reevaluación por el cardiólogo cuando no se alcancen los objetivos nutricionales. Conclusiones: Estas recomendaciones pueden ser de ayuda para la detección precoz y derivación temprana de población vulnerable, su evaluación y tratamiento nutricional y para mejorar el pronóstico de su CC

Immunogenicity and safety of 11- and 12-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccines (11vPHiD-CV, 12vPHiD-CV) in infants: Results from a phase II, randomised, multicentre study.

We assessed 2 investigational 11- and 12-valent vaccines, containing capsular polysaccharides of 10 serotypes as in the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) and CRM197-conjugated capsular polysaccharides of serotypes 19A (11-valent) or 19A and 6A (12-valent). In this phase II, partially-blind, multicentre study (NCT01204658), healthy infants were randomised (1:1:1:1) to receive 11vPHiD-CV, 12vPHiD-CV, PHiD-CV, or 13-valent CRM197-conjugate pneumococcal vaccine (PCV13), at 2, 3, and 4 (primary series), and 12-15 months of age (booster dose), co-administered with DTPa-HBV-IPV/Hib. Confirmatory objectives assessed non-inferiority of investigational vaccines to comparators (PHiD-CV for common serotypes; PCV13 for 19A and 6A), in terms of percentage of infants with pneumococcal antibody concentrations ≥0.2 μg/mL and antibody geometric mean concentrations, post-primary vaccination. Reactogenicity and safety were assessed. 951 children received ≥1 primary dose, 919 a booster dose. Pre-defined immunological non-inferiority criteria were met simultaneously for 9/11 11vPHiD-CV serotypes (all except 23F and 19A) and 10/12 12vPHiD-CV serotypes (all except 19A and 6A); thus, non-inferiority objectives were reached. For each PHiD-CV serotype, percentages of children with antibody concentrations ≥0.2 µg/mL were ≥96.7% post-primary (except 6B [≥75.2%] and 23F [≥81.1%]), and ≥98.1% post-booster vaccination. For each PHiD-CV serotype except serotype 1, ≥81.0% and ≥93.9% of children had opsonophagocytic activity titres ≥8, post-primary and booster vaccination. AEs incidence was similar across all groups. SAEs were reported for 117 children (29 in the 11vPHiD-CV group, 26 in the 12vPHiD-CV group, 38 in the PHiD-CV group and 24 in the PCV13 group); 4 SAEs were considered vaccination-related. No fatal events were recorded. Addition of 19A and 6A CRM197-conjugates did not alter immunogenicity of the PHiD-CV conjugates; for both investigational vaccines post-booster immune responses to 10 common serotypes appeared similar to those elicited by PHiD-CV. Safety and reactogenicity profiles of the investigational vaccines were comparable to PHiD-CV. Clinical trial registry: NCT01204658