Consenso colombiano de la enfermedad inflamatoria intestinal pediátrica

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Introduction: Pediatric ulcerative colitis (CUP), pediatric Crohn's disease (PCD), and pediatric inflammatory bowel disease not classifiable (PIDNCID) have clinical and psychosocial particularities that differentiate them from those of adults and may condition different therapeutic approaches due to possible nutritional, growth and developmental repercussions, representing a challenge for the pediatrician and gastroenterologist. Objective: Develop expert consensus evidence-based recommendations for the timely and safe diagnosis and treatment of Pediatric Inflammatory Bowel Disease (PID) in children under 18 years of age for professionals caring for these patients and healthcare payers. Methodology: Through a panel of experts from the Colombian College of Pediatric Gastroenterology, Hepatology and Nutrition (COLGAHNP) and a multidisciplinary group, 35 questions were asked regarding the clinical picture, diagnosis, and treatment of PID. Through a critical review and analysis of the literature with particular emphasis on the main clinical practice guidelines (CPGs), randomized clinical trials (RCTs), and meta-analyses of the last ten years, from which the experts made 77 recommendations that responded to each of the research questions with their respective practical points. Subsequently, each of the statements was voted on within the developer group, including the statements that achieved > 80%. Results: All statements scored > 80%. PID has greater extension, severity, and evolution towards stenosis, perianal disease, extraintestinal manifestations, and growth retardation compared to adult patients, so its management should be performed by multidisciplinary groups led by pediatric gastroenterologists and prepare them for a transition to adulthood. Porto's criteria allow a practical classification of PID. In CPE, we should use the Paris classification and perform ileocolonoscopy and esophagogastroduodenoscopy, since 50% have upper involvement, using the SES-CD (UCEIS/Mayo in CUP) and taking multiple biopsies. Initial labs should include inflammatory markers and fecal calprotectin and rule out intestinal infections. Treatment, induction, and maintenance of PID should be individualized and decided according to risk stratification. Follow-up should use PCDAI and PUCAI for the last 48 hours. Immunologists and geneticists should evaluate patients with early and infantile PID. Conclusion: A consensus guideline is provided with evidence-based recommendations on timely and safe diagnosis and treatments in patients with ILD.

Variants in the Sequence of the Probe Hybridization Site May Affect MLPA Performance in Patients with Duchenne/Becker Muscular Dystrophy.

BACKGROUND: The MLPA (multiplex ligation dependent probe amplification) technique is currently the test most widely used to detect mutations in the Duchenne/Becker muscular dystrophy (DMD) gene in the initial assessment. However, several studies have suggested that MLPA results require implementing other detection methods due to false duplication. Our aim was to evaluate variables that could alter the peak ratio in MLPA in individuals with Duchenne/Becker muscular dystrophy (DMD/BMD) who present sequence variants at the probe hybridization site, such as the location of sequence variants (SVs), melting temperature of the probe, and the type of variant. METHODS: We analyzed patients with clinical suspicion of DMD/BMD through the MLPA technique. The DMD gene was sequenced in patients with normal results in MLPA. RESULTS: Of 111 patients, 72 had an abnormal MLPA result, of which 10 had a single exon abnormal peak, and 39 had a normal peak ratio. Out of 10 patients, 4 (40%) with a single exon abnormal peak ratio had SV at the hybridization site of the probe. In the other 6, the deletion was confirmed. Out of 39 patients with a normal peak ratio, 11 presented SVs at the hybridization site of the probe, and DMD/BMD was confirmed. CONCLUSIONS: In cases of abnormal peak ratio results of MLPA in a single exon, it would be valuable to sequence the DMD gene to assess whether variants in the probe hybridization site might result in a false positive that could be interpreted as an exon deletion.

Preimplantation genetic testing in assisted reproduction.

In the last years technologies have been developed that allow obtaining genetic information in less time and at lower cost, revolutionizing the genetic diagnosis in reproductive medicine, with availability of genetic tests from conception. High throughput sequencing analyses have increased the ability to detect embryos with genetic diseases, which has contributed to the better selection of embryos for in-vitro fertilization and, therefore, better reproductive outcomes. The preimplantation genetic testing (PGT) includes three subcategories of PGT for aneuploidies (PGT-A), PGT for single gene/monogenic disorders (PGT-M), and PGT for chromosome structural rearrangements (PGT-SR). This review provides an overview of the evolution of preimplantation genetic testing, the advantages and disadvantages of these technologies and their applicability in reproductive medicine as well as a description of the legislation and bioethics aspects. Advances in preimplantation genetic testing are changing clinical practice, posing new challenges for genetic counseling and alternative plausible to substantially reduce the risk of an adverse reproductive outcome related to the transfer of abnormal embryos. Despite the overall important implantation rates achieved following transfer of euploid embryos, PGT-A did not improve overall pregnancy outcomes in all women. There is a definite need for studies to identify the causes of why not all euploid embryos implant. Also, debate continues regarding the accuracy and the safety of this approach, and the currently available evidence is insufficient to support PGT-A in routine clinical practice. The general recommendation is that PGT-A, PGT-M and PGT-SR should be guided according to the antecedents of the couples.

Immunodeficiency in a Patient with 22q11.2 Distal Deletion Syndrome and a p.Ala7dup Variant in the MAPK1 Gene.

The genetic basis for sporadic immunodeficiency in patients with 22q11.2 distal deletion syndrome is unknown. We report an adult with a type 1 (D-F) 22q11.2 distal deletion syndrome and recurrent severe infections due to herpes zoster virus, presenting mild T cell lymphopenia and diminished frequency of naive CD4+ T cells, but increased frequencies of central, effector, and terminally differentiated memory T cells. Antigen-specific CD4+ and CD8+ T cells to influenza, rotavirus, and SEB were conserved in the patient, but responses to tetanus toxoid were temporarily undetectable. Exomic sequencing identified the c.20_22dupCGG (NM_002745.4) variant in the remaining MAPK1 gene of the patient, which adds 1 alanine to the polyalanine amino-terminal tract of the protein (p.Ala7dup). The mother, unlike the father, was heterozygote for the variant. Western blot analysis with the patient's activated PBMCs showed a 91% reduction in the MAPK1 protein. Further studies will be necessary to determine whether or not the variant present in the remaining MAPK1 gene of the patient is pathogenic.

Disorders of Sexual Development: Current Status and Progress in the Diagnostic Approach.

Disorders of sexual development (DSD) are conditions with an atypical chromosomal, gonadal or phenotypic sex, which leads to differences in the development of the urogenital tract and different clinical phenotypes. Some genes have been implicated in the sex development during gonadal and functional differentiation where the maintenance of the somatic sex of the gonad as either male or female is achieved by suppression of the alternate route. The diagnosis of DSD requires a structured approach, involving a multidisciplinary team and different molecular techniques. We discuss the dimorphic genes and the specific pathways involved in gonadal differentiation, as well as new techniques for genetic analysis and their diagnostic value including epigenetic mechanisms, expanding the evidence in the diagnostic approach of individuals with DSD to increase knowledge of the etiology.

Clinical and Molecular Cytogenetic Characteristics of Five Cases with Isodicentric Y Chromosome.

Isodicentric Y chromosome [idic(Y)] is one of the most common structural abnormalities of the Y chromosome and has been observed in patients with reproductive disorders and in patients with disorders of sexual development. Most idic(Y) chromosomes are found in mosaic form with a 45,X cell line. These chromosomes are highly unstable during mitosis due to the presence of 2 centromers, which explains their probable loss in early mitosis or mitosis of the embryo and therefore the presence of the 45,X line. It has been hypothesized that the proportion of 45,X cells in various tissues probably influences the phenotypic sex of individuals carrying an idic(Y) chromosome, ranging from infertile men, hypospadias, ambiguous genitalia, and Turner syndrome to sex reversal. In this article we present 5 cases of patients with idic(Y) referred for suspected disorder of sex development (DSD), 3 with a male assignment and 2 with a female assignment. All cases have variable clinical characteristics, which were assessed by the transdisciplinary group of Disorders of Sex Development of the Hospital Universitario San Ignacio, Bogotá, Colombia. Patients were analyzed by conventional and molecular cytogenetics using high-resolution G-band and FISH techniques. Our findings highlight the importance of cytogenetic studies in the diagnosis of DSD patients.

Disorders of sex development: Genetic characterization of a patient cohort.

Disorders of sex development (DSDs) are congenital conditions in which the external appearance of the individual does not coincide with the chromosomal constitution or the gonadal sex. In other words, there is an ambiguous or intermediate condition between the male and female phenotypes of the anatomical sex. These atypical conditions are manifested in several ways, ranging from genital ambiguity to phenotypes that are so attenuated that they can go unnoticed or appear normal. Currently, there is a lack of understanding of the factors responsible for these outcomes; however, they are likely to be conditioned by genetic, hormonal and environmental factors during prenatal and postnatal development. The present study determined the genetic etiology of DSDs in Colombian patients by conventional cytogenetic analysis, FISH and MLPA (for SF1, DAX1, SOX9, SRY and WNT4). A cohort of 43 patients with clinical phenotypes of sex development disorder was used in the present study. Using this multistep experimental approach, a diagnostic percentage of 25.58% was obtained: 17 patients (39.53%) were classified as having gonadal development disorders, the majority of which were ovotesticular disorders with numerical and/or structural alterations of the sex chromosomes, 9 patients (20.93%) were classified as having testicular DSD with a 46,XY karyotype, and 3 patients (6.98%) as having ovarian DSD with a 46,XX karyotype. The remaining 14 patients (32.56%) were classified as 'other' since they could not be grouped into a specific class of gonadal development, corresponding to hypospadias and multiple congenital anomalies. These findings highlight the importance of histological and cytogenetic studies in a gonadal biopsy. In 11/43 cases, the multistep experimental protocol presented in the present study yielded etiological or histological findings that could be used to define the medical management of patients with DSDs. In conclusion, for the etiological diagnosis of DSDs, a broad­spectrum approach that includes endocrinological tests, conventional karyotyping, molecular karyotyping by FISH and, molecular tests is required, in addition to gonadal tissue analyses, to identify genetic alterations.

Gene dosage of DAX-1, determining in sexual differentiation: duplication of DAX-1 in two sisters with gonadal dysgenesis.

Two sisters phenotypically normal females, presenting with tumor abdominal mass with histopathological findings of teratoma and gonadoblastoma associated to 46,XY male-to-female sex reversal syndrome, secondary to a duplication in DAX-1, possibly inherited of maternal gonadal mosaicism. Copy number variation and functional effects of the duplication were done by MLPA multiplex ligation-dependent probe amplification and real time PCR. DAX-1, also known as dosage sensitive sex reversal gene (DSS), is considered the most likely candidate gene involved in XY gonadal dysgenesis when overexpressed. The excess of DAX-1 gene disturbs testicular development by down regulation of SF-1, WT1, and SOX9. This is the first report of 46,XY sex reversal in two siblings who have a maternally inherited duplication of DAX-1 associated with reduced levels of expression of downstream genes as SOX9-SF1.

CGH analysis in Colombian patients: findings of 1374 arrays in a seven-year study.

BACKGROUND: Array-based comparative genome hybridization (array CGH) is a first-line test used in the genetic evaluation of individuals with multiple anomalies, developmental delays, and cognitive deficits. In this study, we analyzed clinical indications and findings of array CGH tests of Colombian individuals forwarded to a reference laboratory over a period of seven years in order to evaluate the diagnostic performance of the test in our population. RESULTS: The results of 1374 array CGH analyses of Colombian individuals were referred to the Andean Reference Institute in Colombia (Instituto de Referencia Andino) during a 7-year period (2009-2015). Chromosomal imbalances were detected in 488 cases (35%), whereas 121 cases were classified as nonpathogenic variants, 65 cases (4.7%) were classified as variants of uncertain significance, and 302 cases (22%) were classified as abnormal or pathogenic. The most common findings in the abnormal and/or pathogenic set were deletions, followed by duplications and complex rearrangements. Variants in the carrier status of autosomal recessive diseases were identified as incidental findings in 29 subjects (2%). CONCLUSIONS: Clinical indications preceding the referral of aCGH in Colombian patients are not standardized and result in unexpected pathogenic variants as well as secondary findings that need careful interpretation. Development of local infrastructure will probably improve the communication between all stakeholders, to ensure accurate clinical diagnoses.

Síndrome De Tourette Familiar: Reporte De Caso Y Revisión De La Literatura / Familial Tourette Syndrome: Case Report And Review Of Literature

Resumen El síndrome de Tourette es un trastorno neuropsiquiátrico de inicio en la infancia caracterizado por múltiples tics motores y vocales de al menos un año de duración. Se desconoce su etiología exacta, pero se han involucrado las vías neuronales fronto-subcorticales e interacciones complejas entre factores sociales, ambientales y genéticos. Estudios genéticos han reportado loci de susceptibilidad en genes implicados en conexión sináptica, sin embargo, hace falta evidencia en muestras de mayor tamaño. Este reporte de caso describe un joven de 14 años con historia personal y familiar de síndrome de Tourette, sugiriendo un mecanismo de herencia autosómico dominante.

Abstract Tourette syndrome is a childhood neuropsychiatric disorder characterized by multiple motor and vocal tics of at least one year. Its exact etiology is unknown, but fronto-subcortical neural pathways and complex interactions between social, environmental and genetic factors have been involved. Genetic studies have reported susceptibility loci in genes involved in synaptic connection, however, evidence is needed in larger samples. This case report describes a 14-year-old boy with a personal and family history of Tourette's syndrome, suggesting an autosomal dominant mechanism of inheritance.

Whole-Exome Sequencing Identifies a de novo AHDC1 Mutation in a Colombian Patient with Xia-Gibbs Syndrome.

Xia-Gibbs syndrome is an autosomal dominant multisystem developmental disorder characterized by global developmental delay, hypotonia, obstructive sleep apnea, seizures, retrocerebellar cysts, delayed myelination, micrognathia, and mild dysmorphic features. Using whole-exome sequencing, we identified a de novo AHDC1 frameshift mutation c.2030_2030delG (p.G677Afs*52) in a Colombian patient, which was absent in both parents. Furthermore, we summarized the phenotypes of patients reported in the literature.

Caracterización de las anomalías congénitas desde la inclusión en el sistema de vigilancia Sivigila en Colombia, 2010-2013 / Characterization of Congenital Anomalies since Inclusion in the Sivigila Surveillance System in Colombia, 2010-2013

Introducción: las anomalías congénitas son una alteración estructural o funcional con impacto en la morbilidad-mortalidad infantil y la discapacidad mundial. Las estrategias orientadas a disminuir su impacto las respaldan sistemas de vigilancia. En Colombia, desde el 2010 se incluyó el formato de notificación de anomalías congénitas en el Sistema de Vigilancia (Si vigila). Objetivo: caracterizar epidemiológicamente la notificación del evento desde su inclusión. Materiales y métodos: análisis descriptivo de los eventos notificados entre enero de 2010 y diciembre de 2013. Resultados: se encontró una prevalencia de malformaciones del 0,35 % en Colombia durante el periodo analizado. Las anomalías congénitas con mayor notificación fueron las del sistema nervioso central y las anomalías de extremidades. Conclusiones: la prevalencia notificada para malformaciones congénitas en Colombia es baja. La baja tasa de notificación de anomalías congénitas evidencia la necesidad de realizar capacitaciones para mejorar esta notificación, tener un registro más cercano a la realidad de la población y así poder tomar decisiones para el beneficio de la población y en la generación de conocimiento en este tema.

Introduction: Congemtal anomalías are a structural or functional alteration with impact on infant morbidity and mortalicy and disability worldwide. Strategies aimed to reduce their impact are supported by surveillance Systems. In Colombia, since 2010 the report of congenital anomalies was induded in the surveillance system (Sivígila). Aún: To characterize epidemiologically the notificación of the event from its inclusión. Materials and methods: Is carried out descriptive analysis of the events reported during January of 2010 to December of 2013. Results: We found a prevalence of congenital malformations of 0.35% in Colombia during the analyzed period. The congenital anomalies with more frequent notification were those of the central nervous system and the anomalies of limbs. Conclusions: The prevalence reported for congenical malformations in Colombia ¿s low compared to that reported in the literatura that is between 3.0'?.0% of the population. The low rate of notification for congenital anomalies evidence the need for training to improve the notification of this event, to have a record dorar to the reality of the population and thus be able to take decisions for the benefit of the population and in the generation of knowledge on this topic.

Apendicitis aguda: revisión de la presentación histopatológica en Boyacá, Colombia / Acute appendicitis: review of histopthology in patients in the state of Boyacá, Colombia

Introducción. La apendicitis aguda es una de las principales causas de dolor abdominal y es la indicación quirúrgica más común por abdomen agudo. Existen pocos estudios sobre apendicitis en la población latinoamericana. Objetivo. Evaluar la frecuencia de los hallazgos histopatológicos de la apendicitis en una población de Boyacá (Colombia) y, con mayor detalle, los de apendicitis gangrenosa. Materiales y métodos. Se trata de un estudio descriptivo retrospectivo de los especímenes de apendicitis aguda de la base de datos del Departamento de Patología del Hospital San Rafael de Tunja, durante el periodo de enero a diciembre de 2011. Además, se revisaron de forma retrospectiva las historias clínicas de los pacientes con apendicitis gangrenosa. Resultados. Se encontraron 1.688 informes de histopatología de apendicitis aguda. Las muestras de tejidos provenían de siete áreas diferentes del departamento de Boyacá. Los estadios, por orden de frecuencia, fueron: apendicitis supurativa aguda (49 %), gangrenosa (24 %), apéndice normal (18 %) y apéndice edematoso (7 %). Otros diagnósticos histopatológicos (1 % del total de la muestra) fueron linfoma de Hodgkin, endometriosis, neuroma, tuberculosis apendicular, adenocarcinoma apendicular y tumores neuroendocrinos en el apéndice. Discusión. Se encontró que en la población boyacense, la apendicitis supurativa fue la presentación más frecuente, seguida de la gangrenosa. El diagnóstico de apendicitis gangrenosa mediante el examen físico, representa un reto para el médico. Este es el primer estudio en que se analiza una muestra de diagnósticos histopatológicos de apendicitis a nivel departamental en Colombia.

Introduction: Acute appendicitis is one of the leading causes of abdominal pain and is the most common surgical presentation of acute abdomen. Studies on appendicitis in the Latin American populations are scarce. The aim of this study was to evaluate the pathological findings of appendicitis in a population in the state of Boyacá, Colombia, and, with deeper detail, those with gangrenous appendicitis. Materials and Methods: Retrospective study of all acute appendicitis specimens in the Department of Pathology at San Rafael Hospital in the city of Tunja, Boyacá, between January and December of 2011. Review of clinical records of patients with gangrenous appendicitis was also performed. Results: During the one year period there were 1,688 histopathology reports of acute appendicitis. All specimens came from seven different areas in the state (departamento) of Boyacá. The results were as follows: acute suppurative appendix (49%,) followed by gangrenous-perforated appendix (24%), normal histology (18%), and edematous appendix (7%). Other histopathological diagnoses (1% of the total sample) were Hodgkin´s lymphoma, endometriosis, neuroma, appendicular tuberculosis, appendiceal adenocarcinoma, and neuroendocrine tumors of the appendix. Discussion: We found that in the state of Boyacá's population, suppurative appendicitis was the most common presentation, followed in frequency by gangrenous appendicitis. The diagnosis by physical examination of gangrenous appendicitis is still a challenge for the clinician. This is the first study that reviews appendicitis samples in one Colombian state.

El papel del receptor de glucocorticoide en el estrés temprano: [revisión] / The relevance of glucocorticoid receptor in early stress: [review]

En estudios previos se han relacionado las alteraciones funcionales del eje hipotálamohipofisario-adrenal y el estrés temprano; por ejemplo, el aumento en la producción de corticotropina (ACTH) y glucocorticoide como factor clave en la fisiopatología de trastornos del estrés como la depresión. En este artículo se presentan los resultados de estudios en epigenética en busca del posible nexo entre el estrés temprano, la disminución en la expresión del receptor de glucocorticoide y la hiperactividad del eje hipotálamo-hipofisario-adrenal. De esta manera, se identifica al estrés temprano como modulador del neurodesarrollo de las estructuras cerebrales implicadas en la respuesta frente al estrés, así como el papel del receptor de glucocorticoide en dicho proceso.

Previous studies have shown how Hypothalamic-Pituitary-adrenal Axis dysfunction is related to early life stress; several works show that Hypothalamic-Pituitary-adrenal Axishyperactivity increases production of ACTH and glucocorticoids, indicating a pathophysiological key factor in stress related diseases like depression. This review will discuss results of some epigenetical studies linking early life stress, decreased production of the glucocorticoid receptor and Hypothalamic-Pituitary-adrenal Axis hyperactivity. We conclude how early life stress modulates the expression of the glucocorticoid receptor affecting the development of several brain structures involved in the stress response.