Características genéticas, poblacionales y fenotípicas de pacientes con enfermedad de Hirschsprung / Genetic, population and phenotypic characterístics of patients with hirschsprung disease

La enfermedad de Hirschsprung (HSCR) está causada por la ausencia de células ganglionares en el intestino, debido a defectos en la migración de las células del sistema nervioso entérico durante el desarrollo embrionario. La incidencia es aproximadamente de uno en cada 5000 nacimientos, más frecuente en hombres que en mujeres. Hay dos fenotipos según la longitud del segmento aganglionar: corto (S-HSCR, 80% de los enfermos) y largo (L-HSCR, el 20%). Se han detectado variaciones en la secuencia codificante del proto-oncogén rEt en enfermos con HCSR, lo que sugiere predisposición genética a padecer la enfermedad. Nuestro trabajo ha consistido en encontrar y analizar polimorfismos (SNPs) asociados a la enfermedad, así como su distribución poblacional (sexo y tipo de segmento). En el estudio genético se han analizado dos polimorfismos presentes en el promotor del gen, así como un polimorfismo en el exón 13 fuertemente asociado con la enfermedad. Como poblaciones en este estudio se establecieron una de enfermos con HSCR esporádico y un grupo de individuos sanos.Los resultados obtenidos corroboran que la enfermedad es más frecuente en hombres que en mujeres. El genotipado de rEt indica que los alelos A y G del promotor (c.-200A>G y c.-196C>A) y G del exón 13 (c.2307T>G) están asociados a la población enferma. Los datos apuntan a que no existe relación entre el fenotipo de la enfermedad y la distribución de los polimorfismos analizados. Concluimos que la presencia de ciertos polimorfismos en la secuencia de rEt indica predisposición genética (combinada con otros factores genéticos o ambientales) a padecer la enfermedad (AU)

Hirschsprung disease (HSCR) is caused by the absence of ganglion cells in the intestine due to defects in the migration of enteric nervous system cells during embryologic development. The incidence is one in every 5000 births, more common in men than women. There are two main phenotypes according to the aganglionic segment length: Short (S-HSCR, (80% of patients) and Long (L-HSCR, 20%). Variations have been detected in the coding sequence of the rEt proto-oncogene in patients with HSCR, suggesting a genetic predisposition to the disease. Our aim is to find and analyze polymorphisms (SNPs) associated with the disease. We are interested also in stablish an association between sex and type of aganglionic segment. We analyzed the rEt promoter as well a polymorphism in exon 13 strongly associated to the disease. The populations for the study were a group of 56 patients with sporadic HSCR and 178 healthy controls.The results obtained show that the disease is more common in men than in women (3:1). The rEt genotype shows that alleles A and G of the promoter (c.-200A> G and c.-196C> A) and G of exon 13 (c.2307T> G) are associated with the affected population. Our data suggest neither association between the disease phenotype and the distribution of the polymorphisms analyzed nor with the sex of the patients. The presence of certain polymorphisms in the rEt sequence indicates a genetic predisposition (combined with other genetic or environmental factors) to the disease (AU)

[Genetic, population and phenotypic characteristics of patients with Hirschsprung disease]. / Características genéticas, poblacionales y fenotípicas de pacientes con enfermedad de Hirschsprung.

Hirschsprung disease (HSCR) is caused by the absence of ganglion cells in the intestine due to defects in the migration of enteric nervous system cells during embryologic development. The incidence is one in every 5000 births, more common in men than women. There are two main phenotypes according to the aganglionic segment length: Short (S-HSCR, (80% of patients) and Long (L-HSCR, 20%). Variations have been detected in the coding sequence of the RET proto-oncogene in patients with HSCR, suggesting a genetic predisposition to the disease. Our aim is to find and analyze polymorphisms (SNPs) associated with the disease. We are interested also in stablish an association between sex and type of aganglionic segment. We analyzed the RET promoter as well a polymorphism in exon 13 strongly associated to the disease. The populations for the study were a group of 56 patients with sporadic HSCR and 178 healthy controls. The results obtained show that the disease is more common in men than in women (3:1). The RET genotype shows that alleles A and G of the promoter (c.-200A > G and c.-196C > A) and G of exon 13 (c.2307T > G) are associated with the affected population. Our data suggest neither association between the disease phenotype and the distribution of the polymorphisms analyzed nor with the sex of the patients. The presence of certain polymorphisms in the RET sequence indicates a genetic predisposition (combined with other genetic or environmental factors) to the disease.

Pancreatitis en la fibrosis quística: correlación con el genotipo y estado pancreático / Pancreatitis in cystic fibrosis: association with genotype and pancreatic status

Introducción: La pancreatitis es una rara complicación en la evolución de pacientes con fibrosis quística (FQ). Puede presentarse en forma de episodios agudos, aislados o repetidos, o evolucionar a cronicidad con progresiva destrucción de la glándula. El objetivo de este estudio fue describir las características de una cohorte de pacientes que habían padecido pancreatitis, conocer su frecuencia e intentar encontrar posibles factores de riesgo asociados. Metodología: Estudio retrospectivo descriptivo de pacientes controlados en unidades de FQ de cinco hospitales españoles que habían padecido pancreatitis. Se recogieron datos demográficos, clínicos y analíticos, y relativos al estado pancreático y el genotipo. Resultados: De 520 pacientes, 17 presentaron pancreatitis. Una prevalencia del 3,3%, superior a la descrita en la literatura. Analizando el estado pancreático, se observó que 8 de ellos eran insuficientes pancreáticos (47,06%), hecho que contrasta, en parte, con lo referido clásicamente al considerar esta complicación más típica de pacientes con cierto grado de reserva pancreática. No se encontraron factores de riesgo ni asociaciones significativas con la genética, edad, sexo u otras características. Conclusiones: En nuestra serie, la prevalencia de pancreatitis es superior a la descrita en la literatura, no tratándose de una complicación exclusiva de suficientes pancreáticos. Se produce más frecuentemente durante la adolescencia o en el inicio de la edad adulta. La enfermedad pulmonar es leve en la mayoría. La genética es variable, sin poder establecerse una clara relación genotipo-fenotipo. Se debe observar a largo plazo la evolución de esta patología intercurrente y diseñar estudios más amplios para obtener resultados más significativos (AU)

Introduction: Pancreatitis is an uncommon complication of cystic fibrosis (CF). Either single or recurrent acute episodes can occur and it occasionally may follow a protracted course with relentless destruction of the pancreas. Moreover mild mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been found in many cases of idiopathic chronic pancreatitis. We describe a group of patients with CF who had one or more episodes of pancreatitis. We have estimated its prevalence in a large population of patients with CF across Spain. Methods: A retrospective descriptive study was conducted by collecting the demographic, clinical and laboratory data, pancreatic status and genotype of CF patients who attended the CF Units in 5 Spanish hospitals. Results: The overall number of CF patients under follow-up in the five centres was 520, of which 17 cases with pancreatitis were identified. The prevalence of pancreatitis in this population was 3.3%, higher than previously reported. Noticeably eight of the 17 patients (47.06%) had pancreatic insufficiency. This appears to be, partly, in contrast with that classically found, as this complication is usually associated with patients with a certain level of pancreatic reserve. No associations with genotype, age, gender or other factors were found. Conclusions: The prevalence of pancreatitis in our CF patients was higher than that found in other CF populations, and was not limited to patients with pancreatic sufficiency. It occurred mostly in teenagers and young adults often with mild pulmonary disease. The CF genotype was variable. The course of the patients should be carefully monitored, and further information on the long-term outcome of larger cohorts of patients is needed (AU)

[Pancreatitis in cystic fibrosis: association with genotype and pancreatic status]. / Pancreatitis en la fibrosis quística: correlación con el genotipo y estado pancreático.

INTRODUCTION: Pancreatitis is an uncommon complication of cystic fibrosis (CF). Either single or recurrent acute episodes can occur and it occasionally may follow a protracted course with relentless destruction of the pancreas. Moreover mild mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been found in many cases of idiopathic chronic pancreatitis. We describe a group of patients with CF who had one or more episodes of pancreatitis. We have estimated its prevalence in a large population of patients with CF across Spain. METHODS: A retrospective descriptive study was conducted by collecting the demographic, clinical and laboratory data, pancreatic status and genotype of CF patients who attended the CF Units in 5 Spanish hospitals. RESULTS: The overall number of CF patients under follow-up in the five centres was 520, of which 17 cases with pancreatitis were identified. The prevalence of pancreatitis in this population was 3.3%, higher than previously reported. Noticeably eight of the 17 patients (47.06%) had pancreatic insufficiency. This appears to be, partly, in contrast with that classically found, as this complication is usually associated with patients with a certain level of pancreatic reserve. No associations with genotype, age, gender or other factors were found. CONCLUSIONS: The prevalence of pancreatitis in our CF patients was higher than that found in other CF populations, and was not limited to patients with pancreatic sufficiency. It occurred mostly in teenagers and young adults often with mild pulmonary disease. The CF genotype was variable. The course of the patients should be carefully monitored, and further information on the long-term outcome of larger cohorts of patients is needed.

Estudio de polimorfi smos asociadosa la enfermedad de Hirschsprung / Study of polymorphisms associated to hirschsprung’s disease

La enfermedad de Hirschsprung (HSCR) es un desorden congénito caracterizado por la ausencia de células ganglionares a lo largo del tracto gastrointestinal. Está causada por defectos en la migración de las células del sistema nervioso entérico durante el desarrollo embrionario. La mejora de tratamientos quirúrgicos ha disminuido la mortalidad de los pacientes, lo que facilita el estudio genético de enfermos y sus familiares. Aunque se desconoce la causa genética de la enfermedad, se sospecha que el oncogén RET es el principal involucrado. Se han encontrado alteraciones en este gen en enfermos con HSCR, por lo que algunos autores sugieren que ciertos polimorfismos (SNPs) en el gen podrían causar cierta predisposición genética a padecer esta enfermedad. Nuestro trabajo ha consistido en el análisis del gen RET en pacientes con diagnóstico de HSCR mediante secuenciación directa y genotipado con sondas Taqman®.Los resultados obtenidos indican que ciertos alelos de los polimorfismos p.Leu769Leu (c.2307T>G, Exón 13) p.Gly691Ser (c.2071G>A, Exón 11) y p.Ser904Ser (c.2712C>G, Exón 15) están asociados a losenfermos HSCR, ya que existen diferencias significativas respecto ala población sana (AU)

Hirschsprung’s disease (HSCR) is a developmental disorder characterized by the absence of the enteric ganglia along the intestine. Is regarded as the consequence of the premature arrest of the migration of neural crest cells in the hindgut during the embryonic development to form the enteric nervous system (ENS). Is considered, therefore, a neurocristopathy. The development of surgical approaches has importantly decreased mortality and morbility of Hirschsprung’s patients, which has allowed the emergence of genetic studies of patients and their families. Although the genetic cause of the disease is still unknown, the RET oncogene is the main involved. Alterations in this gene have been found in HSCR patients, so many authors suggest that certain polymorphisms(SNPs) in this gene could be responsible of genetic predisposition to have the disease. Our work has consisted in the genetic analysis of the RET gene in HSCR patients using direct sequencing and genotyping with Taq-Man® probes. Our results show that some alleles of the polymorphismsp.Leu769Leu (c.2307T>G, Exon 13) p.Gly691Ser (c.2071G>A, Exon11) and p.Ser904Ser (c.2712C>G, Exon 15) are associated to the disease since there are significant differences from the healthy population (AU)

[Study of polymorphisms associated to Hirschsprung's disease]. / Estudio de polimorfismos asociados a la enfermedad de Hirschsprung.

Hirschsprung's disease (HSCR) is a developmental disorder characterised by the absence of the enteric ganglia along the intestine. Is regarded as the consequence of the premature arrest of the migration of neural crest cells in the hindgut during the embryonic development to form the enteric nervous system (ENS). Is considered, therefore, a neurocristopathy. The development of surgical approaches has importantly decreased mortality and morbility of Hirschsprung's patients, which has allowed the emergence of genetic studies of patients and their families. Although the genetic cause of the disease is still unknown, the RET oncogene is the main involved. Alterations in this gene have been found in HSCR patients, so many authors suggest that certain polymorphisms (SNPs) in this gene could be responsible of genetic predisposition to have the disease. Our work has consisted in the genetic analysis of the RET gene in HSCR patients using direct sequencing and genotyping with TaqMan probes. Our results show that some alleles of the polymorphisms p.Leu769Leu (c.2307T>G, Exon 13) p.Gly691Ser (c.2071G>A, Exon 11) and p.Ser904Ser (c.2712C>G, Exon 15) are associated to the disease since there are significant differences from the healthy population.