Carrier frequency of the 35delG and A1555G deafness mutations in the Argentinean population. Impact on the newborn hearing screening.

OBJECTIVE: Hearing loss is a complex multifactorial disorder caused by genetic and environmental factors. The 35delG mutation in the GJB2 gene is the most prevalent mutation in Caucasian patients with genetic sensorineural deafness. The A1555G mutation in the mitochondrial 12S rRNA is the main genetic alteration associated with aminoglycoside-induced deafness. The aim of this study was to evaluate the prevalence of both mutations in general population of Argentina. METHODS: A total of 712 samples of unrelated healthy blood donors and 330 newborn dried blood spots were studied by PCR-RFLP. RESULTS: The 35delG mutation was detected in 11/ 712 unrelated blood donors. The carrier frequency found in this sample (1/65) proved to be lower than that found in Southern European countries, mainly Spain and Italy, from where Argentina originally received its major immigration waves. When the populations of Southern Europe were considered altogether, this difference reached statistical significance. The A1555G mutation was not found in any of the 1042 samples tested. CONCLUSIONS: Taking into account the 35delG carrier frequency found in this study, it could be estimated that 130-160 children with congenital deafness due to mutations in the connexin genes would be born per year in Argentina. In contrast, the mitochondrial mutation A1555G appears to be infrequent in general Argentinean population.

Partial distal 5p trisomy resulting from paternal translocation (5;15)(p15.1;p13) in a boy with no mental retardation.

We report a boy with partial distal 5p15.1-->pter trisomy and normal development. We compared the clinical findings in our patient with those previously reported of the same 5p duplicated region. Several cases of autosomal duplications and normal development have been described. The present case is another example of a chromosomal anomaly with little, if any, phenotypic effect without mental retardation.

Prevalence of DFNB1 mutations in Argentinean children with non-syndromic deafness. Report of a novel mutation in GJB2.

OBJECTIVE: Mutations in DFNB1 locus, containing GJB2 (connexin 26) and GJB6 (connexin 30) genes, are the most common cause of autosomal recessive non-syndromic hearing loss. More than 100 mutations in GJB2 have been reported worldwide. Two deletions in GJB6, del(GJB6-D13S1830) and del(GJB6-D13S1854), have been found to be frequent in the Spanish population. The aim of this study was to determine the prevalence of GJB2 mutations and both GJB6 deletions in Argentinean children with non-syndromic deafness. METHODS: This study included 94 unrelated children with moderate to profound non-syndromic sensorineural hearing impairment. Molecular analysis was performed using a tiered approach. All DNA samples were screened for c.35delG mutation by PCR/RFLP. Samples from patients who were not homozygous for c.35delG were analysed for the presence of GJB6 deletions by PCR multiplex. The samples that remained unresolved after screening were further analysed by direct sequencing of GJB2 coding region. Finally, the splice site mutation IVS1+1G-->A was analysed by PCR/RFLP. RESULTS: Sequence variations in the GJB2 and GJB6 genes were found in 49 of the 94 unrelated patients. The most prevalent GJB2 mutation, c.35delG, was found in 40 of the 68 pathogenic alleles with the second most common allele being p.R143W (4/68). Fourteen sequence variations other than c.35delG were identified. Seven already described mutations were present in more than one allele; among them, IVS1+1G-->A, the rare splice site mutation flanking exon 1. In addition to known disease-related alterations, a novel GJB2 mutation, c.262G>C (p.A88P), was also identified. Six alleles were identified carrying GJB6 deletions; the most prevalent was del(GJB6-D13S1830). The frequency of the latter was found to be as high as that found in Spain from where Argentina has received one of its major immigration waves. CONCLUSIONS: The overall frequency of GJB2/GJB6 mutations in the present sample is in agreement with other Caucasian populations. As expected, c.35delG was the most prevalent mutation. The deletion del(GJB6-D13S1830) was the second most common mutation. These findings reinforce the importance of the study of GJB2/GJB6 genes in diagnosis to provide early treatment and genetic counselling.

Prevalencia de la patología genética en pacientes pediátricos internados en un hospital de alta complejidad / Prevalence of genetic pathology in pediatric patients admitted to a tertiary-care hospital

Las enfermedades genéticas son aquellas perturbaciones del estado de la salud en las que intervienen en mayor o menor medida alteraciones de la constitución genética. En algunos casos la constitución genética es claramente determinante de una condición clínica, en otros casos en cambio solo será determinada la susceptibilidad que, en concurrencia con otros factores, predisponen al desarrollo de enfermedades. Los objetivos principales de este trabajo se centraron en analizar como la presencia de patología genética influye en la morbimortalidad de los pacientes hospitalizados evaluando los egresos del año 2007 en el Hospital Juan P. Garrahan, determinar qué porcentaje de pacientes pediátricos egresados de un centro de referencia presentan patología total o parcialmente genética, describir sus características y la carga asistencial que representan. Se realizó un estudio retrospectivo, descriptivo, transversal. Se revisaron 2300 historias clínicas (HC) correspondientes a los egresos del año 2007 en cinco salas de internación: Neonatología, CIM 64, 32, 62 y 73. En las salas se comparó: 1-porcentaje de pacientes con y sin patología genética, 2- días requeridos en una internación entre pacientes con y sin patología genética. 3- reinternaciones. 4- tipo de egreso. En las cinco salas analizadas se observó una mayor prevalencia de patologías total o parcialmente genéticas, en relación a la patología no genética. Analizando la morbimortalidad mediante días de internación requeridos en la hospitalización y número de reinternaciones, se observó que en tres de las cinco salas los días de internación requeridos eran mayores en los pacientes con patología total o parcialmente genética.

Genetic diseases are disorders affecting health in which al-terations in the genetic constitution intervene to a greater or lesser extent. In some cases the genetic constitution clearly determines a clinical condition, in others, however, it merely de-termines a susceptibility which, in association with other factors, predisposes to the development of a certain disease. The aims of this study were to analyze the impact of genetic pathology on the morbidity and mortality of hospitalized patients evalu-ating children discharged from the Juan P. Garrahan Hospital in 2007, to the determine the percentage of pediatric patients discharged from a tertiary care center who presented with a total or partial genetic pathology, to describe their features and the burden of care they represented. A retrospective, descrip-tive, cross-sectional study was conducted. We reviewed 2300 clinical charts (CC) of children discharged from different five wards in 2007: Neonatology and wards 64, 32, 62, and 73. We compared: 1- percentage of patients with and without genetic pathology, 2- days of hospital stay of patients with and with-out genetic pathology, 3- readmissions, 4- type of discharge. On all wards a higher prevalence of totally or partially genetic pathologies than of non-genetic pathologies was found. When comparing morbidity and mortality with days of hospital stay and number of readmissions, we found that in three of five wards days of hospital stay were increased in patients with total or partially genetic pathologies.

High specificity of head circumference to recognize N540K mutation in hypochondroplasia.

Hypochondroplasia (HCH) is a skeletal dysplasia characterized by short stature with disproportionately short arms and legs. Anthopometrics and skeletal features are very similar to achondroplasia but milder. Seventy per cent of affected individuals are heterozygous for a mutation of the FGFR3 gene. Differences in some anthropometric measurements in affected patients with and without N540K mutation were analysed. Diagnosis of the disease was made on the presence of previously standardized criteria: short stature, short limbs and three or more X-ray features. Genomic DNA was extracted from peripheral blood leukocytes by standard procedures. PCR amplification of exons 10, 13 and 15 of FGFR3 was performed. Twenty-six patients were studied (median age was 7.31, range 0.27-20.0 years). Sitting height, body proportions and head circumference (HC) were statistically different in the mutated group. Receiver Operating Characteristic (ROC) analysis was carried out in order to estimate the discriminating power of different cut-off points of HC for recognizing patients with and without the mutation. A figure of 1.86 SD for HC was found to have a sensitivity of 73.3% and specificity of 100% for detecting HCH patients with the mutation. All of them had a HC greater than 1.86?SD. These results contribute to a better characterization of the clinical-molecular relationships in HCH.

ATR-16 due to a de novo complex rearrangement of chromosome 16.

We describe a child with ATR-16 [alpha-thalassemia (thal)/mental retardation], who was referred for genetic evaluation because of minor anomalies and developmental delay. Cytogenetic analysis demonstrated a de novo complex rearrangement of chromosome 16. Fluorescence in situ hybridization (FISH) analysis, using chromosome 16 subtelomeric probes, showed that this patient had a deletion of the distal short arm of chromosome 16 that contains the alpha-globin genes and a duplication of 16q. Analysis of the alpha-globin locus by Southern blot showed a half normal dose of the alpha-globin gene. Microsatellite marker studies revealed that the duplicated 16q region was maternal in origin. Hematological studies revealed anemia, hypochromia and occasional cells with Hb H inclusion bodies. A hematological screening for alpha-thal should be considered in patients with mild developmental delay and a suggestive phenotype of ATR-16 with microcytic hypochromic anemia and normal iron status. The stellate pattern of the iris, a new finding in our patient, may contribute to a better clinical delineation of both syndromes, ATR-16 and/or duplication of 16qter.

Oral-facial-digital syndrome gabrielli type: second report.

We describe a second sporadic case, a girl, with the features of Oral-Facial-Digital, type Gabrielli. We comment on several aspects of this condition and confirm this entity as a unique syndrome, different from the other OFDS. To date, the diagnosis is based only on clinical and radiographic findings.

Trisomy 3 in two paediatric post-transplant lymphomas.

Few cytogenetic data are available concerning the chromosomal constitution of post-transplant lymphomas. We report two paediatric cases of trisomy 3, as a primary anomaly, in post-transplant lymphoproliferative disease (PTLD) associated with B immunophenotype. Using cytogenetic analysis and fluorescence in situ hybridization on chromosome preparations, we found trisomy 3 in both patients and an extra X chromosome in one. Clinical, histological and immunophenotypical data are presented. Trisomy 3 has been observed in different types of non-Hodgkin's lymphomas but it is relatively rare in B-cell lymphomas, with the exception of marginal zone lymphoma and mantle cell lymphoma. To our knowledge, trisomy 3 is an uncommon cytogenetic finding in PTLD. Further cytogenetic studies of these lymphoproliferative disorders might contribute to evaluate the role of these chromosomal anomalies in the pathogenesis of this disease.

Defectos de cierre del tubo neural. Prevención de ocurrencia y recurrencia. Recomendaciones útiles / Neural tube closure defects. Occurrence and recurrence prevention useful recommendations

Los defectos de cierre del tubo neural (DCTN) son anomalías congénitas multifactoriales originadas por interacción entre factores genéticos y ambientales. El principal factor ambiental es el ácido fólico, relacionado con la sintesis de ADN y ARN y transformación de homocisteína en metionina. El principal factor genético es el gen para la enzima MTHFR (cr1p36.3), que permite al folato alcanzar su forma activa. Su polimorfismo más frecuente es C677T, codificante de variante termolábil. En homocigocis para C677T, disminuyen acción reductasa de MTHFR y folato disponible para proliferación celular (malformaciones congénitas) y aumenta homocisteína circulante (trombosis ateriovenosas, accidentes cardio y cerebrovascular). El presente trabajo investiga factores ambientales y genéticos, en niños con espina bífida (DCTN más frecuente) y sus madres en niños y madres de la población general. Desarrolla estudio de caso-control mediante búsqueda bibliográfica (participación de variable estudiadas); entrevistas a casos y controles (influencia de factores ambientales y familiares) y trabajo especifico de laboratorio (polimorfismo C677T). Realiza trabajo descriptivo para cada variable y trabajo analítico comparando casos y controles. Resultados y conclusiones coinciden con la literatura y fundamentarían la utilidad de la prevención primaria: suplementación con folatos a mujeres en edad fértil. No obstante, dado que para algunas variables los resultados no alcanzaron significancia estadística, su validez deberia corroborarse mediante estudios posteriores.

Correlación clínico-molecular en niñas con retardo mental y síndrome de sitio frágil del X / Clinical and molecular correlation in girls with MR and FRA-X syndrome

El síndrome de Fra-X es la causa más frecuente de retardo mental heredable,su incidencia en mujeres se estima en 1 cada 2.500.En los varones,el RM está asociado a un fenotipo clínico-conductual que permitió elaborar un sistema de puntaje de signos para facilitar su detección clínica.El objetivo del presente trabajo fue evaluar la utilidad de dicho sistema de puntaje en una población de niñas con retardo mental.Se realizó para ello un estudio comparativo entre los hallazgos clínicos y los resultados de los estudios moleculares.Material y Método: Durante un período de 6 años se seleccionaron 49 niñas con retardo mentalsin diagnóstico.Se aplicó a cada una de ellas un sistema de selección compuesto por 16 signos clínico-conductales,se realizaron estudios citogénicos y moleculates para diagnóstico de Fra-X y evaluación psicopedagógica

Correlación clínico-molecular en niñas con retardo mental y síndrome de sitio frágil del X / Clinical and molecular correlation in girls with MR and FRA-X syndrome

El síndrome de Fra-X es la causa más frecuente de retardo mental heredable,su incidencia en mujeres se estima en 1 cada 2.500.En los varones,el RM está asociado a un fenotipo clínico-conductual que permitió elaborar un sistema de puntaje de signos para facilitar su detección clínica.El objetivo del presente trabajo fue evaluar la utilidad de dicho sistema de puntaje en una población de niñas con retardo mental.Se realizó para ello un estudio comparativo entre los hallazgos clínicos y los resultados de los estudios moleculares.Material y Método: Durante un período de 6 años se seleccionaron 49 niñas con retardo mentalsin diagnóstico.Se aplicó a cada una de ellas un sistema de selección compuesto por 16 signos clínico-conductales,se realizaron estudios citogénicos y moleculates para diagnóstico de Fra-X y evaluación psicopedagógica

Caracterización de tres microsatelites del gen de fibrosis quistica en familias argentinas / Characterization of 3 microsatellites of the cystic fibrosis gene in Argentine families

La población de Argantina es altamente Heterogénea para las mutaciones del gen regulador de la conductancia de transmembrana de la fibrosis quística (CFTR). El estudio de 14 mutaciones reportadas entre las más frecuentes, detectó ambos alelos mutados (genotipo completo) en sólo el 51 porciento de los pacientes. Este estudio confirmó el diagnóstico de Fibrosis Quística de estos pacientes y posibilitó detectar entres sus familiares, individuos portadores asintomáticos. Sin embargo, en el resto de los pacientes, el análisis molecular directo, no aportó la información necesaria para el asesoriamento familiar. Con el objetivo de estabelecer la transmisióan de microsatélite (IVS17bTA, IVS8CA y IVS17bCA) localizados en regiones intrónicas del gan CFTR. En las 40 familias FQ analizadas, se detectaron diferentes variantes alélicas, 15 para IVS17TA, 10 para IVS8CA y 4 para IVS17CA . El contenido de información polimórfica y de heterocigosis de estos marcadores fue elevado, a exepción de IVS17bCA que resultó poco polimórfico. A través del análisis simultáneo de estos tres microsatélite se pudo asesorar al 100 porciento de las familias. Nuestros resultados demuestran que estos microsatélites, constituyen un excelente gru[po de marcadores, útiles para realizar estudios de ligamiento de población Argentina.

Caracterización de tres microsatelites del gen de fibrosis quistica en familias argentinas / Characterization of 3 microsatellites of the cystic fibrosis gene in Argentine families

La población de Argantina es altamente Heterogénea para las mutaciones del gen regulador de la conductancia de transmembrana de la fibrosis quística (CFTR). El estudio de 14 mutaciones reportadas entre las más frecuentes, detectó ambos alelos mutados (genotipo completo) en sólo el 51 porciento de los pacientes. Este estudio confirmó el diagnóstico de Fibrosis Quística de estos pacientes y posibilitó detectar entres sus familiares, individuos portadores asintomáticos. Sin embargo, en el resto de los pacientes, el análisis molecular directo, no aportó la información necesaria para el asesoriamento familiar. Con el objetivo de estabelecer la transmisióan de microsatélite (IVS17bTA, IVS8CA y IVS17bCA) localizados en regiones intrónicas del gan CFTR. En las 40 familias FQ analizadas, se detectaron diferentes variantes alélicas, 15 para IVS17TA, 10 para IVS8CA y 4 para IVS17CA . El contenido de información polimórfica y de heterocigosis de estos marcadores fue elevado, a exepción de IVS17bCA que resultó poco polimórfico. A través del análisis simultáneo de estos tres microsatélite se pudo asesorar al 100 porciento de las familias. Nuestros resultados demuestran que estos microsatélites, constituyen un excelente gru[po de marcadores, útiles para realizar estudios de ligamiento de población Argentina. (AU)