RESUMO
We present two cases of a family with the diagnosis of multiple osteochondromatosis, which was confirmed by molecular study with nonsense in heterozygosis mutation c.1219CT, (p.Gln407Stop) in the EXT1 gene. In these cases, the Madelung deformity was presented in one patient as an uncommon finding and chondrosarcoma as a feared complication in the other case, highlighting intrafamilial variation, which is why individual and interdisciplinary evaluation is recommended. In addition, before a genetic entity should provide adequate and timely family genetic counseling to all its members.
Se presentan dos casos de una familia con diagnóstico de osteocondromatosis múltiple, el cual fue confirmado por estudio molecular con mutación sin sentido en heterocigosis c.1219CT, (p.Gln407Stop) en el gen EXT1. En el primer caso, en un paciente se presentó deformidad de Madelung como hallazgo infrecuente y en el otro caso, condrosarcoma como complicación temida, resaltando la variación intrafamiliar, por lo que se recomienda la evaluación individual e interdisciplinaria. Además, ante una entidad genética debe brindarse el adecuado y oportuno asesoramiento genético familiar a todos sus integrantes.
Assuntos
Neoplasias Ósseas , Condrossarcoma , Exostose Múltipla Hereditária , Neoplasias Ósseas/genética , Condrossarcoma/genética , Exostose Múltipla Hereditária/genética , Humanos , Mutação , N-Acetilglucosaminiltransferases/genéticaRESUMO
Resumen: Se presentan dos casos de una familia con diagnóstico de osteocondromatosis múltiple, el cual fue confirmado por estudio molecular con mutación sin sentido en heterocigosis c.1219C>T, (p.Gln407Stop) en el gen EXT1. En el primer caso, en un paciente se presentó deformidad de Madelung como hallazgo infrecuente y en el otro caso, condrosarcoma como complicación temida, resaltando la variación intrafamiliar, por lo que se recomienda la evaluación individual e interdisciplinaria. Además, ante una entidad genética debe brindarse el adecuado y oportuno asesoramiento genético familiar a todos sus integrantes.
Abstract: We present two cases of a family with the diagnosis of multiple osteochondromatosis, which was confirmed by molecular study with nonsense in heterozygosis mutation c.1219C>T, (p.Gln407Stop) in the EXT1 gene. In these cases, the Madelung deformity was presented in one patient as an uncommon finding and chondrosarcoma as a feared complication in the other case, highlighting intrafamilial variation, which is why individual and interdisciplinary evaluation is recommended. In addition, before a genetic entity should provide adequate and timely family genetic counseling to all its members.
Assuntos
Humanos , Neoplasias Ósseas/genética , Exostose Múltipla Hereditária/genética , Condrossarcoma/genética , N-Acetilglucosaminiltransferases/genética , MutaçãoRESUMO
Multiple osteochondromatosis (MO), or EXT1/EXT2-CDG, is an autosomal dominant O-linked glycosylation disorder characterized by the formation of multiple cartilage-capped tumors (osteochondromas). In contrast, solitary osteochondroma (SO) is a non-hereditary condition. EXT1 and EXT2, are tumor suppressor genes that encode glycosyltransferases involved in heparan sulfate elongation. We present the clinical and molecular analysis of 33 unrelated Latin American patients (27 MO and 6 SO). Sixty-three percent of all MO cases presented severe phenotype and two malignant transformations to chondrosarcoma (7%). We found the mutant allele in 78% of MO patients. Ten mutations were novel. The disease-causing mutations remained unknown in 22% of the MO patients and in all SO patients. No second mutational hit was detected in the DNA of the secondary chondrosarcoma from a patient who carried a nonsense EXT1 mutation. Neither EXT1 nor EXT2 protein could be detected in this sample. This is the first Latin American research program on EXT1/EXT2-CDG.
Assuntos
Exostose Múltipla Hereditária/genética , Genômica/métodos , Mutação/genética , N-Acetilglucosaminiltransferases/genética , Estudos de Casos e Controles , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , América Latina/etnologia , Perda de Heterozigosidade , Masculino , Regiões Promotoras Genéticas , Estados UnidosRESUMO
GM1 gangliosidosis is a lysosomal storage disorder caused by the absence or reduction of lysosomal beta-galactosidase activity because of mutations in the GLB1 gene. Three major clinical forms have been established: type I (infantile), type II (late infantile/juvenile) and type III (adult). A mutational analysis was performed in 19 patients with GM1 gangliosidosis from South America, mainly from Argentina. Two of them were of Gypsy origin. Main clinical findings of the patients are presented. All 38 mutant alleles were identified: of the 22 different mutations found, 14 mutations are described here for the first time. Among the novel mutations, five deletions were found. Four of them are relatively small (c.435_440delTCT, c.845_846delC, c.1131_1145del15 and c.1706_1707delC), while the other one is a deletion of 1529 nucleotides that includes exon 5 and is caused by an unequal crossover between intronic Alu sequences. All the described patients with GM1 gangliosidosis were affected by the infantile form, except for four unrelated patients classified as type II, III, and II/III (two cases). The two type II/III patients bore the previously described p.R201H mutation, while the adult patient bore the new p.L155R. The juvenile patient bore two novel mutations: p.S434L and p.G554E. The two Gypsy patients are homozygous for the p.R59H mutation as are all Gypsy patients previously genotyped.
Assuntos
Gangliosidose GM1/genética , Mutação , beta-Galactosidase/genética , Adulto , Alelos , Argentina , Sequência de Bases , Pré-Escolar , Análise Mutacional de DNA , Éxons , Gangliosidose GM1/diagnóstico , Haplótipos , Humanos , Lactente , Dados de Sequência Molecular , Deleção de SequênciaRESUMO
Gaucher disease (GD) is caused by a deficiency of beta-glucocerebrosidase activity mainly due to mutations in the gene coding for the enzyme. More than 100 mutations have been identified to date and their frequencies have been established in several populations, including Ashkenazi Jews, among whom the disease is particularly prevalent. In order to study the molecular pathology of the disease in patients from Argentina, we conducted a systematic search for mutations in the glucocerebrosidase gene. Genomic DNA from 31 unrelated GD patients was screened for seven previously described mutations: N370S (1226A-->G), L444P (1448T-->C), D409H (1342G-->C), R463C (1504C-->T), 1263de155, RecNciI, and RecTL. This allowed the identification of 77.4% of the GD alleles: N370S and RecNciI were the most prevalent mutations found (46.8% and 21% respectively). Southern analysis demonstrated three distinct patterns for the RecNciI alleles. In order to identify the remaining alleles, the full coding region of the gene, all the splice sites, and part of the promoter region were analyzed by single-strand conformational polymorphism analysis (SSCP) after polymerase chain reaction amplification. This extensive screening allowed the identification of 13 different mutations, accounting for 93% of the total number of GD alleles. Three novel missense mutations, I161S (599T-->G), G265D (911G-->A), and F411I (1348T-->A), were detected. Twelve polymorphic sites within the glucocerebrosidase gene are in complete linkage disequilibrium and define two major haplotypes, "-" and "+". Mutation N370S was always associated with the "-" haplotype, as described in other populations. Interestingly, the RecNciI alleles with the same Southern-blot pattern were always associated with the same haplotype.
Assuntos
Doença de Gaucher/genética , Glucosilceramidase/genética , Alelos , Argentina/epidemiologia , Análise Mutacional de DNA , Doença de Gaucher/enzimologia , Doença de Gaucher/epidemiologia , Heterogeneidade Genética , Glucosilceramidase/deficiência , Humanos , Mutação , Polimorfismo Genético , Polimorfismo Conformacional de Fita Simples , PrevalênciaRESUMO
As part of a multicenter collaborative study the relative frequency of enteropathogenic agents in children less than 5 years of age with acute diarrhea was determined. Rates of isolation were similar as regards sex, age, and season. The frequency of polymorphonuclear cells (PMN) in the stools was significantly higher among patients requiring admission in comparison with ambulatory patients. Enteropathogenic E. coli (EPEC) was isolated more frequently in that group in comparison with outpatients (p < 0.001), mainly among children less than 5 months of age. The most prevalent agents were EPEC (26.1%), enterotoxigenic E. coli (ETEC) (9.7%), Shigella (8.5%), Rotavirus (5.1%), Giardia (3.6%), Campylobacter (3.2%), and Salmonella (2.4%). The EPEC predominant serogroups were 0 111, 0 55, 0 26, and 0 119. ETEC serotypes 0 153:H45 and 0 128:H21 were more often isolated. The predominant species in the genus Shigella were S. flexneri (80.5%), and S. sonnei (9.5%); in the genus Campylobacter, the species were C. jejuni (81.3%), and C. coli (18.7%). Shigella was clearly related to the presence of PMN in the faeces, in children less than 5 months old. Campylobacter was more frequent in ambulatory patients more than one year of age. Rotavirus was found predominantly in autumn and winter. Salmonella and ETEC were more frequent in summer. Giardia was associated with weight loss. In about 10% of the cases there were simultaneous mixed isolations of two or more agents. Salmonella isolates were sensitive to the majority of antimicrobial agents probed. Many Shigella and E. coli were resistant to sulfamethoxazole-trimethoprim and ampicillin (40-80%). Nearly all enterobacteria were sensitive to gentamicin and norfloxacin.
Assuntos
Diarreia/microbiologia , Enterobacteriaceae/isolamento & purificação , Doença Aguda , Fatores Etários , Animais , Argentina/epidemiologia , Campylobacter/isolamento & purificação , Pré-Escolar , Diarreia/epidemiologia , Diarreia/parasitologia , Resistência Microbiana a Medicamentos , Enterobacteriaceae/efeitos dos fármacos , Feminino , Giardia/isolamento & purificação , Humanos , Lactente , Recém-Nascido , Masculino , Rotavirus/isolamento & purificação , Estações do AnoRESUMO
Como parte de um estudo multicéntrico nacional se investigaron agentes enteropatógenos em 495 niños menores de 5 años con diarrea aguda, entre agosto de 1985 y diciembre de 1988. La tasa total de aislamiento fue similar en relación a la estación, edad y sexo. Estuvieron significantemente asociados a la condición de hospitalización la desnutrición, deshidratación, fiebre, leucocitos en heces y frecuencia de agentes, en especial Escherichia coli enteropatógeno (ECP) (p < 0,001). Los principales agentes enteropatógenos fueron ECEP (26,5//), E. coli enterotosigénico (ECET) (9,7//), Shigella (8,5//). Rotavirus (5,1//), Giardia (3,6//), Campylobacter (3,2//) y Salmonella (2,4//). Los serotipos de ECET 0 153:H45 y 0 128:H21 fueron los más frecuentes. El aislamiento de Shigella se relacionó claramente con la presencia de leucocitos en heces, predominó en niños internados, febriles y en mayores de 5 meses. Campylobacter se presentó en niños de 1 año y ambulatórios. Rotavirus predominó en otoño e invierno. Giardia predominó en niños internados y denutridos. En 10// de los casos hubo asociación de 2 ó mas agentes. Salmonella resultó multisensible a los antimicrobianos probados pero entre 40 y 80// de las cepas de Shigella y E. coli fueron resistentes a sulfametaxazol-trimetoprima y ampicilina (AU)
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Diarreia/microbiologia , Enterobacteriaceae/isolamento & purificação , Resistência Microbiana a Medicamentos , Diarreia/epidemiologia , Campylobacter/isolamento & purificação , Giardia/isolamento & purificação , Rotavirus/isolamento & purificação , Doença Aguda , Fatores Etários , Estações do Ano , Argentina/epidemiologiaRESUMO
As part of a multicenter collaborative study the relative frequency of enteropathogenic agents in children less than 5 years of age with acute diarrhea was determined. Rates of isolation were similar as regards sex, age, and season. The frequency of polymorphonuclear cells (PMN) in the stools was significantly higher among patients requiring admission in comparison with ambulatory patients. Enteropathogenic E. coli (EPEC) was isolated more frequently in that group in comparison with outpatients (p < 0.001), mainly among children less than 5 months of age. The most prevalent agents were EPEC (26.1
), enterotoxigenic E. coli (ETEC) (9.7
), Shigella (8.5
), Rotavirus (5.1
), Giardia (3.6
), Campylobacter (3.2
), and Salmonella (2.4
). The EPEC predominant serogroups were 0 111, 0 55, 0 26, and 0 119. ETEC serotypes 0 153:H45 and 0 128:H21 were more often isolated. The predominant species in the genus Shigella were S. flexneri (80.5
), and S. sonnei (9.5
); in the genus Campylobacter, the species were C. jejuni (81.3
), and C. coli (18.7
). Shigella was clearly related to the presence of PMN in the faeces, in children less than 5 months old. Campylobacter was more frequent in ambulatory patients more than one year of age. Rotavirus was found predominantly in autumn and winter. Salmonella and ETEC were more frequent in summer. Giardia was associated with weight loss. In about 10
of the cases there were simultaneous mixed isolations of two or more agents. Salmonella isolates were sensitive to the majority of antimicrobial agents probed. Many Shigella and E. coli were resistant to sulfamethoxazole-trimethoprim and ampicillin (40-80
). Nearly all enterobacteria were sensitive to gentamicin and norfloxacin.
RESUMO
Como parte de um estudo multicéntrico nacional se investigaron agentes enteropatógenos em 495 niños menores de 5 años con diarrea aguda, entre agosto de 1985 y diciembre de 1988. La tasa total de aislamiento fue similar en relación a la estación, edad y sexo. Estuvieron significantemente asociados a la condición de hospitalización la desnutrición, deshidratación, fiebre, leucocitos en heces y frecuencia de agentes, en especial Escherichia coli enteropatógeno (ECP) (p < 0,001). Los principales agentes enteropatógenos fueron ECEP (26,5//), E. coli enterotosigénico (ECET) (9,7//), Shigella (8,5//). Rotavirus (5,1//), Giardia (3,6//), Campylobacter (3,2//) y Salmonella (2,4//). Los serotipos de ECET 0 153:H45 y 0 128:H21 fueron los más frecuentes. El aislamiento de Shigella se relacionó claramente con la presencia de leucocitos en heces, predominó en niños internados, febriles y en mayores de 5 meses. Campylobacter se presentó en niños de 1 año y ambulatórios. Rotavirus predominó en otoño e invierno. Giardia predominó en niños internados y denutridos. En 10// de los casos hubo asociación de 2 ó mas agentes. Salmonella resultó multisensible a los antimicrobianos probados pero entre 40 y 80// de las cepas de Shigella y E. coli fueron resistentes a sulfametaxazol-trimetoprima y ampicilina