RESUMO
Richieri-Costa-Pereira syndrome is a rare autosomal recessive acrofacial dysostosis that has been mainly described in Brazilian individuals. The cardinal features include Robin sequence, cleft mandible, laryngeal anomalies and limb defects. A biallelic expansion of a complex repeated motif in the 5' untranslated region of EIF4A3 has been shown to cause this syndrome, commonly with 15 or 16 repeats. The only patient with mild clinical findings harbored a 14-repeat expansion in 1 allele and a point mutation in the other allele. This proband is described here in more details, as well as is his affected sister, and 5 new individuals with Richieri-Costa-Pereira syndrome, including a patient from England, of African ancestry. This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16-repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation.
Assuntos
Pé Torto Equinovaro/genética , RNA Helicases DEAD-box/genética , Fator de Iniciação 4A em Eucariotos/genética , Deformidades Congênitas da Mão/genética , Laringe/fisiopatologia , Deformidades Congênitas dos Membros/genética , Síndrome de Pierre Robin/genética , Adolescente , Adulto , Alelos , Brasil/epidemiologia , Criança , Pé Torto Equinovaro/epidemiologia , Pé Torto Equinovaro/fisiopatologia , Expansão das Repetições de DNA/genética , Inglaterra/epidemiologia , Extremidades/fisiopatologia , Feminino , Genótipo , Deformidades Congênitas da Mão/epidemiologia , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Laringe/anormalidades , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Fenótipo , Síndrome de Pierre Robin/epidemiologia , Síndrome de Pierre Robin/fisiopatologia , Mutação Puntual/genética , Adulto JovemRESUMO
Duchenne muscular dystrophy (DMD), a severe and lethal condition, is caused by the absence of muscle dystrophin. Therapeutic trials aiming at the amelioration of muscle function have been targeting the production of muscle dystrophin in affected Duchenne patients. However, how much dystrophin is required to rescue the DMD phenotype remains an open question. We have previously identified two exceptional golden retriever muscular dystrophy (GRMD) dogs with a milder course despite the total absence of muscle dystrophin. Here we report two unusual patients carrying nonsense mutations in the DMD gene and dystrophin deficiency but with an unexpectedly mild phenotype. Three reported polymorphisms, respectively in genes LTBP4, SPP1 and ACTN3 were excluded as possible DMD genetic modifiers in our patients. Finding the mechanisms that protect some rare patients and dogs from the deleterious effect of absent muscle dystrophin is of utmost importance and may lead to new avenues for treatment. Importantly, these observations indicate that it is possible to have a functional large muscle even without dystrophin.