RESUMEN
Dyschondrosteosis (DCO; also called Léri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.
Asunto(s)
Estatura/genética , Genes Homeobox , Proteínas de Homeodominio/genética , Osteocondrodisplasias/genética , Southern Blotting , Humanos , Hibridación Fluorescente in Situ , Fenotipo , Reacción en Cadena de la Polimerasa , Proteína de la Caja Homeótica de Baja Estatura , SíndromeRESUMEN
Molecular genetic studies in congenital long QT syndrome have characterized genes and mechanisms of arrhythmias. At least six genes encoding cardiac potassium and sodium ionic channels have been described with several mutations in each gene. The altered function produces abnormal cardiac repolarization seen on ECG as prolongation of the QT-interval and T-wave abnormalities. This may increase the propensity for ventricular arrhythmias such as Torsade de Pointe, the cause of unexpected syncope and sudden death in young patients. Clinical manifestations vary depending on the genotype present. Gene-specific therapies have recently been tried. Initial therapy of choice for symptomatic and also asymptomatic children is administration of beta-blockers.
Asunto(s)
Muerte Súbita Cardíaca/etiología , Síndrome de QT Prolongado/genética , Síncope/genética , Adulto , Niño , Mapeo Cromosómico , Electrocardiografía , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Terapia Genética , Genotipo , Humanos , Síndrome de QT Prolongado/congénito , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/terapia , Fenotipo , Canales de Potasio/genética , Canales de Sodio/genéticaRESUMEN
The Swedish Enuresis Trial (SWEET) was conducted to evaluate the long-term safety and efficacy of intranasal desmopressin treatment in children with primary, monosymptomatic nocturnal enuresis (PMNE). The study had an open, multicentre design and comprised a 4-wk observation period, a 6-wk dose titration period (with 20-40 microg desmopressin) and a 1-y, long-term treatment period. A treatment-free week was introduced every 3 mo to identify dry patients. In total, 399 children aged 6-12 y with PMNE were recruited. Of these, 245 patients (61%) experienced > or = 50% reduction in the number of wet nights during the last 4 wk of dose titration compared with the observation period. These responders entered the long-term phase of the trial. The mean number of wet nights per week decreased from a median of 5.3 (range 1.3-7.0) during the observation period to a median of 0.8 (range 0.0-5.0) during the last 3-mo period. Seventy-seven children became dry, 63 (83%) within 6 mo of treatment initiation. The percentage of children who became dry was similar in all age groups. Significantly fewer children in the lowest age group were defined as responders (52%; 95% CI 45, 59) among the 6-7-y-olds compared to 65% (56, 74) and 81% (72, 90) in the two older age groups. Desmopressin was well tolerated. No serious drug-related adverse events were recorded and no clinical symptoms of hyponatraemia were reported. The SWEET trial has demonstrated that desmopressin is both safe and effective for the long-term treatment of PMNE, with a significant therapeutic effect also in children of 6-7 y of age.
Asunto(s)
Desamino Arginina Vasopresina/administración & dosificación , Enuresis/tratamiento farmacológico , Fármacos Renales/administración & dosificación , Administración Intranasal , Niño , Intervalos de Confianza , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Enuresis/diagnóstico , Enuresis/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Cuidados a Largo Plazo , Masculino , Cooperación del Paciente , SueciaRESUMEN
We describe a Swedish family with the proband and his brother suffering from severe Romano-Ward syndome (RWS) associated with compound heterozygosity for two mutations in the KVLQT1 (also known as KCNQ1 and KCNA9) gene (R518X and A525T). The mutations were found to segregate as heterozygotes in the maternal and the paternal lineage, respectively. None of the heterozygotes exhibited clinical long QT syndrome (LQTS). No hearing defects were found in the proband. The data strongly indicates that the compound heterozygosity for R518X and A525T is the cause of an autosomal recessive form of RWS in this family. Our findings support the implication of a higher frequency of gene carriers than previously expected. We suggest that relatives of 'sporadic RWS' patients should be considered potential carriers, at risk of dying suddenly from drug-induced LQTS.