RESUMEN
OBJECTIVE: To evaluate the performance of a diagnostic protocol for neonatal/infantile cholestasis in which the main clinical patterns steered the early use of different genetic testing strategies. STUDY DESIGN: An observational study was conducted between 2012 and 2017 in a tertiary care setting on a prospective cohort of children with cholestasis occurring at ≤1 year of age and persisting ≥6 weeks, to measure the detection rate of underlying monogenic diseases. After the exclusion of biliary atresia, a clinically driven genetic testing was performed, entailing 3 different approaches with different wideness: confirmatory single-gene testing; focused virtual panels; and wide search through trio whole-exome sequencing. RESULTS: We enrolled 125 children (66 female, median age 2 months); 96 (77%) patients had hypocholic stools and were evaluated rapidly to exclude biliary atresia, which was the final diagnosis in 74 (59%). Overall, 50 patients underwent genetic testing, 6 with single confirmatory gene testing, 38 through panels, and 6 with trio whole-exome sequencing because of complex phenotype. The genetic testing detection rate was 60%: the final diagnosis was Alagille syndrome in 11, progressive familial intrahepatic cholestasis type 2 in 6, alpha-1-antitrypsin deficiency in 3, and progressive familial intrahepatic cholestasis type 3 in 2; a further 7 genetic conditions were identified in 1 child each. Overall, only 18 of 125 (14%) remained with an indeterminate etiology. CONCLUSIONS: This protocol combining clinical and genetic assessment proved to be an effective diagnostic tool for neonatal/infantile cholestasis, identifying inherited disorders with a high detection rate. It also could allow a noninvasive diagnosis in children presenting with colored stools.
Asunto(s)
Colestasis/diagnóstico , Colestasis/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Algoritmos , Atresia Biliar/diagnóstico , Atresia Biliar/genética , Niño , Preescolar , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/genética , Exoma , Heces , Femenino , Pruebas Genéticas , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Estudios Prospectivos , Atención Terciaria de Salud , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/genéticaRESUMEN
Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder caused by mutations in the cohesion complex and its regulators. The syndrome is characterized by multiple organ system abnormalities, pre- and post-natal growth retardation and typical facial features. Thrombocytopenia is a reduction in platelet count to <150 × 10(9) L. It can be caused by congenital or acquired decreased production, increased destruction, or sequestration of platelets. In recent years, several papers reported thrombocytopenia and immune thrombocytopenia in patients affected by CdLS. In 2011, Lambert et al. estimated the risk of idiopathic thrombocytopenia purpura in CdLS patients to be 31-633 times greater than in the general population. We describe the incidence of thrombocytopenia in 127 Italian CdLS patients, identifying patients with transient or persistent thrombocytopenia, but a lower incidence of true idiopathic thrombocytopenic purpura (ITP).
Asunto(s)
Síndrome de Cornelia de Lange/fisiopatología , Mutación/genética , Proteínas/genética , Trombocitopenia/epidemiología , Adolescente , Adulto , Proteínas de Ciclo Celular , Niño , Preescolar , Estudios de Cohortes , Síndrome de Cornelia de Lange/genética , Femenino , Humanos , Incidencia , Lactante , Italia , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Trombocitopenia/genética , Adulto JovenRESUMEN
We report on a boy with clinical and molecular diagnosis of Cornelia de Lange syndrome (CdLS). Besides the CdLS typical features, he shows split hand and split feet. To the best of our knowledge, only one other patient with similar finding has been reported in CdLS patients.