Consenso mexicano de tirosinemia tipo 1

INTRODUCTION: Tyrosinemia type 1 is a rare disease with autosomal recessive inheritance, featuring various clinical manifestations. These may encompass acute neonatal liver failure, neonatal cholestatic syndrome, chronic hepatitis, cirrhosis, hepatocellular carcinoma, and, alternatively, kidney disorders like renal tubular acidosis, Fanconi syndrome, hypophosphatemic rickets, among other alterations. Diagnosis relies on detecting toxic metabolites in the blood and urine, ideally confirmed through molecular testing. METHOD: A consensus was reached with experts in the field of inborn errors of metabolism (EIM), including eight pediatric gastroenterologists, two EIM specialists, two geneticists, three pediatric nutritionists specialized in EIM, and a pediatric surgeon specializing in transplants. Six working groups were tasked with formulating statements and justifications, and 32 statements were anonymously voted on using the Likert scale and the Delphi method. The first virtual vote achieved an 80% consensus, with the remaining 20% determined in person. RESULTS: The statements were categorized into epidemiology, clinical presentation, diagnosis, nutritional and medical treatment, and genetic counseling. CONCLUSIONS: This consensus serves as a valuable tool for primary care physicians, pediatricians, and pediatric gastroenterologists, aiding in the prompt diagnosis and treatment of this disease. Its impact on the morbidity and mortality of patients with tyrosinemia type 1 is substantial.

INTRODUCCIÓN: La tirosinemia tipo 1 es una enfermedad rara, con herencia autosómica recesiva, con múltiples manifestaciones clínicas, que pueden comprender desde falla hepática aguda neonatal, síndrome colestásico neonatal, hepatitis crónica, cirrosis o hepatocarcinoma, hasta alteraciones renales como acidosis tubular renal, síndrome de Fanconi o raquitismo hipofosfatémico, entre otras. El diagnóstico se basa en la presencia de metabolitos tóxicos en la sangre y la orina, idealmente con la confirmación molecular de la enfermedad. MÉTODO: Se realizó un consenso con expertos en el área de los errores innatos del metabolismo (EIM): ocho gastroenterólogos pediatras, dos médicos especialistas en EIM, dos genetistas, tres nutriólogas pediatras especializadas en EIM y un cirujano pediatra especialista en trasplantes. Se formaron seis mesas de trabajo encargadas de desarrollar los enunciados con sus justificaciones y fueron votados anónimamente 32 enunciados en una escala Likert con un método Delphi. La primera votación fue virtual, obteniendo consenso del 80% de los enunciados, y la segunda fue presencial, obteniendo el 20% restante. RESULTADOS: Los enunciados fueron divididos en epidemiología, cuadro clínico, diagnóstico, tratamiento nutricional y médico, y consejo genético. CONCLUSIONES: Este consenso constituye una valiosa herramienta para los médicos de atención primaria, pediatras y gastroenterólogos pediátricos, ya que ayuda a diagnosticar y tratar rápidamente esta enfermedad. Su impacto en la morbilidad y mortalidad de los pacientes con tirosinemia tipo 1 es sustancial.

Not enough by half: NFAT5 haploinsufficiency in two patients with Epstein-Barr virus susceptibility.

Introduction: The transcription factor Nuclear factor of activated T cells 5 (NFAT5), pivotal in immune regulation and function, can be induced by osmotic stress and tonicity-independent signals. Objective: We aimed to investigate and characterize two unrelated patients with Epstein-Barr virus susceptibility and no known genetic etiology. Methods: After informed consent, we reviewed the electronic charts, extracted genomic DNA, performed whole-exome sequencing, filtered, and prioritized their variants, and confirmed through Sanger sequencing, family segregation analysis, and some functional assays, including lymphoproliferation, cytotoxicity, and characterization of natural killer cells. Results: We describe two cases of pediatric Mexican patients with rare heterozygous missense variants in NFAT5 and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis. Discussion: NFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.