STAT3 gain-of-function mutation in an adult patient / Paciente adulto portador de una mutación con ganancia de función en el gen STAT3

Abstract Germline gain-of-function (GOF) mutation of the signal transducer and activator of transcription 3 (STAT3) gene causes a disease clinically characterized by a significant lymphoproliferation, includ ing lymphadenopathy and/or hepatosplenomegaly, as well as childhood onset autoimmunity. Here we present an adult patient who, during his early years of life, presented recurrent infections, autoimmune hemolytic anemia and benign lymphoproliferative disease, characterized by hepatosplenomegaly and lymphadenopathy, being diagnosed with common variable immunodeficiency (CVID) at 13 years of age. He was diagnosed with lymphocytic interstitial pneumonia at the age of 20. When he was 40 years old, after a diagnostic review, it was decided to perform genetic studies. A heterozygous mutation in STAT3 NM_003150 c.2141C>T, p.P714L was detected by whole exome sequencing and validated by Sanger. Previously published functional studies performed in two siblings showed that this mutation resulted in gain-of-function. They were initially diagnosed with autoimmune lymphoproliferative syndrome, and later with STAT3 GOF as a second genetic defect. Our patient developed severe pulmonary disease and died, without access to treatment targeted to his molecular defect due to the advanced nature of his pulmonary involvement and the fact that many of the therapies were still in develop ment at that time. The diagnosis of STAT3 GOF mutations should be suspected in patients with early-onset of lymphoproliferative disease, autoimmunity and hypogammaglobulinemia. This must be considered especially in the group of CVID patients with these characteristics, in order to allow the implementation of treatments target ing the molecular defect (JAK inhibitors and Il-6 receptor antagonists) that could modify the disease evolution.

Resumen Mutaciones en línea germinal con ganancia de función (GOF) del gen transductor de señales y acti vador de la transcripción 3 (STAT3) provocan una enfermedad caracterizada por importante linfoproliferación, incluyendo linfadenopatías y/o hepatoesplenomegalia, así como autoinmunidad de inicio en la infancia. Presen tamos un paciente adulto que, durante sus primeros años de vida, presentó infecciones recurrentes, anemia hemolítica autoinmune y enfermedad linfoproliferativa benigna, caracterizada inicialmente por hepatoespleno megalia y linfoadenopatías, diagnosticado de inmunodeficiencia común variable (IDCV) a los 13 años. A los 20 años, al ser estudiado por compromiso pulmonar, se diagnosticó neumonía intersticial linfocítica. A los 40 años, tras revisión diagnóstica se decidió realizar estudios genéticos. Por secuenciación del exoma completo se detectó una mutación heterocigota en STAT3 NM_003150 c.2141C>T, p.P714L, que se validó por Sanger. Estudios funcionales previamente publicados realizados en dos hermanos con diagnóstico inicial de síndrome linfoproliferativo autoinmune, mostraron que esta mutación daba lugar a una ganancia de función. Nuestro pa ciente desarrolló enfermedad pulmonar grave y falleció a los 41 años, sin posibilidad de acceder a tratamiento dirigido a su defecto molecular por lo avanzado de su compromiso pulmonar y a que muchas de las terapias se encontraban en ese momento en desarrollo. El diagnóstico de mutaciones STAT3 GOF debe sospecharse en pacientes con enfermedad linfoproliferativa temprana, autoinmunidad e hipogammaglobulinemia. Esto debe ser considerado especialmente en pacientes con IDCV con estas características, para permitir la implementación de tratamientos dirigidos al defecto molecular (inhibidores de JAK y antagonistas del receptor de Il-6) que podrían modificar la evolución de la enfermedad.

A novel mutation of the IL12RB1 gene in a child with nocardiosis, recurrent salmonellosis and neurofibromatosis type I: First case report from Thailand.

Genetic defects of interleukin (IL)-12/23-and interferon (IFN)-γ-mediated immunity can cause in-creased susceptibility to intracellular microbes. Among these defects, a mutation of the gene encoding the IL-12 receptor β1 (IL-12Rβ1) is the most common worldwide. A 12-year old Thai boy with pre-existing neurofibromatosis type 1 (NF1) was evaluated for primary immunodeficiency after a history of tuberculous lymphadenitis, recurrent Salmonella infections and nocardiosis. Flow cytometry of phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) revealed a defect in the IL-12Rβ1 surface expression. A genetic study showed a novel nonsense homozygous mutation of the IL12RB1 gene in exon 4 (402C>A), confirming the diagnosis of IL-12Rβ1 deficiency. This is the first case report of a primary IL-12Rβ1 deficiency in Thailand with the interesting finding of a coexisting NF1.