Search

Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation. By using whole-exome sequencing, we identified two novel STAT3 mutations, p.E616del and p.C426R, in two unrelated pediatric patients with IGF-I deficiency and immune dysregulation. The functional analyses showed that both variants were gain-of-function (GOF), although they were not constitutively phosphorylated. They presented differences in their dephosphorylation kinetics and transcriptional activities under interleukin-6 stimulation. Both variants increased their transcriptional activities in response to growth hormone (GH) treatment. Nonetheless, STAT5b transcriptional activity was diminished in the presence of STAT3 GOF variants, suggesting a disruptive role of STAT3 GOF variants in the GH signaling pathway. This study highlights the broad clinical spectrum of patients presenting activating STAT3 mutations and explores the underlying molecular pathway responsible for this condition, suggesting that different mutations may drive increased activity by slightly different mechanisms. Fil: Gutiérrez, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Scaglia, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Keselman, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Martucci, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Karabatas, Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Domené, Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Martin, Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Pennisi, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Blanco, Miguel. Hospital Universitario Austral, Endocrinología; Argentina Fil: Sanguineti, Nora. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Bezrodnik, Liliana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Area de Inmunología. Grupo de Inmunología; Argentina Fil: Di Giovanni, Daniela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Area de Inmunología. Grupo de Inmunología; Argentina Fil: Caldirola, María Soledad. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Area de Inmunología. Grupo de Inmunología; Argentina Fil: Esnaola Azcoiti, María. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Area de Inmunología. Grupo de Inmunología; Argentina Fil: Gaillard, María Isabel. Cincinnati Children's Hospital Medical Center, Gastroenterology, Hepatology and Nutrition ; Estados Unidos Fil: Denson, Lee A.. Cincinnati Children's Hospital Medical Center, Gastroenterology, Hepatology and Nutrition; Estados Unidos Fil: Zhang, Kejian. Cincinnati Children's Hospital Medical Center,Human Genetics ; Estados Unidos Fil: Husami, Ammar. Cincinnati Children's Hospital Medical Center,Human Genetics ; Estados Unidos Fil: Yayah Jones, Nana-Hawa. Cincinnati Children's Hospital Medical Center, Cincinnati Center for Growth Disorders, Division of Endocrinology; Estados Unidos Fil: Hwa, Vivian. Cincinnati Children's Hospital Medical Center, Cincinnati Center for Growth Disorders, Division of Endocrinology,; Estados Unidos Fil: Revale, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Agrobiotecnología de Rosario; Argentina Fil: Vázquez, Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Agrobiotecnología de Rosario; Argentina Fil: Jasper, Héctor. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Kumar, Ashish. Cincinnati Children's Hospital Medical Center,Division of BM Transplantation and Immunodeficiency ; Estados Unidos Fil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina

Purpose Several studies have shown that subcutaneous immunoglobulin (SCIG) infusions demonstrate similar efficacy to intravenous Ig (IVIG) in preventing infections in patients with primary immunodeficiency diseases (PID), and are safe and well tolerated in this population. This open, prospective/retrospective, multicenter study was designed to compare the effectiveness, safety and tolerability of a 16 % liquid human IgG preparation (Beriglobina P), administered SC, with previous IVIG treatment in PID pediatric patients in Argentina. Methods Fifteen subjects were enrolled in the study, and a total of 13 subjects (aged 6–18 years) completed the 36-week SCIG treatment period. All children had previously received IVIG treatment. The dose of SCIG equaled the previous IVIG dose and subjects received an average weekly dose of 139 mg/kg (range 105–181) during the SCIG period. Results Significantly higher serum IgG trough levels were recorded on SCIG treatment at 16, 24, and 36 weeks, when compared with previous IgG trough levels on steady-state IVIG treatment. The annualized infection rate was 1.4 infections/subject/year during the IVIG administration period compared with 0.4 infections/subject/year during the SCIG period. All subjects who completed the study chose to continue administering SCIG at home after the study had ended. Conclusions These data confirm that self-administered SCIG therapy is a well-tolerated and effective alternative to IVIG therapy for children with PID. Fil: Bezrodnik, Liliana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutierrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gómez Raccio, Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutierrez"; Argentina Fil: Belardinelli, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutierrez"; Argentina Fil: Regairaz, Lorena. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutierrez"; Argentina. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor Maria Ludovica" de la Plata; Argentina Fil: Díaz Ballve, Damacia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutierrez"; Argentina Fil: Seminario, Gisela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutierrez"; Argentina Fil: Moreira, Ileana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutierrez"; Argentina Fil: Riganti, Carlos. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Pedro Elizalde" (ex Casa Cuna); Argentina Fil: Cantisano, Claudio. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Pedro Elizalde" (ex Casa Cuna); Argentina Fil: Díaz, Héctor. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Pedro Elizalde" (ex Casa Cuna); Argentina Fil: Di Giovanni, Daniela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutierrez"; Argentina

International audience; Background : Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients.Objective : Our objective was to assess the effect of mycobacterial disease in patients with CGD.Methods : We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria.Results : Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients.Conclusion : Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

The signal transducer and activator of transcription (STAT) family of proteins regulate gene transcription in response to a variety of cytokines. STAT5B, in particular, plays an important role in T cells, where it is a key mediator of interleukin-2 (IL-2) induced responses. STAT5B deficiency causes a rare autosomal recessive disorder reported in only a handful of individuals. There are currently ten published cases of STAT5B deficiency, four of which are Argentinians. Fil: Bezrodnik, Liliana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Di Giovanni, Daniela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Caldirola, María Soledad. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Esnaola Azcoiti, María. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Torgerson, Troy. University of Washington; Estados Unidos Fil: Gaillard, María Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens orAspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas. Fil: Cabral Marques, Otavio. Universidade de Sao Paulo; Brasil Fil: Klaver, Stefanie. Universidade de Sao Paulo; Brasil Fil: Schimke, Lena F. Universidade de Sao Paulo; Brasil Fil: Ascendino, Évelyn H. Universidade de Sao Paulo; Brasil Fil: Khan, Taj Ali. Universidade de Sao Paulo; Brasil Fil: Pereira, Paulo Vítor Soeiro. Universidade de Sao Paulo; Brasil Fil: Falcai, Angela. Universidade de Sao Paulo; Brasil Fil: Vargas Hernández, Alexander. Instituto Politécnico de México; México Fil: Santos-Argumedo, Leopoldo. Instituto Politécnico de México; México Fil: Bezrodnik, Liliana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Moreira, Ileana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Seminario, Gisela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Di Giovanni, Daniela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Raccio, Andrea Gómez. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Porras, Oscar. Hospital Nacional de Niños, “Dr. Carlos Sáenz Herrera”; Costa Rica Fil: Weber, Cristina Worm. Pediatric Allergy & Immunology Clinic; Brasil Fil: Ferreira, Janaíra Fernandes. Albert Sabin Hospital; Brasil Fil: Tavares, Fabiola Scancetti. Hospital de Base do Distrito Federal; Brasil Fil: de Carvalho, Elisa. Hospital de Base do Distrito Federal; Brasil Fil: Valente, Claudia França Cavalcante. Hospital de Base do Distrito Federal; Brasil Fil: Kuntze, Gisele. Integrated Center of Pediatric Specialties; Brasil Fil: Galicchio, Miguel. Hospital de Niños ; Argentina Fil: King, Alejandra. Hospital ; Chile Fil: Rosário Filho, Nelson Augusto. Universidade Federal do Paraná; Brasil Fil: Grota, Milena Baptistella. Universidade Estadual de Campinas; Brasil Fil: dos Santos Vilela, Maria Marluce. Universidade Estadual de Campinas; Brasil Fil: Di Gesu, Regina Sumiko Watanabe. Conceição Children’s Hospital; Brasil Fil: Lima, Simone. Childrens Hospital ; Brasil Fil: de Souza Moura, Leiva. Childrens Hospital ; Brasil Fil: Talesnik, Eduardo. Pontificia Universidad Católica de Chile; Chile Fil: Mansour, Eli. Universidade Estadual de Campinas; Brasil Fil: Roxo Junior, Pérsio. Universidade de Sao Paulo; Brasil Fil: Aldave, Juan Carlos. Hospital Nacional ; Perú Fil: Goudouris, Ekaterine. Universidade Federal do Rio de Janeiro; Brasil Fil: Pinto Mariz, Fernanda. Universidade Federal do Rio de Janeiro; Brasil Fil: Berrón Ruiz, Laura. Instituto Nacional de Pediatría; México Fil: Staines Boone, Tamara. Unidad Médica de Alta Especialidad #25; México Fil: Calderón, Wilmer O. Córdova. Clínica Montefiori; Perú Fil: del Carmen Zarate Hernández, María. Universidad Autónoma de Nuevo León; México Fil: Grumach, Anete S.. Universidade Federal do ABC; Brasil Fil: Sorensen, Ricardo. Children’s Hospital of New Orleans; Estados Unidos Fil: Durandy, Anne. Inserm; Francia Fil: Torgerson, Troy R.. University of Washington; Estados Unidos Fil: Carvalho, Beatriz Tavares Costa. Universidade de Sao Paulo; Brasil Fil: Espinosa Rosales, Francisco. Instituto Nacional de Pediatría; México Fil: Ochs, Hans D.. University of Washington; Estados Unidos Fil: Condino Neto, Antonio. Universidade de Sao Paulo; Brasil

Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Pro missense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function.The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [-5.90 SD score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, -3.7 SDS, and IGF-binding protein-3, -4.5 SDS) were consistent with GHI and IGFD.Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the βD' strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-γ. The phosphorylated p.Phe646Ser, however, could not drive transcription.A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 βD' strand for full STAT5b transcriptional activities. Whether the phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.