Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies

Erythropoiesis defect observed in STAT3 GOF patients with severe anemia.

STAT3 mediates inflammation and modulates immunity. We found that in addition to its role in autoimmunity, over-activated STAT3 interferes in early erythro-myeloid precursor development and reduces commitment towards the erythroid lineage by interfering with the erythropoietin-STAT5 signalling pathway

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor kappa B essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftmentwas documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlyingmutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.St. Giles FoundationRockefeller UniversityINSERMParis Descartes UniversityCentre de Reference des Deficits Immunitaires Hereditaires (CEREDIH)German Ministry for Education and ResearchNational Institute for Health Research and GOSH Biomedical Research CentreRobert A. Good/Jeffrey Modell FellowshipNecker Hosp Sick Children, AP HP, Study Ctr Immunodeficiencies, Paris, FranceTokyo Med & Dent Univ, Dept Pediat & Dev Biol, Tokyo, JapanNiigata Univ, Grad Sch Med & Dent Sci, Dept Pediat, Niigata, JapanAnn & Robert H Lurie Childrens Hosp Chicago, Div Pediat Dermatol, Chicago, IL 60611 USANorthwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USACincinnati Childrens Hosp, Med Ctr, Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH USAKyoto Univ, Grad Sch Med, Dept Pediat, Kyoto, JapanHirosaki Univ, Grad Sch Med, Dept Pediat, Hirosaki, Aomori, JapanUniv Hosp, Pediat Oncohematoimmunol Unit, Angers, FranceUniv Lyon 1, Sch Med, Genet Unit, Hosp Civils Lyon, Bron, FranceEmory Univ, Dept Pediat, Div Bone Marrow Transplant, Aflac Canc & Blood Disorders Ctr Childrens Hlth, Atlanta, GA 30322 USAUniv Zurich, Univ Childrens Hosp Zurich, Div Stem Cell Transplantat, Zurich, SwitzerlandUniv Hosp, Dept Biochem & Genet, Angers, FranceNatl Inst Pediat, Clin Immunol Dept, Mexico City, DF, MexicoNatl Inst Pediat, Program Hematopoiet Stem Cell Transplantat, Mexico City, DF, MexicoUCL, Great Ormond St Inst Child Hlth, London, EnglandNatl Jewish Hlth, Dept Pediat, Immunodeficiency Diag & Treatment Program, Denver, CO USAOregon Hlth & Sci Univ, Dept Pediat Dermatol, Portland, OR 97201 USAStarship Hosp, Starship Blood & Canc Ctr, Paediat Haematol, Auckland, New ZealandUniv Wales Hosp, Immunodeficiency Ctr Wales, Cardiff, S Glam, WalesUniv Freiburg, Ctr Chron Immunodeficiency, Freiburg, GermanyNewcastle Univ, Inst Cellular Med, Primary Immunodeficiency Grp, Newcastle Upon Tyne, Tyne & Wear, EnglandNewcastle Tyne Hosp NHS Fdn Trust, Great North Childrens Hosp, Paediat Immunol Dept, Newcastle Upon Tyne, Tyne & Wear, EnglandUniv Fed Sao Paulo, Inst Biomed Sci, Dept Pediat, Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, BrazilGreat Ormond St Hosp Children NHS Fdn Trust, Blood & Marrow Transplant Unit, London, EnglandNIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USANIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USAParis Descartes Univ, Imagine Inst, Paris, FranceNecker Hosp Sick Children, AP HP, Pediat Hematol Immunol & Rheumatol Unit, Paris, FranceCambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, EnglandOxford Univ Hosp NHS Fdn Trust, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford, EnglandNecker Hosp Sick Children, INSERM, UMR1163, Lab Human Genet Infect Dis,Necker Branch, Paris, FranceRockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USAHoward Hughes Med Inst, New York, NY USATexas Childrens Hosp, Baylor Coll Med, Sect Immunol Allergy & Rheumatol, Ctr Human Immunobiol, Houston, TX 77030 USAUniv Fed Sao Paulo, Inst Biomed Sci, Dept Pediat, Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, BrazilWeb of Scienc

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion:: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome