ABSTRACT
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.
Subject(s)
Immune System Diseases , Immunologic Deficiency Syndromes , Child , Humans , Autoimmunity/genetics , Cohort Studies , Gain of Function Mutation , Immunologic Deficiency Syndromes/genetics , Mutation , STAT3 Transcription Factor/genetics , Cell Proliferation , LymphocytesABSTRACT
A novel low-loss, single-step-growth 1.3-microm GaInNAs saturable Bragg reflector mode-locking element has been developed. Combined radial thickness and postgrowth annealing control have permitted a tuning range of 46 nm for passive mode locking to be demonstrated from one wafer. With this structure, stabilized mode locking was obtained from quasi-cw diode-pumped Nd:YLF and Nd:YALO lasers operating at 1314 and 1342 nm, respectively, with average on-time output powers of as much as 20 W and pulse durations as low as 22 ps.
ABSTRACT
We report what we believe to be the first demonstration of a Kerr-lens mode-locked Cr(3+):LiSrAlF(6)laser that is pumped by a single narrow-stripe AlGaInP laser diode with a diffraction-limited output beam. A novel low-loss three-mirror laser cavity design is described in which strong, localized Kerr lensing was exploited such that 75-fs-duration pulses were obtained for only 36mW of incident pump power. This pump power was maintained for 18h by just three AA batteries as the electrical power source. We have shown that mode locking can be sustained for pump powers as low as 22mW.
