---
title: "Case report: ADMIO type 1 linked to de novo STAT3 gain-of-function mutation"
id: "frontiers-in-immunology-16-a-case-report-of-admio-type-1-caused-by-a-de-novo-stat3-gain-of-function"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-16-a-case-report-of-admio-type-1-caused-by-a-de-novo-stat3-gain-of-function"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1824739"
published_at: "2026-08-28T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Case report: ADMIO type 1 linked to de novo STAT3 gain-of-function mutation
## Provenance & Clinical Metadata
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1824739)
- **Published At:** 2026-08-28T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source title indicates a single case report describing **ADMIO type 1** attributed to a **de novo STAT3 gain-of-function (GOF) mutation**. The publication venue is Frontiers in Immunology. - The provided SOURCE JINA body contains only site navigation and metadata; the article body, clinical details, methods, diagnostic data, genotype, treatment, outcomes, and discussion were not included. - Because the full article text and data were not present in the source, no additional clinical facts, laboratory values, imaging, genetic variant details, or management recommendations can be reported from the source. - Any interpretation, mechanism discussion, or management guidance beyond the article title would be speculation and is not provided here. - For clinicians seeking details from this case report, the original article at Frontiers in Immunology should be consulted; the SOURCE JINA export did not include the case narrative, results, or conclusions.
## Clinical Analysis & Structured Key Points
Frontiers | A case report of ADMIO type 1 caused by a de novo STAT3 gain-of-function mutation A, p.A703T). Symptoms recurred frequently during corticosteroid tapering. Due to his genetic findings, targeted therapy was required. Initial treatment with tocilizumab provided short-lived benefit. Following recurrent lymphadenitis and polyarthritis, adalimumab, tofacitinib, ruxolitinib emerged as a key anti-inflammatory intervention to treat the disease. This case enriches the rare disease database and helps raise clinicians’ awareness of and attention to ADMIO type 1 disease."> CASE REPORT article Front. Immunol. , 28 August 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1824739 Published in Frontiers in Immunology Inflammation 7 impact factor 11.3 citescore Editor & Reviewers Edited by M V Michael V Volin Reviewed by R D Rofaida Desoki P E Pervin Elvan TOKGUN Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Figure 6 View in article Figure 7 View in article Table 1 Main clinical manifestations of ADMIO type 1. View in article CASE REPORT article Front. Immunol. , 28 August 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1824739 A case report of ADMIO type 1 caused by a de novo STAT3 gain-of-function mutation L H Lan Huang † Y Y Yang Yue † Y Z Yuanhui Zhu H H Houhua Hao F G Fengjun Guan * Department of Pediatric Nephrology and Rheumatology Immunology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China Article metrics View details Abstract Infantile-onset Multisystem Autoimmune Disease type 1(ADMIO, 1) is a rare hereditary autoimmune disorder primarily caused by STAT3 gain-of-function (GOF) mutations. This article presents a case of ADMIO type 1 resulting from a de novo STAT3 GOF mutation. The subject is a male infant who presented with a recurrent rash on both lower limbs. He had a 9-month history of vasculitis, initially diagnosed as Henoch-Schönlein purpura(HSP), with recurrent purpura, ankle arthritis, livedo reticularis, and chronic diarrhea. Diagnosis was confirmed via whole-exome sequencing identifying a heterozygous STAT3 mutation (c.2107G>A, p.A703T). Symptoms recurred frequently during corticosteroid tapering. Due to his genetic findings, targeted therapy was required. Initial treatment with tocilizumab provided short-lived benefit. Following recurrent lymphadenitis and polyarthritis, adalimumab, tofacitinib, ruxolitinib emerged as a key anti-inflammatory intervention to treat the disease. This case enriches the rare disease database and helps raise clinicians’ awareness of and attention to ADMIO type 1 disease. 1 Introduction Henoch-Schönlein purpura is an allergic vasculitis that affects the small arteries and capillaries of the skin and other organs. Its main clinical manifestations include non-thrombocytopenic purpura, arthritis or arthralgia, abdominal pain, gastrointestinal bleeding, and renal involvement. It is also known as Henoch-Schönlein purpura or IgA vasculitis. ADMIO type 1(Infantile-onset Multisystem Autoimmune Disease, 1), also known as STAT3 -related early-onset multisystem autoimmune disease and STAT3 GOF sydrome, is a rare autosomal dominant disorder primarily caused by GOF mutations in the STAT3 gene. Its prevalence is less than 1 in 1,000,000. ADMIO type 1 typically presents in infancy or early childhood with various autoimmune manifestations and immune dysregulation ( 1 – 9 ). Most affected children exhibit lymphadenopathy, autoimmune cytopenia, multi-organ autoimmunity affecting the lungs, gastrointestinal tract, liver, or endocrine system, recurrent infections, and short stature ( Table 1 ). Laboratory and imaging evaluations reveal thyroid dysfunction, leukopenia, erythrocytopenia, thrombocytopenia, positive Coombs tests, positive autoantibodies, positive infection markers, aberrant T-cell subset differentiation(e.g., increased double-negative T cells), reduced IgE levels, and positive findings on lung, lymph node, or joint ultrasonography. The characteristics of ADMIO type 1 include lymphoproliferation and early-onset solid organ autoimmune diseases. Elevated serum inflammatory cytokine levels, autoimmune antibody abnormalities, and whole-exome sequencing variations are common. Symptoms may appear sequentially, with the respiratory system, endocrine system, and immune system being the most commonly involved systems at onset, while involvement of the circulatory system is rare. Asymptomatic genetic mutations are also possible, and there is a wide range of phenotypic variability. Table 1 System Clinical Manifestations Symptoms of the patient Growth and Development Short stature, growth retardation + Head and neck Dental abnormalities - Respiratory System Interstitial pneumonia + Digestive System Autoimmune enteritis, celiac disease, autoimmune hepatitis, celiac disease + Skeletal System Arthritis + Skin, Nails and Hair Eczema, dermatitis + Endocrine System Type 1 diabetes mellitus, hypothyroidism (in some patients), delayed puberty - Hematological System Autoimmune cytopenia, autoimmune hemolytic, autoimmune thrombocytopenia, lymphadenopathy, hepatosplenomegaly, leukemia, lymphoma + Immunological System Positive serum autoantibodies, recurrent infections, altered T-cell regulation, hypoglobulinemia, increased number of double-negative T cells (CD4 - , CD8 - ), arthritis, ocular inflammation + Urinary System Chronic renal impairment, kidney stones, renal tubular dysplasia - Others Onset in early childhood, variable presentation, mostly caused by de novo mutations + Main clinical manifestations of ADMIO type 1. STAT3 GoF disease is inherited in an autosomal dominant manner. Previous reports of STAT3 GoF mutations confirms the variable expressivity of this rare condition with variable phenotypic severity and variable age of onset of the various manifestations, challenging the notion of a unique phenotypic pattern for this disease. Milner JD ( 10 ) documented three patients ( 11 ) with the c.2107G>A, p.Ala703Thr mutation, who came from one family, demonstrating autosomal dominant familial inheritance. Nevertheless, the constellation of phenotypes observed in this case is distinctive ( 12 – 21 ). Regarding other mutations associated with this disease, Leiding JW ( 22 ) and colleagues have identified 191 cases to date, in which the severity of symptoms correlates with the structural domain of STAT3 affected by the mutation, such as c.2144C>A, p.P715Q (presenting with leukocytosis). Herein, we report a patient with a heterozygous missense STAT3 mutation associated with Henoch-Schönlein purpura and slowly progressive polyarthritis. 2 Case presentation We report a case of an 18-month-old boy(6years old now) with a history of dermatitis and vasculitis, presenting with recurrent purpura of the lower extremities, chronic diarrhea, recurrent upper respiratory tract infections, and growth retardation. The physical examination reveals scattered purpura and ecchymosis on both lower extremities, exhibiting a color gradient from light red to dark red, whose lesions are roundish in shape. Additionally, livedo reticularis and pitting edema are present on the dorsum of both feet and ankle joints. No family history of similar conditions was noted. After excluding infectious etiologies (CMV, EBV, HIV, MP, RSV, AdV, FluA-B, PIV1-3), he was initially diagnosed with HSP and diarrheal disease. Based on the early-onset Henoch-Schönlein purpura accompanied by recurrent livedo reticularis, we first performed whole-exome sequencing(When he was 1 year old). The results allowed us to exclude autoimmune diseases caused by other genes, such as STAT1 GOF, CTLA4/LRBA deficiency, and APLS, and in vitro cellular assays(Homology Modeling of STAT3 protein structure prediction and Luciferase reporter assay) ruled out loss-of-function (LOF) mutations in the STAT3 gene. In addition to the purpura and swelling in the ankle joints, joint ultrasound, MRI, and arthrocentesis revealed progressive inflammatory changes in the knee joints, with subsequent involvement of the hip joints. Bilateral knee joint effusion, arthritis, and synovial thickening were particularly prominent. Arthrocentesis of the knee joint cavity showed sterile inflammation. Routine analysis, biochemical tests, and routine bacterial cultures of the joint fluid revealed no significant abnormalities. Infectious causes such as febrile arthritis, joint trauma, and acute osteomyelitis were excluded. His parents were both wild-type, indicating a de novo mutation in the patient. Notably, joint symptoms appeared approximately two years after the genetic diagnosis, with recurrent relapses during glucocorticoid tapering and withdrawal. Joint examination revealed limited range of motion, restricted ambulation with antalgic gait, and a weakly positive ballottement test. The patient exhibited increased cytokine levels(IL-1B, IL-5, IL-8, IL-12, INF-γ, TNF-α), which arrived up to 10 times of normal level. Joint ultrasound showed joint effusion and synovial thickening, with fluid accumulation in the suprapatellar bursa. Joint MRI revealed synovial thickening, consistent with arthritis. At 4 years and 7 months of age, arthrocentesis was performed, and the findings were consistent with sterile arthritis. Specifically, the patient developed arthritis without apparent triggers, involving two or more joints. Rheumatoid arthritis and juvenile idiopathic arthritis were excluded. Given the severity of arthritis leading to activity limitation and significantly elevated cytokine levels and ultrasound results revealed inguinal and cervical lymphadenopathy in the patient as well as chest CT suggested interstitial pneumonia, autoimmune disease was considered the underlying cause ( 23 , 24 ). Between the ages of 3 years and 4 years and 3 months, the child experienced approximately 5 relapses of purpura, complicated by bacterial upper respiratory tract infection and vasculitis. 5 months later, he began to develop knee joint effusion, accompanied by arthritis of the ankle and hip joints. During the periods of glucocorticoid use, dose tapering, maintenance, or withdrawal, his polyarthritis recurred repeatedly and severely affected his ability to walk. Therefore, he received his first dose of tocilizumab 160 mg intravenously. At 4 years and 8 months, he was diagnosed with ADMIO type 1. Oral tofacitinib was initiated at a dose of 5 mg/2.5 mg twice daily. After 3 months of symptom relief, he experienced a refractory recurrence of arthritis at the age of 5 years, so the treatment was switched to adalimumab 20 mg subcutaneously/2w. After a period of symptom relief, the symptoms rebounded. Targeted therapy was switched for the third time to ruxolitinib at the age of 5 years and 5 months. He has received regular ruxolitinib treatment for 11 months ( Figure 1 ). Figure 1 Overview of clinical history and management. Whole-exome sequencing (WES) ( Figure 2 ) identified a heterozygous STAT3 missense variant of the patient’s, a gene associated with autoinflammatory disorders. According to the ACMG/AMP guidelines, this ariant was classified as likely pathogenic. According to 2015 guidelines criteria, it shows:Genomic location: Chr17: 40469237G>A (GRCh37) {or g.40469237G>A(17q21.2)};cDNA (NM_139276.2: exon22): c.2107G>A;Protein Change: p.Ala703Thr (p.A703T);DbSNP(rsID):869312894;Mutation type: heterozygous missense mutation. The classification as likely pathogenicity is supported by the following items:reported cases of the same amino acid alteration (PS1); de novo occurrence (PS2) ;location in functional domains(PM1);the allele frequency in population databases (gnomAD v4.1.1) is extremely low(PM2);multiple in silico prediction tools predict a deleterious effect(PP3); ClinVar databases indicate pathogenic(PP5). But in Clinvar and Franklin databases, this variant is classified as pathogenic. According to the latest 2024 IUIS (International Union of Immunological Societies) classification of IEIs (Inborn Errors of Immunity), STAT3 GOF is categorized as a disease of immune dysregulation ( 25 ). Figure 2 Heterozygous mutation of STAT3 gene on chromosome 17(arrow). 3 Conclusion 3.1 Computer simulation prediction The impact of the Ala703Thr mutation on STAT3 was investigated by constructing a 3D model of STAT3 using Discovery Studio, based on STAT3 structures available in the Protein Data Bank (PDB codes: 6QHD, 4E68, 6NJS, 6UNQ). All experimental structures were determined by X-ray crystallography with good quality and resolutions ranging from 2.25 Å to 3.15 Å. This model allowed comparison between the wild-type and mutant proteins, with a focus on the region surrounding residue Ala703. In native STAT3 , Ala703 is located near Tyr705 and forms three hydrogen bonds with the main chain of Lys707, similar to Ala705. Like almost all alanine residues in STAT3 , the essential side chain of Ala703 plays a key role in establishing tighter interactions within specific protein subregions to ensure proper protein folding, according to the model. The lack of the essential alanine group on the main and side chains of phosphorylated tyrosine 705 negatively affects the extensive hydrogen bond network around residue 703. The substitution of alanine at position 703 with threonine fails to participate in all the hydrogen bonding interactions facilitated by alanine. Since tyrosine 705 is the primary site for dimerization following STAT3 tyrosine protein phosphorylation, upon phosphorylation of Tyr705, its main and side chains form hydrogen bonds with amino acids such as Arg609 in the SH2 domain of another STAT3 monomer to mediate dimerization. The missense mutation from alanine to threonine at residue 703 leads to a loose conformation in the main chain hydrogen bond region among Ala703, Tyr705, and Lys707, indirectly affecting the phosphorylation of Y705 and the stability of the SH2 binding pocket. This may be associated with STAT3 dysfunction, such as the development of autoimmune diseases. Therefore, according to the 3D model, the mutation adversely affects protein folding and also negatively impacts subsequent STAT3 dimerization, indicating structural support for a GOF mechanism ( Figure 3 ). Whether it results in enhanced activity of STAT3 monomers, delayed or impaired STAT3 dephosphorylation, increased stability of aberrantly formed STAT3 dimers, or enhanced affinity for DNA targets are downstream mechanisms that urgently require further investigation ( 21 , 26 – 32 ). Figure 3 Three-dimensional model of STAT3 (A) Residue Ala703 is highlighted with a red circle. (B) Close-up view of the Ala703 subregion in STAT3 (ribbon diagram). Phosphorylated tyrosine residue is represented as Ptr705, Lys707 residue is shown in grayish-blue, and hydrogen bonds are depicted as green dashed lines. 3.2 Comprehensive immunological examination and assessment The patient’s later-onset joint symptoms were not isolated but were closely related to his initial symptoms. He developed the disease during infancy. Although multiple early symptoms did not appear simultaneously with the STAT3 GOF gene mutation, they progressively affected the patient’s knee and ankle joints ( Figure 4 ), lungs, as well as the cervical and inguinal lymph nodes over the course of the disease. Therefore, we should evaluate his symptoms comprehensively and in relation to one another, rather than separately. Thus, ADMIO type 1 disease resulting from the STAT3 GOF mutation is considered ( 33 – 35 ). Figure 4 Sep.15.2024 Osag fs T1WI left: Effusion in left knee joint and suprapatellar bursa, accompanied by synovial thickening and synovitis (4). Sep.2 Synovial thickening of the left knee joint, increased blood flow (Grade I), and fluid depth of approximately 0.5cm in the suprapatellar bursa (5,6) May 28.2025 No evidence of effusion in the left hip joint; fluid depth of approximately 0.2cm in the right hip joint (7,8) July 17.2025 No evidence of effusion in the left hip joint;fluid depth of approximately 0.3cm in the right hip joint (9,10). The evidence supporting the pathogenicity of our variant comes from the whole-exome sequencing report and the sequential appearance of typical phenotypes, which certainly also contributed to the delayed diagnosis in our case. Since the patient’s clinical manifestations are consistent with ADMIO type 1, according to the literature, a de novo mutation may also represent an autosomal dominant inheritance pattern. Furthermore, although whole-exome sequencing did not identify a gain-of-function (GOF) mutation pattern, we cannot definitively exclude the presence of intronic variants, as the entire gene was not sequenced. Western blot analysis revealed enhanced protein expression following the mutation at this site in the patient, which is opposite to the typical loss-of-function (LOF) mutation pattern characteristic of STAT3 LOF mutations. For this variant, western blot assay suggested that mutant protein exhibits elevated expression levels. Enzyme activity experiment demonstrated that the enzymatic activity of the mutant was significantly higher than that of the wild-type, resulting in sustained downstream phosphorylation and continuous activation, thus confirming a gain of function. Additionally, reduced protein degradation, prolonged half-life, and increased expression levels of the mutant protein further support a gain-of-function effect. Regarding signaling pathway activity, experiments demonstrated hyperactivation of downstream pathways (p-JAK2, p-STAT3, p-ERK, p-AKT), indicating sustained pathway activation, which is a typical manifestation of GOF. CCK8—cellular functional assays confirmed that the mutant cells exhibited increased proliferation, decreased apoptosis, enhanced migration, and abnormal differentiation, characterized by overgrowth and overactivation, which consistents with the gain-of-function phenotype. In the patient, in silico studies indicated that A703T mutation is located within a critical functional domain (the SH2 domain), and substitution of alanine at position 703 with threonine prevents normal STAT3 tyrosine site dimerization, thereby activating downstream signaling and impairing proper termination, leading to aberrant downstream activation through disruption of the spatial structure. Dual-luciferase reporter assay results revealed that the mutant GAS-MUT exhibited higher luciferase activity than GAS-WT, indicating that the GAS-MUT construct unexpectedly conferred a significantly enhanced transcriptional activation capacity. This suggests that the GAS-MUT functions as a GOF mutant in the context of STAT3-mediated transcriptional regulation ( Figure 5 ). Finally, regarding the inheritance pattern, autosomal dominant inheritance is the most typical mode of transmission for GOF mutations, where heterozygosity alone is sufficient to cause disease. Figure 5 Vitro functional analysis of STAT3 mutants. (A) Protein expression of the JAK-STAT3 pathway. (B) Relative luciferase activity of GAS-WT and GAS-MUT following transfection with wild-type or mutant STAT3 plasmids. In ADMIO type 1, joint MRI typically shows sterile arthritis and synovial thickening. Similar arthritis-associated autoimmune diseases caused by analogous gene mutations have been observed in other autosomal dominant disorders (ADMIO2 caused by ZAP70 gene mutation), consistent with our findings ( 36 ). Although the symptoms lack specificity, involvement of the immune system and the osteoarticular system is also a common manifestation of ADMIO type 1. In addition, rare cases of interstitial lung disease, diabetes mellitus ( 37 ), and lymphoma associated with ADMIO type 1 have been reported. With the increasing use of NGS technologies, detection of STAT3 heterozygous mutations may occur even in asymptomatic patients with ADMIO type 1. In cases with a mild phenotype, afte
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