A De Novo STAT6 p.D419G Variant Causing Severe Multi-Organ Allergic Disease: Case Report on a Transformative Response with Dupilumab

A De Novo STAT6 p.D419G Variant Causing Severe Multi-Organ Allergic Disease: Case Report on a Transformative Response with Dupilumab | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A De Novo STAT6 p.D419G Variant Causing Severe Multi-Organ Allergic Disease: Case Report on a Transformative Response with Dupilumab Laila Sheather, Hanan Ahmed This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8129352/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 15 You are reading this latest preprint version Abstract Background: Signal transducer and activator of transcription 6 (STAT6) gain-of-function (GOF) variants cause severe, early-onset multi-organ allergic disease through IL-4/IL-13-mediated type 2 immunity. We report a patient with a de novo STAT6 p.D419G variant and her remarkable response to targeted therapy. Case Presentation: A 39-year-old woman of Middle Eastern origin presented with lifelong severe atopic disease beginning before age 2, including treatment-refractory atopic dermatitis, severe asthma requiring intubation, IgE-mediated food allergies, eosinophilic gastrointestinal disease, and recurrent infections. She demonstrated persistently elevated serum IgE (peak >17,000 kU/L, consistently >5,000 kU/L) and eosinophilia (peak 1.5 × 10⁹/L). Whole exome sequencing identified a de novo heterozygous STAT6 variant (NM_001178079.2) c.1256A>G (p.D419G). Notably, brain MRI revealed vascular malformations in the circle of Willis, including hypoplastic vertebrobasilar arteries and persistent trigeminal artery. She required daily prednisone (average 20 mg) for years, resulting in cataracts and low bone mineral density. At age 34, dupilumab (300 mg subcutaneously every 2 weeks) was initiated, targeting the dysregulated IL-4/IL-13 pathway. Over five years of treatment, she achieved complete corticosteroid cessation, with her Eczema Area and Severity Index declining from 65 (very severe) to 2.2 (mild), normalization of spirometry, and improvement in biomarkers (IgE decreased to 3,263 kU/L, eosinophils to 0.2 × 10⁹/L). Her quality of life improved dramatically, enabling the pursuit of personal, academic, and professional goals. Conclusion: This case demonstrates the severe phenotype of STAT6-GOF and highlights the transformative potential of precision medicine using IL-4Rα-blocking therapy. Early recognition of STAT6-GOF clinical "red flags" and genetic testing enables targeted treatment, avoiding prolonged corticosteroid exposure and its complications. The presence of cerebrovascular malformations warrants further investigation into potential associations with STAT6-GOF. Figures Figure 1 Figure 2 Figure 3 Background Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that plays a key role in interleukin-4 (IL-4) and interleukin-13 (IL-13) signalling, leading to T helper 2 (T H 2) differentiation, immunoglobulin E (IgE) class switching, B cell survival and proliferation, and eosinophil activation. 1 – 5 This transcription factor is a key driver of the allergic immune response, 1 and recent research has identified STAT6 gain-of-function disease, manifesting as severe and early-onset multi-organ allergic disease. 6 – 11 For many years, patients with lifelong severe allergic disease and multi-organ involvement were managed without a unifying diagnosis, making it difficult for clinicians to find appropriate treatment and consult other clinicians managing similar patients. Recent advancements in genetic testing, molecular diagnosis, and biologic therapies have enabled the precise identification of immune dysregulation and the targeted treatment of associated conditions. 12 – 16 These advancements show remarkable headway in precision medicine, transforming the quality of life and treatment outcomes for our patient. Our patient was first identified as part of the aggregate described by Sharma et al. 2023, 5 which recognized 16 patients from 10 families across the world with STAT6-GOF mutations causing severe early-onset allergic response disruption and widespread systemic symptoms (Fig. 1 ). We present the case of a 39-year-old female with a de novo STAT6 (NM_001178079.2) c.1256A > G (p.D419G) variant, highlighting her clinical course and response to dupilumab, an IL-4Rα antagonist blocking IL-4/IL-13 signalling. This treatment course enabled her to cease corticosteroids completely and transformed her quality of life, restoring her daily functioning and facilitating progression towards her personal, educational, and professional goals. Case presentation Our patient is a 39-year-old female of Middle Eastern origin with lifelong early-onset severe allergic disease and a confirmed de novo STAT6 c.1256A > G (p.D419G) variant, as identified by whole-exome sequencing (WES) performed on the patient, her mother, and one maternal uncle. She was born to non-consanguineous parents and has three healthy younger brothers. Family history is significant for food sensitivities, with her brother experiencing hives and mild allergies. Her father passed away from non-small cell lung cancer at age 55. She experienced delayed puberty and is of short stature, measuring at the 3rd percentile for height and the 15th percentile for weight, using the World Health Organization (WHO) adapted growth charts for Canada. Before the age of 2, she developed severe refractory atopic dermatitis, pneumothorax requiring chest tube insertion, IgE-mediated food allergies to peanuts, tree nuts, milk, and eggs, and asthma with an attack at age 2 requiring intubation. She was followed at Sick Kids Hospital in Toronto until she was 11 years old, with no unifying diagnosis. Further symptoms included lichenification of most of her skin with frequent flares, multiple bacterial skin infections, including Staphylococcus aureus abscesses and Candida, three separate episodes of varicella zoster virus causing chickenpox, hypermobility, and infrequent but chronic spontaneous urticaria and angioedema without a clear trigger. However, her episodes of chronic spontaneous urticaria and angioedema resolved spontaneously a few years after the onset of the first episode. Throughout her twenties and thirties, she experienced persistent asthma, recurrent bronchitis, rhinoconjunctivitis, perennial allergic rhinitis, eczema, and multiple dental abscesses. In her twenties, she experienced gastrointestinal symptoms later diagnosed as eosinophilic esophagitis and eosinophilic gastroenteritis, but this later resolved in 2024 as evidenced by repeat gastroscopy and colonoscopy. She has had numerous ocular manifestations, including recurrent giant papillary conjunctivitis since age 4, right retinal detachment at age 16, and left eye Christmas tree anterior and posterior cortical cataract requiring surgery. In past years, serial bloodwork confirmed eosinophilia, with a peak of 1.5 × 10⁹/L in 2019 when she first presented to this clinic, and elevated serum IgE, peaking at 16,000–17,000 kU/L at six months of age and consistently > 5000 kU/L throughout her thirties (Table 1 ). At age 35, a brain MRI was conducted in consideration of another STAT6 patient who, unfortunately, passed away from a brain aneurysm. This MRI found anomalous vasculature in the circle of Willis with hypoplastic vertebrobasilar arteries, a persistent left-sided congenital trigeminal artery and a hypoplastic A1 segment of the right anterior cerebral artery, and no aneurysm. The consulted neurosurgeon is monitoring those vascular abnormalities, as there is a risk of progression to aneurysmal malformations. Whole exome sequencing (WES) was performed on the patient, her mother, and one maternal uncle, which identified a de novo heterozygous variant for STAT6 (NM_001178079.2) at c.1256A > G, p.D419G. Our patient trialled multiple therapies, with the best response from oral corticosteroids. For much of her adult life, our patient has been dependent on prednisone with varying doses that averaged 20mg per day. Prolonged use of systemic corticosteroids is known to be associated with cataracts, 17 and low bone mineral density. 18 Our patient experienced both complications, consistent with her years of daily prednisone use. The patient was initiated on dupilumab (300 mg subcutaneously every 2 weeks), an anti-IL-4R alpha subunit monoclonal antibody that targets the IL-4/IL-13 pathway dysregulated by STAT6-GOF, at the age of 34. She experienced substantial clinical improvement and was weaned off prednisone completely. Over the past five years of treatment, her dupilumab dose has remained stable without the need for adjustment. The therapeutic response to dupilumab was remarkable. At the age of 39, her serum IgE levels reached a low of 3263 kU/L, marking the first time they had fallen below 5000 kU/L, while her eosinophil count was 0.2 × 10⁹/L. Her Eczema Area and Severity Index (EASI) score fell dramatically from a peak of 65 (very severe) to 2.2 (mild). Additionally, in-office spirometry showed normal spirometry with resolution of airflow obstruction. Her gastrointestinal symptoms also resolved, and gastroscopy confirmed remission of eosinophilic esophagitis and eosinophilic gastrointestinal disease. Our patient’s uncontrolled disease had a profound impact on her quality of life, sleep, concentration, and social involvement. However, after targeted treatment, her sleep quality and allergic symptoms improved, restoring her daily functioning and allowing her to reengage in her academic and personal goals. Table 1 Key Laboratory Trends from 2013 to 2025. Our patient presented to the clinic in 2019, with only previous lab work available in 2013 and 2014. Out of an abundance of caution during the COVID-19 pandemic, no relevant blood work was drawn in 2020. Parameter 2013 2014 2019 2021 2022 2023 2024 2025 Eosinophils (×10⁹/L) 1.80 → 1.46 2.35 → 1.76 1.50 0.60 − 0.80 1.70→1.30 0.80 → 0.40 0.30 1.10 → 0.20 IgE (kU/L) – – > 6000 > 5000 > 5000 > 5000 4834 3263 IgA (g/L) 1.46 – 1.49 2.13 2.05 1.35 → 1.40 – 1.31 → 1.26 IgG (g/L) – – 9.31 11.15 12.67 10.95 → 10.42 – 10.01 → 10.44 IgM – – 1.85 2.09 2.03 1.61 → 1.84 – 1.85 → 1.93 Hemoglobin 120 117 135 141 150 142 – 152 Neutrophils 4.15 4.15 6.5 4.9 4.7 2.9 → 3.1 – 2.6 Eosinophils 0.39 (on oral prednisone) 1.76 1.5 0.8 1.7 0.8 → 0.4 – 0.2 Basophils 0.12 0.04 0.1 0.1 0.1 0.1 → 0.0 – 0.1 Monocytes 0.39 0.56 1.0 0.8 0.5 0.4 – 0.4 Lymphocytes 2.08 2.75 7.1 3.3 2.7 2.9 → 2.4 – 2.2 B cell – – 7% 18% – – – – B cell kappa – – 56% 52% – – – – B cell lambda – – 44% 48% – – – – B cell kappa:lambda ratio – – 1.27 1.08 – – – – Total T cells – – 40% 70% – – – – CD4 – – 76% 49% – – – – CD8 – – 23% 18% – – – – CD4/CD8 – – 3.3 2.72 – – – – NK – – 1% 11% – – – – 25-hydroxy Vitamin D (nmol/L) 61 – 66 54 63.7 – 65.6 165.2 The variant c.1256A > G; p.D419G is a rare, de novo missense change in the STAT6 DNA-binding domain located on chromosome 12, genomic position 57496661, cDNA position 1256. In silico pathogenicity prediction models support this variant as pathogenic. Discussion STAT6 biology and disease mechanism STAT6 is a transcription factor downstream of IL-4 and IL-13. Type I (IL-4Rα/γc) or type II (IL-4Rα/IL-13Rα1) receptor engagement activates Janus family protein kinases (JAKs), leading to IL-4Rα phosphorylation, STAT6 phosphorylation, dimerization, and translocation to the nucleus (Fig. 2 ). 3 Activated STAT6 triggers a type-2 immune response, promoting T H 2 differentiation, IgE class switching, B cell survival and proliferation, and eosinophil activation. 1 – 5 Germline STAT6-GOF variants, including the p.D419G variant, have been implicated in this pathway (Fig. 2 ). 6 Through continuous phosphorylation secondary to delayed dephosphorylation, heightened STAT6 target gene transcription, and a T H 2-biased polarization, these changes manifest as early-onset multi-organ allergic disease, including markedly elevated IgE levels and eosinophilia (Fig. 2 ). 6 – 11 Through WES, our patient was found to have a de novo STAT6 mutation (NM_001178079.2) at c.1256A > G, p.D419G. Notably, an identical de novo variant has also been described in a different kindred hailing from East Asia, with other STAT6 amino acid variants having been found in patients of diverse ethnicities, including European, Middle Eastern, Hispanic, South Asian, East Asian, and Southeast Asian. 6 Since Sharma et al. (2023) 6 first defined STAT6-GOF variants in 16 patients with primary atopic disorder, an increasing number of cases have been recognized, broadening the understanding of the disease’s heterogeneity. Sharma et al. proposed the following clinical “red flags” for STAT6-GOF: (i) early life onset; (ii) peripheral blood eosinophilia; (iii) elevated serum IgE; (iii) widespread, treatment-resistant atopic dermatitis; (iv) multiple food and drug allergies; (v) severe (and even fatal) anaphylaxis; (vi) recurrent skin and respiratory infections; (vii) eosinophilic gastrointestinal disorder, including eosinophilic esophagitis; (viii) asthma; (ix) allergic rhinoconjunctivitis; (x) short stature; and possibly (xi) vascular malformations of the brain (Fig. 1 ). 6 Remarkably, our patient meets all of these criteria and, notably, presents with vascular malformations in the circle of Willis. Cranial MRI revealed hypoplastic vertebrobasilar arteries, a persistent left-sided congenital trigeminal artery and a hypoplastic A1 segment of the right anterior cerebral artery. Previous studies have suggested that STAT6 signalling may be linked to the activation of vascular smooth muscle cells, 20 as well as the promotion of angiogenesis. 21 Given that vascular smooth muscle cell activation and angiogenesis have been implicated in the pathogenesis of cerebral vascular malformations, 22–23 it is plausible that STAT6 variants may contribute to these malformations; however, direct evidence is currently lacking. Furthermore, studies have reported intracranial aneurysms in patients with STAT1 gain-of-function (GOF) and STAT3 loss-of-function (LOF) mutations; 24–28 However, the specific role of STAT proteins in aneurysm pathogenesis remains unclear. 28 Vascular abnormalities are not a primary manifestation and have not been consistently identified in the aggregate of STAT6-GOF patients. However, the presentation of two patients with vascular malformations, including the incidence of a fatal brain aneurysm, justifies further investigation into the relationship between STAT6 upregulation and vascular abnormalities. Further questions are raised regarding the extent of STAT6 end-organ manifestations, including vascular malformations. One consideration is whether neurovascular imaging should be incorporated into the initial workup of STAT6-GOF patients. Although the prevalence of vascular anomalies in STAT6-GOF patients remains unclear, early detection and surveillance may improve long-term outcomes, prolong life, and inform the vascular impacts of STAT6-GOF. There is also emerging evidence of increased lymphoma risk in some STAT6-GOF kindreds 7 , 11 . The Catalogue of Somatic Mutations in Cancer (COSMIC) database documented p.D419 variants as somatic mutations in lymphoma, with experimental evidence supporting a gain-of-function phenotype. 6 , 30 , 31 However, more evidence is needed as the underlying mechanism remains unclear. Our patient required high doses of prednisone for many years before initiation of treatment with dupilumab, an IL-4Rα-blocking monoclonal antibody used for treatment of allergic diseases, including atopic dermatitis, asthma, chronic rhinosinusitis and eosinophilic esophagitis. 32 Dupilumab inhibits IL-4/IL-13 dependent activation of receptor-associated JAKs and prevents downstream phosphorylation of particular tyrosine residues that activate STAT6 by binding the IL-4Rα subunit (Fig. 3 ). 32 Over five years of treatment, she demonstrated a marked clinical improvement, with EASI score declining to mild levels, spirometry normalized with resolution of airflow obstruction, and a remarkable improvement in biomarkers, including IgE serum levels and eosinophil counts. She was successfully weaned off prednisone and daily antihistamines, eliminating systemic corticosteroid exposure. She experienced life-changing benefits on dupilumab, being able to pursue academic, personal, and professional goals, as well as a marked subjective improvement in concentration, sleep, and functioning. Janus kinase (JAK) inhibitors have also shown promising results as an alternative or adjunctive treatment, particularly in refractory cases. 32 – 33 The therapeutic rationale for JAK inhibitors or IL-4/IL-13 inhibitors is direct: STAT6 phosphorylation is decreased and the TH2-driven inflammatory response is minimized by either directly inhibiting JAKs or by blocking IL-4/IL-13 upstream (Fig. 3 ). In our patient, precision medicine using IL-4Rα-blocking biologics provided sustained clinical improvement, consistent with previously reported outcomes of dupilumab in STAT6-GOF patients . 9, 32–33 Although genetic testing is becoming increasingly accessible, many clinical immunologists still lack access to sequencing or research laboratories to support advanced diagnostic workup for suspected STAT6-GOF variants. 33 By highlighting specific clinical presentations of STAT6-GOF, we hope to increase awareness among clinicians, enabling earlier recognition of these “red flags” and timely initiation of diagnostic evaluation and treatment. Conclusion This case illustrates the core phenotype of STAT6-GOF mutations, presenting as severe, early-onset, multisystem atopic disease with persistently elevated IgE and eosinophilia. Whole exome sequencing of a de novo STAT6 c.1256A > G (p.D419G) variant provided a unifying diagnosis and direction for therapeutic relief. The successful use of dupilumab targeting the IL-4/IL-13–STAT6 axis enabled cessation of systemic corticosteroids and a profound reduction is skin disease activity, and improvement in pulmonary function and immunologic biomarkers. In the future, we expect that new STAT6 variants will be identified through the recent recognition of STAT6-GOF as a PAD. While vascular malformations are not yet a defining symptom of STAT6-GOF, this patient’s cerebrovascular malformations together with a fatal aneurysm reported in a previous STAT6-GOF warrant caution and investigation into This case highlights the value of precision medicine in allergic disorders, using exome sequencing to clarify treatment and targeted therapy. For clinicians, unexplained severe early-onset allergic symptoms warrant early genetic testing. In our patient, dupilumab alleviated the severity of allergic symptoms and reduced systemic corticosteroid exposure, thereby improving her quality of life. These findings align with emerging evidence supporting the efficacy of dupilumab and JAK inhibitors in STAT6-GOF. Increased awareness of STAT6-GOF will not only facilitate earlier diagnosis and targeted treatment but may also clarify the disease’s full clinical spectrum. Declarations Author Contributions: L.S.: Investigation (chart review), data curation, visualization (Table 1; Figures 1–3), writing manuscript and reviewing edits. H.A.: Conceptualization, supervision, writing manuscript and reviewing edits. All authors reviewed and approved the final manuscript. Consent for publication: Written informed consent to publish this case report and any accompanying images was obtained from the patient. A copy of the signed consent form is held by the corresponding author and is available for review by the Editor upon request. Funding Declaration: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Ethics and Consent to Participate: This case report complies with the Declaration of Helsinki and relevant institutional policies. In accordance with McMaster Research Ethics Board (REB) guidance and the Tri-Council Policy Statement (TCPS 2), single-patient, de-identified case reports do not constitute human subjects research requiring REB review; therefore, formal ethics approval was not sought. Written informed consent for participation and publication was obtained from the patient. The authors hold a copy of this approval and it is available to the Editor upon request. Data availability: All relevant data are included in this article. Additional de-identified information may be available from the corresponding author on reasonable request, subject to institutional policies and patient privacy. Acknowledgements: We thank the patient for generously sharing her history and permitting publication of this report. 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Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 10 Feb, 2026 Reviews received at journal 10 Feb, 2026 Reviews received at journal 06 Feb, 2026 Reviews received at journal 21 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviews received at journal 19 Jan, 2026 Reviewers agreed at journal 19 Jan, 2026 Reviewers agreed at journal 13 Jan, 2026 Reviewers invited by journal 13 Jan, 2026 Editor assigned by journal 21 Nov, 2025 Submission checks completed at journal 21 Nov, 2025 First submitted to journal 16 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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15:03:26","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":83960,"visible":true,"origin":"","legend":"","description":"","filename":"bb819a4f81854d1da5de304724d3eb4e1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8129352/v1/e467f48ef1d0f8ef2af22af2.xml"},{"id":100546984,"identity":"121809bb-e6c2-49ab-99bc-72a72fab0b14","added_by":"auto","created_at":"2026-01-19 08:13:49","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":93532,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8129352/v1/bd05c9e18835083f1ecac8e3.html"},{"id":100432297,"identity":"3701e5aa-04de-46e0-8702-4cd131f6c361","added_by":"auto","created_at":"2026-01-16 15:03:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":671735,"visible":true,"origin":"","legend":"\u003cp\u003eReported “red flag” clinical manifestations of gain-of-function STAT6 variants. Symptoms suggested as “red flags” for STAT6-GOF include early-life onset, short stature, severe atopic disease, elevated serum IgE, recurrent skin and lung infections, peripheral blood eosinophilia, eosinophilic gastrointestinal disorders, and possible brain malformations.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8129352/v1/2e2242742b06db48070660ef.png"},{"id":100546296,"identity":"e07dd782-50f4-40b9-b7ec-0e94dd320d38","added_by":"auto","created_at":"2026-01-19 08:05:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":228496,"visible":true,"origin":"","legend":"\u003cp\u003eIL-4/IL-13 JAK-STAT6 signalling in type II inflammation. IL-4 signals through the Type I receptor complex (IL-4Rα/γc heterodimer), while IL-13 signals through the Type II receptor complex (IL-4Rα/IL-13Rα1 heterodimer). Upon cytokine binding, receptor-associated Janus kinases (JAK1, JAK2, JAK3) phosphorylate signal transducer and activator of transcription 6 (STAT6), leading to STAT6 dimerization, nuclear translocation, and transcription of target genes. Phosphorylated STAT6 (pSTAT6) dimerizes and translocates to the nucleus, where it induces transcription of genes involved in Type 2 immune responses, including IgE production, eosinophil recruitment, mucus hypersecretion, and tissue remodelling. This pathway drives the pathogenesis of atopic inflammatory diseases. IL-4Rα = interleukin-4 receptor alpha; JAK = Janus kinase; STAT6 = signal transducer and activator of transcription 6. Aspects of figure include illustrations from NIAID NIH BioArt Source (\u003ca href=\"http://bioart.niaid.nih.gov/bioart/125\"\u003ebioart.niaid.nih.gov/bioart/125\u003c/a\u003e, \u003ca href=\"http://bioart.niaid.nih.gov/bioart/125\"\u003ebioart.niaid.nih.gov/bioart/\u003c/a\u003e510, \u003ca href=\"http://bioart.niaid.nih.gov/bioart/125\"\u003ebioart.niaid.nih.gov/bioart/\u003c/a\u003e18).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8129352/v1/a14efb1757f40fb0ce90c409.png"},{"id":100432301,"identity":"02dec75b-e750-454b-9240-c6b39dd96a17","added_by":"auto","created_at":"2026-01-16 15:03:26","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":587519,"visible":true,"origin":"","legend":"\u003cp\u003eDupilumab’s mechanism of action through the inhibition of IL-4/IL-13 signalling through the JAK-STAT6 pathway. Dupilumab is a human monoclonal antibody that binds to the interleukin-4 receptor alpha (IL-4Rα) subunit, blocking both IL-4 and IL-13 signalling, both key mediators of type II inflammation. IL-4 signals through the Type I receptor complex (IL-4Rα/γc heterodimer), while IL-13 signals through the Type II receptor complex (IL-4Rα/IL-13Rα1 heterodimer). Upon cytokine binding, receptor-associated Janus kinases (JAK1, JAK2, JAK3) phosphorylate signal transducer and activator of transcription 6 (STAT6), leading to STAT6 dimerization, nuclear translocation, and transcription of target genes.\u0026nbsp; Aspects of figure include illustrations from NIAID NIH BioArt Source (\u003ca href=\"http://bioart.niaid.nih.gov/bioart/125\"\u003ebioart.niaid.nih.gov/bioart/125\u003c/a\u003e, \u003ca href=\"http://bioart.niaid.nih.gov/bioart/125\"\u003ebioart.niaid.nih.gov/bioart/\u003c/a\u003e510, \u003ca href=\"http://bioart.niaid.nih.gov/bioart/125\"\u003ebioart.niaid.nih.gov/bioart/\u003c/a\u003e18).\u003c/p\u003e\n\u003cp\u003eAlthough genetic testing is becoming increasingly accessible, many clinical immunologists still lack access to sequencing or research laboratories to support advanced diagnostic workup for suspected STAT6-GOF variants.\u003csup\u003e33\u003c/sup\u003e By highlighting specific clinical presentations of STAT6-GOF, we hope to increase awareness among clinicians, enabling earlier recognition of these “red flags” and timely initiation of diagnostic evaluation and treatment.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8129352/v1/9c9f7afdae0a8356ce663812.jpeg"},{"id":100554264,"identity":"69ad4716-345b-4130-b71c-e214422e87c2","added_by":"auto","created_at":"2026-01-19 08:38:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1935325,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8129352/v1/271e3beb-bfb7-4c30-b841-797d58de7726.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A De Novo STAT6 p.D419G Variant Causing Severe Multi-Organ Allergic Disease: Case Report on a Transformative Response with Dupilumab","fulltext":[{"header":"Background","content":"\u003cp\u003eSignal transducer and activator of transcription 6 (STAT6) is a transcription factor that plays a key role in interleukin-4 (IL-4) and interleukin-13 (IL-13) signalling, leading to T helper 2 (T\u003csub\u003eH\u003c/sub\u003e2) differentiation, immunoglobulin E (IgE) class switching, B cell survival and proliferation, and eosinophil activation.\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This transcription factor is a key driver of the allergic immune response,\u003csup\u003e1\u003c/sup\u003e and recent research has identified STAT6 gain-of-function disease, manifesting as severe and early-onset multi-organ allergic disease.\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFor many years, patients with lifelong severe allergic disease and multi-organ involvement were managed without a unifying diagnosis, making it difficult for clinicians to find appropriate treatment and consult other clinicians managing similar patients. Recent advancements in genetic testing, molecular diagnosis, and biologic therapies have enabled the precise identification of immune dysregulation and the targeted treatment of associated conditions.\u003csup\u003e\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e These advancements show remarkable headway in precision medicine, transforming the quality of life and treatment outcomes for our patient.\u003c/p\u003e \u003cp\u003eOur patient was first identified as part of the aggregate described by Sharma et al. 2023,\u003csup\u003e5\u003c/sup\u003e which recognized 16 patients from 10 families across the world with STAT6-GOF mutations causing severe early-onset allergic response disruption and widespread systemic symptoms (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). We present the case of a 39-year-old female with a de novo STAT6 (NM_001178079.2) c.1256A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.D419G) variant, highlighting her clinical course and response to dupilumab, an IL-4Rα antagonist blocking IL-4/IL-13 signalling. This treatment course enabled her to cease corticosteroids completely and transformed her quality of life, restoring her daily functioning and facilitating progression towards her personal, educational, and professional goals.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eOur patient is a 39-year-old female of Middle Eastern origin with lifelong early-onset severe allergic disease and a confirmed de novo STAT6 c.1256A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.D419G) variant, as identified by whole-exome sequencing (WES) performed on the patient, her mother, and one maternal uncle. She was born to non-consanguineous parents and has three healthy younger brothers. Family history is significant for food sensitivities, with her brother experiencing hives and mild allergies. Her father passed away from non-small cell lung cancer at age 55. She experienced delayed puberty and is of short stature, measuring at the 3rd percentile for height and the 15th percentile for weight, using the World Health Organization (WHO) adapted growth charts for Canada.\u003c/p\u003e \u003cp\u003eBefore the age of 2, she developed severe refractory atopic dermatitis, pneumothorax requiring chest tube insertion, IgE-mediated food allergies to peanuts, tree nuts, milk, and eggs, and asthma with an attack at age 2 requiring intubation. She was followed at Sick Kids Hospital in Toronto until she was 11 years old, with no unifying diagnosis. Further symptoms included lichenification of most of her skin with frequent flares, multiple bacterial skin infections, including Staphylococcus aureus abscesses and Candida, three separate episodes of varicella zoster virus causing chickenpox, hypermobility, and infrequent but chronic spontaneous urticaria and angioedema without a clear trigger. However, her episodes of chronic spontaneous urticaria and angioedema resolved spontaneously a few years after the onset of the first episode.\u003c/p\u003e \u003cp\u003eThroughout her twenties and thirties, she experienced persistent asthma, recurrent bronchitis, rhinoconjunctivitis, perennial allergic rhinitis, eczema, and multiple dental abscesses. In her twenties, she experienced gastrointestinal symptoms later diagnosed as eosinophilic esophagitis and eosinophilic gastroenteritis, but this later resolved in 2024 as evidenced by repeat gastroscopy and colonoscopy. She has had numerous ocular manifestations, including recurrent giant papillary conjunctivitis since age 4, right retinal detachment at age 16, and left eye Christmas tree anterior and posterior cortical cataract requiring surgery.\u003c/p\u003e \u003cp\u003eIn past years, serial bloodwork confirmed eosinophilia, with a peak of 1.5 \u0026times; 10⁹/L in 2019 when she first presented to this clinic, and elevated serum IgE, peaking at 16,000\u0026ndash;17,000 kU/L at six months of age and consistently\u0026thinsp;\u0026gt;\u0026thinsp;5000 kU/L throughout her thirties (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At age 35, a brain MRI was conducted in consideration of another STAT6 patient who, unfortunately, passed away from a brain aneurysm. This MRI found anomalous vasculature in the circle of Willis with hypoplastic vertebrobasilar arteries, a persistent left-sided congenital trigeminal artery and a hypoplastic A1 segment of the right anterior cerebral artery, and no aneurysm. The consulted neurosurgeon is monitoring those vascular abnormalities, as there is a risk of progression to aneurysmal malformations.\u003c/p\u003e \u003cp\u003eWhole exome sequencing (WES) was performed on the patient, her mother, and one maternal uncle, which identified a de novo heterozygous variant for STAT6 (NM_001178079.2) at c.1256A\u0026thinsp;\u0026gt;\u0026thinsp;G, p.D419G.\u003c/p\u003e \u003cp\u003eOur patient trialled multiple therapies, with the best response from oral corticosteroids. For much of her adult life, our patient has been dependent on prednisone with varying doses that averaged 20mg per day. Prolonged use of systemic corticosteroids is known to be associated with cataracts,\u003csup\u003e17\u003c/sup\u003e and low bone mineral density.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Our patient experienced both complications, consistent with her years of daily prednisone use.\u003c/p\u003e \u003cp\u003eThe patient was initiated on dupilumab (300 mg subcutaneously every 2 weeks), an anti-IL-4R alpha subunit monoclonal antibody that targets the IL-4/IL-13 pathway dysregulated by STAT6-GOF, at the age of 34. She experienced substantial clinical improvement and was weaned off prednisone completely. Over the past five years of treatment, her dupilumab dose has remained stable without the need for adjustment. The therapeutic response to dupilumab was remarkable. At the age of 39, her serum IgE levels reached a low of 3263 kU/L, marking the first time they had fallen below 5000 kU/L, while her eosinophil count was 0.2 \u0026times; 10⁹/L. Her Eczema Area and Severity Index (EASI) score fell dramatically from a peak of 65 (very severe) to 2.2 (mild). Additionally, in-office spirometry showed normal spirometry with resolution of airflow obstruction. Her gastrointestinal symptoms also resolved, and gastroscopy confirmed remission of eosinophilic esophagitis and eosinophilic gastrointestinal disease. Our patient\u0026rsquo;s uncontrolled disease had a profound impact on her quality of life, sleep, concentration, and social involvement. However, after targeted treatment, her sleep quality and allergic symptoms improved, restoring her daily functioning and allowing her to reengage in her academic and personal goals.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eKey Laboratory Trends from 2013 to 2025.\u003c/span\u003e Our patient presented to the clinic in 2019, with only previous lab work available in 2013 and 2014. Out of an abundance of caution during the COVID-19 pandemic, no relevant blood work was drawn in 2020.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2013\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2025\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEosinophils (\u0026times;10⁹/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.80 \u0026rarr; 1.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.35 \u0026rarr; 1.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.60 \u0026minus;\u0026thinsp;0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.70\u0026rarr;1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.80 \u0026rarr; 0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.10 \u0026rarr; 0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgE (kU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;6000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4834\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3263\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgA (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.35 \u0026rarr; 1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.31 \u0026rarr; 1.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgG (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.95 \u0026rarr; 10.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10.01 \u0026rarr; 10.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.61 \u0026rarr; 1.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.85 \u0026rarr; 1.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e152\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.9 \u0026rarr; 3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEosinophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.39 (on oral prednisone)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.8 \u0026rarr; 0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.1 \u0026rarr; 0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.9 \u0026rarr; 2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB cell kappa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB cell lambda\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB cell kappa:lambda ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal T cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD4/CD8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25-hydroxy Vitamin D (nmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e63.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e65.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e165.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe variant c.1256A\u0026thinsp;\u0026gt;\u0026thinsp;G; p.D419G is a rare, de novo missense change in the STAT6 DNA-binding domain located on chromosome 12, genomic position 57496661, cDNA position 1256. In silico pathogenicity prediction models support this variant as pathogenic.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSTAT6 biology and disease mechanism\u003c/p\u003e \u003cp\u003eSTAT6 is a transcription factor downstream of IL-4 and IL-13. Type I (IL-4Rα/γc) or type II (IL-4Rα/IL-13Rα1) receptor engagement activates Janus family protein kinases (JAKs), leading to IL-4Rα phosphorylation, STAT6 phosphorylation, dimerization, and translocation to the nucleus (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Activated STAT6 triggers a type-2 immune response, promoting T\u003csub\u003eH\u003c/sub\u003e2 differentiation, IgE class switching, B cell survival and proliferation, and eosinophil activation.\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Germline STAT6-GOF variants, including the p.D419G variant, have been implicated in this pathway (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Through continuous phosphorylation secondary to delayed dephosphorylation, heightened STAT6 target gene transcription, and a T\u003csub\u003eH\u003c/sub\u003e2-biased polarization, these changes manifest as early-onset multi-organ allergic disease, including markedly elevated IgE levels and eosinophilia (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThrough WES, our patient was found to have a de novo STAT6 mutation (NM_001178079.2) at c.1256A\u0026thinsp;\u0026gt;\u0026thinsp;G, p.D419G. Notably, an identical de novo variant has also been described in a different kindred hailing from East Asia, with other STAT6 amino acid variants having been found in patients of diverse ethnicities, including European, Middle Eastern, Hispanic, South Asian, East Asian, and Southeast Asian.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSince Sharma et al. (2023)\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e first defined STAT6-GOF variants in 16 patients with primary atopic disorder, an increasing number of cases have been recognized, broadening the understanding of the disease\u0026rsquo;s heterogeneity. Sharma et al. proposed the following clinical \u0026ldquo;red flags\u0026rdquo; for STAT6-GOF: (i) early life onset; (ii) peripheral blood eosinophilia; (iii) elevated serum IgE; (iii) widespread, treatment-resistant atopic dermatitis; (iv) multiple food and drug allergies; (v) severe (and even fatal) anaphylaxis; (vi) recurrent skin and respiratory infections; (vii) eosinophilic gastrointestinal disorder, including eosinophilic esophagitis; (viii) asthma; (ix) allergic rhinoconjunctivitis; (x) short stature; and possibly (xi) vascular malformations of the brain (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRemarkably, our patient meets all of these criteria and, notably, presents with vascular malformations in the circle of Willis. Cranial MRI revealed hypoplastic vertebrobasilar arteries, a persistent left-sided congenital trigeminal artery and a hypoplastic A1 segment of the right anterior cerebral artery. Previous studies have suggested that STAT6 signalling may be linked to the activation of vascular smooth muscle cells,\u003csup\u003e20\u003c/sup\u003e as well as the promotion of angiogenesis.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Given that vascular smooth muscle cell activation and angiogenesis have been implicated in the pathogenesis of cerebral vascular malformations,\u003csup\u003e22\u0026ndash;23\u003c/sup\u003e it is plausible that STAT6 variants may contribute to these malformations; however, direct evidence is currently lacking. Furthermore, studies have reported intracranial aneurysms in patients with STAT1 gain-of-function (GOF) and STAT3 loss-of-function (LOF) mutations;\u003csup\u003e24\u0026ndash;28\u003c/sup\u003e However, the specific role of STAT proteins in aneurysm pathogenesis remains unclear.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e Vascular abnormalities are not a primary manifestation and have not been consistently identified in the aggregate of STAT6-GOF patients. However, the presentation of two patients with vascular malformations, including the incidence of a fatal brain aneurysm, justifies further investigation into the relationship between STAT6 upregulation and vascular abnormalities.\u003c/p\u003e \u003cp\u003eFurther questions are raised regarding the extent of STAT6 end-organ manifestations, including vascular malformations. One consideration is whether neurovascular imaging should be incorporated into the initial workup of STAT6-GOF patients. Although the prevalence of vascular anomalies in STAT6-GOF patients remains unclear, early detection and surveillance may improve long-term outcomes, prolong life, and inform the vascular impacts of STAT6-GOF. There is also emerging evidence of increased lymphoma risk in some STAT6-GOF kindreds\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The Catalogue of Somatic Mutations in Cancer (COSMIC) database documented p.D419 variants as somatic mutations in lymphoma, with experimental evidence supporting a gain-of-function phenotype.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e However, more evidence is needed as the underlying mechanism remains unclear.\u003c/p\u003e \u003cp\u003eOur patient required high doses of prednisone for many years before initiation of treatment with dupilumab, an IL-4Rα-blocking monoclonal antibody used for treatment of allergic diseases, including atopic dermatitis, asthma, chronic rhinosinusitis and eosinophilic esophagitis.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Dupilumab inhibits IL-4/IL-13 dependent activation of receptor-associated JAKs and prevents downstream phosphorylation of particular tyrosine residues that activate STAT6 by binding the IL-4Rα subunit (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Over five years of treatment, she demonstrated a marked clinical improvement, with EASI score declining to mild levels, spirometry normalized with resolution of airflow obstruction, and a remarkable improvement in biomarkers, including IgE serum levels and eosinophil counts. She was successfully weaned off prednisone and daily antihistamines, eliminating systemic corticosteroid exposure. She experienced life-changing benefits on dupilumab, being able to pursue academic, personal, and professional goals, as well as a marked subjective improvement in concentration, sleep, and functioning. Janus kinase (JAK) inhibitors have also shown promising results as an alternative or adjunctive treatment, particularly in refractory cases.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e The therapeutic rationale for JAK inhibitors or IL-4/IL-13 inhibitors is direct: STAT6 phosphorylation is decreased and the TH2-driven inflammatory response is minimized by either directly inhibiting JAKs or by blocking IL-4/IL-13 upstream (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In our patient, precision medicine using IL-4Rα-blocking biologics provided sustained clinical improvement, consistent with previously reported outcomes of dupilumab in STAT6-GOF patients .\u003csup\u003e9, 32\u0026ndash;33\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAlthough genetic testing is becoming increasingly accessible, many clinical immunologists still lack access to sequencing or research laboratories to support advanced diagnostic workup for suspected STAT6-GOF variants.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e By highlighting specific clinical presentations of STAT6-GOF, we hope to increase awareness among clinicians, enabling earlier recognition of these \u0026ldquo;red flags\u0026rdquo; and timely initiation of diagnostic evaluation and treatment.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case illustrates the core phenotype of STAT6-GOF mutations, presenting as severe, early-onset, multisystem atopic disease with persistently elevated IgE and eosinophilia. Whole exome sequencing of a de novo STAT6 c.1256A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.D419G) variant provided a unifying diagnosis and direction for therapeutic relief. The successful use of dupilumab targeting the IL-4/IL-13\u0026ndash;STAT6 axis enabled cessation of systemic corticosteroids and a profound reduction is skin disease activity, and improvement in pulmonary function and immunologic biomarkers.\u003c/p\u003e \u003cp\u003eIn the future, we expect that new STAT6 variants will be identified through the recent recognition of STAT6-GOF as a PAD. While vascular malformations are not yet a defining symptom of STAT6-GOF, this patient\u0026rsquo;s cerebrovascular malformations together with a fatal aneurysm reported in a previous STAT6-GOF warrant caution and investigation into\u003c/p\u003e \u003cp\u003eThis case highlights the value of precision medicine in allergic disorders, using exome sequencing to clarify treatment and targeted therapy. For clinicians, unexplained severe early-onset allergic symptoms warrant early genetic testing. In our patient, dupilumab alleviated the severity of allergic symptoms and reduced systemic corticosteroid exposure, thereby improving her quality of life. These findings align with emerging evidence supporting the efficacy of dupilumab and JAK inhibitors in STAT6-GOF. Increased awareness of STAT6-GOF will not only facilitate earlier diagnosis and targeted treatment but may also clarify the disease\u0026rsquo;s full clinical spectrum.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor Contributions:\u0026nbsp;\u003cbr\u003e\u0026nbsp;L.S.: Investigation (chart review), data curation, visualization (Table 1; Figures 1\u0026ndash;3), writing manuscript and reviewing edits.\u003c/p\u003e\n\u003cp\u003eH.A.: Conceptualization, supervision, writing manuscript and reviewing edits.\u003c/p\u003e\n\u003cp\u003eAll authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eConsent for publication: Written informed consent to publish this case report and any accompanying images was obtained from the patient. A copy of the signed consent form is held by the corresponding author and is available for review by the Editor upon request.\u003c/p\u003e\n\u003cp\u003eFunding Declaration: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eEthics and Consent to Participate: This case report complies with the Declaration of Helsinki and relevant institutional policies. In accordance with McMaster Research Ethics Board (REB) guidance and the Tri-Council Policy Statement (TCPS 2), single-patient, de-identified case reports do not constitute human subjects research requiring REB review; therefore, formal ethics approval was not sought. Written informed consent for participation and publication was obtained from the patient. The authors hold a copy of this approval and it is available to the Editor upon request.\u003c/p\u003e\n\u003cp\u003eData availability: All relevant data are included in this article. Additional de-identified information may be available from the corresponding author on reasonable request, subject to institutional policies and patient privacy.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: We thank the patient for generously sharing her history and permitting publication of this report.\u003c/p\u003e\n\u003cp\u003eCompeting Interest Declaration: The authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWang W, et al. The roles of STAT6 in regulating B cell fate, activation, and function. Immunol Lett. 2021;233ISSN:0165\u0026ndash;2478.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakeda K, et al. Essential role of Stat6 in IL-4 signalling. 521 Nat. 1996;380:627\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo Y, et al. JAK-STAT signaling in human disease: from genetic syndromes to clinical inhibition. 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J Allergy Clin Immunol Glob. 2025;4(3):100494. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jacig.2025.100494\u003c/span\u003e\u003cspan address=\"10.1016/j.jacig.2025.100494\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"allergy-asthma-and-clinical-immunology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aaci","sideBox":"Learn more about [Allergy, Asthma \u0026 Clinical Immunology](http://aacijournal.biomedcentral.com/)","snPcode":"13223","submissionUrl":"https://submission.nature.com/new-submission/13223/3","title":"Allergy, Asthma \u0026 Clinical Immunology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8129352/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8129352/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background: Signal transducer and activator of transcription 6 (STAT6) gain-of-function (GOF) variants cause severe, early-onset multi-organ allergic disease through IL-4/IL-13-mediated type 2 immunity. We report a patient with a de novo STAT6 p.D419G variant and her remarkable response to targeted therapy. Case Presentation: A 39-year-old woman of Middle Eastern origin presented with lifelong severe atopic disease beginning before age 2, including treatment-refractory atopic dermatitis, severe asthma requiring intubation, IgE-mediated food allergies, eosinophilic gastrointestinal disease, and recurrent infections. She demonstrated persistently elevated serum IgE (peak \u003e17,000 kU/L, consistently \u003e5,000 kU/L) and eosinophilia (peak 1.5 × 10⁹/L). Whole exome sequencing identified a de novo heterozygous STAT6 variant (NM_001178079.2) c.1256A\u003eG (p.D419G). Notably, brain MRI revealed vascular malformations in the circle of Willis, including hypoplastic vertebrobasilar arteries and persistent trigeminal artery. She required daily prednisone (average 20 mg) for years, resulting in cataracts and low bone mineral density. At age 34, dupilumab (300 mg subcutaneously every 2 weeks) was initiated, targeting the dysregulated IL-4/IL-13 pathway. Over five years of treatment, she achieved complete corticosteroid cessation, with her Eczema Area and Severity Index declining from 65 (very severe) to 2.2 (mild), normalization of spirometry, and improvement in biomarkers (IgE decreased to 3,263 kU/L, eosinophils to 0.2 × 10⁹/L). Her quality of life improved dramatically, enabling the pursuit of personal, academic, and professional goals.\nConclusion: This case demonstrates the severe phenotype of STAT6-GOF and highlights the transformative potential of precision medicine using IL-4Rα-blocking therapy. Early recognition of STAT6-GOF clinical \"red flags\" and genetic testing enables targeted treatment, avoiding prolonged corticosteroid exposure and its complications. The presence of cerebrovascular malformations warrants further investigation into potential associations with STAT6-GOF.","manuscriptTitle":"A De Novo STAT6 p.D419G Variant Causing Severe Multi-Organ Allergic Disease: Case Report on a Transformative Response with Dupilumab","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-16 15:03:17","doi":"10.21203/rs.3.rs-8129352/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-10T20:45:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-10T17:08:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-06T11:21:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-21T17:28:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128310532662709133483500396933882987270","date":"2026-01-20T21:59:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"275651861771945235301363844686837250574","date":"2026-01-20T17:10:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"331258976196329318765343271864035675060","date":"2026-01-20T16:38:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"72573356484919943436934835940748355175","date":"2026-01-20T07:44:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-19T17:47:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"234487725207399917374914071450067949077","date":"2026-01-19T08:18:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"264322944140816670076997621061571226522","date":"2026-01-13T17:51:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-13T14:31:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-21T05:26:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-21T05:24:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"Allergy, Asthma \u0026 Clinical Immunology","date":"2025-11-16T20:07:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"allergy-asthma-and-clinical-immunology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aaci","sideBox":"Learn more about [Allergy, Asthma \u0026 Clinical Immunology](http://aacijournal.biomedcentral.com/)","snPcode":"13223","submissionUrl":"https://submission.nature.com/new-submission/13223/3","title":"Allergy, Asthma \u0026 Clinical Immunology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dcc737f8-a87e-476e-981f-798950a0743c","owner":[],"postedDate":"January 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-02-10T20:54:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-16 15:03:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8129352","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8129352","identity":"rs-8129352","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}