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STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Cutaneous warts are an exceedingly common cutaneous viral infection for which existing treatment options are often painful, expensive, and only marginally effective. Extensive warts may occur in the setting of primary immunodeficiencies, wherein they can co‐occur with other diseases of immune dysfunction, such as atopic dermatitis (AD). Dupilumab, an IL‐4 receptor α (IL‐4Rα)‐blocking monoclonal antibody, is a biologic agent recently approved for the treatment of moderate‐to‐severe eczema. Here, we report a case of a young girl with both severe AD and diffuse filiform warts, which resolved shortly after initiating treatment for AD with dupilumab. [ABSTRACT FROM AUTHOR]

Morphea is a rare multifactorial autoimmune disorder characterized by a complex and dynamic interplay between Th1 and Th2 signaling. Active clinical trials are currently investigating the safety and efficacy of dupilumab for the treatment of primary morphea. Here, we present two cases of morphea that developed in pediatric atopic dermatitis patients treated with dupilumab. These findings may support a causal relationship between IL-4 receptor blockade and the development of the early inflammatory phase of morphea. [ABSTRACT FROM AUTHOR]

Introduction: Paraneoplastic pemphigus (PNP) is a rare, often fatal, autoimmune blistering disease of the skin and mucous membranes. In children, PNP is frequently associated with Castleman disease (CD). This series describes five cases of PNP associated with CD. Methods: Data were collected retrospectively from the medical records of patients with a diagnosis of PNP and CD from January 2013 to June 2022. Patients ≤22 years old with clinical and immunopathologic evidence of PNP were included; CD was diagnosed histopathologically. Results: Two children, two adolescents, and one young adult (two males, three females) were included. The average age at disease presentation was 11.8 years (range: 7–22 years). Oral (n = 5) and anogenital (n = 3) mucositis were common. Four patients had "unicentric" CD (UCD); one patient had "multicentric" CD (MCD). Castleman tumors were in the retroperitoneum (n = 4) or axilla (n = 1). One patient had myasthenia gravis without thymoma. Three patients had bronchiolitis obliterans (BO). Three patients had complete resection of their CD; two had partial resection. Three patients remain alive with a median follow‐up of 13 months (range: 12 months to 13 years); two are clinically stable with resolution of mucocutaneous lesions; one has persistent BO requiring ongoing ventilatory support. Patients who remain alive had UCD with complete resection; all deceased patients had partial resection and BO. Conclusion: Most patients had UCD, and the retroperitoneum was the most common location. Patients with MCD, incomplete resection, and BO died; patients with UCD and complete resection remain alive, even in the setting of BO. Consideration of PNP is critical when pediatric patients present with mucositis as PNP may be clinically indistinguishable from more common causes of mucositis. [ABSTRACT FROM AUTHOR]

Background The cblE disorder is an inherited disorder of vitamin [B.sub.12] metabolism that results in elevated levels of homocysteine and decreased methionine in body fluids. Renal complications have been reported in patients with cblC disease, but not in those with cblE disease. The renal complications of cblC disease include thrombotic microangiopathy (TMA), neonatal hemolytic uremic syndrome, chronic renal failure, tubulointerstitial nephritis and proximal renal tubular acidosis. Previously, we reported a patient with cblC disease who had an atypical glomerulopathy that manifested with proteinuria and progressive renal insufficiency. Case-Diagnosis/Treatment Studies were done on cultured fibroblasts. Renal biopsy tissue was examined by light and electron microscopy. There was decreased incorporation of labeled methyltetrahydrofolate and decreased synthesis of methylcobalamin. Complementation analysis placed the patient into the cblE complementation group. The findings from the histological and ultrastructural studies of renal biopsy were similar, but not identical, to those of idiopathic membranoproliferative glomerulonephritis (MPGN) and overlapped with those of TMA. Conclusions We describe a patient with cblE disease who had an atypical glomerulopathy similar to MPGN. Additional findings included migraine headaches, hypothyroidism and livedo reticularis. Keywords Vitamin [B.sub.12] * Cobalamin metabolism * cblE disorder * Membranoproliferative glomerulonephritis * Thrombotic microangiopathy, Introduction Although inadequate vitamin [B.sub.12] [cobalamin (cbl)] intake or absorption accounts for most patients who present with symptoms of cobalamin deficiency [1], a small but significant number have specific mutations [...]

The mainstay of treatment for atopic dermatitis (AD)‐like graft‐versus‐host disease (GVHD) in both pediatric and adult patients includes oral corticosteroids with or without other systemic immunosuppressive therapies. To our knowledge, we report the first case series of dupilumab in the treatment of AD‐like GVHD in a pediatric cohort of four patients, where we observed clinical improvement of GVHD as well as a reduction in itch in 3/4 (75%) patients. Our findings suggest that dupilumab is not only effective in treating AD‐like GVHD, but also reduces systemic immunosuppression in the pediatric transplant population. The ability to reduce the length and amount of immunosuppression as well as improve quality of life suggest that dupilumab may serve as a safe and effective therapeutic option in our transplant population with GVHD. [ABSTRACT FROM AUTHOR]