A novel gain‐of‐function mutation in STAT5B is associated with treatment‐resistant severe atopic dermatitis

Abstract

To the Editor, Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways are among the major cellular pathways that integrates signals from cytokines, growth factors and hormones to regulate proliferation, survival, differentiation, as well as apoptosis. 1 STAT proteins are critical mediators of cytokine signals that regulate gene expression programs underlying key processes involved in the immune system. STAT5B is a cytosolic protein involved in signal transduction in response to several cytokines, including IL-2, IL-7 and IL-15. STAT5 signalling promotes T cell proliferation and survival, maintain FOXP3+ regulatory T (Treg) cells, and expand Treg cells that promote cancers by inhibiting the antitumor activity and leading to the progression of tumours. Consistent with these findings, exaggerated STAT5B activity is often linked to malignancies. 2 Somatic heterozygous gain-of-function mutations (GOF) in STAT5B, N642H mutation, have been described in multiple leukaemias and lymphomas in humans. [2][3][4] Increased STAT5 signalling has also been shown to cause allergic and myeloproliferative phenotypes in murine models. 5,6 Interestingly, in correlation with these findings, somatic heterozygous GOF STAT5B N642H mutation has been reported in two independent children with neonatal-onset urticaria, diarrhoea, granulomatous skin lesions and some infectious episodes but without any signs of neoplasm. It was also noteworthy that there were markedly elevated levels of eosinophils. 7 Since there are only two described patients with an identical mutation in the STAT5B gene with nonneoplastic phenotype, we expand the repertoire of such mutations reporting a patient with a novel heterozygous STAT5B mutation presenting with treatment-resistant severe atopic dermatitis, urticarial rash and hair loss.A 7-year-old girl born to non-consanguineous parents presented with treatment-resistant atopic dermatitis, urticarial rash, hair loss, multiple food allergies, allergic rhinitis and allergic asthma was admitted to hospital. She was a full-term born baby with no complaints up to 1-month-old who was later found to have atopic eczema with cow's milk, egg and nuts allergies. She had recurrent otitis at 2-3 years of age, atopic dermatitis with hair loss, and angioedema attacks with walnut by 5 years of age. Partial response was seen with dietary elimination of cow's milk, egg and nuts until 3 years of age and dietary elimination continues with nuts. She has been using topical corticosteroids, calcineurin inhibitors and intermittent systemic corticosteroid for more than 4 years. The patient's allergic asthma is under control with inhaler corticosteroid prophylaxis. She has no respiratory tract infections, abscesses or diarrhoea. Her family history How to cite this article: Kasap N, Aslan K, Karakurt LT, et al.A novel gain-of-function mutation in STAT5B is associated with treatment-resistant severe atopic dermatitis.