Dominant-negative signal transducer and activator of transcription (STAT)3 variants in adult patients: A single center experience

Oded Shamriz; Limor Rubin; Amos J Simon; Atar Lev; Ortal Barel; Raz Somech; Maya Korem; Sigal Matza Porges; Tal Freund; David Hagin; Ben Zion Garty; Amit Nahum; Vered Molho Pessach; Yuval Tal

doi:10.3389/fimmu.2022.1044933

Dominant-negative signal transducer and activator of transcription (STAT)3 variants in adult patients: A single center experience

Front Immunol. 2022 Dec 20:13:1044933. doi: 10.3389/fimmu.2022.1044933. eCollection 2022.

Authors

Oded Shamriz^{1

2}, Limor Rubin¹, Amos J Simon^{3

4}, Atar Lev⁴, Ortal Barel^{5

6}, Raz Somech⁴, Maya Korem⁷, Sigal Matza Porges^{8

9}, Tal Freund¹⁰, David Hagin¹⁰, Ben Zion Garty^{11

12

13}, Amit Nahum¹⁴, Vered Molho Pessach¹⁵, Yuval Tal¹

Affiliations

¹ Allergy and Clinical Immunology Unit, Department of Medicine, Hadassah Medical Organization, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
² The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
³ Sheba Cancer Research Center and Institute of Hematology, Sheba Medical Center, Ramat Gan, Israel.
⁴ Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Tel-Hashomer Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁵ The Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel.
⁶ Sheba Medical Center, Wohl Institute of Translational Medicine, Ramat Gan, Israel.
⁷ Department of Clinical Microbiology and Infectious Diseases, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
⁸ Department of Human Genetics, Institute for Medical Research, the Hebrew University of Jerusalem, Jerusalem, Israel.
⁹ Department of Biotechnology, Hadassah Academic College, Jerusalem, Israel.
¹⁰ Allergy and Clinical Immunology Unit, Department of Medicine, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹¹ Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.
¹² Felsenstein Medical Research Center, Rabin Medical Center, Petach-Tikva, Israel.
¹³ Allergy and Clinical Immunology Unit, Schneider Children's Medical Center, Petach-Tikva, Israel.
¹⁴ Pediatrics Department A, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
¹⁵ Pediatric Dermatology Service, Department of Dermatology, Hadassah Medical Organization, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

Abstract

Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) caused by dominant negative (DN) variants in the signal transducer and activator of transcription 3 gene (STAT3) is characterized by recurrent Staphylococcal abscesses, severe eczema, chronic mucocutaneous candidiasis (CMC), and non-immunological facial and skeletal features.

Objectives: To describe our experience with the diagnosis and treatment of adult patients with AD-HIES induced by DN-STAT3 variants.

Methods: The medical records of adult patients (>18 years) treated at the Allergy and Clinical Immunology Clinic of Hadassah Medical Center, Jerusalem, Israel, were retrospectively analyzed. Immune and genetic workups were used to confirm diagnosis.

Results: Three adult patients (2 males; age 29-41 years) were diagnosed with DN-STAT3 variants. All patients had non-immunological features, including coarse faces and osteopenia. Serious bacterial infections were noted in all patients, including recurrent abscesses, recurrent pneumonia, and bronchiectasis. CMC and diffuse dermatophytosis were noted in two patients. Two patients had severe atopic dermatitis refractory to topical steroids and phototherapy. Immune workup revealed elevated IgE in three patients and eosinophilia in two patients. Whole exome sequencing revealed DN-STAT3 variants (c.1166C>T; p.Thr389Ile in two patients and c.1268G>A; p. Arg423Gln in one patient). Variants were located in DNA-binding domain (DBD) and did not hamper STAT3 phosphorylation Treatment included antimicrobial prophylaxis with trimethoprim/sulfamethoxazole (n=2) and amoxycillin-clavulanic acid (n=1), and anti-fungal treatment with fluconazole (n=2) and voriconazole (n=1). Two patients who had severe atopic dermatitis, were treated with dupilumab with complete resolution of their rash. No adverse responses were noted in the dupilumab-treated patients.

Discussion: Dupilumab can be used safely as a biotherapy for atopic dermatitis in these patients as it can effectively alleviate eczema-related symptoms. Immunologists and dermatologists treating AD-HIES adult patients should be aware of demodicosis as a possible manifestation. DN-STAT3 variants in DBD do not hamper STAT3 phosphorylation.

Keywords: adults; dupilumab; hyper IgE syndrome; inborn errors of imunity; stat3.

MeSH terms

Abscess
Adult
Dermatitis, Atopic* / drug therapy
Dermatitis, Atopic* / genetics
Eczema*
Female
Humans
Job Syndrome* / diagnosis
Job Syndrome* / genetics
Job Syndrome* / therapy
Male
Retrospective Studies
STAT3 Transcription Factor* / genetics
STAT3 Transcription Factor* / metabolism

Substances

STAT3 Transcription Factor
STAT3 protein, human