Autosomal-dominant hyper-IgE syndrome is associated with appearance of infections early in life and/or neonatal rash: Evidence from the Italian cohort of 61 patients with elevated IgE

Lorenzini, Tiziana; Giacomelli, Mauro; Scomodon, Omar; Cortesi, Manuela; Rivellini, V.; Dotta, Laura; Soresina, Annarosa; Dellepiane, Rosa Maria; Carrabba, Maria; Cossu, Fausto; Cancrini, Caterina; Specchia, Fernando; Giardino, Giuliana; Pignata, Claudio; Plebani, Alessandro; Pietrogrande, Maria Cristina; Badolato, Raffaele

doi:10.1016/j.jaip.2019.02.012

Cited by 12 publications

(10 citation statements)

References 8 publications

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“…STAT3 Linker domain mutations are rare (35,36) and constitute <2% in the larger series (1,2,29,37) and few publications as case reports are found in the literature (35). Majority of reported variants in STAT3 are missense variety, and non-sense variants in the STAT3 gene are not frequent (1,2,29,37).…”

Section: Discussionmentioning

confidence: 99%

Clinical Profile of Hyper-IgE Syndrome in India

et al. 2021

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Introduction: Hyper-IgE Syndrome (HIES) is a rare inborn error of immunity (IEI) characterized by a constellation of symptoms related to susceptibility to Staphylococcal skin and pulmonary infections, eczema, raised serum IgE (>2,000 IU/ml), craniofacial anomalies, and recurrent bone fractures. Data on HIES from the Indian subcontinent is scarce and restricted to small case series and case reports. This is the first compilation of national data on HIES.Materials and Methods: A total 103 cases clinically diagnosed and treated as HIES were analyzed from nine centers. Cases with clinical and/or molecular diagnosis of DOCK8 deficiency were not included. Patients were divided into two groups: group I for whom a heterozygous rare variant of STAT3 was identified, and group II, with clinical features similar to those of AD STAT3 deficiency, but without any genetic diagnosis.Results: Genetic diagnosis was available in 27 patients (26.2%) and all harbored rare variants in the STAT3 gene. Majority of these STAT3 HIES patients presented with recurrent skin abscesses (77.7%) or pneumonia (62.9%) or both (59.2%). Other features included eczema (37%), candidiasis (55.5%), facial dysmorphism (55.5%), recurrent fractures (11.1%), and retained primary teeth (7.4%). Mycobacterial infections were seen in a significant 18.5%. Mortality was seen in three subjects (11.1%). A similar trend in the clinical presentation was observed when all the 103 patients were analyzed together. Twenty percent of patients without a rare variant in the STAT3 gene had an NIH score of ≥40, whereas, 51.9% of STAT3 HIES subjects had scores below the cut off of ≥40. TH17 cell numbers were low in 10/11 (90.9%) STAT3 HIES tested. Rare variants observed were 8 in exon 21; 8 in exon 13; 3 in exon 10; 2 in exon 15, and one each in exon 6, 16, 17, 19, 22, and splice site downstream of exon 12. Seven variants were novel and included F174S, N567D, L404Sfs*8, G419 =, M329K, T714I, R518X, and a splice site variant downstream of exon 12.Conclusions: The report includes seven novel STAT3 variants, including a rare linker domain nonsense variant and a CC domain variant. Mycobacterial diseases were more frequent, compared to western literature.

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Section: Discussionmentioning

confidence: 99%

Clinical Profile of Hyper-IgE Syndrome in India

et al. 2021

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“…Bacterial infections in STAT3-HIES are common and dominated by Staphylococcus aureus, affecting primarily skin and lungs, though other epithelial sites are also represented. Dermatological infection commonly begins with a newborn papulopustular rash resembling neonatal acne; this is present in 50% of patients within the first 2 weeks of life and pustulates, exudes pus, and crusts, before developing into eczema [29][30][31]; this rash isolates Staphylococcus aureus and improves with anti-staphylococcal antibiotics, distinguishing it from other neonatal pustuloses [29]. The resultant eczema is present in most patients and becomes colonized with a narrow range of S. aureus strains expressing higher prevalence of methicillin resistance and Panton-Valentine leucocidin [32], probably reflecting a high antibiotic burden exerting selection pressure on skin commensals.…”

Section: Bacterial Infectionmentioning

confidence: 99%

STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions

2021

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The hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Since the prototypical HIES description 55 years ago, areas of significant progress have included description of key disease-causing genes and differentiation into clinically distinct entities. The first two patients reported had what is now understood to be HIES from dominant-negative mutations in signal transduction and activator of transcription 3 (STAT3-HIES), conferring a broad immune defect across both innate and acquired arms, as well as defects in skeletal, connective tissue, and vascular function, causing a clinical phenotype including eczema, staphylococcal and fungal skin and pulmonary infection, scoliosis and minimal trauma fractures, and vascular tortuosity and aneurysm. Due to the constitutionally expressed nature of STAT3, initial reports at treatment with allogeneic stem cell transplantation were not positive and treatment has hinged on aggressive antimicrobial prophylaxis and treatment to prevent the development of end-organ disease such as pneumatocele. Research into the pathophysiology of STAT3-HIES has driven understanding of the interface of several signaling pathways, including the JAK-STAT pathways, interleukins 6 and 17, and the role of Th17 lymphocytes, and has been expanded by identification of phenocopies such as mutations in IL6ST and ZNF341. In this review we summarize the published literature on STAT3-HIES, present the diverse clinical manifestations of this syndrome with current management strategies, and update on the uncertain role of stem cell transplantation for this disease. We outline key unanswered questions for further study.

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“…In this study, we will add further, longitudinal and more detailed information to the previous reported article [32].…”

Section: Discussionmentioning

confidence: 97%

Long Term Longitudinal Follow up of AD-HIES Cohort: Impact of Early Diagnosis and Enrolment to IPINet Centres on Natural History of Job Syndrome

Carrabba

Dellepiane²,

Cortesi³

et al. 2022

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The Job Syndrome or Autosomal Dominant Hyper Immunoglobulin E Syndrome (AD-HIES, LOF-STAT3 gene) is a very rare inborn error of immunity disorder with multi-organ involvement and long-life post-infective damages. Longitudinal registries are of main importance to improve knowledge on natural history and management of these rare disorders. This study aims to describe the natural history of 30 Italian patients recorded in the IPINet registry with AD-HIES, with a cumulative observational-time of 721.1 patient-years. Age at disease onset was < 12 months in the 66.7% of patients, but the mean time of diagnostic delay was 13.7 years. At diagnosis skin involvement was present in 93.3% of patients (eczema 80.8%, abscess 66.7%). At the follow up eczema was still present in 63.3% and abscess in 56.7%. Respiratory complications such as bronchiectasis and pneumatoceles were present at diagnosis in the 46.7% and 43.3% respectively. Antimicrobial prophylaxis resulted in decrease of pneumonia from 76.7–46.7%. Antifungal prophylaxis decreased mucocutaneous candidiasis occurrence from 70–56.7%. In the course of SARS-CoV-2 pandemic, seven patients developed COVID-19. Survival analyses showed that 27 out of 30 patients are still alive, while three patients died at age of 28, 39 and 46 as consequence of lungs bleeding, lymphoma and sepsis, respectively. Our study shows that many severe complications can affect AD-HIES patients. Analysis of a cumulative follow-up of 278.7 patient-years has shown that early diagnosis, adequate management at expertise centres for primary immunodeficiency, prophylactic antibiotic and antifungal therapy improve outcome and can positively influence patients’ life expectancy.

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Autosomal-dominant hyper-IgE syndrome is associated with appearance of infections early in life and/or neonatal rash: Evidence from the Italian cohort of 61 patients with elevated IgE

Cited by 12 publications

References 8 publications

Clinical Profile of Hyper-IgE Syndrome in India

Clinical Profile of Hyper-IgE Syndrome in India

STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions

Long Term Longitudinal Follow up of AD-HIES Cohort: Impact of Early Diagnosis and Enrolment to IPINet Centres on Natural History of Job Syndrome

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