Name: Autoinflammation, immune dysregulation, and eosinophilia | Acronym: AIIDE
Alt. names: Autoinflammatory keratinization disease | AiKD | JAK1-GOF | JAK1 gain-of-function | JAK1 associated inflammatory disease | JAID | JAACD syndrome

Gene: JAK1 | MOI: Autosomal dominant | Mechanism of action: Gain of Function

No. of cases in DB: 30 | First reported in: 2017

Last updated on: 2024-11-09 by Xiao P. Peng

OMIM: 618999

Orphanet: -

MONDO: 0033558

DOID: -

ClinGen:

Description

At least 5 patients from 3 unrelated families have now been identified with heterozygous JAK1 gain-of-function (GOF) variants (H596D, A634D, S703I) conferring atopic, immune dysregulatory and inflammatory phenotypes (PMID: 28111307, 32750333, 35046931, 36546480). Patients present with severe steroid-resistant atopic dermatitis, environmental allergies, and asthma along with poor growth, short stature, and hepatosplenomegaly. Patients may also develop autoimmune or inflammatory GI, hepatic, thyroid, skin or renal involvement. Congenital structural cardiac, brain and vascular anomalies were also found in some patients, and a possible link to neurodevelopmental abnormalities and autism has also been proposed (PMID: 35046931). Laboratory studies show peripheral eosinophilia with normal IgE levels, as well as eosinophilic infiltration of the liver and GI tract on pathology. Patients may also show elevated inflammatory markers, monocytosis, neutrophilia and lymphocytosis, as well as gene expression signatures consistent with Th2 polarization and hyperactive signaling through JAK/STAT and NF-kB pathways. Recently, a somatic S703I mutation was described leading to this condition (PMID:32750333). Marie Jeanpierre and colleagues at the Imagine Institute characterized 5 novel monoallelic JAK1 variants via structural studies using AlphaFold2 and in vitro overexpression in U4C cell lines. They found that these led to different levels of hyperphosphorylation of STATs at baseline. Three of the variants appeared to cause loss of cis-regulation of kinase catalytic activity through conformational destabilization of the ‘closed’ and inactive JAK1 form, while only 2 variants were shown to transactivate JAK2, indicating that the underlying mechanisms could be different depending on the type of variant. Detailed immunophenotyping from 2 patients showed unbalanced Th cell differentiation with decreased frequencies of Th1 and Tregs. [Publication pending, presented at ESID 2024]

Management

Treatment with JAK inhibitors, such as ruxolitinib and tofacitinib, results in dramatic clinical improvement. Treatment with a more JAK1-selective inhibitor such as upadacitinib has also been reported to help ameliorate symptoms associated with severe allergic inflammation, though with apparently lesser efficacy than the broader spectrum JAK inhibitors mentioned previously (PMID: 36546480). At least some patients (the family with the A634D mutation) have been described with long-term sustained response to ruxolitinib in terms of overall growth and development, atopic symptoms, dysregulated myelopoiesis, and GI and liver disease (PMID: 36546480).