# Oncostatin M receptor deficiency as a novel candidate genetic cause of autosomal recessive hyper-IgE syndrome

## TL;DR

A new genetic cause for a rare immune disorder is identified, involving a receptor linked to elevated IgE levels and immune dysfunction.

## Contribution

OSMR deficiency is proposed as a novel autosomal recessive cause of hyper-IgE syndrome.

## Key findings

- A patient homozygous for an OSMR variant shows impaired STAT3 signaling and elevated IgE.
- OSMR deficiency leads to immune cell abnormalities and a fibroblast-restricted phenotype.
- Reconstitution of fibroblasts restored normal cellular function.

## Abstract

Here, Andersen and colleagues describe a patient with asthma, pulmonary aspergillosis, and elevated IgE homozygous for a deleterious variant in the oncostatin M receptor. The variant results in absence of OSMR surface expression and impaired OSM-induced STAT3 phosphorylation, suggesting that OSMR deficiency may underlie hyper-IgE syndrome, thereby representing a novel genetic etiology of autosomal recessive HIES.

Hyper-IgE syndrome (HIES) is characterized by elevated serum IgE levels, eczema, and recurrent skin and pulmonary infections, classically caused by autosomal dominant (AD) STAT3 loss-of-function variants. Here we describe a patient presenting with elevated IgE levels, atopic eczema, chronic pulmonary aspergillosis, and bone fractures, homozygous for a rare missense variant in the oncostatin M receptor (OSMR) gene. We demonstrate that the patient OSMR V436D variant is deleterious and leads to decreased OSMR surface expression and impaired OSM-induced STAT3 phosphorylation. Blood profiling showed elevated IgE-expressing plasmablasts and peripheral T follicular helper cells and atypical memory B cells. A germinal center model revealed a B cell–extrinsic defect in concordance with a largely fibroblast-confined phenotype. Finally, reconstitution of patient fibroblasts led to functional complementation of the cellular phenotype. We propose OSMR deficiency as a novel genetic etiology of AR-HIES, resembling the clinical and immunological phenotype of STAT3 AD-HIES, but mediating its phenotypic profile mainly in the stromal rather than hematopoietic compartment.