Clinical aspects of STAT3 gain-of-function germline mutations: A Systematic Review

Publication date: Available online 27 February 2019

Source: The Journal of Allergy and Clinical Immunology: In Practice

Author(s): Alexandre Fabre, Sarah Marchal, Vincent Barlogis, Bernard Mari, Pascal Barbry, Pierre-Simon Rohrlich, Lisa R. Forbes, Tiphanie P. Vogel, Lisa Giovannini-Chami

Abstract

Background

STAT3 gain-of-function (GOF) germline mutations have been recently described. A comprehensive overview of this early-onset multiorgan autoimmune and lymphoproliferative disease has not yet been compiled.

Objective

We have conducted a systematic review of published STAT3 GOF cases in order to describe clinical, diagnostic and therapeutic aspects of the disease.

Methods

A systematic review including articles published before 10/10/2018 in Pubmed, WoS and CENTRAL databases was performed. We described cases of patients with STAT3 GOF germline mutations with genetic analysis and a concordant phenotype if functional analyses were not performed for the mutation.

Results

The search identified 18 publications describing 42 unique patients. Twenty-eight different mutations were described. Onset of disease was very early with an average age of 3 (0.5-5) years old. The most frequent manifestations were: autoimmune cytopenias (28/42), lymphoproliferation (27/42), enteropathy (24/42), interstitial lung disease (15/42), thyroiditis (13/42), diabetes (10/42), and post-natal growth failure (15/21). Immunodeficiency was not always a predominant feature. Most patients required significant immunosuppressive therapy. Five patients received hematopoietic stem cell transplantation, 4 died from complications. Improvement of symptoms was observed for 8 out of 9 patients that received targeted biotherapies.

Conclusions

STAT3 GOF syndrome is a new clinical entity to consider when confronted with a patient with early-onset poly-autoimmunity, lymphoproliferation, and growth failure. At this time, precise therapeutic guidelines are lacking, but use of anti-IL-6 receptor and JAK inhibitor biologics are attractive possibilities.

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