A. Genetic Testing
Discussion
Our patient had genetic testing which revealed an abnormal gain of
function (GOF) mutation at the signal transducer and activator of
transcription 3 (STAT3). The STAT family of transcription regulators is
important for cellular proliferation, survival, and regulation of
inflammation and autoimmunity. These mutations are inherited in an
autosomal dominant manner and can occur as de novo or sporadic
mutation. Clinical presentation of these patients is diverse and can be
multi-systemic. Patients can develop autoimmune complications and
immunodeficiency. Autoimmune complications include warm autoimmune
hemolytic anemia, immune thrombocytopenia (ITP), diabetes, atopic
dermatitis, hepatitis, autoimmune enteropathy, rheumatoid arthritis, and
Interstitial lung disease (ILD). A recent series of 42 patients found
that patients usually present early in life (average age 3 years) with
the most frequent manifestations of disease being: autoimmune cytopenias
(67%), lymphoproliferation (65%), enteropathy (57%), interstitial lung
disease (36%), thyroiditis (31%), diabetes (24%), and postnatal growth
failure (35%) (1). STAT3 GOF typically manifests with
early endocrine and gastrointestinal disease, and hematologic disease
and ILD present later in life.
Diagnosis is established by genetic testing. Currently there are
ongoing randomized controlled trials to guide therapy in this condition.
Targeted therapy such as anti-IL-6 receptor inhibitors (tocilizumab)
with or without a JAK-inhibitor (ruxolitinib or tofacitinib) has been
used with some benefit in small series (2).
Immunoglobulin replacement therapy is indicated for patients with
hypogammaglobulinemia. Avoidance of live vaccinations and genetic
counseling are recommended.
In conclusion, STAT3 GOF syndrome is a newly described entity usually
managed by hematologists and immunologists, but awareness amongst
pulmonologists is paramount as these patients can present later in life
with ILD and the diagnosis can be attained non-invasively.
References
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Fabre, Alexandre, et al. “Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review.” The Journal of Allergy and Clinical Immunology: In Practice, vol. 7, no. 6, 2019
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Forbes L, Vogel T, et al. Jakinibs for the treatment of immune
dysregulation in patients with gain-of-function signal transducer and
activator of transcription 1 (STAT1) or STAT3 mutations. Journal of Allergy and Clinical Immunology. Volume 142, Issue 5, November 2018, Pages 1665-1669
