A Case of Autoimmunity and Immunodeficiency: The Answer May Be in the Genes

Abstract

Introduction: Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) mutation is a newly described disease characterized by early-onset poly autoimmunity, lymphoproliferation, and interstitial lung disease, in the setting of growth failure. Case description A 34-year old Caucasian male presented to our pulmonary clinic with a long standing and progressive dyspnea on exertion associated with non-productive. His medical history was remarkable for failure to thrive, recurrent sinus and respiratory tract infections, juvenile arthritis, autoimmune hemolytic anemia, and hypogammaglobulinemia. Seven years prior to presentation he developed a right hemithorax empyema complicated by a fibrothorax for which he underwent decortication. He subsequently had a gradual deterioration in respiratory status with exertional dyspnea and cough, culminating to his visit. On examination, he had a BMI of 18.25 kg/m2, he was normoxic on room air and had bibasilar rales. No clubbing was noted. His hemoglobin was 12.1 mg/dL, white blood cell count was 4.5 with relative lymphopenia (11% lymphocytes). Computed tomography of the chest demonstrated bilateral reticulations, bronchiectasis, mosaic attenuation and lymphadenopathy involving the right lower paratracheal, bilateral hilar and subcarinal lymph nodes (Figure 1). He underwent an Endobronchial Ultrasound with Transbronchial biopsies of his lymph nodes, which revealed normal lymphoid tissue. On account of his failure to thrive, cytopenias, arthritis, hypogammaglobulinemia, recurrent respiratory infections and interstitial lung disease, a diagnosis of Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) germline mutation was considered. This was then confirmed with genetic testing. He was started on an Interleukin-6 receptor inhibitor and was referred to lung transplant. Discussion STAT3 GOF mutation is a new clinical entity that typically presents with earlyonset poly autoimmunity, lymphoproliferation, and interstitial lung disease, in the setting of growth failure. According to a systematic review (n = 42), disease onset on average is 3 years of age. The most frequent manifestations of disease were: autoimmune cytopenias (28 of 42), lymphoproliferation (27 of 42), enteropathy (24 of 42), interstitial lung disease (15 of 42), thyroiditis (13 of 42), diabetes (10 of 42), and postnatal growth failure (15 of 21). Diagnosis is established by genetic testing. Treatment with targeted molecules in the STAT3 pathway seem efficacious, IL-6 receptor inhibitors (tocilizumab) with or without a Jak inhibitor (ruxolitinib or tofacitinib) have been used with good effect. In conclusion, STAT3 GOF syndrome is a new diagnosis that should be entertained when evaluating a patient with early-onset polyautoimmunity, hypogammaglobulinemia, and ILD.