Germline Mutation Leading to a Pathogenic STAT3 Gain of Function

Introduction A STAT3 gain-of-function (GOF) mutation leads to enhanced STAT3 signaling, leading to generalized autoimmunity caused by impaired regulatory T cell development and enhanced Th17 cell function. It is characterized by fevers, lymphoproliferation, recurrent infections, hypogammaglobulinemia, low IgE levels, and multiorgan autoimmunity, including type 1 diabetes and enteropathy. Case Description An 11-year-old male with a history of recurrent otitis media and asthma presented with two weeks of intermittent umbilical pain, non-bloody nonbilious diarrhea, and emesis. On physical exam he was afebrile, had splenomegaly (13.8 cm), and generalized lymphadenopathy. Infectious and oncologic evaluation was negative, including a cervical lymph node biopsy. Immune workup was notable for hypogammaglobulinemia, including IgG 457 [568-1490 mg/dL], IgA 28 [58-358 mg/dL], IgM 30 [48-226 mg/dL], IgE 4 [≤100 KU/L], unprotected vaccine titers, and CD4+ lymphopenia to 504 [650-1500 cell/μL]. Given his profound lymphadenopathy, autoimmune lymphoproliferative syndrome (ALPS) screening was pursued, which revealed an increased double-negative T cell population; however, caspase-10, FAS, and FASLG gene sequencing were normal. Whole-exome sequencing revealed a pathogenic, dominant, and heterozygous GOF mutation in STAT3 (variant c.2144C>T [p.Pro715Leu]). Of note, family history of this child’s 43-year-old father was positive for autoimmune lung (with a partial lung resection), intestinal, and liver disease, followed since childhood as “idiopathic” multiorgan disease. The father’s genetic screening returned positive with the same GOF mutation in STAT3. Discussion This case highlights the need to consider STAT3 GOF in patients with multiorgan autoimmune disease, lymphadenopathy, hypogammaglobulinemia with specific antibody deficiency, and T cell lymphopenia with low serum IgE levels. Low serum IgE levels in patients can be a simple and cost-effective way to distinguish between STAT3 GOF versus loss of function, seen in Job Disease.