Case Report: Signal Transducer and Activator of Transcription 3 Gain-of-Function and Spectrin Deficiency: A Life-Threatening Case of Severe Hemolytic Anemia

Abstract

STAT3 gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of STAT3 GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a de novo STAT3 gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of STAT3 GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.

Keywords: STAT3 gain-of-function; autoimmune lymphoproliferative syndrome; hematopoietic stem cell transplantation; hemolytic anemia; hereditary spherocytosis; lymphadenopathy; primary immune regulatory disorders; spectrin deficiency.

Figure 1

Timeline of patient’s clinical presentation, diagnosis and treatment. Clinical features (solid black lines), diagnosis (black dotted lines), treatment (solid gray lines), hypothesis (dashed black lines) and hematopoietic stem cell transplantation (HSCT) outcome (double dashed lines) are indicated.

Figure 2

Patient’s immune reconstitution: T, B, and NK cell populations.