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.

Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study

“…A de novo heterozygous germline STAT3 P715L mutation previously described ( 42 – 44 ) was identified in P18, presenting with life-threatening AIHA and other clinical findings associated with STAT3 gain-of-function (GOF) ( 44 , 45 ).…”

“…Of note, two patients remained in the T memory area of the PCA plot after therapy: P13 and P18, respectively affected by KS and STAT3 GOF disease ( 49 , 66 ). For P18, such lack of response was most likely due to the life-threatening clinical contingency that brought the patient directly to HSCT ( 44 ), without attempting targeted treatment with JAK-inhibitors and tocilizumab ( 26 ). The complex immunologic background of KS, due to an altered methylation of crucial transcription factors ( 51 ), may explain the persistence of T memory-skewed subsets in P13, which could possibly be reversed only by future applications of epigenome editing ( 67 ).…”

“…Interestingly, a novel variant in UNC13D gene (R1075W) was detected in P22, who presented a CVID-like clinical phenotype with bilineage autoimmune cytopenia (AIN+ITP) and hypogammaglobulinemia. A de novo heterozygous germline STAT3 P715L mutation previously described (42)(43)(44) was identified in P18, presenting with life-threatening AIHA and other clinical findings associated with STAT3 gain-of-function (GOF) (44,45).…”

Treatment of inborn errors of immunity patients with inflammatory bowel disease phenotype by allogeneic stem cell transplantation

“…In case of other — more novel — immune dysregulation diseases such as STAT3 ‐GOF, DOCK8 deficiency, CTLA‐4 deficiency, and LRBA deficiency, treatment experience is more limited. AlloHSCT in STAT3 ‐GOF has, to our knowledge and accessibility, only been reported in seven individuals, with four patients dying due to TRM including GVHD, haemophagocytic lymphohistiocystosis (HLH), and severe viral infections 46–49 …”

STAT3 gain-of-function syndrome

“…Lymphopenia and reduced functional lymphocyte responses more commonly occurred in patients receiving pulse or chronic steroids ( 4 ). Approximately half of patients have a humoral deficiency including hypogammaglobulinemia, B cell lymphopenia and reduced memory B cells ( 4 , 5 , 39 , 40 ). A major caveat to immunophenotyping of the peripheral blood of patients is that this may not represent the local immune response at sites of inflammation/autoimmunity.…”