SOCS1 Haploinsufficiency Presenting as Severe Enthesitis, Bone Marrow Hypocellularity, and Refractory Thrombocytopenia in a Pediatric Patient with Subsequent Response to JAK Inhibition

Abstract

Haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1) is a recently discovered autoinflammatory disorder with significant rheumatologic, immunologic, and hematologic manifestations. Here we report a case of SOCS1 haploinsufficiency in a 5-year-old child with profound arthralgias and immune-mediated thrombocytopenia unmasked by SARS-CoV-2 infection. Her clinical manifestations were accompanied by excessive B cell activity, eosinophilia, and elevated IgE levels. Uniquely, this is the first report of SOCS1 haploinsufficiency in the setting of a chromosomal deletion resulting in complete loss of a single SOCS1 gene with additional clinical findings of bone marrow hypocellularity and radiologic evidence of severe enthesitis. Immunologic profiling showed a prominent interferon signature in the patient’s peripheral blood mononuclear cells, which were also hypersensitive to stimulation by type I and type II interferons. The patient showed excellent clinical and functional laboratory response to tofacitinib, a Janus kinase inhibitor that disrupts interferon signaling. Our case highlights the need to utilize a multidisciplinary diagnostic approach and consider a comprehensive genetic evaluation for inborn errors of immunity in patients with an atypical immune-mediated thrombocytopenia phenotype. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-022-01346-x.

Protein kinases: drug targets for immunological disorders

“…Finally, children with gain-of-function STAT1 mutations or loss-of-function mutations in the STAT1 inhibitor SOCS1 have enhanced type 1 immune responses at the cost of loss of type 3 immunity, resulting in chronic mucocutaneous candidiasis and splenomegaly. Tofacitinib blocks IFN signalling by inhibiting STAT1 activation and has been effective in treating these two conditions 82 , 83 . For a drug conceived from research on patients with primary immunodeficiency, it is gratifying to see its use in treating patients with inborn errors of immunity.…”

“…blocks IFN signalling by inhibiting STAT1 activation and has been effective in treating these two conditions 82,83 . For a drug conceived from research on patients with primary immunodeficiency, it is gratifying to see its use in treating patients with inborn errors of immunity.…”

One gene to rule them all – clinical perspectives of a potent suppressor of cytokine signaling – SOCS1

“…Other organ autoimmunity includes hepatitis, pancreatitis, thyroiditis, coeliac disease and alopecia ( 11 , 31 ). Additionally, autoimmune cytopenias such as immune thrombocytopenia (ITP) or autoimmune hemolytic anemia (AIHA) are quite common ( 11 , 29 , 31 , 32 , 34 ). Another group of patients present with autoinflammatory phenotypes, as for instance, allergic diseases like asthma or rhinoconjunctivitis, and with granulomatous organ involvement such as granulomatous lymphocytic interstitial lung disease (GLILD), organizing pneumonia, and granulomatous uveitis ( 11 , 34 ).…”

“…SOCS1-HI manifests as a genetically heterogeneous disease with no straightforward structure-function relations: The location of the different variants meanwhile identified does not predict clinical manifestations or disease severity. Complete heterozygous deletions of SOCS1 ( 32 ) may exhibit less severe phenotypes than heterozygous C-terminal variants ( 34 ). As in other inborn errors of immunity with autosomal dominant inheritance, family members with SOCS1-HI may show an incomplete clinical penetrance ( 31 ).…”

“…Encouraged by these findings, clinicians embraced in-label use of JAK inhibitors in SOCS1-HIi patients with manifestations of autoinflammatory diseases. In 2022, a patient with heterozygous SOCS1-deletion and severe enthesitis-related arthritis showed significant improvement upon tofacitinib treatment, even stabilizing immunocytopenia (ITP) that was poorly controlled with conventional immunosuppression ( 32 ).…”