Immune dysregulation syndrome with de novo CTLA4 germline mutation responsive to abatacept therapy

Regulatory T-cells (Tregs) are major mediators of mammalian self-tolerance via cytotoxic T-lymphocyte antigen 4 (CTLA4) signaling pathways. An immune dysregulation syndrome associated with heterozygous germline mutations in CTLA4 was recently reported. Clinical features include recurrent infections, systemic lymphadenopathy, various autoimmune conditions, hypogammaglobulinemia, and autosomal dominant inheritance, characteristic of primary immunodeficient disease (PID). PID symptoms are variable and few patients with sporadic de novo CTLA4 germline mutations have been described. Here, we report the case of a 26-year-old man with an immune dysregulation syndrome and a de novo CTLA4 germline mutation. The patient exhibited several clinical features associated with PID. Next-generation sequencing revealed a CTLA4 germline mutation, c.436G>A; p.G146R, in exon 2 of CTLA4. Sanger sequencing confirmed the patient was the only member of his family with this germline mutation. The patient was diagnosed with an immune dysregulation syndrome associated with de novo germline CTLA4 mutation, complicated by steroid-refractory rheumatoid arthritis. Treatment with abatacept, a CTLA4-immunoglobulin fusion molecule, was initiated, resulting in dramatic resolution of the patient's clinical symptoms. As PID with CTLA4 germline mutation is rare and patients may be under-diagnosed, physicians should be aware of the features of PID.