Diagnostic Utility of Genetic Testing in a Complex Multisystem Presentation: A Case of CTLA4 Haploinsufficiency

CTLA4 haploinsufficiency is caused by mutations in the CTLA4 gene. The loss of this important immune checkpoint leads to uncontrolled production of lymphocytes, causing infiltration of T cells into multiple organs (gastrointestinal [GI], bone marrow, kidneys, lungs, and central nervous system [CNS]). The clinical manifestations include recurrent infections, enteropathy, lymphadenopathy, and hepatosplenomegaly. 13-year-old male with a history of recurrent respiratory infections, cough, and headaches. He was initially followed by neurology for headaches when he was found to have severe thrombocytopenia on screening labs. He eventually developed recurrent episodes of prolonged bleeding and was diagnosed with immune thrombocytopenia purpura, for which he was treated with transfusions, high-dose intravenous immunoglobulin [IVIG], and eltrombopag. Symptoms continued to worsen as he developed recurrent fevers, weight loss, decreased appetite, and diarrhea, and was found to have leukopenia, lymphadenopathy, splenomegaly, and bronchiectasis. Genetic testing was performed, which revealed a pathogenic variant in the CTLA4 gene, c.223 C> T p.(R75W), heterozygous, consistent with CTLA4-related immune dysregulation. The immune workup was notable for increased double-negative T (DNT) cells and sIL-2R, all of which are expected in CTLA4 haploinsufficiency. MRI of the brain did not demonstrate inflammation or demyelination. He initiated abatacept therapy, which binds to CD80/CD86 to downregulate T cell activation. Trimethoprim/sulfamethoxazole prophylaxis was started due to abatacept therapy and immunodeficiency. Since starting abatacept treatment, immune monitoring labs have demonstrated improvement in markers of T cell activation, and the patient is also experiencing symptomatic improvement. Hematopoietic stem cell transplantation was also discussed; however, given high mortality and improvement with abatacept, deferred for now as a treatment option. This case highlights the importance of early genetic testing in diagnosing complex patients with immunodysregulation, particularly in the presence of targeted therapies, such as those available for CTLA4 haploinsufficiency. Diagnostic delays are still common and may lead to ominous long-term consequences.