Expansion of the CTLA-4 haploinsufficiency phenotype. Report of twins presenting a novel mutation.

CTLA-4 is a critical inhibitory checkpoint molecule of immune activation. Patients with CTLA-4 haploinsufficiency present unchecked T-cell activation that promotes survival of autoreactive T-cells, resulting in autoimmunity and lymphoproliferation. In addition, B-cell numbers and antibody levels progressively decline over time therefore these patients have been historically labeled as CVID.
Case Two 32-year-old monozygotic twins, healthy until age 12 when they both develop chronic diarrhea and recalcitrant warts. The first twin was hospitalized at the age of 17 due to malnutrition, hydroelectrolytic imbalance triggered by chronic diarrhea. Endoscopy showed chronic duodenitis with partial villous atrophy, which raised suspicion of celiac disease, thus, a gluten-free diet was started. He subsequently developed Leptospira meningitis and endocarditis during this hospital admission. At age of 27 he was hospitalized due to PJP. Laboratory evaluation showed decreased immunoglobulin titers. Tetanus and pneumococcal antibodies were unprotective. Lymphocyte subpopulations showed decreased T and B cells, lymphoproliferation to PHA and Treg were normal. Monthly IVIG and prophylactic cotrimoxazole were started. In addition, he received HPV vaccine with which warts decreased significantly. The second twin presented milder symptoms. The history of opportunistic infections, hypogammaglobulinemia and chronic diarrhea associated with T-cell lymphopenia, was highly suggestive of CID. Panel genetic testing of both twins identified a CTLA-4 c.160G>C VUS. CTLA-4 transendocytosis was absent, confirming CTLA-4 haploinsufficiency diagnosis. Genetic testing of parents confirmed this variant to be de novo, with this the variant was reclassified as pathogenic.
This clinical history was compatible with CTLA-4 haploinsufficiency, but the warts and PJP pneumonia exceed the common clinical features described in these patients. Additional testing revealed that both twins have elevated sCD25, follicular T helper expansion and absent CTLA-4 transendocytosis assay. This emphasizes the importance of functional studies to accurately determine the diagnosis in the face of VUS and unusual disease manifestations.

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Scroll to Top