# CTLA-4 haploinsufficiency presenting with chronic myeloid leukemia, bullous pemphigoid, and PLA2R-positive membranous nephropathy: a case report

## TL;DR

A young adult with a rare immune disorder developed leukemia, skin blisters, and kidney disease, showing the importance of early genetic diagnosis and multidisciplinary care.

## Contribution

This case report expands the known clinical features of CTLA-4 haploinsufficiency by linking it to chronic myeloid leukemia and other rare conditions.

## Key findings

- CTLA-4 haploinsufficiency was confirmed through genetic and functional testing in a patient with CML, bullous pemphigoid, and MGN.
- Multidisciplinary treatment led to remission of CML, resolution of skin lesions, and normalization of kidney function.
- The case highlights the need to consider immune disorders in young adults with multisystem autoimmunity and hematologic issues.

## Abstract

Cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) haploinsufficiency is a primary immune-regulatory disorder characterized by T-cell overactivation and multisystem autoimmunity. Malignancies, particularly lymphomas and gastric cancer, have been reported in approximately 12–13% of individuals with CTLA-4 haploinsufficiency, but associations with chronic myeloid leukemia (CML) are very rarely described. We report a young adult with genetically and functionally confirmed CTLA-4 haploinsufficiency who developed a triad of BCR-ABL1–positive chronic myeloid leukemia (CML), bullous pemphigoid, and PLA2R-positive membranous glomerulonephritis (MGN), highlighting diagnostic and management lessons across immunology, hematology, dermatology, and nephrology.

A 21-year-old woman with Hashimoto thyroiditis and iron-deficiency anemia was found to have BCR-ABL1–positive CML. Within months she developed recurrent infections and paraneoplastic blistering disease. Whole-exome sequencing detected a heterozygous CTLA4 c.529_530insT (p.Tyr177LeufsTer2) frameshift; flow cytometry showed reduced CTLA-4 expression, establishing functional haploinsufficiency. Six months later she presented with edema and nephrotic-range proteinuria; serology revealed markedly elevated anti-PLA2R antibodies, and kidney biopsy confirmed immune-complex MGN. Management included a TKI (imatinib/nilotinib as indicated over the course), low-dose corticosteroids, monthly IVIG for infection/immune modulation, and rituximab for bullous disease and MGN. This resulted in molecular remission of CML, resolution of skin lesions, and sustained normalization of proteinuria over 12 months.

The convergence of CML, bullous pemphigoid, and PLA2R-positive MGN in CTLA-4 haploinsufficiency broadens the clinical phenotype and underscores the importance of considering inborn errors of immunity in young adults with refractory, multisystem autoimmunity and hematologic abnormalities. Early genetic diagnosis can guide targeted immunomodulation and organ preservation, and multidisciplinary care is essential for optimal outcomes.

The online version contains supplementary material available at 10.1186/s13223-026-01011-7.