Kidney-predominant FOXP3-related immune dysregulation with ALPS-like lymphoproliferation: a case report

Abstract Background FOXP3 controls regulatory T-cell development and function. Pathogenic variants in X-linked FOXP3 cause IPEX syndrome. Classic IPEX includes early enteropathy, insulin-dependent diabetes, and eczema. Some patients show non-classic disease. These forms may involve the kidney, blood, or lymph nodes. Method We report a 3-year-old boy with a kidney-predominant presentation. He had periorbital edema, progressive pallor, cervical lymphadenopathy, proteinuria, and kidney dysfunction. He did not have the classic IPEX triad. Kidney biopsy showed mixed glomerular and tubulointerstitial injury. The biopsy showed glomerulosclerosis, capsular adhesions, podocyte foot-process effacement, immune deposits, and interstitial inflammation and fibrosis. Immune testing showed non-neoplastic lymphoproliferation. The findings resembled autoimmune lymphoproliferative syndrome (ALPS). They included lymphadenopathy, reactive lymphoid hyperplasia, and increased double-negative T cells. Next-generation sequencing found a hemizygous FOXP3 variant, NM_014009.4:c.746A > T (p.Glu249Val). The variant was absent from population databases. In silico tools predicted a harmful effect. Sanger sequencing confirmed the variant in the patient. His mother was a heterozygous carrier. His father tested negative. This pattern supported maternal transmission, not a de novo event. Results The patient received prednisone at 1 mg/kg/day at first. The dose was tapered after 1 month. Proteinuria decreased from 1328 mg/24 h to 871 mg/24 h. Kidney function did not worsen during available follow-up. The lymphoproliferative features improved clinically. Conclusion This case suggests that FOXP3-related immune dysregulation can present with kidney-predominant disease. It can also appear with ALPS-like lymphoproliferation. This may occur without the classic IPEX triad. FOXP3 testing may help selected boys with unexplained nephropathy and immune abnormalities. This is a single case without functional testing. For this reason, the link between the variant and the phenotype remains suggestive, not proven.