CHAPLE-Like Enteropathy and Renal Microangiopathy in an Adult Patient With CD46 Deficiency.

BACKGROUND

Protein-losing enteropathy is a rarely reported feature of CD46-associated disease and may resemble CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) syndrome. Associated hypogammaglobulinemia may be mistaken for primary antibody deficiency.

METHODS

We describe a 23-year-old woman with childhood-onset enteropathy and hypogammaglobulinemia who had received immunoglobulin replacement for presumed common variable immunodeficiency since age 5. Multidisciplinary reassessment incorporated intestinal and renal histopathology, whole-exome sequencing, family segregation, and longitudinal evaluation of the response to eculizumab.

RESULTS

Duodenal biopsy demonstrated intestinal lymphangiectasia, whereas kidney biopsy revealed chronic thrombotic microangiopathy with concurrent PLA2R-negative membranous nephropathy. Serum C3 and C4 were within reference ranges. Sequencing identified homozygous CD46 c.565T>G (p.Tyr189Asp), with no pathogenic CD55 variant. The diagnostic laboratory reported the CD46 finding as a variant of uncertain significance. Family segregation and published functional evidence supported its clinical relevance, although patient-specific functional confirmation was unavailable. Eculizumab promptly improved abdominal pain, vomiting, and oral intake. By April 2026, following dose escalation, serum albumin reached 4.3 g/dL and IgG 554 mg/dL, whereas proteinuria decreased from 5.95 to 2.4 g/day.

CONCLUSION

This case supports considering CD46-associated disease in adults with a CHAPLE-like phenotype, particularly when enteric protein loss and hypogammaglobulinemia coexist with renal microangiopathy despite normal C3 and C4. The response to complement blockade supports a complement-mediated disease process. Documented protein loss should prompt reassessment of a presumptive diagnosis of primary antibody deficiency.