Pediatric Rheumatology Online Journal → August 2003 →  Immunodeficiency Syndromes → Abstract #164

A NOVEL SPLICE-SITE MUTATION IN FOXP3 CAUSES A LATE-ONSET FORM OF THE IMMUNE DYSREGULATION, POLYENDOCRINOPATHY, ENTEROPATHY, X-LINKED (IPEX) SYNDROME

T. R. Torgerson,¹ E. Gambineri,¹ M. Hannibal,² C. A. Wallace,¹ H. D. Ochs.¹

¹Pediatric Immunology, Rheumatology, and Infectious Diseases, University of Washington, Seattle, WA; ²Pediatric Genetics, University of Washington, Seattle, WA

The Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome (IPEX) is a rare X-linked recessive disorder of overwhelming autoimmunity and immune dysfunction. Affected males typically present in early infancy with severe diabetes, thyroiditis, intractable diarrhea, hemolytic anemia, and eczema leading to death by age 2. Many patients have high titer autoantibodies to endocrine organs, bowel, and blood cells and some develop severe bacterial and viral infections. The causative gene for IPEX has recently been identified as FOXP3, an eleven exon gene that codes for a 431 amino acid protein with significant sequence homology to a large family of DNA-binding proteins known as Forkhead or Winged-Helix proteins. We have identified a 13-year-old male with multiple autoimmune manifestations who has a novel mutation of FOXP3 within the 5' splice-acceptor site of exon 5. His disease course has been less fulminant than the majority of IPEX cases but he has had significant morbidity including chronic enteropathy with persistent diarrhea that began at six months of age. Colonoscopy was consistent with Crohn's disease. He developed hyperthyroidism at age 5, presumptively of autoimmune etiology and was treated with I¹²⁵ ablative therapy. He has had variable eczema since childhood but two years ago, he began to develop severe, recurrent Staphylococcal skin infections with multiple abscesses. At that time he was noted to be profoundly neutropenic with unremitting absolute neutrophil counts of 100-200/mm, the result of anti-neutrophil antibodies. We hypothesize that this patient's milder phenotype is the result of a low level of normally spliced FOXP3 mRNA that is made despite a splice site mutation in exon 5. Our data suggest that a diagnosis of IPEX should be considered in any male patient with multiple autoimmune phenomena, particularly if these include inflammatory bowel disease plus an endocrine abnormality, dermatitis, or elevated IgE level.