title: Mechanistic associations of a mild phenotype of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome.
abstract: OBJECTIVE
  The syndrome of immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a rare disorder resulting in the expression of multiple autoimmune and allergic features. Early onset enteropathy and type 1 diabetes (T1D) are the most common clinical features. The IPEX syndrome is caused by mutations of the FOXP3 gene, which is essential for the development of regulatory T cells (Treg). We describe 2 unrelated patients with IPEX syndrome with a mild clinical phenotype and with novel FOXP3 mutations and the phenotypic and functional characterization of their Treg cells.
  
  
  METHODS
  The FOXP3 gene was analyzed by sequencing amplimers from genomic DNA. Treg cells were characterized by evaluating the number of CD4+CD25+ T cells and their functional ability to suppress the proliferation of autologous CD4+CD25- effector T cells stimulated with anti-CD3 and anti-CD28 antibodies.
  
  
  RESULTS
  A 7-year-old boy and a 24-year-old man presented with autoimmune enteropathy characterized by early onset persistent diarrhea not associated with T1D or other endocrinopathies. These 2 patients carry novel FOXP3 mutations that do not abrogate the function of the forkhead domain. They have normal numbers of CD4+CD25+ T lymphocytes, however, these show severely defective suppressive function in vitro.
  
  
  CONCLUSIONS
  Our 2 patients show that IPEX patients may present with early onset enteropathy and long-term survival without T1D or other endocrinopathies. This milder phenotype may be associated with FOXP3 mutations that do not abrogate the function of the forkhead domain.
authors.affiliation: Direzione Scientifica, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy. debenedetti@opbg.net
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Benedetti
authors.forename: Antonella
authors.initials: A
authors.lastname: Insalaco
authors.forename: Antonella
authors.initials: A
authors.lastname: Diamanti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cortis
authors.forename: Flaminia
authors.initials: F
authors.lastname: Muratori
authors.forename: Andrea
authors.initials: A
authors.lastname: Lamioni
authors.forename: Rita
authors.initials: R
authors.lastname: Carsetti
authors.forename: Roberto
authors.initials: R
authors.lastname: Cusano
authors.forename: Rita
authors.initials: R
authors.lastname: De Vito
authors.forename: Lucia
authors.initials: L
authors.lastname: Perroni
authors.forename: Manuela
authors.initials: M
authors.lastname: Gambarara
authors.forename: Massimo
authors.initials: M
authors.lastname: Castro
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Bottazzo
authors.forename: Alberto G
authors.initials: AG
authors.lastname: Ugazio
mesh_terms: D000328:Adult; D001707:Biopsy, Needle; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D051858:Forkhead Transcription Factors / Q000235:genetics; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D009154:Mutation; D010641:Phenotype; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D011504:Protein-Losing Enteropathies / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D035583:Rare Diseases; D012720:Severity of Illness Index; D013577:Syndrome
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors