Mechanistic associations of a mild phenotype of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome.
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.
De Benedetti
Fabrizio
F
Direzione Scientifica, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy. debenedetti@opbg.net
Insalaco
Antonella
A
Diamanti
Antonella
A
Cortis
Elisabetta
E
Muratori
Flaminia
F
Lamioni
Andrea
A
Carsetti
Rita
R
Cusano
Roberto
R
De Vito
Rita
R
Perroni
Lucia
L
Gambarara
Manuela
M
Castro
Massimo
M
Bottazzo
Gian Franco
GF
Ugazio
Alberto G
AG
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
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors