Single centre experience of haematopoietic SCT for patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an X-linked recessive disorder with mutations in FOXP3 causing absence of regulatory activity by CD4+CD25+ Foxp3+ regulatory T cells, which results in unchecked effector T-cell activation and mediating organ-specific autoimmunity.1 IPEX syndrome should be considered in any young male infant with intractable diarrhoea and/or gut villous atrophy and failure to thrive (FTT). Without treatment, many patients die in the first 2 years of life because of sepsis or FTT.2 Management of children with autoimmune enteropathy is challenging. Supportive care includes total parental nutrition (TPN), blood transfusions, treatment of autoimmune manifestations together with long-term immunosuppressive drug treatment, which may reduce clinical manifestations, but is not curative and drug toxicities limit this approach.3 Previous studies have shown that haematopoietic SCT (HSCT) is curative, however, side effects of conditioning or infections post transplant may be life-threatening, and early reports were unfavourable, with late death post transplantation described.4 We report five patients with IPEX syndrome and a confirmed mutation in FOXP3 who underwent HSCT between 2003 and 2010 at the Northern Supra-Regional Service for Paediatric Immunodeficiency in the United Kingdom. Clinical and laboratory data were collected from each patient’s medical case notes. Written consent was obtained from parents at the time of admission for HSCT. Median age at presentation was 1 week (range 3–28 days). All presented with severe watery diarrhoea and FTT requiring TPN (Table 1). All had typical villous atrophy and lymphocytic infiltration in small bowel biopsies. Two had myopathic facies with low muscle tone and weakness at presentation, persisting following transplantation, a feature not previously noted. All patients had raised serum IgE levels (450 kU/L), four out of five (80%) had haemolytic anaemia with a positive direct Coombs test, peripheral blood eosinophilia (2 × 109/L) and positive autoantibodies, and three out of five (60%) had eczema (Table 1). Despite the presence of autoantibodies, including anti-islet cell antibodies in three out of five patients, no patient developed endocrinopathy. Median age at HSCT was 10 months (range 6–10 months), four from unrelated donors and one matched sibling (Table 2). Three received umbilical cord blood as a stem cell source (two were 8/10 HLA matched, one was 10/10) and two received BM (both 10/10 HLA matched). Three received BU of 16 mg/kg/CY of 200 mg/kg, one received treosulfan of 14 g/m2/CY of 200 mg/kg and one received treosulfan of 12 g/m2/fludarabine of 150 mg/m2 as cytoreductive conditioning, according to European guidelines and centre practice current at the time. All received serotherapy with alemtuzumab (Campath-1H; range 0.3–1 mg/kg) except patient 1 who had a fully matched sibling donor. Four received cyclosporine as GvHD prophylaxis, two with additional mycophenolate mofetil (MMF) and one tacrolimus and MMF. Neutrophil engraftment (>0.5 × 109/L) occurred between day +14 to +22, platelet engraftment (>50 × 109/L) between day +25 to +30 except patient 5 who always had a platelet count >50 × 109/L. 100% donor T-cell chimerism was achieved in two out of five patients, and three had stable mixed donor chimerism with 32–68% donor T cells. All patients had a CD4+ T-cell absolute count of 1000–2200 cells/μL and CD8+ T cells of 450–2300 cells/μL by 52 weeks post HSCT. FOXP3 mutations result in heterogeneous biological abnormalities, which may lead to a lack of differentiation of CD4+CD25+ bright regulatory T cells or a dysfunction in these cells.5 In patient 5, CD4+CD25+ bright regulatory T cells were present and Foxp3 protein expression was normal before HSCT. In patient 4, Foxp3 protein expression became normal post HSCT (Table 2). Only patient 4 developed GvHD limited to skin (grade II), which resolved with systemic corticosteroid therapy. Two developed biopsy-proven minimal change nephrotic syndrome post HSCT, which responded to treatment with corticosteroid and high-dose i.v. Ig; both resolved by 5 months post transplant. Pneumonitis was also seen post transplant in two patients. All are alive and well between 3.5 and 10 years from HSCT, with resolution of enteropathy. TPN was stopped within 100 days post transplant except in patient 5 who developed three episodes of intestinal obstruction post HSCT requiring surgical resection of jejunum resulting in short bowel syndrome. His gut biopsy before HSCT showed eosinophilic enteropathy; the histology of jejunum following surgical resection showed severe chronic mucosal injury with ulceration and large areas of complete epithelial atrophy of the mucosa. A residual framework of granulation tissue was also present and the adjacent mucosa was severely atrophic, which confirmed a severely chronically damaged mucosa with a segment of complete lack of epithelial regeneration. He slowly recovered but was TPN dependent for almost 13 months. Currently, he is fed via a jejunal tube and growing within the normal range. Increasing numbers of case reports are documenting successful outcome of HSCT for IPEX syndrome, with a total of 28 published, 15 patients in detail.3, 5, 6, 7, 8, 9, 10 Here, we have described the successful transplant course of five patients with IPEX syndrome, the biggest single centre series to date. All are alive with resolution of enteropathy and commencement of enteral feeding and have discontinued immunosuppression. Despite significant inflammation pre-transplant, in all five, only one patient developed grade II skin GvHD. Overall, 100% donor T-cell chimerism was achieved in two out of five patients, and three have mixed donor chimerism. It has been reported that mixed chimerism, with only donor Treg population, is sufficient to suppress the autoimmune process and resolve enteropathy,6, 8 although it may take a long time because of previous severe gut damage. The patients’ complex management was achieved by rigorous multi-disciplinary teamwork emphasizing the importance of managing this group of children in specialized centres. In conclusion, HSCT is curative in children with IPEX syndrome, with restoration of T regulatory CD4+ function as indicated by resolution of disease. GvHD was not a common or significant complication in our series. Umbilical cord blood transplantation is successful. Stable mixed chimerism is sufficient to cure disease although the minimum level has not been determined. Also reduced intensity conditioning regimens can be considered. Myopathic facies are previously undescribed feature in some patients. The authors declare no conflict of interest.