Late-onset of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (IPEX) with intractable diarrhea

We describe a 12-year-old boy born at term from natural birth after an uncomplicated pregnancy from unrelated parents, referred to our hospital for severe enteritis started one month before with liquid mucus-haematic diarrhoea (height: 50^th centile, weight: 10^th centile, regularly vaccinated). No potentially triggering events have been reported, such as vaccinations, viral infections or changes in nutrition. In his past history he had recurring episodes of mild atopic dermatitis since the first year of life, a high level of total IgE (400 UI/L), and a constipated bowel (once every two/three days).

On admission, he was dehydrated (7% of weight loss). Blood tests revealed hypoproteinaemia and hypogammaglobulinemia (Table 1), so albumin was replaced.

Abdominal ultrasound highlighted wall thickening of the bowel loops. Esophagogastroduodenoscopy (EGDS) and colonoscopy revealed ulcerative lesions at the stomach, duodenum, terminal ileum and colon, giving rise to a suspect of inflammatory bowel disease. Biopsies revealed villous blunting and inflammatory infiltration of the mucosa. After starting intravenous methylprednisolone, metronidazole and parenteral nutrition a partial remission was observed.

Ten days later, for a worsening of symptoms, EGDS and colonoscopy were repeated, with a superimposable picture. Particularly, the biopsies of the colon showed lympho-granulocytic acute inflammation with Graft versus Host Disease-like aspect, a lesion typically reported in IPEX (Figure 1) [30]. Due to the inability to control the symptoms the patient underwent ileostomy.

Despite the age of the patient was atypical for the onset of IPEX, we evaluated the presence of autoantibodies to harmonin, which resulted positive (>100 U.A.). Then, diagnosis was confirmed by the genetic examination of FOXP3 gene, revealing a mutation in the exon 9 (1040G > A), with substitution of Arginine to Histidine (R347H). The mother resulted negative. The total number of lymphocyte and lymphocyte subpopulations was normal, particularly T_REG were 5% of the total number.

Intravenous cyclosporine (range: 200-350 mg/dl) and methylprednisolone (2 mg/kg) were started, which reduced diarrhea and abdominal pain. After sixty days of parenteral nutrition the patient returned to oral feeding with the normalization of albumin levels (Table 1). Because of the onset of post-prandial hyperglycaemias, we excluded T1DM (Table 1) and glycaemia normalized after tapering steroid therapy. For a new worsening of the disease we introduced sirolimus (0.15 mg/kg/day; range: 8-12 mg/dl). The patient improved with a progressive reduction of intensity and frequency of abdominal pain and mucus emission. A new colonoscopy highlighted a marked decrease of the inflammation. After thirty-four days since the beginning of sirolimus, cyclosporine was suspended. After twelve months the patient is well, without recurrence of the disease.

This case indicates that IPEX can have an atypical age of presentation. Thus, it should always be considered in the differential diagnosis of intractable diarrhea.

Four patients have been previously reported with IPEX with the same amino-acid substitution (R347H) found in our patient. The age of onset for all these subjects was within the first year of life and the first symptoms were recurrent ear infection, high IgE levels, T1DM, and gastritis. All had gastrointestinal symptoms with failure to thrive: two intractable diarrhea, two severe gastritis with mucosal atrophy or eosinophilic infiltration. Other symptoms were: coombs-negative haemolytic anaemia, food allergy, pancreatic exocrine failure, intractable hypertension, intestinal metaplasia, steatorrhea, and hypogammaglobulinemia. Patients received corticosteroid and calcineurin inhibitors. One patient died after allogeneic hematopoietic stem cell transplantation (HSCT) due to an infection.

Recently, evidence that patients with a severe form of IPEX may have circulating FOXP3⁺ T cells, as it is the case of our patient, which suggests that the cellular basis for the disease may be a result of a functional defect of Treg cells [1],[26]. Mainly, R347H mutated-FOXP3 has been demonstrated as effective as wild-type-FOXP3 in converting normal T cell into Treg in vitro [31] and in maintaining the ability to suppress the production of cytokines, hallmark of Treg cells, conferring suppressive capacity on CD4⁺ T cells.

In 2005, three patients were successfully treated with sirolimus [19]. Since then, 16 patients received sirolimus and nine are in complete or partial remission (Table 2). Considering that sirolimus seems to be as effective as the calcineurin inhibitors, with less toxic effects, it can be considered as a valid therapeutic option for bringing these patients to HSCT in their best clinical condition.