Severe Gastritis in an Insulin‐dependent Child With an IPEX Syndrome

Gastric mucosal atrophy is a rare finding in children and it is seldom seen even in association with Helicobacter pylori infection (1). Atrophic gastritis predisposing to gastric tumours is observed in 20% of patients with autoimmune type 1 insulin-dependent diabetes mellitus (IDDM) patients with parietal cell antibodies (2). Evidence for type 1 diabetes being an autoimmune process is based on the presence of “diabetes autoantibodies” (3). The role of CD4+CD25+ regulatory T cells in protecting against a variety of autoimmune diseases is admitted (4). Autoimmune gastritis is a disease caused by a CD4+T cell response to the gastric H+/K+-ATPase encoded by Atp4a and Atp4b H+/K+-ATPase. In recent experimental work on mice, it is proposed that prevention of autoimmune gastritis requires extrathymic T cell deletion and suppression by regulatory T cells (5). We report the case of a boy with early IDDM who developed an extensive exfoliative gastritis progressing toward mucosal atrophy with intestinal and malpighian metaplasia. An attenuated form of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) was eventually confirmed by FoxP3 mutation. CASE REPORT The patient is the firstborn of nonidentical twin boys who was diagnosed with IDDM at the age of 22 months. Following ingestion of a “hoax” candy at the age of 8 months, he presented a profusely bleeding gastritis, sloughing of a severely damaged mucosa with exfoliating hemorrhagic pangastritis, ulcerated mucosa, severe gland distortion, and submucosal eosinophilic infiltration contrasting with normal oesophagus and duodenum. Extensive work-up using cultures, polymerase chain reaction, and serology in blood, stools, and gastric biopsies excluded infection by Helicobacter pylori, other bacteria, viruses, parasites, and fungi. Antibodies against parietal cells, intrinsic factor, salivary glands, reticulin, endomysium, extractable nuclear antigen, antinuclear antigen, smooth and striated muscle, colon, skin, β cells, thyroglobulin, glomerular basal membrane, and adrenal glands were negative. Adrenal and thyroid functions as well as gastric hydrochloric acid production were normal. The complement system, leucocytes, lymphocytes, and subclasses CD4, CD8 and acquired immunity against vaccinations were normally expressed. Concentrations of total γ-globulins IgG, IgA, IgM, and IgE were within normal ranges but with low levels of IgG2. Circulating immune complexes were not detected. On gastric biopsies, cytokine dosage showed production of interferon-γ and tumor necrosis factor-α but IL-2, IL-4, IL-5, and IL-10 were negative. Despite treatment with omeprazole and parenteral nutrition, the gastritis progressed towards an atrophic mucosa with eosinophilic infiltration of antral and fundic submucosae, lymphoid nodules, and clusters of intestinal metaplasia extending from fundus to antrum while oesophagus, duodenum, and colon remained normal. Partial endoscopic and histologic remission was observed after 4 months of immunosuppressive treatment with prednisolone. However, a prepyloric ulceration evolved into pyloric stenosis despite successful control of acid secretion with omeprazole. The patient remained under the 10th centile for height and weight and developed vitamin B12 deficiency. Temporary partial remission was obtained after a second course of parenteral nutrition, vitamin B12 supplements, and treatment with ciclosporine and high-pulse doses of prednisolone while the gastric fundus was invaded by an oesophageal-like mucosa with ciliated cells (Fig. 1). Intestinal metaplasia of the gastric mucosa represents a well-known precancerous lesion and, therefore, the efficacy of the immunosuppressive treatment was regularly checked by gastric biopsies to detect early dysplasia. Although the stomach was the only part of the digestive tract involved, a gastrectomy was long postponed because it would complicate the diabetic control of this adolescent. Finally, at the age of 15 years, because of persistent failure to thrive, poor quality of life, and potential precancerous changes of the gastric mucosa, he underwent a total gastrectomy. At the age of 16 years, he presented with steatorrhea with abnormal sweat test and low level of faecal elastase-1 together with echographic images of pancreatic atrophy, compatible with cystic fibrosis. However, the patient was heterozygous for the ΔF508del and complete sequencing of the cystic fibrosis transmembrane regulator gene did not reveal a second mutation. After a long-lasting respiratory infection he developed bronchiectasis together with hypo-γ-globulinemia currently compensated by repeated γ-globulin injections. At the age of 19 years, the diagnosis of immune dysregulation in conjunction with an endocrinopathy was reviewed in the light of new descriptions of atypical cases of IPEX. Molecular analysis confirmed an IPEX syndrome in this patient presenting a mutation of the FoxP3 gene R347H inherited from his mother. The twin brother has developed normally and is in good health (Dr L. Perroni, Laboratory of Human Genetics, Ospedali Galliera, Genova).FIG. 1: Fundic malpighian metaplasia and ciliar cells.DISCUSSION The protracted evolution of the patient is puzzling. First, his IDDM was not classical type 1 autoimmune diabetes, because he had no autoantibodies (6). Second, no extrinsic factors that could provoke the gastritis were found. An autoimmune gastritis was suspected because of the predisposition of insulin-dependent patients to autoimmune diseases and because of the partial clinical and histological response to aggressive immunosuppressive therapy although no parietal cell antibodies were detected. Nonspecific cytotoxic activity was suggested by the increased levels of γ-intestinal trefoil factor and tumor necrosis factor-α in the gastric mucosa. The patient's gastritis followed a special and severe evolution towards atrophy and dysplasia including unusual ciliated dysplasia. Such ciliated dysplasia has not only been described in gastric adenocarcinoma but also in elderly patients from the Pacific basin presenting gastric intestinal metaplasia (7) and in a model of mice lacking the H+/K+-ATPase α-subunit (8). Third, at the time of the gastritis, the serum IgG levels were normal and he expressed adequate responses to the previous vaccinations similar to a report of another IPEX case (9). When the patient developed a hypo-γ-globulinemia, a common variable immunodeficiency was considered the relevant explanation for the long evolution of his immune disease. A syndrome including IDDM, diarrhoea, haemolytic anaemia, eczematous rashes, exaggerated responses to viral diseases and pathologic evidence of autodestruction of endocrine glands was reported as early as 1982, but our patient did not correspond to the description of the clinical characteristics established from data collected in 8 of the 17 male infants of the same family who died early (10). Recently the gene FoxP3 coding for IPEX was identified (11). It maps to Xp11.23-Xq13.3, a region close to the Wiskott-Aldrich syndrome protein gene (12). Its genetic equivalence with the mutation observed in the scurfy mouse was observed. When Scurfin, the FoxP3 gene product, is absent or inactive, T cells proliferate, resulting in early-onset autoimmune disease (13). In patients with IPEX, FoxP3 mutations result in heterogeneous biological abnormalities, leading not necessarily to a lack of differentiation of CD4+ CD25+ high T regulatory cells but rather to a dysfunction in these cells and in effector T cells (14). Several mutations within this gene have been described in patients with IPEX (15) with atypical presentations and prolonged survival in boys ages 7 to 24 years, such as isolated pemphigus (16), psoriasis and alopecia (17), and isolated enteropathies (18). Another type of IPEX syndrome has also been reported without mutation of the FoxP3 gene in the sister of an affected boy: an autosomal locus can, therefore, be suspected (15). The evolution of our patient, now age 22 years, is atypical because of his unusual gastritis, long survival and late onset of pulmonary symptoms, and pancreatic insufficiency as well as sweat test compatible with cystic fibrosis, despite the absence of the usual cystic fibrosis transmembrane regulator mutations. Conclusions This unusual presentation with delayed diagnosis of IPEX offers more questions than answers, as do many other cases of the IPEX syndrome with clinical, genetic, and biological heterogeneities. The mechanism of the gastropathy leading to severe intestinal and malpighian metaplasia is another unusual poorly understood feature.