Abstract
Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder that has become a model of monogenic autoimmunity. IPEX is caused by mutations in FOXP3 gene, a master regulator of regulatory T cells (Treg). Cases reported in the last 20 years demonstrate that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes (T1D) and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features (e.g., atrophic gastritis, interstitial lung disease, nephropathy etc.). Several atypical presentations have recently been reported, suggesting that IPEX incidence might be underestimated. Immunosuppression (IS) treatment strategies can control the disease, however at the moment allogeneic hematopoietic stem cell transplantation (HSCT) is the only available definitive cure, therefore it is important to achieve a prompt diagnosis. This review aims to describe unusual clinical phenotypes, beyond classical IPEX. Overall, our analysis contributes to increase awareness and finally improve diagnosis and treatment intervention in IPEX in order to ensure a good quality of life.
Highlights
Polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare congenital disorder caused by mutations in the Forkhead Box Protein 3 (FOXP3) gene, a master regulator of regulatory T cells (Treg)
We propose to further classify atypical IPEX in cases characterized by late-onset, mild disease course, no enteropathy and/or unusual clinical features
Gastrointestinal ◦ Chronic/intermittent diarrhea resistant to formula switching ◦ Early-onset IBD or treatment-resistant IBD ◦ Coeliac disease not responding to gluten-free diet
Summary
Polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare congenital disorder caused by mutations in the Forkhead Box Protein 3 (FOXP3) gene, a master regulator of regulatory T cells (Treg). Research has shed light on its clinical spectrum and molecular features, and IPEX has become a model of monogenic autoimmunity and immune dysregulation [4]. IPEX is a rare disease, more than 300 affected patients have been published so far [7], indicating an increasing awareness of the disorder [8]. Cases reported in the last two decades demonstrate that IPEX clinical spectrum is much more heterogeneous, suggesting that its incidence might be underestimated [8]. Some reported patients only present with single organ involvement [10] or display unusual clinical features [11]. Mild cases with late disease onset [12] and less severe disease course [13] have been described
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