**1. Introduction**

Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobin E (IgE) mediated food hypersensitivity disorder that primarily affects formula-fed infants and young children [1,2]. The clinical manifestation of FPIES is characterized by profuse and repetitive vomiting, usually occurring within a few hours of feeding, accompanied by lethargy and pallor; diarrhea may also occur within 24 h. Symptoms usually resolve hours after the elimination of the causative food from the diet. Infants who consume foods such as cow's milk or soy-based formula daily may experience chronic weight loss and failure to thrive [3]. FPIES is considered part of a spectrum of allergic diseases that affect only the gut [4]. Although the true incidence of FPIES is not known, large population-based cohort studies from Israel and Spain have reported the cumulative incidence of cow's milk FPIES to be 0.34% and 0.35%, respectively [5,6]. Furthermore, the lifetime prevalence of physician-diagnosed FPIES was reported in the United States, with an estimated prevalence of 0.51% [7]. Because FPIES can be diagnosed clinically and an intestinal biopsy is not performed routinely, little is known about this condition. Specifically, the pathophysiology of FPIES has not been clearly defined and requires further characterization [4].

**Citation:** Okazaki, F.; Wakiguchi, H.; Korenaga, Y.; Takahashi, K.; Yasudo, H.; Fukuda, K.; Shimokawa, M.; Hasegawa, S. Food Protein-Induced Enterocolitis Syndrome in Children with Down Syndrome: A Pilot Case-Control Study. *Nutrients* **2022**, *14*, 388. https://doi.org/ 10.3390/nu14020388

Academic Editor: Carla Mastrorilli

Received: 21 December 2021 Accepted: 13 January 2022 Published: 17 January 2022

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Several immunological alterations have been reported to be associated with FPIES. Previous studies have suggested the involvement of antigen-specific T cells and their production of proinflammatory cytokines that regulate the permeability of the intestinal barrier [8]. A recent study showed that the levels of transforming growth factor (TGF) β and interleukin (IL)-10 were significantly lower in children with FPIES than in those with tolerance acquisition [4,6,8]; therefore, TGF-β and IL-10 were proposed as potential biomarkers of FPIES [4,9].

Down syndrome (DS) is caused by a trisomy of human chromosome 21 and occurs in approximately one in 1000 newborns [10–12]. Because the immune system in individuals with DS is altered, accompanied by signs of deficiency and dysregulation, there is a high incidence and prevalence of autoimmune diseases among such individuals [13]. A recent cohort study revealed a lower percentage of allergic sensitization in children with DS than in healthy controls, and no DS children aged 0–2 years had allergic sensitization [14].

We have previously reported two DS children with FPIES [15]. The clinical course of FPIES suggested that this condition may be more severe and require a longer duration to establish tolerance in DS children than in those without DS. However, little is known about the clinical features of FPIES in patients with DS. This study aimed to clarify the clinical features of FPIES in children with DS.
