**3. Results**

Among 43 children with DS, five (11.6%) were diagnosed with FPIES (Figure 1). In the FPIES and non-FPIES groups, sex, gestational age, and median birth weight were approximately the same (Table 1). In the FPIES and non-FPIES groups, more than 60% of children were born by vaginal delivery. Neonatal asphyxia was observed in less than one-fourth, and neonatal jaundice in approximately half of the children. Neonatal asphyxia in this study was defined as an Apgar score ≤7 at one min after birth, and neonatal jaundice was defined as requiring phototherapy. There were no breast milk-only infants in either group, and mixed feeding infants accounted for approximately 80% of the total children in both groups.

**Table 1.** Demographic characteristics of children with DS.



**Table 1.** *Cont.*

ASD, atrial septal defect; AVSD, atrioventricular septal defect, DORV, double outlet right ventricle; DS, Down syndrome; FPIES, food protein-induced enterocolitis syndrome; PDA, patent ductus arteriosus; PVP, pulmonary valve prolapse; TAM, transient abnormal myelopoiesis; TOF, tetralogy of Fallot; VSD, ventricular septal defect. † Fisher's exact test. ‡ Mann–Whitney U test.

Comorbidities of cardiac disease, gastrointestinal disease, and hematological disorder were found in most children with DS in both groups (Table 1). There was no significant difference in comorbidities between the two groups; however, gastrointestinal disease was more common in the FPIES group (40.0% vs. 10.5%, respectively, *p* = 0.136). There was no significant difference in the total surgical history of children with DS between the two groups; however, surgery for gastrointestinal disease was more common in the FPIES group (Table 2). Furthermore, the surgical history of colostomy was significantly higher in the FPIES group than in the non-FPIES group (40.0% vs. 2.6%, respectively, *p* = 0.032).

**Table 2.** Surgical history of children with DS.


BT, Blalock-Taussig; DS, Down syndrome; FPIES, food protein-induced enterocolitis syndrome; PA, pulmonary artery. † Fisher's exact test. § Two of them underwent surgery for either intracardiac repair or BT shunt. \* Significant at *p* < 0.05.

The serum total IgE levels were determined in all children less than 12 months of age in the FPIES group and six of 38 children in the non-FPIES group (Table 3). The median serum total IgE levels were less than the detection limit (<11 IU/mL) in both groups, and there was no significant difference between the groups. The antigen-specific IgE levels were less than the detection limit (<0.35 kUA/L) in all children in the FPIES group (Table 4), while they were not determined for the non-FPIES group.

**Table 3.** Serum total IgE level in children with DS.


DS, Down syndrome; FPIES, food protein-induced enterocolitis syndrome; IgE, immunoglobin E. † Fisher's exact test. ‡ Mann–Whitney U test.


**Table 4.** Clinical features of FPIES in children with DS.

ASD, atrial septal defect; AVSD, atrioventricular septal defect; CM, cow's milk formula; DS, Down syndrome; FPIES, food protein-induced enterocolitis syndrome; IgE, immunoglobin E; N/A, not applicable; PA, pulmonary artery; TAM, transient abnormal myelopoiesis; TOF, tetralogy of Fallot.

In the FPIES group, the median age of onset in five cases was 84 days (Table 4). The causative foods were cow's milk formula in four cases and wheat in one case. Repetitive vomiting and diarrhea were observed in all five cases. Bloody stools and abdominal distension were observed in two cases. Fever and metabolic acidosis were observed in four cases. Severe dehydration was observed in two cases with metabolic acidosis. In the case of severe dehydration, the causative food was cow's milk formula. All five cases were diagnosed as severe according to the guidelines [16], and the patients required infusion.

Cardiac disease was observed in three cases. In Case 2, pulmonary artery banding was performed 50 days after birth for pulmonary hypertension with tetralogy of Fallot. Thirty-four days after the surgery, the brand of formula milk was changed, and vomiting and bloody stool appeared. Intracardiac repair was performed at the age of 12 months for tetralogy of Fallot. In Case 4, the patient did not require surgery for atrial septal defect. In Case 5, intracardiac repair was performed at the age of 19 months for atrioventricular septal defect. Gastrointestinal disease was observed in two cases. In Case 4, colostomy was performed 63 days after birth for rectovaginal fistula. In Case 5, colostomy was performed 1 day after birth for imperforate anus. The postoperative nutrition was formula milk for both cases. In Cases 4 and 5, the closure of colostomy was performed at the age of 23 months and 16 months, and tolerance was acquired at 49 months and 18 months of age, respectively. In Case 3, there were multiple episodes of repetitive vomiting after ingestion of wheat food, such as "udon" noodles and pancakes, at 10 months of age. Case 3 was a recent case in which the parent did not agree to the second oral food challenge; therefore, we could not confirm the acquisition of tolerance. In Case 1, the oral food challenge was performed six times, and finally, it took 11 years for the subject to acquire tolerance to cow's milk formula. The median age of tolerance in the four cases was 37.5 months.
