Demographic Features
In this study, 22 children with VEO-IBD were all identified as IL10RA gene mutations, all patients were born in 8 different provinces in northern China and were unrelated. Among the 22 patients, 12 were male and 10 were female, the median age of diagnosis was 170 (IQR: 67.5–473.5) days, consanguineous marriage was denied in all patients. Three patients had a positive family history (13.6%, 3/22).
Genotypes of IL-10RA
All of the 22 patients were identified with IL10RA mutations, and among them, 4 patients (18.2%, 4/22) had homozygous mutations, 18 patients (81.8%, 18/22) had compound heterozygous mutations (Table 1). Altogether, 11 mutant sites were detected in IL10RA. Among the identified IL10RA mutations, 10 mutations had been previously described, including c.C301T (p.R101W), c.G537A (p.T179T), c.349C>T(p.R117C), c.436_437CC>G(P.146fs), c.251C>T(p.T84I), c.493C>T(p.R165X), c.106G>A(p.A36T), c.269T>C( p.L90P), c.299T>G(p.V100G), c.205T>C(p.W69R). 1 novel mutation was identified c.635G>C (p.R212P). Among the patients with IL10RA mutations, c.C301T (p.R101W) (86.4%, 19/22) and c.G537A (p.T179T) (36.4%, 8/22) were the most common mutations. We identified 4 patients (18.2%, 4/22) with same IL10RA p.R101W homozygous mutations, and 6 patients (27.3%, 6/22) had same compound heterozygote IL10RA p.R101W/p. T179T mutations. All patients were born in unrelated families. Parents were heterozygotes for the mutation in all our patients.
Characteristics of the IL10RA Mutations
Among these patients, 81.8% (18/22) of patients had onset of disease within 1 month after birth, all of these patients showed symptoms within 6 months of life, the median age of onset of symptoms, including diarrhea, fever and oral ulcer, was 8.5 (IQR: 3.0–24.0) days. Regarding the first symptoms experienced by the patients, diarrhea, fever and oral ulcers were experienced in 81.8% (18/22), 50% (11/22) and 22.7% (5/22) of patients, respectively. The time of onset of diarrhea, fever and oral ulcers were 6.5(IQR: 2.5-16.0)days, 10(IQR:9.0-19.0) days and 13.4±6.39 days, respectively.
Furthermore, all patients had diarrhea, whereas 68.2% (15/22) patients reported hematochezia and 95.5% (21/22) had fever. 77.3% (17/22) of patients suffered from perianal lesions, including fissure, skin tag, abscess, perianal fistula, rectoperineal fistula, rectovaginal fistula and rectovestibular fistula. Among the 22 patients, perianal abscess was identified in 10 patients (45.5%), perianal fistula was found in 8 (36.4%) patients, 5(22.7%) patients had rectoperineal fistula, 1 patient presented with rectovaginal fistula, and rectovestibular fistula was detected in 1 patient. For other extra-intestinal involvement, 16 patients (72.7%) had skin rash, 1 patient (4.5%) had arthritis, and oral ulcers were experienced by 63.6% (14/22) of the patients.
The average weight-for-age Z score and height-for-age Z score on initial diagnosis were -2.07(IQR: -2.61~-1.78) and -1.74±1.34 respectively.
Laboratory Testing
The patients displayed increased white blood cell counts (17.21×109/L, [IQR:11.64-19.95]) (reference value: 4-10×109/L), platelet counts (554.64±238.54×109/L) (reference value: 100-400×109/L), C-reactive protein (87.36±57.39mg/L) (reference value < 8 mg/L), and erythrocyte sedimentation rate (23 mm/h, [IQR:9-63.5]) (reference value < 15 mm/h) and low expression of hemoglobin (78.5±11.96g/L) (reference value: 110-160 g/L), albumin (24.84±6.62g/L) (reference value: 33-55 g/L).
Endoscopic and Pathologic Analysis
In this study, 14 patients underwent gastroscopy and 20 patients received colonoscopy, 2 patients underwent surgery due to intestinal perforation and intestinal necrosis respectively before endoscopy because of their critical condition. Patients showed prominent colonic involvement(95.5%, 21/22), there was no patient had ileocolonic disease. Only 2 patients had gastric ulcer and duodenal ulcer, 1 patient had small bowel involvement. For disease behavior, 16 patients (16/22, 72.7%) had nonstricturing and nonpenetrating disease, 4 patients (4/22, 18.2%) suffered from penetrating disease and 2 patients (2/22, 9.1%) had stricturing disease found on colonoscopy.
Colonoscopy revealed that colonic aphthous and deep ulcers and deep were common (85%, 17/20), and cobblestone change was found in 5 patients (25%, 5/20). Typical histopathological evaluation showed unspecific acute or chronic colitis with multiple ulcerations, crypt structural deformation, cryptitis, and crypt abscess.
Treatment and Prognoses
During this process, all patients received antibiotics. 20 patients (90.9%, 20/22) received enteral nutrition, 13 patients (59.1%, 13/22) were transfused with concentrated red cells and albumin, and 8 patients (36.4%, 8/22) had immune globulin transfusion. 5 patients were treated with steroids, but colonic inflammation persisted despite steroid medication. 4 patients were treated with thalidomide (1.5–2mg/kg. d, adjusted dose according to treatment effect), 1 patient received both infliximab and thalidomide, no adverse effects of thalidomide have been identified in these patients.
4 patients (18.2%, 4/22) had experienced surgery during the course. Among them, 3 patients underwent enterostomy because of intestinal perforation, perianal diseases and intestinal necrosis, intestinal perforation repair was performed in 1 patient. 2 patients underwent umbilical cord blood transplantation (UCBT) in Children’s Hospital of Fudan University, Shanghai.
As of April 1, 2020, 2 patients lost to follow-up, 9 patients were dead, the mortality rate was 45% (9/20), and 11 patients (55%, 11/20) were alive. Among the 11 patients, 2 patients remained stable and showed no gastrointestinal symptoms after UCBT, 1 patient achieved sustained clinical remission receiving thalidomide, 2 patients were clinically improved with thalidomide, and clinical improvement was also achieved in 1 patient with exclusive enteral nutrition (EEN). The remaining 5 patients still had recurrent disease activity. None of the patients developed lymphoma.