Hematopoietic stem cell transplantation for CYBB heterozygous mutation resulting in very early onset inflammatory bowel disease in children: a case report

Abstract

Background: Inflammatory bowel disease (IBD) is a heterogeneous group of disorders associated with environmental triggers and dysregulated immune responses resulting in chronic, recurrent intestinal inflammation. Very early-onset IBD (VEO-IBD) refers to patients with symptoms or diagnosis before the age of 6 years and is widely thought to be associated with monogenic mutations. Traditional drug therapy is often ineffective in this patient population, while hematopoietic stem cell transplantation (HSCT) represents the definitive cure for patients with gene mutations.

Case presentation: We report a case of VEO-IBD associated with a monogenic mutation in a 2-year-old girl presenting mainly with gastrointestinal symptoms, including recurrent hematochezia and abdominal pain for more than 3 months. A gastroscopy revealed erosive gastritis and bulbar duodenitis, while a colonoscopy indicated erosive colitis. Abnormal results were obtained from the dihydrohodamine (DHR) assay and immunoglobulin testing. Whole-exome sequencing identified a heterozygous and de novo nonsense mutation (c.388 C > T; p.R130X) in the CYBB gene leading to deficiency of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) (encoded by CYBB), a critical component of phagocytes. HSCT was performed successfully, and the DHR assay showed that normal neutrophil function was restored. Six months after HSCT, clinical remission was observed, and a repeat colonoscopy revealed intestinal mucosal healing was attained.

Conclusions: Patients with CYBB mutations often develop recurrent or severe bacterial or fungal infections, mostly in the lungs, skin, lymph nodes, and liver. Here, we report on a young female child with CYBB mutations presenting predominantly with gastrointestinal symptoms. This study explores the mechanisms of inflammatory bowel disease caused by a monogenic mutation in CYBB to improve early diagnosis and effective treatment rates of this patient population.

Keywords: CYBB; Children; Dihydrorhodamine assay; Gene mutations; Hematopoietic stem cell transplantation; Very early-onset inflammatory bowel disease.

Fig. 1

The represented endoscopy images before and after hematopoietic stem cell transplantation. (A) Endoscopy images characteristics as mucosal erythema and erosions in gastric antrum and colon before hematopoietic stem cell transplantation. (B) Endoscopy images showed gastric antrum and colonic mucosa erythema and erosion disappear after hematopoietic stem cell transplantation

Fig. 2

DHR histogram of the patient and his parents’ granulocytes. The histogram and stimulation index (SI) of the patient’s granulocytes (2 A) demonstrated a typical X-CGD pattern. The DHR of her mother’s granulocytes (2B) and her father’s granulocytes (2 C) demonstrated a normal histogram

Fig. 3

CYBB gene sequencing and parental verification results of child A: There was a heterozygous mutation of c.388 C > T in the CYBB gene (p.R130X), which was a de novo mutation. B (father of the child) and C (mother of the child) revealed no variation during sequencing. Arrows indicate mutation sites

Fig. 4

DHR assay after HSCT. DHR assay of granulocytes from the patient at 8 weeks after HSCT (4 A) showed abnormal histogram with the SI of 28.85, 16 weeks after HSCT (4B) showed normal histogram with the SI of 408.90, the normal neutrophil function was restored