In this case, the heterozygous and de novo mutation c.388 C > T(p.R130X)was located in the second exon of
CYBB gene and generated a premature stop codon, which was determined to be a pathogenic variant according to American College of Medical Genetics and Genomics guidelines.
CYBB encodes the gp91 subunit of NADPH oxidase, and mutations impair the respiratory burst of all types of phagocytes [
7]. The mutation was absent from her parents. and her parents had the normal neutrophil function. No mutation could be found on the patient’s other
CYBB allele. Nevertheless, we had to consider two possibilities: The patient could have been compound heterozygous with a mutation on the second
CYBB allele outside the sequenced regions or the patient’s cells could have had an extremely skewed X chromosome inactivation pattern. An example was described before a female with a de novo mutation in gp91-phox coinciding with an extreme X chromosome inactivation ratio resulted in X-linked CGD [
8]. However, X chromosome inactivation pattern was not assessed due to the lack of recipient’s blood stored before HSCT. At present, X chromosome inactivation pattern might be performed on other somatic tissues, but the parents are not willing to do any more tests. Mutations in
CYBB have been documented in multiple patients with X-CGD [
9]. Patients with CGD usually present with recurrent or severe infections; the most common sites are the lungs, skin, and lymph nodes [
10]. In our case, a mutation was identified in our patient, who presented with disease onset at a young age. The clinical manifestations were recurrent hematochezia and abdominal pain, and abnormal findings were found during the diagnostic workup (respiratory burst test and immunoglobulin test). The patient had a history of lymph node abscess prior to admission, and the white blood cell count was slightly higher, although the inflammatory markers were within normal range, probably related to antibiotic use prior to admission at our institution. Indeed,
CYBB deficiency is an X-recessive disease, usually not clinically expressed in females. However, it is also plausible that common single nucleotide polymorphism in
CYBB alter the expression or function of gp91-phox, determining differences in susceptibility to complex disorders such as autoimmune or infectious diseases [
11]. In contrast, Shahram and colleagues [
12] reported a case with a mutation at the same site. The male child with consanguinous parents was diagnosed with chronic granulomatosis when he was 3 years old. He developed recurrent infections such as disseminated bacillus Calmette-Guérin (BCG) infection, otitis media, perianal abscess, pneumonia, and pulmonary abscess. The respiratory burst test showed the inability of phagocytes to generate ROS. He also had a maternal cousin with CGD. Therefore,
CYBB mutations lead to clinical heterogeneity. Interestingly, although mutations of the same gene and site yield different clinical phenotypes, similarities prevail, including elevated inflammatory markers, abscess formation and dysfunction of phagocytes.
VEO-IBD accounts for 6-15% of children’s IBD [
13]. Recent epidemiologic evidence suggests that the incidence of pediatric IBD is increasing, especially in VEO-IBD [
14]. Early diagnosis is often challenging since the symptoms are atypical with younger age. Our case was initially misdiagnosed as cow’s milk protein allergy, leading to delayed diagnosis and treatment. It has been established that IBD has a multifactorial pathogenesis. Recent studies have suggested that VEO-IBD is associated with monogenic mutations [
15]. Currently, IL-10 receptor deficiencies are the most common in China, and patients often present with severe ileocolonic inflammation and are often complicated with severe anal fistula [
16]. A study in China [
17] reported 39 cases of infant IBD, including 33 cases (85%) with moderate or severe disease activity index scores, resulting in 10 cases of death during the neonatal period. Accordingly, emphasis should be placed on avoiding misdiagnosis of allergies or infections in cases with recurrent diarrhea, hematochezia and malnutrition, especially those with early-onset age and VEO-IBD should be suspected. Indeed, further research is warranted to elucidate the features and mechanisms of this disease to improve the diagnostic and therapeutic efficacy rates.
Current evidence suggests that HSCT can heal intestinal mucosa, relieve clinical symptoms, and restore mitochondrial activity in phagocytes [
18], consistent with our findings. HSCT represents a definitive cure for patients with
CYBB mutations and IL-10 receptor deficiencies [
19]. However, HSCT in IBD patients with
IKBKG and
TTC7A mutations can cause GVHD, severe infection, and even intestinal atresia [
20]. Therefore, to achieve accurate treatment, it is necessary to ascertain whether gene mutations are present in VEO-IBD patients before treatment.
Moreover, genetic syndromes, such as Turner syndrome, Down syndrome, and glycogen storage disease type Ib, mainly characterized by chromosomal abnormalities, can present with IBD or are at high risk of developing IBD [
21]. Therefore, the diagnosis should not be limited to clinical, endoscopic and pathological findings for patients with recurrent gastrointestinal symptoms in the early postnatal period. Indeed, a genetic analysis should be conducted to determine monogenic mutations, and early diagnosis and treatment should be performed. Importantly, HSCT can achieve a good therapeutic effect for patients with VEO-IBD caused by
CYBB gene mutation. Our study contributes to the understanding of the rare disease and provides the foothold for further studies to improve the long-term prognosis of this patient population by improving the diagnosis and treatment efficacy rates. Only one patient was discussed in the present study. Further studies with more patients and longer follow-ups are warranted to improve current knowledge on such rare diseases.