A novel mutation in NCF2 resulting in very-early-onset colitis and juvenile idiopathic arthritis in a patient with chronic granulomatous disease

Abstract

BackgroundChronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease primarily presents with recurrent infections, and patients may also present with inflammatory conditions, including noninfectious colitis, and an increased frequency of autoimmunity. We report here a patient with CGD in whom the presentation, unlike the classical presentation of CGD, was predominantly of an inflammatory and autoimmune phenotype.Case presentationA 3-year-old Pakistani female presented with bloody diarrhea since the age of 7 days, followed by the development of perianal abscesses and fistula. There was no other history of recurrent infections. The patient subsequently developed joint pain and stiffness with persistently elevated inflammatory markers and elevated anti-cyclic citrullinate peptide (anti-CCP) antibody titer. She was diagnosed with oligoarticular juvenile idiopathic arthritis and colitis. The diagnosis of CGD was later made and was based on the absence of NADPH oxidase activity in the patient’s neutrophils upon phorbol myristate acetate (PMA) stimulation using the dihydrorhodamine-1,2,3 (DHR) flow cytometry test. Targeted next-generation sequencing revealed an unreported deletion mutation in exon 10 as a homozygous loss-of-function variant of the human neutrophil oxidase factor 2 (NCF2) (NCF2: NM_001190789, nucleotide change: c.855_856del:p.T285fs). The gene encodes a protein subunit, p67phox, in the NADPH enzyme complex.ConclusionsThe case emphasizes the importance of maintaining high clinical suspicion of immunodeficiency and CGD in patients with very-early-onset colitis and autoimmune disorders. This case is important due to its rarity and because it might represent a previously undiscovered mutation, which is possibly more common in the patient’s ethnic group. Other mutations in NCF2 have been linked to inflammatory bowel disease and autoimmunity, but without CGD, suggesting similarities in the pathogenesis.

A novel variant in the neutrophil cytosolic factor 2 (NCF2) gene results in severe disseminated BCG infectious disease: A clinical report and literature review

“…The gastrointestinal organs are most frequently affected by inflammation (Magnani et al, 2014; Rosenzweig, 2008), and noninfectious colitis is considered a common finding in CGD. Well‐defined immune‐mediated diseases are also reported in patients with CGD, such as systemic lupus erythematous, discoid lupus, and juvenile rheumatoid arthritis, among others (AlKhater, 2019; de Ravin et al, 2008). Various immunological mechanisms have been found to play a role in favoring the development of inflammation and granulomas in CGD patients (Petersen & Smith, 2013; Rosenzweig, 2008).…”

“…Many variants in the NCF2 gene leading to CGD with a range in severity have been identified (Table 2) (AlKhater, 2019; Baba et al, 2014; Badalzadeh et al, 2012; Bakri et al, 2009; Ben‐Farhat et al, 2016; Chou et al, 2015; El Kares et al, 2006; Gentsch et al, 2010; Kannengiesser et al, 2008; Koker et al, 2009, 2013; Martel et al, 2012; Raptaki et al, 2013; Roesler et al, 2012; Roos et al, 2014; Teimourian, de Boer, & Roos, 2010; Vignesh et al, 2017; Wu, Wang, Zhang, & Chen, 2017). Part of this variability is due to the residual activity of the p67 phox protein as observed in patients with an Ala202Val substitution (Koker et al, 2013; Roos et al, 2014) or in patients with a splice variant that deletes exons 11 and 12 (Roesler et al, 2012), all of which have a less severe form of CGD with a delayed onset compared with p67 phox null mutations (Table 2).…”

“…Part of this variability is due to the residual activity of the p67 phox protein as observed in patients with an Ala202Val substitution (Koker et al, 2013; Roos et al, 2014) or in patients with a splice variant that deletes exons 11 and 12 (Roesler et al, 2012), all of which have a less severe form of CGD with a delayed onset compared with p67 phox null mutations (Table 2). There have been reports that partially active p67 phox is associated with an inflammatory phenotype (AlKhater, 2019; Chou et al, 2015; Muise et al, 2012). The gastrointestinal organs are most frequently affected by inflammation (Magnani et al, 2014; Rosenzweig, 2008), and noninfectious colitis is considered a common finding in CGD.…”

Current status of use of high throughput nucleotide sequencing in rheumatology

“…Applications for WES and targeted DNA (panel) sequencing (n=169, 24%) include identification of pathogenic mutations (mostly point mutations, small insertions and deletions) that can aid in diagnosis of monogenic autoinflammatory diseases and vasculitis, 48 FMF, 49 gout 50 or familial RA, SLE and primary Sjögren’s syndrome 51 or Uveitis. 52 Of note, while HTS assays are powerful tools for large cohorts, we find many case reports using WES and gene panel sequencing in, for example, in a young patient with cutaneous vasculitis 53 or JIA, 54 as well as in a patient with RA experiencing immune dysregulation syndrome after abatacept therapy. 55 …”

Neutrophil cytosolic factor 2 (NCF2) gene polymorphism is associated with juvenile‐onset systemic lupus erythematosus, but probably not with other autoimmune rheumatic diseases in children

“…In addition to CGD, a number of studies provide evidence that changes in the NCF2 gene sequence may be associated with the development of lupus and lupus‐like diseases (Jordan & Baxter, 2020), less commonly with inflammatory bowel disease (O’Neill et al, 2015), coeliac disease (Gutierrez‐Achury et al, 2016), systemic sclerosis (Márquez et al, 2018) and juvenile idiopathic arthritis (JIA). The latter was found in a patient with CGD (AlKhater, 2019). All these diseases are autoimmune and are characterized by impaired immunological tolerance.…”