Chronic Granulomatous Disease Due to Neutrophil Cytosolic Factor (NCF2) Gene Mutations in Three Unrelated Families

Vignesh, Pandiarajan; Rawat, Amit; Kumar, Ankur; Suri, Deepti; Gupta, Anju; Lau, Yu Lung; Chan, Koon Wing; Singh, Surjit

doi:10.1007/s10875-016-0366-2

Cited by 11 publications

(9 citation statements)

References 12 publications

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Section: Discussionsupporting

confidence: 87%

“…Similar to our case, Vignesh et al [22] described three patients from India with a diagnosis of CGD due to NCF2 defects. All 3 patients had signs of colitis from early infancy, while in two of the three cases, colitis was an initial presenting feature of the disease [22]. One child, a 2-year-old boy, who was ill since birth and developed fulminant colitis at 1½ years, had a homozygous deletion in NCF2 (c835_836delAC:p. T279fsX294), which resulted in a stop codon in exon 10 and reduced expression of the p67 phox protein.…”

Section: Discussionsupporting

confidence: 87%

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

AlKhater

2019

Allergy Asthma Clin Immunol

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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.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 87%

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

AlKhater

2019

Allergy Asthma Clin Immunol

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“…NCF2 gene variants were more common in patients from North India (15/22; 68.1%) compared to patients from West or South India (7/22; 31.9%). Majority of the patients with NCF2 gene variants from North India (10/15; 66.7%) had a common dinucleotide deletion in exon 9 (c.835_836delAC; p.Thr279GlyTer16) ( 31 ) of the gene resulting in alteration of the reading frame and termination ( Figures 3 , 4 ). CYBA gene variants in contrast were exclusively seen in patients from South and West India.…”

Section: Resultsmentioning

confidence: 99%

Clinical, Immunological, and Molecular Profile of Chronic Granulomatous Disease: A Multi-Centric Study of 236 Patients From India

et al. 2021

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BackgroundChronic granulomatous disease (CGD) is an inherited defect in phagocytic respiratory burst that results in severe and life-threatening infections in affected children. Single center studies from India have shown that proportion of autosomal recessive (AR) CGD is more than that reported from the West. Further, affected patients have high mortality rates due to late referrals and difficulties in accessing appropriate treatment. However, there is lack of multicentric collaborative data on CGD from India.ObjectiveTo describe infection patterns, immunological, and molecular features of CGD from multiple centers in India.MethodsA detailed proforma that included clinical and laboratory details was prepared and sent to multiple centers in India that are involved in the care and management of patients with inborn errors of immunity. Twelve centers have provided data which were later pooled together and analyzed.ResultsOf the 236 patients analyzed in our study, X-linked and AR-CGD was seen in 77 and 97, respectively. Male female ratio was 172:64. Median age at onset of symptoms and diagnosis was 8 and 24 months, respectively. Common infections documented include pneumonia (71.6%), lymphadenitis (31.6%), skin and subcutaneous abscess (23.7%), blood-stream infection (13.6%), osteomyelitis (8.6%), liver abscess (7.2%), lung abscess (2.9%), meningoencephalitis (2.5%), splenic abscess (1.7%), and brain abscess (0.9%). Forty-four patients (18.6%) had evidence of mycobacterial infection. Results of molecular assay were available for 141 patients (59.7%)—CYBB (44.7%) gene defect was most common, followed by NCF1 (31.9%), NCF2 (14.9%), and CYBA (8.5%). While CYBA variants were documented only in Southern and Western parts of India, a common dinucleotide deletion in NCF2 (c.835_836delAC) was noted only in North Indian population. Of the 174 patients with available outcome data, 67 (38.5%) had expired. Hematopoietic stem cell transplantation was carried out in 23 patients, and 12 are doing well on follow-up.ConclusionsIn India, proportion of patients with AR-CGD is higher as compared to Western cohorts, though regional differences in types of AR-CGD exist. Clinical profile and mortality rates are similar in both X-linked and AR-CGD. However, this may be a reflection of the fact that milder forms of AR-CGD are probably being missed.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

AlKhater

Deswarte

Casanova

et al. 2020

Molec Gen & Gen Med

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Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder (PID) affecting NADPH oxidase activity. The rarest form of the disease is considered to be caused by NCF2 gene bi‐allelic variant. Here, we report the clinical and molecular characterization of a patient presenting with early‐onset severe disease due to bi‐allelic NCF2 variant. Methods Gene mutational analysis was performed by whole‐exome and Sanger sequencing. Results The patient presented with a history of fever and rash since the age of 1 month, followed by destructive osteomyelitis and necrotizing lymphadenopathy. The patient received the Bacillus Calmette‐Guérin (BCG) vaccine at birth; she was subsequently diagnosed with disseminated BCG infection. Whole‐exome sequencing identified a private (unreported) homozygous variant in NCF2 (c.290C > A) that results in a nonconservative change, p.Ala97Asp, in the p67phox protein. The variant is located in the third helix of the TRP domain, which is crucial for the binding of GTPase RAC2 to the NADPH oxidase complex. Conclusion We identified a novel NCF2 variant located in the region interacting with RAC2 that is linked to a severe and early CGD phenotype in the setting of disseminated BCG infection. Our findings support postponing BCG vaccination until 6–12 months of age and after PID assessment.

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Chronic Granulomatous Disease Due to Neutrophil Cytosolic Factor (NCF2) Gene Mutations in Three Unrelated Families

Cited by 11 publications

References 12 publications

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

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

Clinical, Immunological, and Molecular Profile of Chronic Granulomatous Disease: A Multi-Centric Study of 236 Patients From India

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

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