D2.344 - Unraveling the Mysteries of Chronic Granulomatous Disease: A Case of detected Protein Deficiency Amidst Negative Genetic Screening
Case report
Background:
Chronic granulomatous disease (CGD) is a rare inborn error of immunity arising from loss-of-function mutations in the NADPH oxidase complex, crucial for the respiratory burst in phagocytes. This defect impairs the generation of reactive oxygen species, leading to inadequate pathogen clearance and resulting in severe bacterial and fungal infections, as well as granuloma formation. In regions with prevalent consanguinity, CGD typically follows an autosomal recessive inheritance pattern. Notably, approximately 50% of CGD patients develop inflammatory bowel disease (IBD) in childhood. Herein, we present a unique case of CGD-IBD in which genetic testing yielded negative results, instigating further analysis of CGD associated proteins.
Case Presentation:
A 7-year-old boy of Southeast-Asian descent, born to consanguineous parents, was referred to the immunology clinic from gastroenterology for a suspected diagnosis of CGD. His medical history included chronic constipation, recurrent abdominal pain, poor growth, diarrhea, blood in stool, and persistent iron deficiency anemia despite iron therapy. Additional symptoms included intermittent fever, oral aphthosis, and a history of infections, such as left mandibular bacterial lymphadenitis requiring surgical intervention, Entamoeba histolytica infection treated with metronidazole, and Clostridium difficile infection managed with vancomycin. There is no significant family history of Immunodeficiency.
Endoscopic evaluation revealed chronic inflammation with lymphocytic infiltrates in gastric antrum; multinucleated giant cells in the duodenum; multiple granulomas, cryptitis, and architectural distortion in the duodenum, transverse colon, and cecum, with eosinophilia in the terminal ileum. Dihydrorhodamine flow cytometry showed severe deficiency of neutrophil oxidative burst, confirming CGD suspicion. Immunoglobulin levels, lymphocyte subsets, vaccine titers, and G6PD assay were normal. Whole genome sequencing was performed but was negative for recessive or de novo variants in the coding region or splice sites of known CGD genes or other genes that could explain the phenotype. Testing for CGD protein levels detected a loss of p47-phox. Long-read sequencing identified a large intronic insertion in NCF1, which encodes p47-phox. At present, the patient is 9-years-old and clinically stable on Trimethoprim / Sulfamethoxazole and Itraconazole prophylaxis.
Discussion:
This case of CGD-IBD highlights the difficulties in detecting NCF1 mutations and the necessity of advanced genetic analysis in patients with persistent neutrophil dysfunction to confirm the diagnosis, guide treatment and mitigate mortality risk.
