Revisiting Fatal Granulomatous Disease of Childhood Through an Autopsy: Still Lethal in the Developing World!

Abstract

To the editor: Chronic granulomatous disease (CGD) is an inherited, functional, phagocytic disorder due to a defect in any of the proteins constituting the NADPH oxidase complex. The disease is known to result in recurrent life-threatening bacterial and fungal infections and dysregulated granulomata formation. The age at presentation is variable with cases reported in early infancy and late adulthood. However, the vast majority of cases are diagnosed before the age of 5 years. Children with X-linked CGD, especially when they present early in life tend to have a very severe disease [1], as in the index patient. A 6-month-old boy, first born to a non-consanguineous couple presented with fever for 2 months and a slowly progressive neck swelling. He also had a history of bilateral purulent ear discharge during this period. He was exclusively breastfed. His birth, development, immunization and family history were unremarkable. Examination revealed tachycardia, tachypnoea, pallor, multiple tender, non-fluctuant, nonmatted, cervical, axillary, and inguinal lymph nodes. Bilateral crepitations and hepato-splenomegaly were noted on systemic examination. Laboratory investigations revealed hemoglobin 73 g/L, total leucocyte count 11.3 × 10/L with neutrophilic predominance (80%), platelet count 714 × 10/L, an elevated erythrocyte sedimentation rate (75 mm in the 1st hour), C-reactive protein 120 mg/L, and an elevated procalcitonin (68.97 ng/mL). Fine needle aspiration of lymph node culture grew methicillin-resistant Staphylococcus aureus (MRSA). Stain for acid-fast bacilli and periodic acid-Schiff stain did not highlight the presence of any organisms. Blood cultures were sterile on multiple occasions. Work-up for tuberculosis was negative and HIV ELISA was non-reactive. Contrast-enhanced computerized tomography (CECT) of the neck and chest showed necrotic cervical lymphadenopathy, bilateral maxillary sinusitis and left parotitis, and patchy consolidation with few nodules in bilateral lungs with mediastinal lymphadenopathy, likely of infective etiology. Serum immunoglobulin profi le showed hypergammaglobulinemia; IgG 18.6 g/L (3.0–9.0 g/L), IgA 0.38 g/L (0.15–0.7 g/L), and IgM 2.75 g/L (0.4–1.6). Nitro blue tetrazolium test (NBT) showed no reduction of dye as compared to control, suggestive of the possibility of CGD. Dihydrorhodamine assay (DHR) showed a stimulation index of 1.35 as compared to a control of 132.31 confirming the diagnosis of CGD. Stimulation index or Neutrophil oxidative index is calculated by dividing the Median fluorescence intensity (MFI) of neutrophils stimulated with PMA by that of unstimulated neutrophils (SI = MFI Stimulated/MFI Unstimulated). DHR assay of the mother showed a double peak suggestive of a carrier state for X-linked CGD. b558 staining by flow cytometry showed absent expression in the patient and mosaic pattern of expression in the mother, consistent with X-linked CGD due to gp91phox defect. Genetic analysis revealed a frame-shift mutation in exon 5 of the CYBB gene (c.426delT p.E143fs158X). At admission, the * Amit Rawat [email protected]