A 4-year-old boy is evaluated due to 4 days of fever and leg pain. Medical history includes recurrent skin abscesses and lymphadenitis. A maternal uncle died of recurrent infections during childhood. The patient is at the 10th percentile for height and weight. Temperature is 38.3 C (100.9 F). Examination shows an ill-appearing patient with point tenderness over the right lower tibia. There are healed incisions over the thighs and neck from prior drainage sites. Imaging reveals evidence of tibial osteomyelitis. Blood and bone cultures grow Serratia marcescens. Evaluation of the patient's neutrophils by dihydrorhodamine flow cytometry shows an absence of fluorescence. This patient's condition is most likely due to impaired activity of which of the following enzymes?

Question

A 4-year-old boy is evaluated due to 4 days of fever and leg pain.  Medical history includes recurrent skin abscesses and lymphadenitis.  A maternal uncle died of recurrent infections during childhood.  The patient is at the 10th percentile for height and weight.  Temperature is 38.3 C (100.9 F).  Examination shows an ill-appearing patient with point tenderness over the right lower tibia.  There are healed incisions over the thighs and neck from prior drainage sites.  Imaging reveals evidence of tibial osteomyelitis.  Blood and bone cultures grow Serratia marcescens.  Evaluation of the patient's neutrophils by dihydrorhodamine flow cytometry shows an absence of fluorescence.  This patient's condition is most likely due to impaired activity of which of the following enzymes?

Quizplus · Accepted Answer

11ec160b_3a70_6b27_9249_e38f7f4c9223_MD0001_00 This patient's abnormal flow cytometry findings are characteristic of chronic granulomatous disease (CGD), an X-linked condition caused by NADPH oxidase deficiency. NADPH oxidase is a membrane-bound complex within phagolysosomes that catalyzes the reduction of oxygen to superoxide during the respiratory burst. The production of reactive oxygen species facilitates the intracellular killing of organisms ingested by phagocytes. Patients with CGD have impaired intracellular killing, resulting in recurrent bacterial and fungal infections (eg, abscesses, lymphadenitis, osteomyelitis) caused by certain catalase-positive organisms (eg, Serratia). Diagnostic tests for CGD involve the assessment of neutrophil superoxide production: Dihydrorhodamine (DHR) testing assesses the production of superoxide radicals by measuring the oxidation of DHR to rhodamine, a fluorescent green compound that can be detected on flow cytometry. An absence of increased fluorescent intensity correlates with impaired oxidation/respiratory burst and a diagnosis of CGD. Nitroblue tetrazolium (NBT) testing involves adding NBT to a sample of the patient's neutrophils. Properly functioning neutrophils produce reactive oxygen species, which reduce the pale NBT to dark blue formazan that precipitates within the cells. The compound has no change in color in patients with CGD. (Choice A) Adenosine deaminase deficiency is an autosomal recessive disorder that causes severe combined immunodeficiency. This condition results in a profound decrease in B and T lymphocytes with variable immunoglobulin deficiencies; DHR testing would be normal. (Choice B) Cytochrome c oxidase is a multisubunit complex that acts as the terminal enzyme of the mitochondrial respiratory chain. Deficiency results in variable myopathic and encephalopathic, not infectious, findings. (Choice C) Lysozyme is an enzyme that helps destroy bacterial cell walls; deficiency increases the risk of gram-positive infections. However, a defect in lysozyme would not explain this patient's abnormal DHR testing. (Choice D) Myeloperoxidase, an enzyme found in neutrophil azurophilic granules, aids in intracellular killing by catalyzing the production of hypochlorite (bleach) from hydrogen peroxide and chloride. Although DHR testing can be abnormal in myeloperoxidase deficiency, patients are usually asymptomatic; a minority have invasive Candida infections. In contrast, this child's severe bacterial infections (lymphadenitis, abscess, Serratia osteomyelitis) make this diagnosis unlikely. Educational objective: Chronic granulomatous disease is due to NADPH oxidase deficiency, which leads to an inability of neutrophils to generate a respiratory burst and produce the reactive oxygen species necessary to kill organisms in their phagolysosomes. Absence of fluorescence on dihydrorhodamine flow cytometry testing can confirm the diagnosis. __________ References: Chronic granulomatous disease. (http://www.ncbi.nlm.nih.gov/pubmed/29630223)

A 4-Year-Old Boy Is Evaluated Due to 4 Days of Fever