Introduction: We report the case of a 17-year-old female with pediatric systemic lupus erythematosus (pSLE) diagnosed at 7 years of age. At age 12, she developed recurrent and refractory thrombocytopenia that has been managed with rituximab. Her infectious disease history includes bacteremia and pneumonia due to Streptococcus pneumoniae, along with recurrent urinary tract infections, herpes simplex virus blepharitis, persistent right eyelid hordeolum, facial folliculitis, and an episode of multiple skin abscesses located on the neck, axillae, and chest.
Methods: Trio Whole-exome sequencing was performed.
Results: The patient was found to have biallelic variants in NCF4. One variant, p.R58C, has been previously shown to cause p40phox deficiency. The second variant, c.824+1G>A, is novel and expected to cause a loss of the donor splice site. NCF4 encodes for the p40phox protein, which is part of the cytosolic subunit of the NADPH oxidase complex. Loss-of-function variants in p40phox are associated with an autosomal recessive, mild form of Chronic Granulomatous Disease (CGD), characterized by variable hyperinflammation, autoimmunity, and peripheral infections but no invasive infections. This genetic result prompted a more in-depth investigation of CGD. A Dihydrorhodamine test (DHR) was performed to evaluate neutrophil oxidative burst. The patient’s DHR showed a significantly decreased stimulation index using PMA. Further neutrophil evaluation showed that neutrophils from the patient had severely impaired oxidative burst upon stimulation with zymosan and S. aureus, confirming the cellular phenotype seen in p40phox deficient patients.
Conclusions: Here, we present the first case of a patient with pSLE harboring biallelic variants in the NCF4 gene. This case offers a unique clinical presentation of autoimmunity associated with a rare genetic etiology of CGD, confirming the relationship between defective oxidative burst and autoimmunity. Nonclassical presentations of inborn errors of immunity and severe or refractory phenotypes continue to require multidisciplinary care and investigation.
