Inherited p40phox Deficiency Differs From Classic Chronic Granulomatous Disease

Abstract

To characterize clinical and laboratory aspects of p40phox deficiency, a unique autosomal recessive form of chronic granulomatous disease (CGD) previously described in only 1 patient.The population included 24 patients with p40phox deficiency from 12 families in 8 countries. Both male and female patients are reported, with age ranging from 1 to 47 years.Clinical history of each case was collected, including autoinflammatory manifestations and infection history. Laboratory analysis included both gene sequencing and numerous functional studies of the immune system.Mean age at diagnosis for symptomatic patients was 15 years (range: 1–46 years). Twenty patients were symptomatic. Four were asymptomatic (age 1–10 years, recognized by family history). Of the symptomatic patients, skin inflammation was present in 50%, and granulomatous gastrointestinal manifestations were present in 50%, with varied presentation from oral ulcers to severe Crohn-like inflammatory bowel disease. Cutaneous infections were reported in 42%. The phorbol myristate acetate–induced dihydrorhodamine (DHR) oxidation test gave normal or just below normal results for all patients.Excessive inflammatory lesions of the skin (lupuslike) and gastrointestinal tract (Crohn-like) are common in patients with p40phox deficiency. Compared with classic CGD, it is often diagnosed later in life and demonstrates a normal DHR laboratory test result (the laboratory test widely used for diagnosis of CGD). Patients experience peripheral bacterial infections, but fungal infections and invasive infections of any type are not common. Identification of 4 asymptomatic children demonstrates that there is incomplete clinical penetrance, at least until adolescence.It is essential for pediatricians to be aware of this disease and how it differs from classic CGD. Patients may be under their care who have been managed by other subspecialists (dermatology, rheumatology, gastroenterology) but have never been recognized to have an underlying p40phox deficiency. Additionally, immunologists are only recently learning that this form of CGD is not detectable by routine DHR. Therefore, if a patient has clinical signs and symptoms that fit the diagnosis, immunology consultation is warranted even if the immune system has been evaluated in the past. Genetic testing should be considered to confirm the diagnosis.