Sarcoidosis in Chronic Granulomatous Disease

Abstract

In addition to increased susceptibility to infections in patients with chronic granulomatous disease (CGD), a higher incidence of sterile inflammatory disorders in these patients has been noted. However, sarcoidosis has not been reported previously in CGD. In this report, we describe two patients who have CGD and a disorder consistent with sarcoidosis on the basis of unequivocal clinical-radiographic presentations, their responses to treatment, and serum angiotensin-converting enzyme levels. Serum angiotensin-converting enzyme levels were measured in 26 other patients with CGD to establish an appropriate reference range. A possible relationship between CGD and sarcoidosis is discussed. C HRONIC GRANULOMATOUS DISEASE (CGD) is a rare primary immunodeficiency with an incidence of 1 in 200 000 to 250 000 live births. 1 Mutations in any 1 of the 4 genes (CYBB, CYBA, NCF-1, or NCF-2) encoding the subunits (gp91 phox , p22 phox , p47 phox , and p67 phox , respectively) of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex result in defective production of microbicidal reactive oxidant species. 2 Patients with CGD therefore are more susceptible to recurrent suppurative infections. Granulomas, typically caseating, in the setting of infections are a hallmark of CGD. The mechanism for granuloma formation remains unclear and may be related to factors such as increased susceptibility to infections and poor clearance of microorganisms. In addition, a significant subset of patients with CGD have noninfectious inflammatory problems that are often autoimmune in character. The reason for this association is poorly understood.Sarcoidosis, a multiorgan granulomatous disease, occurs at a frequency of 1 to 50 per 100 000 individuals with a cause that remains unknown despite its first description Ͼ100 years ago. 3 The pathognomonic finding of sarcoidosis is noncaseating epithelioid granulomas, although necrosis is occasionally seen. 4 Clinically, sarcoidosis can have a spectrum of presentations and severity. 5 Pulmonary involvement is the most common, occurring in ϳ90% of the patients, mostly including bilateral hilar lymphadenopathy. 6 Extrathoracic localizations include peripheral lymph nodes, skin (erythema nodosum, and lupus pernio), eyes (uveitis, iridocyclitis, and keratoconjunctivitis), joints, liver, and spleen. Neurosarcoidosis is a serious and much more rare complication that is seen in 5% to 15% of patients. 3 In the absence of specific tests for sarcoidosis, it is essentially a diagnosis of exclusion. However, in addition to typical clinical-radiographic findings and histopathologic evidence of noncaseating granulomas, diagnosis can be supported by raised serum angiotensin-converting enzyme (ACE) levels.To date, we have been unable to identify a report of sarcoidosis in patients with CGD. Here we report a diagnostic dilemma in 2 patients with CGD and features that are compatible with sarcoidosis and not explainable by their underlying CGD and discuss possible relationships between CGD and sar...

Advances in treatment for chronic granulomatous disease

“…Patients often develop signiWcant pulmonary dysfunction due to their recurrent pneumonias and non-infectious inXammatory granulomas. Almost 10% of patients eventually require oxygen supplementation due to hypoxia [5][6][7][8][9][10][11][12][13].…”

Clinical and Histopathological Features and a Unique Spectrum of Organisms Significantly Associated with Chronic Granulomatous Disease Osteomyelitis during Childhood

“…Patients often do not display symptoms commensurate with the extent of their disease and may present for care late in the course of infection. In addition, noninfectious granulomata, a clinical manifestation of immune dysregulation, are also described in patients with CGD [6][7][8][9][10]. Interestingly, defined macroscopic and microscopic patterns have been described to suggest CGD diagnosis in some of these conditions [6][7][8].…”

“…As mentioned above, CGD is not only characterized by increased susceptibility to infectious diseases, but its altered inflammatory mechanisms are also a constitutive part of this entity. Thus, particular inflammatory patterns associated or not associated with certain types of infections should be considered a rule rather than an exception in patients with CGD [6][7][8][9][10][20][21][22].…”

X-linked primary immunodeficiencies as a bridge to better understandingX-chromosome related autoimmunity

“…Defective apoptosis and inappropriate digestion of CGD neutrophils, combined with abnormal antiinflammatory responses, may cause self-reactivity, leading to autoimmune manifestations, both in CGD patients and in carriers of X-linked CGD. Altogether, these variety of abnormalities associated with impaired NADPH oxidase activity may help explain why CGD patients are prone to autoimmune diseases, and especially to Th1-associated diseases, such as sarcoidosis [67], Crohn's disease [68], and rheumatoid arthritis [69] as well as obstructive lesions due to granulomas, discoid lupus, SLE, ITP, Kawasaki disease and Behçet syndrome [59,68,[70][71][72]. In addition, female carriers of X-linked CGD (that show random X-chromosome inactivation, and hence have both normal and mutant cells in the periphery) show increased incidence of autoimmune features, such as lupus-like cutaneous manifestations (frequently associated with photosensitivity), oral ulcers, Raynaud's phenomenon and a variety of joint symptoms (reviewed in [70,72]).…”