Abstract
Chronic granulomatous Disease (CGD) is a rare innate immunodeficiency disorder caused by mutations in one of the six genes (CYBA, CYBB, NCF1, NCF2, NCF4, and CYBC1/EROS) encoding the superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH)—oxidase complex in phagocytes. In the Western population, the most prevalent form of CGD (about two-thirds of all cases) is the X-linked form (X-CGD) caused by mutations in CYBB. The autosomal recessive forms (AR-CGD), due to mutations in the other genes, collectively account for the remaining one-third of CGD cases. We investigated the clinical and molecular features of 22 Jordanian, 7 Libyan, and 2 Iraqi CGD patients from 21 different families. In addition, 11 sibling patients from these families were suspected to have been died from CGD as suggested by their familial and clinical history. All patients except 9 were children of consanguineous parents. Most of the patients suffered from AR-CGD, with mutations in CYBA, NCF1, and NCF2, encoding p22phox, p47phox, and p67phox proteins, respectively. AR-CGD was the most frequent form, in Jordan probably because consanguineous marriages are common in this country. Only one patient from non-consanguineous parents suffered from an X910 CGD subtype (0 indicates no protein expression). AR670 CGD and AR220 CGD appeared to be the most frequently found sub-types but also the most severe clinical forms compared to AR470 CGD. As a geographical clustering of 11 patients from eight Jordanian families exhibited the c.1171_1175delAAGCT mutation in NCF2, segregation analysis with nine polymorphic markers overlapping NCF2 indicates that a common ancestor has arisen ~1,075 years ago.
Highlights
Chronic granulomatous disease (CGD) is a rare congenital immunodeficiency syndrome with an incidence of 1 in ∼250,000 individuals
Clinical and genetic characteristics of CGD were analyzed in 22 Jordanian, seven Libyan and, two Iraqi patients from 21 families (Tables 1, 2); 14 families were from Jordan (H, M, N, O, P, Q, R, T, X, Y, AB, AK, AM, and AN), five from Libya (W, Z, AH, AI, and AJ), and two from Iraq (S and AD)
All patients suffered from AR-CGD except one patient in the R family who suffered from X-CGD
Summary
Chronic granulomatous disease (CGD) is a rare congenital immunodeficiency syndrome with an incidence of 1 in ∼250,000 individuals. The disease results from defects in one of the five components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytes, i.e., the membrane proteins gp91phox (or NOX2) and p22phox (together forming cytochrome b558) and the cytosolic components p47phox, p67phox, and p40phox [1]. These proteins are present in phagocytic leukocytes (neutrophils, eosinophils, monocytes, and macrophages). Most of the patients underwent extensive clinical and laboratory investigations to clarify the relationship between the identification of the mutated protein and the clinical severity in very rare AR-CGD forms affecting p22phox and p67phox mainly and p47phox too, and in one case of X-CGD affecting NOX2.
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