Chronic granulomatous disease: Clinical, functional, molecular, and genetic studies. The Israeli experience with 84 patients

Abstract

Chronic granulomatous disease (CGD) is an innate immunodeficiency with a genetic defect of the nicotinamide adenosine dinucleotide phosphate, reduced, oxidase components. This leads to decreased reactive oxygen species (ROS) production, which renders patients susceptible to life‐threatening infections. Over the course of 30 years, we diagnosed CGD in 84 patients from 61 families using functional, molecular, and genetic studies. The incidence of CGD in Israel is 1.05 per 100,000 live‐births in the Jewish population and 1.49 in the Israeli Arab population. We diagnosed 52 patients (62%) with autosomal recessive inheritance (AR‐CGD) and 32 (38%) with X‐linked recessive inheritance (XLR‐CGD). Consanguinity was detected in 64% of AR‐CGD families (14% in Jews and 50% in Israeli Arabs). We found 36 different mutations (23 in XLR‐CGD and 13 in AR‐CGD patients), 15 of which were new. The clinical spectrum of CGD varied from mild to severe disease in both XLR and AR forms, although the AR subtype is generally milder. Further, residual ROS production correlated with milder clinical expression, better prognosis and improved overall survival. Patients with recurrent pyogenic infections developed fibrosis and hyperinflammatory states with granuloma formation. The management of CGD has progressed substantially in recent years, evolving from a fatal disease of early childhood to one of long‐term survival. Our present cohort displays an encouraging 81% overall long term survival. Early hematopoietic stem cell transplantation is advisable before tissue damage is irreversible. Successful transplantation was performed in 18/21 patients. Therapeutic gene modification could become an alternative cure for CGD. Am. J. Hematol. 92:28–36, 2017. © 2016 Wiley Periodicals, Inc.

Inherited p40phox deficiency differs from classic chronic granulomatous disease

“…Nevertheless, the frequency of inflammatory lesions is lower than in patients with classic CGD (48). A few of the patients showed autoimmunity, but, strikingly, none had the invasive bacterial and fungal infections commonly seen in patients with classic CGD (7)(8)(9)18). Consistent with these findings, the clinical outcome of p40 phox deficiency is better than that of classic CGD.…”

“…Moreover, 4 patients remained asymptomatic at 1 to 10 years of age, and the age at clinical onset ranged from 1 to 17 years in patients with symptoms. The incomplete clinical penetrance observed at 1 to 10 years of age also contrasts strongly with observations for classic CGD (7)(8)(9)18). Thus, the healthy siblings of probands should be tested immunologically and genetically.…”

“…The XR (gp91 phox [phagocyte oxidase]) form of CGD is clinically more severe than the AR p47 phox -deficient form (7,9,17). AR p22 phox and p67 phox deficiencies appear to be as severe as XR CGD (18,19). Patients are routinely placed on prophylactic antimicrobial therapy, and the only curative treatment widely available is allogeneic hematopoietic stem cell transplantation (HSCT) (20).…”

A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews

“…Gene conversion between a wild-type NCF1 gene on a normal allele and a pseudogene on an allele with the c.579G>A mutation-bearing NCF1 gene is one possibility (figure 6). We suppose this happened in the past and was amplified in the Ashkenazi population by a founder effect, because it leads to an Ashkenazi allele and to an allele with only pseudogenes and thus to the occurrence of p47 phox –deficient CGD, which is unknown sofar in the Ashkenazi population 15. Judging from the STR1 repeat configuration around the mutated NCF1 , such an event must either have happened more than about 2000 years ago (because around that time the c.579G>A mutation was introduced into the Kavkazi Jewish population5) or be the result of exchange of genetic material between the Ashkenazi group and another population (in other Middle-Eastern populations the mutation goes along with other STR1 configurations, among them 14 repeats as in the father in this study).…”

Considerations in the Diagnosis of Chronic Granulomatous Disease

“…The diagnosis of CGD is usually established early in life, and the majority of patients are diagnosed with the disease before they are 5 years old [3, 5, 6, 10]. Although the disease can present in adulthood, most such cases are AR forms in which residual production of superoxide can be seen.…”