Novel mutations in the CYBB gene causing X-linked chronic granulomatous disease: a case report of 2 patients

Introduction: Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency caused by mutations in the NADPH complex characterized by recurrent infections, inflammation and autoimmunity. While autosomal recessive forms exist, X-linked CGD makes up the majority of cases, which is caused by mutations in the CYBB gene. Patients are at high risk for infections with catalase positive bacteria and fungi. The prognosis has improved significantly with improvements in disease detection and management, including prophylactic antibiotic and antifungal therapy. Hematopoietic stem cell transplantation (HSCT) is a curative option for patients with a suitable donor. Aim: To report the clinical presentation, immune features and genetic mutations in 2 patients with novel mutations in the CYBB gene causing X-linked CGD who underwent HSCT. Results: Case 1: Patient 1 is a 14-year-old patient who initially presented with disseminated aspergillosis at the age of 3. He was noted to have an abnormal neutrophil oxidative burst index (NOBI) and genetic testing revealed a mutation in the CYBB gene (c.883_87dupGTGGT) consistent with CGD. He successfully underwent HSCT at age 4. At age 10 he developed a primary intracranial rhabdomyosarcoma in the posterior cranial fossa. Case 2: Patient 2 is a 4-year-old male who was worked up for CGD after developing a perianal abscess at 1 month of age followed by Moraxella bacteremia at 2 months of age. He had 2 abnormal NOBIs and genetic testing identified a novel mutation in the CYBB gene that was thought to explain his phenotype (c.941delA). He underwent an HSCT (10/10 HLA matched unrelated donor). Both patients have had normalization of their NOBI post-transplant and remain free of significant infections. Discussion: We report the clinical presentation, immune features and genetic mutations in 2 patients with novel mutations in the CYBB gene causing X-linked CGD. Identifying pathogenic mutations causing CGD is important for a better understanding of genotype–phenotype associations and disease course in this patient population. Statement of novelty: We describe 2 pediatric patients diagnosed with X-linked chronic granulomatous disease due to novel mutations in the CYBB gene.

Systemic Redox Imbalance in Patients with Chronic Granulomatous Disease

The aim of our study was to evaluate redox status, enzymatic and non-enzymatic antioxidant barriers, oxidative damage of proteins, lipids and DNA, as well as concentration of coenzyme Q10 and vitamins A and E in patients with chronic granulomatous disease (CGD). The study was performed on fifteen Caucasian individuals (median age 24 years and seven months) diagnosed with CGD. The mutation in the NCF1 gene was confirmed in ten patients, and in the CYBB gene in five patients. We demonstrated high levels of total oxidant status (TOS) and oxidative stress index (OSI), lipids (↑8-isoprostanes (8-isoP), ↑4-hydroxynonenal (4-HNE)), proteins (↑advanced oxidation protein products (AOPP)) and DNA (↑8-hydroxy-2’-deoxyguanosine (8-OHdG)) oxidation products in CGD individuals as compared to sex- and age-matched healthy controls. We showed enhanced serum enzymatic activity of catalase (CAT) and superoxide dismutase-1 (SOD) and significantly decreased coenzyme Q10 concentration. Our study confirmed redox disturbances and increased oxidative damage in CGD patients, and indicated the need to compare redox imbalance depending on the type of mutation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The question regarding effectiveness of antioxidant therapy in patients with CGD is open, and the need to establish guidelines in this area remains to be addressed.

Variable Presentation of the CYBB Mutation in One Family, Approach to Management, and a Review of the Literature

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder marked by abnormal phagocytic function. CGD affects primarily neutrophils and manifests as an early predisposition to severe life-threatening infections. Additionally, patients with CGD are predisposed to unique autoimmune manifestations. While generally spared from infectious complications, heterozygous carriers of the abnormal genes implicated in CGD pathogenesis can still present with autoimmune disorders. A mutation in the CYBB gene is the only X-linked variant of this disease. This article describes a family with the CYBB mutation, its heterogenous presentation, and reviews the literature discussing disease management.

DNA-diagnosis of X-linked chronic granulomatous disease

Хроническая гранулематозная болезнь (ХГБ) - наследственное заболевание, относящееся к группе первичных иммунодефицитов с нарушением функции фагоцитоза. Наиболее частой является Х-сцепленная форма ХГБ, которая развивается в результате молекулярного дефекта, возникающего в гене CYBB. В статье представлены результаты молекулярной диагностики Х-сцепленной ХГБ у пациентов из разных регионов России в лаборатории ДНК-диагностики Медико-генетического научного центра. Chronic granulomatous disease (CGD) is a hereditary disease belonging to the group of primary immunodeficiencies with impaired phagocytosis function. The most frequent is the X-linked form of CGB, which develops as a result of a molecular defect arising in the CYBB gene. The article presents the results accumulated in the Laboratory of DNA Diagnostics of the Medical Genetic Research Center during the molecular diagnosis of X-linked CGD in patients from different regions of Russia.