CYBA, NCF1, NCF2, NCF4, and CYBB genes

Also known as: CYBA deficiency; recessive chronic granulomatous diseases; x-linked chronic granulomatous disease; NCF1 or SOC2 deficiency; NCF2 deficiency; NCF4 deficiency








1. The disease

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, macrophages, monocytes and eosinophils) caused by mutations in one of five genes that encode the subunits of phagocyte NADPH oxidase: CYBA, NCF1, NCF2, NCF4, or CYBB genes. NADPH oxidase is responsible for bactericidal activity of phagocytes, thus CGD leads to impaired killing of bacteria and fungi. Mutations in CYBA, NCF1, NCF2, and NCF4 genes cause autosomal recessive CGD – a mutation must be present in the copies inherited from both the mother and the father – for the disease to manifest itself. Mutation of CYBB causes X-linked CGD – in which case males are primarily affected as they have a single X chromosome, and therefore, only one abnormal copy of the CYBB gene is required to cause the disorder.

2. The symptoms

CGD is characterized by severe recurrent bacterial and fungal infections and abnormal inflammatory response resulting in granuloma formation and other inflammatory disorders. The majority of affected individuals present symptoms during infancy and early childhood, although CGD may present any time from infancy to late adulthood. Infants are usually initially asymptomatic at birth and in the neonatal period. Lack of early signs or symptoms does not exclude the diagnosis.

  • Infections and granulomatous lesions are typically the first manifestations of CGD. Infections usually involve the lung, lymph nodes, liver, bone, and skin. Granulomas usually involve the genitourinary system and gastrointestinal tract.
  • Affected individuals frequently present growth retardation and failure to thrive.

3. Actions to take in case of early diagnosis:

  • Infants with a positive genetic test (having 2 mutations or 2 copies of a single mutations in autosomal recessive CGD or males with 1 mutation in X-linked CGD gene) should continue breastfeeding
  • Infants with a positive genetic test should have confirmatory CGD testing through one of the following methods:
    • Dihydrorhodamine (DHR) test, which serves as a superoxide production evaluation, to distinguish the following forms of CGD: (1) complete forms characterized by absent to extremely reduced production of superoxide, (2) hypomorphic forms characterized by reduced protein expression/function and residual superoxide production, and (3) mosaic forms commonly observed in female carriers of X-linked CGD.
    • Nitroblue tetrazolium (NBT) test, which provides a qualitative determination of phagocyte NADPH oxidase activity.  In individuals with CGD, neutrophil production of superoxide is absent or extremely reduced. DHR has replaced NBT recently.
  • CGD is a lifelong condition that requires lifetime management and regular follow-up with an immunology specialist and a multidisciplinary approach to care, including pediatrics and genetics.
  • Lifelong prevention of fungal and bacterial infections should be initiated as soon as possible. Antibacterial and antifungal prophylaxis with daily doses of trimethoprim-sulfamethoxazole (antibacterial) and itraconazole (anti-fungal) are recommended. Interferon-gamma (IFN-gamma), 3 times weekly, is also recommended.
  • Hematopoietic stem cell transplantation (HSCT) may be curative and is increasingly used. Gene therapy has been successful in a few cases and is expanding. In those with severe infections, granulocyte transfusions are sometimes used.
  • Aggressive approach to infections and antifungal and antibacterial prophylaxis has increasingly improved survival in CGD, and is now approximately 90% at age ten years. Patients with X-linked CGD tend to have lower overall rates of survival when compared to those with the autossomal recessive CGD.
  • Genetic counselling is highly recommended for family planning and evaluation of at-risk family members such as siblings, especially in X-linked cases.
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