Chronic Granulomatous Disease
- Author: Roman Janusz Nowicki, MD, PhD; Chief Editor: Dirk M Elston, MD more...
Chronic granulomatous disease (CGD) is a rare (∼1:250,000 births) disease caused by mutations in any one of the five components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes.
CGD is a primary immunodeficiency that affects phagocytes of the innate immune system and leads to recurrent or persistent intracellular bacterial and fungal infections and to granuloma formation. In approximately two thirds of patients, the first symptoms of CGD appear during the first year of life in the form of infections, dermatitis (sometimes seen at birth), gastrointestinal complications (obstruction or intermittent bloody diarrhea due to colitis), and a failure to thrive. The clinical picture can be quite variable, with some infants having several of these complications and others appearing to be far less ill. Cutaneous disease occurs in 60-70% of patients.
Also see Pediatric Chronic Granulomatous Disease.
Chronic granulomatous disease (CGD) is a genetically heterogeneous immunodeficiency disorder resulting from the inability of phagocytes to kill microbes they have ingested. This impairment in killing is caused by any of several defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which generates the microbicidal respiratory burst. In CGD, phagocytes ingest bacteria normally, but they cannot kill them.
Patients with CGD are susceptible to severe and recurrent infections due to catalase-positive organisms and organisms resistant to nonoxidative killing. Catalase-negative bacteria, such as streptococci and pneumococci that have the capacity to generate hydrogen peroxide, are killed as they usually are. The intracellular survival of ingested bacteria leads to the development of granulomata in the lymph nodes, skin, lungs, liver, gastrointestinal tract, and/or bones.
CGD is usually inherited in an X-linked recessive fashion. Most patients (approximately 80%) are males, who have hemizygous mutations on the X-linked gene coding for gp91phox. The gene responsible for this form of the disease has been mapped to the p21.1 region of the X chromosome. However, among chronic granulomatous disease subtypes, the autosomal recessive (AR) forms may be associated with milder disease. The extent to which environmental and secondary genetic factors influence phenotypic expression of disease is unknown. A wide variety of molecular defects have been described in the genes for the gp91phox component, the p22phox component, and the p67phox component. These defects include frame shifts; deletions; and nonsense, missense, splice-region, and regulatory-region mutations.[5, 6, 7]
In contrast, a GT deletion at the beginning of exon 2 accounts for the defective genetic function in almost all patients with p47phox deficiency. Another protein, p40phox, has been implicated in the regulation of the NADPH oxidase, but no individual with a mutation in the protein has been found to date. A new variant of CGD has been described; this form is caused by an inhibitory mutation in Rac2, which regulates activity of the neutrophil respiratory burst and actin assembly.
The exact incidence of chronic granulomatous disease (CGD) is unknown. CGD affects approximately 1 infant per 200,000-250,000 live births.
The prevalence of CGD varies among the populations investigated, with studies reporting variations from 1 case per 1 million individuals to 1 case per 160,000 individuals.[10, 11]
Chronic granulomatous disease affects persons of all races.
Approximately 80% of patients with CGD are male, because the main cause of the disease is a mutation in an X-chromosome–linked gene. However, defects in autosomal genes may also underlie the disease and cause CGD in both males and females.
Symptom onset typically occurs at a young age, although the diagnosis has been at an older age in some patients.[12, 13, 14] Typically, patients with CGD have recurrent pyogenic infections that start in the first year of life. Occasionally, the onset may be delayed until the patient is aged 10-20 years.
Segal BH, Romani L, Puccetti P. Chronic granulomatous disease. Cell Mol Life Sci. 2009 Feb. 66(4):553-8. [Medline].
Hauck F, Heine S, Beier R, Wieczorek K, Müller D, Hahn G. Chronic granulomatous disease (CGD) mimicking neoplasms: a suspected mediastinal teratoma unmasking as thymic granulomas due to X-linked CGD, and 2 related cases. J Pediatr Hematol Oncol. 2008 Dec. 30(12):877-80. [Medline].
Rae J, Noack D, Heyworth PG, Ellis BA, Curnutte JT, Cross AR. Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22(phox). Blood. 2000 Aug 1. 96(3):1106-12. [Medline].
Jurkowska M, Bernatowska E, Bal J. Genetic and biochemical background of chronic granulomatous disease. Arch Immunol Ther Exp (Warsz). 2004 Mar-Apr. 52(2):113-20. [Medline].
Jurkowska M, Kurenko-Deptuch M, Bal J, Roos D. The search for a genetic defect in Polish patients with chronic granulomatous disease. Arch Immunol Ther Exp (Warsz). 2004 Nov-Dec. 52(6):441-6. [Medline].
Stasia MJ, Bordigoni P, Floret D, et al. Characterization of six novel mutations in the CYBB gene leading to different sub-types of X-linked chronic granulomatous disease. Hum Genet. 2005 Jan. 116(1-2):72-82. [Medline].
Noack D, Rae J, Cross AR, et al. Autosomal recessive chronic granulomatous disease caused by defects in NCF-1, the gene encoding the phagocyte p47-phox: mutations not arising in the NCF-1 pseudogenes. Blood. 2001 Jan 1. 97(1):305-11. [Medline].
Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore). May 2000. 79(3):170-200.
Ahlin A, De Boer M, Roos D, et al. Prevalence, genetics and clinical presentation of chronic granulomatous disease in Sweden. Acta Paediatr. 1995 Dec. 84(12):1386-94. [Medline].
Oh HB, Park JS, Lee W, Yoo SJ, Yang JH, Oh SY. Molecular analysis of X-linked chronic granulomatous disease in five unrelated Korean patients. J Korean Med Sci. 2004 Apr. 19(2):218-22. [Medline].
Lun A, Roesler J, Renz H. Unusual late onset of X-linked chronic granulomatous disease in an adult woman after unsuspicious childhood. Clin Chem. 2002 May. 48(5):780-1. [Medline].
Wolach B, Scharf Y, Gavrieli R, de Boer M, Roos D. Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB. Blood. 2005 Jan 1. 105(1):61-6. [Medline].
Fijolek J, Wiatr E, Gawryluk D, Bestry I, Bernatowska E, Jablonski W. [Chronic granulomatous disease recognised in 42-years-old patient]. Pneumonol Alergol Pol. 2008. 76(1):58-65. [Medline].
Carnide EG, Jacob CA, Castro AM, Pastorino AC. Clinical and laboratory aspects of chronic granulomatous disease in description of eighteen patients. Pediatr Allergy Immunol. 2005 Feb. 16(1):5-9. [Medline].
Sarwar G, de Malmanche T, Rassam L, Grainge C, Williams A, Arnold D. Chronic granulomatous disease presenting as refractory pneumonia in late adulthood. Respirol Case Rep. 2015. 3(2):54-6. [Medline]. [Full Text].
Chowdhury MM, Anstey A, Matthews CN. The dermatosis of chronic granulomatous disease. Clin Exp Dermatol. 2000 May. 25(3):190-4. [Medline].
Dohil M, Prendiville JS, Crawford RI, Speert DP. Cutaneous manifestations of chronic granulomatous disease. A report of four cases and review of the literature. J Am Acad Dermatol. 1997 Jun. 36(6 Pt 1):899-907. [Medline].
Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics. 2004 Aug. 114(2):462-8. [Medline].
Johnston RB Jr. Clinical aspects of chronic granulomatous disease. Curr Opin Hematol. 2001 Jan. 8(1):17-22. [Medline].
Bylund J, Campsall PA, Ma RC, Conway BA, Speert DP. Burkholderia cenocepacia induces neutrophil necrosis in chronic granulomatous disease. J Immunol. 2005 Mar 15. 174(6):3562-9. [Medline].
Agudelo-Florez P, Lopez JA, Redher J, et al. The use of reverse transcription-PCR for the diagnosis of X-linked chronic granulomatous disease. Braz J Med Biol Res. 2004 May. 37(5):625-34. [Medline].
Yamazaki-Nakashimada MA, Stiehm ER, Pietropaolo-Cienfuegos D, Hernandez-Bautista V, Espinosa-Rosales F. Corticosteroid therapy for refractory infections in chronic granulomatous disease: case reports and review of the literature. Ann Allergy Asthma Immunol. 2006 Aug. 97(2):257-61. [Medline].
Gallin JI, Alling DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med. 2003 Jun 12. 348(24):2416-22. [Medline].
Marciano BE, Wesley R, De Carlo ES, et al. Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis. 2004 Sep 1. 39(5):692-9. [Medline].
Nunoi H, Ishibashi F, Mizukami T, Hidaka F. Clinical evaluation of interferon-gamma treatment to chronic granulomatous disease patients with splice site mutations. Jpn J Infect Dis. 2004 Oct. 57(5):S25-6. [Medline].
Wang J, Mayer L, Cunningham-Rundles C. Use of GM-CSF in the treatment of colitis associated with chronic granulomatous disease. J Allergy Clin Immunol. 2005 May. 115(5):1092-4. [Medline].
Martinez CA, Shah S, Shearer WT, Rosenblatt HM, Paul ME, Chinen J, et al. Excellent survival after sibling or unrelated donor stem cell transplantation for chronic granulomatous disease. J Allergy Clin Immunol. 2012 Jan. 129(1):176-83. [Medline].
Horwitz ME, Barrett AJ, Brown MR, et al. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med. 2001 Mar 22. 344(12):881-8. [Medline].
Seger RA, Gungor T, Belohradsky BH, et al. Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000. Blood. 2002 Dec 15. 100(13):4344-50. [Medline].
Grez M, Becker S, Saulnier S, et al. Gene therapy of chronic granulomatous disease. Bone Marrow Transplant. 2000 May. 25 Suppl 2:S99-104. [Medline].
Kume A, Dinauer MC. Gene therapy for chronic granulomatous disease. J Lab Clin Med. 2000 Feb. 135(2):122-8. [Medline].
Malech HL, Choi U, Brenner S. Progress toward effective gene therapy for chronic granulomatous disease. Jpn J Infect Dis. 2004 Oct. 57(5):S27-8. [Medline].
Seger RA. Modern management of chronic granulomatous disease. Br J Haematol. 2008 Feb. 140(3):255-66. [Medline].
Kuhns DB, Alvord WG, Heller T, et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010 Dec 30. 363(27):2600-10. [Medline].
Bassiri-Jahromi S, Doostkam A. Fungal infection and increased mortality in patients with chronic granulomatous disease. J Mycol Med. 2012. 22:52-7. [Medline].
Carruthers JA, Greaves MW. Chronic granulomatous disease. Br J Dermatol. 1976 Jul. 95 Suppl 14:72-4. [Medline].
Curnutte JT. Chronic granulomatous disease: the solving of a clinical riddle at the molecular level. Clin Immunol Immunopathol. 1993 Jun. 67(3 Pt 2):S2-15. [Medline].
Curnutte JT. Recent advances in chronic granulomatous disease. Curr Opin Pediatr. 1990. 2:907-15.
Goldblatt D, Thrasher AJ. Chronic granulomatous disease. Clin Exp Immunol. 2000 Oct. 122(1):1-9. [Medline].
Heyworth PG, Cross AR, Curnutte JT. Chronic granulomatous disease. Curr Opin Immunol. 2003 Oct. 15(5):578-84. [Medline].
Holland S, Seger R, Sullivan KE. The chronicles of chronic granulomatous disease. Clin Immunol. 2005 Aug. 116(2):99-100. [Medline].
Lekstrom-Himes JA, Kuhns DB, Alvord WG, Gallin JI. Inhibition of human neutrophil IL-8 production by hydrogen peroxide and dysregulation in chronic granulomatous disease. J Immunol. 2005 Jan 1. 174(1):411-7. [Medline].
Ma JS, Chen PY, Fu LS, et al. Chronic granulomatous disease: a case report. J Microbiol Immunol Infect. 2000 Jun. 33(2):118-22. [Medline].
Rosenzweig SD. Inflammatory manifestations in chronic granulomatous disease (CGD). J Clin Immunol. 2008 May. 28 Suppl 1:S67-72. [Medline].
Westbroek W, Adams D, Huizing M, et al. Cellular defects in Chediak-Higashi syndrome correlate with the molecular genotype and clinical phenotype. J Invest Dermatol. 2007 Nov. 127(11):2674-7. [Medline].
Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000 May. 79(3):155-69. [Medline].