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Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3(CGD3)

MedGen UID:
462759
Concept ID:
C3151409
Disease or Syndrome
Synonyms: CGD, AUTOSOMAL RECESSIVE CYTOCHROME b-POSITIVE, TYPE III; GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 3; Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type III; GRANULOMATOUS DISEASE, CHRONIC, DUE TO NCF4 DEFICIENCY
 
Gene (location): NCF4 (22q12.3)
 
Monarch Initiative: MONDO:0013507
OMIM®: 613960

Disease characteristics

Excerpted from the GeneReview: Chronic Granulomatous Disease
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis). Granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival. [from GeneReviews]
Authors:
Jennifer W Leiding  |  Steven M Holland   view full author information

Additional descriptions

From OMIM
Autosomal recessive chronic granulomatous disease-3 (CGD3) is an immunodeficiency disorder characterized by recurrent pyogenic infections and granulomatous inflammation with onset usually in the first decade of life. Most patients present with colitis and features of inflammatory bowel disease. Other common manifestations include lupus-like skin lesions, skin granulomas, Staphylococcal abscesses, oral ulcers, and periodontitis. Patients usually do not have invasive infections and are not markedly susceptible to fungal infections. The disorder results from variable loss of phagocyte superoxide production due to NADPH oxidase dysfunction; it is generally less severe than other genetic types of CGD (summary by Matute et al., 2009; van de Geer et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of CGD, see the X-linked form (CGDX; 306400).  http://www.omim.org/entry/613960
From MedlinePlus Genetics
Chronic granulomatous disease is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body from foreign invaders such as bacteria and fungi. Individuals with chronic granulomatous disease may have recurrent bacterial and fungal infections. People with this condition may also have areas of inflammation (granulomas) in various tissues that can result in damage to those tissues. The features of chronic granulomatous disease usually first appear in childhood, although some individuals do not show symptoms until later in life.

People with chronic granulomatous disease typically have at least one serious bacterial or fungal infection every 3 to 4 years. The lungs are the most frequent area of infection; pneumonia is a common feature of this condition. Individuals with chronic granulomatous disease may develop a type of fungal pneumonia, called mulch pneumonitis, which causes fever and shortness of breath after exposure to decaying organic materials such as mulch, hay, or dead leaves. Exposure to these organic materials and the numerous fungi involved in their decomposition causes people with chronic granulomatous disease to develop fungal infections in their lungs. Other common areas of infection in people with chronic granulomatous disease include the skin, liver, and lymph nodes.

Inflammation can occur in many different areas of the body in people with chronic granulomatous disease. Most commonly, granulomas occur in the gastrointestinal tract and the genitourinary tract. In many cases the intestinal wall is inflamed, causing a form of inflammatory bowel disease that varies in severity but can lead to stomach pain, diarrhea, bloody stool, nausea, and vomiting. Other common areas of inflammation in people with chronic granulomatous disease include the stomach, colon, and rectum, as well as the mouth, throat, and skin. Additionally, granulomas within the gastrointestinal tract can lead to tissue breakdown and pus production (abscesses). Inflammation in the stomach can prevent food from passing through to the intestines (gastric outlet obstruction), leading to an inability to digest food. These digestive problems cause vomiting after eating and weight loss. In the genitourinary tract, inflammation can occur in the kidneys and bladder. Inflammation of the lymph nodes (lymphadenitis) and bone marrow (osteomyelitis), which both produce immune cells, can lead to further impairment of the immune system.

Rarely, people with chronic granulomatous disease develop autoimmune disorders, which occur when the immune system malfunctions and attacks the body's own tissues and organs.

Repeated episodes of infection and inflammation reduce the life expectancy of individuals with chronic granulomatous disease; however, with treatment, most affected individuals live into mid- to late adulthood.  https://medlineplus.gov/genetics/condition/chronic-granulomatous-disease

Clinical features

From HPO
Abdominal pain
MedGen UID:
7803
Concept ID:
C0000737
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the abdomen.
Colitis
MedGen UID:
40385
Concept ID:
C0009319
Disease or Syndrome
Ulcerative colitis is a chronic disorder that affects the digestive system. This condition is characterized by abnormal inflammation of the inner surface (epithelium) of the rectum and colon. The rectum and colon make up most of the length of the large intestine. The inflammation usually causes open sores (ulcers) to develop in the large intestine. Ulcerative colitis usually appears between the age of 15 and 30, although it can develop at any age. The inflammation tends to flare up multiple times throughout a person's life, which causes recurring signs and symptoms.\n\nThe most common symptoms of ulcerative colitis are cramping abdominal pain and frequent diarrhea, often with blood, pus, or mucus in the stool. Other signs and symptoms include nausea, loss of appetite, bowel urgency, fatigue, and fevers. Chronic bleeding from the inflamed and ulcerated intestinal tissue can cause a shortage of red blood cells (anemia) in some affected individuals. People with this disorder have difficulty absorbing enough fluids and nutrients from their diet and often experience weight loss. Affected children usually grow more slowly than normal. Less commonly, ulcerative colitis causes problems with the skin, joints, eyes, kidneys, or liver, which are most likely due to abnormal inflammation.\n\nToxic megacolon is a rare complication of ulcerative colitis that can be life-threatening. Toxic megacolon involves a widening (dilation) of the colon and an overwhelming inflammatory response. Ulcerative colitis also increases the risk of developing colon cancer, especially in people whose entire colon is inflamed and in those who have had ulcerative colitis for 8 years or more.\n\nUlcerative colitis is one common form of inflammatory bowel disease (IBD). Another type of IBD, Crohn's disease, also causes chronic inflammation of the intestines. Unlike ulcerative colitis, which affects only the inner surface of the large intestine, Crohn's disease can cause inflammation in any part of the digestive system, and the inflammation extends deeper into the intestinal tissue.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Anoperineal fistula
MedGen UID:
324365
Concept ID:
C1835798
Anatomical Abnormality
The presence of a fistula (abnormal tunnel) between the anal canal and the perineum.
Recurrent sinusitis
MedGen UID:
107919
Concept ID:
C0581354
Disease or Syndrome
A recurrent form of sinusitis.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Perioral eczema
MedGen UID:
473409
Concept ID:
C1396126
Disease or Syndrome
A type of eczema that occurs in the lips and perioral area.
Elevated erythrocyte sedimentation rate
MedGen UID:
57727
Concept ID:
C0151632
Finding
An increased erythrocyte sedimentation rate (ESR). The ESR is a test that measures the distance that erythrocytes have fallen after one hour in a vertical column of anticoagulated blood under the influence of gravity. The ESR is a nonspecific finding. An elevation may indicate inflammation or may be caused by any condition that elevates fibrinogen.
Elevated circulating C-reactive protein concentration
MedGen UID:
892906
Concept ID:
C4023452
Finding
An abnormal elevation of the C-reactive protein level in the blood circulation.
Recurrent aphthous stomatitis
MedGen UID:
445425
Concept ID:
C2937365
Disease or Syndrome
Recurrent episodes of ulceration of the oral mucosa, typically presenting as painful, sharply circumscribed fibrin-covered mucosal defects with a hyperemic border.

Recent clinical studies

Etiology

Sibley CT, Estwick T, Zavodni A, Huang CY, Kwan AC, Soule BP, Long Priel DA, Remaley AT, Rudman Spergel AK, Turkbey EB, Kuhns DB, Holland SM, Malech HL, Zarember KA, Bluemke DA, Gallin JI
Circulation 2014 Dec 2;130(23):2031-9. Epub 2014 Sep 19 doi: 10.1161/CIRCULATIONAHA.113.006824. PMID: 25239440Free PMC Article

Diagnosis

Sibley CT, Estwick T, Zavodni A, Huang CY, Kwan AC, Soule BP, Long Priel DA, Remaley AT, Rudman Spergel AK, Turkbey EB, Kuhns DB, Holland SM, Malech HL, Zarember KA, Bluemke DA, Gallin JI
Circulation 2014 Dec 2;130(23):2031-9. Epub 2014 Sep 19 doi: 10.1161/CIRCULATIONAHA.113.006824. PMID: 25239440Free PMC Article

Therapy

Sibley CT, Estwick T, Zavodni A, Huang CY, Kwan AC, Soule BP, Long Priel DA, Remaley AT, Rudman Spergel AK, Turkbey EB, Kuhns DB, Holland SM, Malech HL, Zarember KA, Bluemke DA, Gallin JI
Circulation 2014 Dec 2;130(23):2031-9. Epub 2014 Sep 19 doi: 10.1161/CIRCULATIONAHA.113.006824. PMID: 25239440Free PMC Article

Clinical prediction guides

Kim JJ, Yun SW, Yu JJ, Yoon KL, Lee KY, Kil HR, Kim GB, Han MK, Song MS, Lee HD, Byeon JH, Sohn S, Hong YM, Jang GY, Lee JK; Korean Kawasaki Disease Genetics Consortium
Pediatr Cardiol 2015 Feb;36(2):438-44. Epub 2014 Sep 30 doi: 10.1007/s00246-014-1032-1. PMID: 25266886
Sibley CT, Estwick T, Zavodni A, Huang CY, Kwan AC, Soule BP, Long Priel DA, Remaley AT, Rudman Spergel AK, Turkbey EB, Kuhns DB, Holland SM, Malech HL, Zarember KA, Bluemke DA, Gallin JI
Circulation 2014 Dec 2;130(23):2031-9. Epub 2014 Sep 19 doi: 10.1161/CIRCULATIONAHA.113.006824. PMID: 25239440Free PMC Article

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