Most chronic granulomatous disease patients are children 0 to 2 years old when first diagnosed, but manifestations can be delayed to the second, third or even fourth decade of life. Patients usually have short stature. Initial disease signs often involve the skin and evolve as recurrent pyodermas and abscesses of the scalp or skin folds [1] or infectious, ecxematoid or seborrheic dermatitis [2]. Other variants, described in both toddlers and newborns include pustular, papulopustular and maculopapular lesions involving the auricular, retro auricular, perioral, periorbital, perinasal, inguinal, neck, axillar or interdigital teguments. Subcutaneous abscesses rapidly develop from these lesions and have prolonged evolution.

At the time of the initial diagnosis, infection may be localized in the lungs [3], liver, spleen or bones. Pneumonia is the most frequent type of infection in these patients. Otitis, gingival abscesses, lymphadenitis or septicemia can also be initial signs of the disease. Fever is a common accompanying trait. Gastrointestinal involvement often manifests as diarrhea or intermittent bloody stools, secondary to colitis.

Associated signs include cutaneous photosensitivity, hypermelanotic macule, conjunctival secretions, as an expression of chronic blepharoconjunctivitis, serosanguineous nasal discharge, chronic suppurated paronychia and recurrent ulcerative stomatitis. The oral pain prevents alimentation and when associated with malabsorbtion leads to weight loss and failure to thrive. Hepatic and perihepatic abscesses manifest as fever and malaise. Anal region inspection sometimes highlights the presence of abscesses and fistulae [4].

Other symptoms refer to the presence of obstructive granulomas in the genito-urinary and gastrointestinal tract. Abdominal pain may be suggestive for these, but clinical diagnosis requires maintaining a high level of suspicion. Also, a brain abscess, arising from hematogenous or contiguous and spread of an infection during childhood may be suggestive for this diagnosis.

Some patients exhibit several of the symptoms discussed above by the time they present to the hospital, making clinical diagnosis much easier, while others develop signs of disease at a much slower rate. In this case, a careful history inquiry is crucial.

• Splenomegaly

  The patient also had finger clubbing, splenomegaly, and massive lymphadenopathy in the cervical, axillary, and preauricular areas (Panel A) and the epitrochlear and inguinal areas (Panel B) of his body. Blood cultures grew Staphylococcus aureus. [nejm.org]

  Two weeks later, fever with splenomegaly, pancytopenia, low fibrinogen levels, and elevated ferritin and soluble CD25 levels were noted. [wwwnc.cdc.gov]

  […] these symptoms Eczema 0000964 Gingivitis Inflamed gums Red and swollen gums [ more ] 0000230 Inflammatory abnormality of the eye 0100533 Liver abscess 0100523 Meningitis 0001287 Sepsis Infection in blood stream 0100806 Skin ulcer Open skin sore 0200042 Splenomegaly [rarediseases.info.nih.gov]

• Recurrent Infection

  CGD may involve many organs and present with recurrent infections and inflammations. Radiologists should consider the possibility of CGD when a patient presents with atypical and recurrent infection. [ncbi.nlm.nih.gov]

  Diagnosis of chronic granulomatous disease is based on patient’s signs and symptoms and history of specific recurrent infections. [dermnetnz.org]

• Fever

  Two children who presented with fever, enlarged liver and spleen and ascites were found to have Pseudomonas cepacia septicaemia which proved fatal despite appropriate antibiotics and maximum supportive care. [ncbi.nlm.nih.gov]

  Fevers, however, are very common and an infectious focus should always be searched for in any child presenting with a fever before attributing the fever to the disorder itself and not to an ongoing infection. [lecturio.com]

• Lymphadenopathy

  Granulibacter usually causes chronic and recurrent lymphadenopathies. We report the fatal case of a 4-year-old boy with chronic granulomatous disease, who presented with sepsis after a few days of abdominal pain and diarrhea. [ncbi.nlm.nih.gov]

  Most common presentation is a young patient with short stature, dermatitis, gingivitis, anemia of chronic disease, recurrent lymphadenopathy, hepatosplenomegaly, hepatic abscesses and multifocal, recurrent osteomyelitis. [radiopaedia.org]

• Weight Loss

  In 2014, a 36-year-old white man from Georgia, USA, who had X-linked CGD was hospitalized with cervical and abdominal lymphadenopathy; he had 1-year history of fever, malaise, and weight loss. [wwwnc.cdc.gov]

  Patients with chronic granulomatous disease are unlikely to complain of constitutional symptoms such as weight loss, fatigue and malaise. [lecturio.com]

  These digestive problems cause vomiting after eating and weight loss. In the genitourinary tract, inflammation can occur in the kidneys and bladder. [ghr.nlm.nih.gov]

  CASE REPORT A 4-year-old boy was brought to the Emergency Department (ED) from a rural area with complaints of fever, headache, and weight loss. He was suffering from these symptoms for the past 4 months, which had worsened in the past week. [surgicalneurologyint.com]

• Malaise

  In 2014, a 36-year-old white man from Georgia, USA, who had X-linked CGD was hospitalized with cervical and abdominal lymphadenopathy; he had 1-year history of fever, malaise, and weight loss. [wwwnc.cdc.gov]

  Patients with chronic granulomatous disease are unlikely to complain of constitutional symptoms such as weight loss, fatigue and malaise. [lecturio.com]

  Hepatic and perihepatic abscesses manifest as fever and malaise. Anal region inspection sometimes highlights the presence of abscesses and fistulae. [symptoma.com]

  If suspected (e.g. by unexplained fever, malaise and weight loss) the diagnosis is best made by CT scans (Garcia‐Eulate et al, 2006). Needle biopsy may be used for microorganism isolation (mostly S. aureus) and susceptibility testing. [onlinelibrary.wiley.com]

• Pneumonia

  We present a 9-year-old boy with medical history revealing recurrent pneumonia, suppurative lymphadenitis, diarrhea, and otitis. The patient was hospitalized with severe pneumonia. [ncbi.nlm.nih.gov]

  Shetty AK, Arvin AM, Gutierrez KM: Nocardia farcinica pneumonia in chronic granulomatous disease. Pediatrics. 1999, 104: 961-964. 10.1542/peds.104.4.961 62. Kato M: [Mycoplasma pneumoniae pneumonia in patients with chronic granulomatous disease]. [clinicalmolecularallergy.biomedcentral.com]

  […] abscesses that need surgery to drain them When to Contact a Medical Professional If you or your child has this condition and you suspect pneumonia or another infection, call your provider right away. [mountsinai.org]

• Diarrhea

  We report the fatal case of a 4-year-old boy with chronic granulomatous disease, who presented with sepsis after a few days of abdominal pain and diarrhea. [ncbi.nlm.nih.gov]

  Most children (75%) present early with severe recurrent bacterial and fungal infections, frequently involving the skin (abscesses and boils), lungs (pneumonia and lung abscesses), swollen lymph nodes, diarrhea, and liver and spleen abscesses. [nicklauschildrens.org]

  Other symptoms included diarrhea (39%), nausea and vomiting (24%), and constipation (2%). Obstruction occurred in 35% of patients involving gastric, esophageal, duodenal, and other locations. [pediatrics.aappublications.org]

• Vomiting

  A 12-year-old boy was admitted to the hospital because of fever, chills, sweats, productive cough, nausea, and vomiting. He had been subject to recurrent pneumonias since the age of 5 years. [nejm.org]

  Symptoms related to the presence of granulomas causing inflammation and/or obstructing the gut (e.g.difficulty swallowing, pain, nausea and vomiting and bloody diarrhea etc.) and genitourinary system (e.g. painful urination etc) are frequent. [nicklauschildrens.org]

  Other symptoms included diarrhea (39%), nausea and vomiting (24%), and constipation (2%). Obstruction occurred in 35% of patients involving gastric, esophageal, duodenal, and other locations. [pediatrics.aappublications.org]

  They can include: Recurrent infections caused by bacteria and fungi Abscesses in the liver, lungs, skin or spleen Granulomas (masses of cells that develop at sites of inflammation or infection) Chronic abdominal pain with diarrhea, nausea and vomiting [my.clevelandclinic.org]

• Failure to Thrive

  Up to 50% of patients present with diarrhea, abdominal pain, and failure to thrive. Pneumonia, abscesses, cellulitis, adenitis and osteomyelitis are common. [orpha.net]

• Abdominal Pain

  Abdominal pain or abdominal symptoms voiced by a child with CGD must be evaluated thoroughly and, when not infection-related, treated with corticosteroids (in some cases, long-term). [pediatrics.aappublications.org]

  We report the fatal case of a 4-year-old boy with chronic granulomatous disease, who presented with sepsis after a few days of abdominal pain and diarrhea. [ncbi.nlm.nih.gov]

  They can include: Recurrent infections caused by bacteria and fungi Abscesses in the liver, lungs, skin or spleen Granulomas (masses of cells that develop at sites of inflammation or infection) Chronic abdominal pain with diarrhea, nausea and vomiting [my.clevelandclinic.org]

  Patients with genitourinary tract granulomas usually present with recurrent dysuria, lower abdominal pain and urinary retention. [lecturio.com]

• Recurrent Diarrhea

  Of the 18 patients, 8 were complicated by recurrent diarrhea, 1 by liver abscess (P31), and 1 by recurrent diarrhea as well as liver abscess (P46). [hindawi.com]

  Oct 11, 2018 · Severe combined immunodeficiency (SCID) is a life-threatening syndrome of recurrent infections, diarrhea, dermatitis, and failure to thrive. (M2. Hi all! [vectoria.my]

• Periodontitis

  Cohen MS, Leong PA, Simpson DM: Phagocytic cells in periodontal defense. Periodontal status of patients with chronic granulomatous disease of childhood. J Periodontol 1985; 56: 611-7. 9. [czytelniamedyczna.pl]

  Some patients with chemotactic disorders have severe periodontitis and early tooth loss. Three of these syndromes are termed Papillon-Lefebre syndrome, prepubertal periodontitis and juvenile periodontitis. [primaryimmune.org]

  McDonnell, Systemic disease and periodontitis: manifestations of neutrophil dysfunction, Periodontology 2000, 32, 1, (82-104), (2003). [doi.org]

  Impaired phagosomal maturation in neutrophils leads to periodontitis in lysosomal-associated membrane protein-2 knockout mice. J Immunol. 2008; 180 :475–482. [ PubMed ] [ Google Scholar ] Huang J, Canadien V, Lam GY, et al. [ncbi.nlm.nih.gov]

• Aphthous Stomatitis

  He also had recurrent otitis media, tonsillitis, and aphthous stomatitis. Two months before the visit reported here, he had had Aspergillus versicolor pneumonia complicated by granulomatous appendicitis. [wwwnc.cdc.gov]

  stomatitis, pyoderma gangrenosum, and vasculitis-like skin rash on face and limbs. [bloodjournal.org]

• Aphthous Ulceration

  X-linked carriers of gp91phox chronic granulomatous disease may be asymptomatic or develop various usually less severe symptoms, including joint pain with a lupus-like syndrome, aphthous ulcers, chorioretinal lesions, and photosensitivity (1). 1. [msdmanuals.com]

  However, carriers of X-CGD have a notable incidence of discoid lupus erythematosus, photosensitivity, Raynaud phenomenon, and aphthous ulcers. [emedicine.medscape.com]

• Hepatosplenomegaly

  Multifocal and recurrent unusual osteomyelitis, recurrent hepatic abscesses, hepatosplenomegaly, and lymphadenitis. For lung involvement see - pulmonary manifestations of chronic granulomatous disease. [radiopaedia.org]

  In addition, septicopyemia, thrush, and hepatosplenomegaly were also commonly observed, accounting for 23%, 23%, and 40% of the cases. Lesions due to BCG vaccination occurred in more than half of the patients. [ncbi.nlm.nih.gov]

  In 1950, a 12-month-old child was referred to the University of Minnesota Hospitals with a syndrome consisting of chronic suppurative lymphadenitis, hepatosplenomegaly, pulmonary infiltrations, and an eczematoid dermatitis about the eyes, nose, and mouth [doi.org]

  Suppurative lymphadenitis, hepatosplenomegaly, pneumonia, and hematologic evidence of chronic infection are common. Skin, lymph node, lung, liver, and perianal abscesses; stomatitis; and osteomyelitis also occur. Growth may be delayed. [merck.com]

  […] monocytes White blood cells cannot generate superoxide ion which kills microorganisms in lysosomes Either Y linked or autosomal recessive Diagnose with nitro blue tetrazolium test (almost always positive) Clinically, patients have recurrent lymphadenitis, hepatosplenomegaly [pathologyoutlines.com]

• Hepatomegaly

  […] neutrophils 0001874 Chronic obstructive pulmonary disease 0006510 Cutaneous photosensitivity Photosensitive skin Photosensitive skin rashes Photosensitivity Sensitivity to sunlight Skin photosensitivity Sun sensitivity [ more ] 0000992 Fever 0001945 Hepatomegaly [rarediseases.info.nih.gov]

  Affiliated tissues include neutrophil, bone and bone marrow, and related phenotypes are recurrent respiratory infections and hepatomegaly Disease Ontology : 12 A phagocyte bactericidal dysfunction characterized by an inability to resist repeated infectious [malacards.org]

  One should not assume that an elevated ESR or chronic organomegaly (e.g., lymphadenopathy or hepatomegaly) is “normal” for these patients. [clinicaladvisor.com]

  On physical examination, hepatomegaly and a palpable spleen tip were noted. [nejm.org]

  Hepatomegaly was reported in 17% patients (8/48), and all of them were complicated by liver function damage (Table 1). 3.4. [hindawi.com]

• Chest Pain

  Signs and symptoms associated with infections include: Fever Chest pain when inhaling or exhaling Swollen and sore lymph glands A persistent runny nose Skin irritation that may include a rash, swelling or redness Swelling and redness in your mouth Gastrointestinal [mayoclinic.org]

  Pneumonias due to the fungus Aspergillus may come on very slowly, initially only causing fatigue, and only later causing cough or chest pain. Fungal pneumonias often do not cause fever. [primaryimmune.org]

  […] infection Chest pain Chiari malformation Chickenpox Chilblains Chipped, broken or cracked tooth Chiropractic Chlamydia Cholangiocarcinoma Cholecystitis (acute) Cholera Cholesteatoma Cholesterol (high) Chorionic villus sampling Chronic fatigue syndrome [nhs.uk]

• Arthritis

  A small percentage of children develop autoimmune manifestations (e.g., rheumatoid arthritis, systemic lupus erythematosus, colitis, autoimmune hepatitis) and warrant immunosuppression. [ncbi.nlm.nih.gov]

  The most common symptoms of the disease include: Pneumonia Spleen and liver abscesses Osteomyelitis—a bone infection Suppurative arthritis—the invasion of a joint by a bacterial infection, which causes arthritis Superficial skin infections such as cellulitis [danafarberbostonchildrens.org]

  168(42):3612-3614 Summary: Summary Blau syndrome: a chronic granulomatous, genetic disease Ugeskr Læger 2006;168(42):3612-3614 Blau syndrome is a rare hereditary granulomatous disease presenting in patients of young age with exanthema, granulomatous arthritis [ugeskriftet.dk]

  Arthritis Rheum 34: 101–105. View Article Google Scholar 11. Lee BW, Yap HK (1994) Polyarthritis resembling juvenile rheumatoid arthritis in a girl with chronic granulomatous disease. Arthritis Rheum 37: 773–776. View Article Google Scholar 12. [doi.org]

  […] injury (RSI) Respiratory tract infections (RTIs) Restless legs syndrome Restricted growth (dwarfism) Retinal detachment Retinal migraine Retinoblastoma (eye cancer in children) Rett syndrome Reye's syndrome Rhesus disease Rheumatic fever Rheumatoid arthritis [nhs.uk]

• Dermatitis

  Author information 1 Department of Dermatology, St Mary's Hospital, London, UK. [email protected] Abstract Dermatoses such as eczematous dermatitis and cutaneous infection are recognized presentations of primary immunodeficiency (PID). [ncbi.nlm.nih.gov]

  Most common presentation is a young patient with short stature, dermatitis, gingivitis, anemia of chronic disease, recurrent lymphadenopathy, hepatosplenomegaly, hepatic abscesses and multifocal, recurrent osteomyelitis. [radiopaedia.org]

  In 1950, a 12-month-old child was referred to the University of Minnesota Hospitals with a syndrome consisting of chronic suppurative lymphadenitis, hepatosplenomegaly, pulmonary infiltrations, and an eczematoid dermatitis about the eyes, nose, and mouth [doi.org]

  Other Complications Dermatological manifestations in patients with CGD include atopic dermatitis-like disease but with systemic or deep seated infections [131], facial granulomata [132] and discoid lupus, and seborrheic dermatitis-like disease [133]. [clinicalmolecularallergy.biomedcentral.com]

• Photosensitivity

  Showing of 21 | Medical Terms Other Names Learn More: HPO ID 80%-99% of people have these symptoms Abnormality of neutrophils 0001874 Chronic obstructive pulmonary disease 0006510 Cutaneous photosensitivity Photosensitive skin Photosensitive skin rashes [rarediseases.info.nih.gov]

  X-linked carriers of gp91phox chronic granulomatous disease may be asymptomatic or develop various usually less severe symptoms, including joint pain with a lupus-like syndrome, aphthous ulcers, chorioretinal lesions, and photosensitivity (1). 1. [msdmanuals.com]

  Associated signs include cutaneous photosensitivity, hypermelanotic macule, conjunctival secretions, as an expression of chronic blepharoconjunctivitis, serosanguineous nasal discharge, chronic suppurated paronychia and recurrent ulcerative stomatitis [symptoma.com]

  However, carriers of X-CGD have a notable incidence of discoid lupus erythematosus, photosensitivity, Raynaud phenomenon, and aphthous ulcers. [emedicine.medscape.com]

• Night Sweats

  (excessive) Sweating at night Swine flu (H1N1) Swollen ankles, feet and legs (oedema) Swollen arms and hands (oedema) Swollen glands Syphilis Back to top T Tapeworms Tay-Sachs disease Teeth grinding (bruxism) Temporal arteritis Temporomandibular disorder [nhs.uk]

• Seizure

  The child showed slow improvement, however, the treatment course was complicated by fever, seizures, and hyponatremia. Repeat CT scans did not show residual or recurrent abscesses [ Figure 1b ]. [surgicalneurologyint.com]

  Q6 month old male infant brought to the emergency room for recurrent seizure sincebirth. Baby was macrosomic and had macroglossia at birth and there is no maternalhistory of diabetes. [slideshare.net]

  Feeling sick (nausea) Female genital mutilation (FGM) Femoral hernia repair Fever in children Fibroids Fibromyalgia First aid Fits (children with fever) Fits (seizures) Flat feet Flat head syndrome Floaters and flashes in the eyes Flu Fluoride Foetal [nhs.uk]

  Of the seven ineligible patients, two were using prohibited concomitant medication, two had serious active infections and no signed form giving informed consent, one had a history of seizure disorder and no signed form giving consent, and two declined [doi.org]

Laboratory studies are used in order to diagnose neutrophil dysfunction and to pinpoint the presence of infection. An usual panel must include a complete cell blood count, that will most often show peripheral leukocytosis with neutrophilia. Anemia is encountered in many cases, and the red blood cells are hypochromic and microcytic, as in most chronic inflammatory conditions. These findings are, however, nonspecific. A more eloquent test is the nitroblue tetrazolium (NBT) dye test. In vitro stimulation of the phagocytic system can be achieved by adding phorbol myristate acetate or Escherichia coli antigens in normal neutrophils, but not in diseased ones, that fail to turn oxidized nitroblue tetrazolium to formazan. This test can also be performed prenatally, but not before weeks 16 to 18 of gestation. If clinical judgment and genetic council deem appropriate, earlier diagnosis can be achieved by deoxyribonucleic acid (DNA) obtained from chorionic villi or amniotic fluid testing by polymerase chain reaction [5]. Maternal DNA contamination of the specimen can be detected by short tandem repeat analysis. However, the physician should keep in mind that obtaining the fluid or tissue specimens are invasive procedures, with unpredictable outcomes. If the nitroblue tetrazolium dye test is unavailable, the physician could order a flow cytometric reduction of dihydrorhodamine, a test that offers the same information.

As in all other diseases characterized by frequent infection, hypergammaglobulinemia can be encountered. All types of immunoglobulins can be increased, but immunoglobulin E can also be normal.

Important information for the therapeutic plan is offered by microbiological studies. Culture should be accompanied by an antibiogram to make treatment effective. Aspergillus species are frequently encountered [6], followed by Serratia, Nocardia and Burkholderia. This latter microorganism has been shown to produce more severe infections than the other two, with a resulting higher death incidence. Osteomyelitis can be caused by Staphylococcus aureus, Aspergillus nidulans or Salmonella species. Other frequently encountered catalase-positive microorganisms, such as Escherichia coli species, Klebsiella species and Listeria species. However, a trend towards an increase of age at the moment of death has been observed, due to more appropriate therapeutic plans [7].

Imaging studies offer relevant information regarding the extent of the infection. Pulmonary disease consists of lung abscesses, empyema and recurrent or persistent pneumonia. An encapsulating pneumonia is considered to be quite typical for chronic granulomatous disease, while hilar lymphadenopathy and reticulonodular lung aspects are frequently seen, as well. Computer tomography may be needed in unclear cases, as well as in patients where the suspicion of intraparenchymal abscesses are suspected.

Other useful tests, unfortunately not widely available include chemiluminescence testing, direct measurements of superoxide anion production and of oxygen consumption, polymerase chain reaction and allele-specific restriction enzyme analysis [8].

Histological analysis on skin biopsy specimens shows granulomata formation, suppurative inflammation, as well as the presence of histiocytes, neutrophils and macrophages. The periodic acid-Schiff staining reaction is positive. Necrosis areas are sometimes observed.

• Colonic Stricture

  Colonic strictures were observed in 24% of patients; 80% were in the anorectal area. [ncbi.nlm.nih.gov]

Antibiotics and prednisone represent the corner stones of medical therapy in chronic granulomatous disease [9]. Antibiotic therapy needs to be intense and prolonged and infection prophylaxis must be vigorously implemented. Broad-spectrum systemic antibiotics should be used as soon as infection is documented. In severe cases, granulocyte transfusions may be in order, especially in invasive aspergilosis cases [10].

Chronic granulomatous disease patients are immunocompromised by their disease, but also by therapy: corticosteroid administration is often required for increased periods of time and tumor necrosis factor-α (TNF-α) inhibitors, if deemed necessary for their anti-inflammatory properties, must be used with caution because of its tendency to increase the risk of potentially severe infections. Sulfasalazine and azathioprine are recommended in cases where corticoid doses need to be decreased or corticoids have caused unacceptable side effects. Hydroxychloroquine and methotrexate are used in patients suffering from lupus-like syndromes or articular inflammation. However, methotrexate treatment should be closely monitored regarding side effects, especially mucositis, that can be mistaken for manifestation of the disease itself.

After the acute infection has been eradicated, lifelong continuous prophylaxis is required and achieved by trimethoprim-sulfamethoxazole, interferon (INF)–gamma and antimycotics administration. Aspergillus species infection is usually effectively prevented by continuous itraconazole administration [11], but, if infection has already occurred, amphotericin B should be added to the therapeutic plan. Interferon-gamma subcutaneous therapy is recommended for the entire duration of the patient's life after diagnosis, due to its proven effect on monocyte and neutrophil function [12].

Hematopoietic stem cell transplantation from matched donors is another important therapeutic measure, that should be undertaken as early as possible [13]. Bone marrow transplantation is another viable option [14], but donors and recipients should be perfectly matched [15].

Surgical care in chronic granulomatous disease refers to the excision of granulomas and abscesses. Rectal abscesses can prove particularly difficult to manage, due to recurrent postoperative infection in these patients.

Gene therapy for this disease is currently undergoing clinical trials, but progress seems to already have been made by certain investigators [16].

The prognosis depends on the time clinical signs of the disease are first noted: the sooner the patient is symptomatic, the more grim the prognosis is considered to be. However, prognosis is improved by early diagnosis [17]. Life expectancy is commonly 30-40 years and death usually occurs secondary to bacterial and fungal infections [18]. Reactive oxygen intermediates are an accurate survival predictor [19]. Granulomatous complications are more frequently expected in individuals suffering from X-linked disease.

Chronic granulomatous disease is a genetic condition, with either X-linked recessive or autosomal recessive transmission. Either way, the substrate is represented by defects of one of the components of nicotinamide adenine dinucleotide phosphate oxidase, affected by regulatory-region, missense, nonsense or splice-region mutations, deletions or frame shifts [20]. Hemizygous mutations represent the vast majority. The genes that have been demonstrated to be involved are those coding the for the gp91phox, the p67phox [21], the p47phox and the p22phox components [22]. X-linked transmitted disease patients are affected by CYBB gene mutations, while autosomal recessive transmitted illness individuals suffer from NCF4, NCF1, NCF2, or CYBA genes abnormalities.

Other authors call attention to the fact that the disease may also be caused by Rac2 inhibitory mutations [23] or by bacillus Calmette-Guerin vaccination [24].

Chronic granulomatous disease is a rare pathology, affecting approximately 1 in 200,000-250,000 live births in general, with limits varying from 1 case in 1 million to 1 individual in 160.000 [25] [26]. This condition affects patients regardless of their age, but a predilection for the male sex has been observed, as in any X-linked disease [27]. Patients usually become symptomatic during the first year of life, but delayed diagnosis has also been reported [28].

The substrate of the disease consists in the inability of the phagocytes to destroy the microorganisms. Their microbe ingestion ability, however, remains unaffected [29]. The dysfunction of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex makes patients prone to develop catalase-positive organisms infections. Microorganisms that are resistant to nonoxidative killing are another source of morbidity and mortality.

Two mechanisms of microorganism survival inside the phagocyte have been postulated. One refers to a direct role of reactive oxygen species, while the other discusses their implication in proteolytic enzymes release form the phagocyte granules [30]. Both mechanisms may be implicated in disease pathophysiology. Phagocytes that have ingested microorganisms but are unable to destroy them organize into granulomata, located in the skin, gastrointestinal tract, lungs, bones, liver or lymph nodes.

As in most genetic diseases, primary prevention is only applicable to the potential offspring of the patients, by means of genetic counseling. Secondary prophylaxis is achieved by early diagnosis and treatment of infections and offering advice on infection avoidance.

Chronic granulomatous disease is an infrequent pathology affecting males more frequently than females, defined by phagocytic dysfunction as a result of X-linked or autosomal recessive mutation of either one of the five domains of the nicotinamide adenine dinucleotide phosphate oxidase. The genetic abnormality causes the inability to generate superoxide, a vital component of phagocytic mediated immunity. Symptoms are initially more or less severe [31], but the propensity for severe infection persists throughout the entire lifetime. Early diagnosis and aggressive treatment are crucial for patient survival and wellbeing. Therapeutic measures consist of aggressive bacterial and fungal treatment followed by continuous, life-long prophylaxis trimethoprim-sulfamethoxazole, itraconazol and interferon (INF)–gamma administration. Gene therapy is an option in certain cases, whereas others benefit from allogeneic hematopoietic stem cell transplantation or bone marrow transplantation.

Chronic granulomatous disease is a rare genetic condition affecting white blood cells, that are responsible for the immunity. Genetic diseases are present at birth, therefore symptoms usually arise during the childhood, even the first year of life, despite the fact that the child appears healthy at birth. An immune system deficiency implies the fact that the body is vulnerable to infection that would not represent a problem for otherwise healthy individuals. For chronic granulomatous disease patients, even initially minor infections can become lethal in time. Milder forms, that go unrecognized during the teenage period or even adulthood are also possible.

Medical tests patients are subjected to aim to diagnose and locate the infection and its etiological agent and to establish the type of dysfunction of the immune system (since this condition is characterized by the fact that antibody production, for instance, remains normal). Once the genetic substrate has been identified, the only curative treatment remains gene therapy, but good results have been achieved with allogeneic hematopoietic stem cell transplantation and bone marrow transplantation. However, before that, the patient will most likely require prolonged and repeated hospitalization periods that make bacterial and fungal infection treatment possible. Their prevention partially lies in the hands of the patient, who is strongly advised to pay special attention to skin hygiene, an important entry point for dangerous microbes.

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