Clinical Features and Genetic Analysis of 48 Patients with Chronic Granulomatous Disease in a Single Center Study from Shanghai, China (2005-2015): New Studies and a Literature Review.

Chronic Granulomatous Disease (CGD) is a rare inherited primary immunodeficiency, which is characterized by recurrent infections due to defective phagocyte NADPH oxidase enzyme. Nowadays, little is known about Chinese CGD patients. Here we report 48 CGD patients in our single center study, which is the largest cohort study from Mainland China. The ratio of male to female was 11 : 1. The mean onset age was 0.29 years old, and 52% patients had an onset within the 1st month of life. The mean diagnosis age was 2.24 years old. 11 patients (23%) had died with an average age of 2.91 years old. 13 patients (28%) had positive family histories. The most prevalent infectious sites were the lungs (77%), followed by gastrointestinal tract (54%), lymph nodes (50%), and skin (46%). 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. X-linked CGD due to CYBB gene mutations accounted for 75% of the cases, and 11 of them were novel mutations. Autosomal recessive inheritance accounted for 6% patients, including 1 patient with CYBA, 1 with NCF1, and 1 with NCF2 gene mutations.

Ocular Manifestations of X-linked Chronic Granulomatous Disease: About Two Atypical Case Reports.

PURPOSE: Two atypical cases of ocular localizations of chronic granulomatous disease are reported. METHODS: The first case is about a 22-year-old woman carrier of the disease who developed active intraocular inflammation and choroidal granulomas successfully treated by steroids. The second is about a 2-year-old boy consulting for unilateral anterior uveitis and subsequent anterior chamber granuloma development as first signs of the disease. RESULTS: X-linked chronic granulomatous disease is a rare inherited primary immunodeficiency syndrome characterized by disorders of phagocytic cells resulting in recurrent infections and development of granulomas. Ophthalmological manifestations are not rare and are mainly represented by surface and intraocular inflammation with possible choroidal granulomas. The two cases reported here are atypical, one of active inflammation in a carrier and the other revealing the disease. CONCLUSION: Ophthalmologists must be aware of chronic granulomatous disease and the possible ocular involvement of this disorder.

Chronic granulomatous disease carrier with recurrent poor obstetric outcome.

BACKGROUND: Chronic granulomatous disease is a primary immunodeficiency disorder characterized by severe recurrent bacterial and fungal infections. Female carriers of the X-linked form of the disorder usually are unaffected and rarely have serious infections. CASE: A 22-year-old pregnant patient known to be a carrier of the X-linked form of chronic granulomatous disease had a history of chorioamnionitis during her two previous pregnancies. During her third pregnancy, she presented again with the same diagnosis, which resulted in delivery at 25 weeks of gestation. CONCLUSION: Carriers of chronic granulomatous disease should be monitored closely during pregnancy, as if they have the disease. To decrease the risk of infectious morbidity and mortality, obstetricians should have a low threshold for starting prophylactic antibiotics early during pregnancy, even if the patient is asymptomatic.

Neonatal Sweet syndrome: a potential marker of serious systemic illness.

Sweet syndrome is an inflammatory disease characterized by fever and painful erythematous plaques with a dermal neutrophilic infiltrate. It is most common in adults, where it is often parainflammatory or paraneoplastic, but is rare in children. We describe 3 cases of neonatal Sweet syndrome, including 1 patient who had myelodysplastic syndrome and immunodeficiency, the first report of a premalignancy underlying infantile Sweet syndrome. We reviewed the literature on patients presenting with neutrophilic dermatosis in the first 6 months of life. Of 20 cases, 6 had a probable viral etiology, 4 primary immunodeficiencies, 3 neonatal lupus syndrome, 1 gastrointestinal involvement, 1 HIV, and 5 probable genetic cases. Three of these had chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome, caused by mutations in the PSMB8 gene. Most children who presented within the first 6 weeks of life had either a serious underlying condition, such as primary immunodeficiency, or a genetic Sweet syndrome, with 2 fatalities among this latter group. The outcome of postinfective cases was good. Extracutaneous involvement was unusual, whereas postinflammatory scarring and cutis laxa occurred in a minority of patients. In conclusion, Sweet syndrome in the neonatal period often heralds a serious underlying disorder and requires thorough investigation.

Diagnóstico prenatal y nueva mutación en enfermedad granulomatosa crónica ligada al cromosoma X / Prenatal diagnosis and novel mutation in X-linked chronic granulomatous disease

Introducción: La enfermedad granulomatosa crónica (EGC) es una inmunodeficiencia primaria poco frecuente que se produce por la inactivación del complejo enzimático NADPH oxidasa. Estos pacientes presentan la función fagocítica alterada, lo que les hace más susceptibles a padecer infecciones bacterianas y/o fúngicas. Métodos: Se estudió a un niño de 6 años con sospecha de EGC. El estudio funcional de NADPH oxidasa estaba alterado, diagnosticándose de EGC. Simultáneamente, se nos informó del segundo embarazo de la madre y se solicitó consejo genético. Resultados: Se identificó una mutación nueva causante de enfermedad mediante secuenciación directa del gen CYBB (EGC ligada al X) en el paciente afecto. Al mismo tiempo, se hizo el estudio prenatal cuyo resultado fue la identificación de la misma mutación en el feto. Conclusiones: Es necesario hacer el estudio molecular de la EGC para realizar el diagnóstico de certeza de la enfermedad del paciente con el objetivo de ofrecer diagnóstico prenatal y consejo genético en futuros embarazos (AU)

Background: Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency caused by the alteration of the enzyme complex NADPH oxidase, which affects the phagocytic function.CGD patients are susceptible to recurrent infections mainly caused by bacteria and/or fungi. Methods: We studied a 6 year-old boy with suspicion of CGD. The diagnosis was confirmed based on the functional study of NADPH oxidase. Simultaneously, the second pregnancy of the mother was reported and genetic counselling was requested. Results: We identified a new disease-causing mutation by direct sequencing of the CYBB gene (X-linked CGD). The prenatal study resulted in the identification of the same mutation in the foetus. Comments: Molecular genetics characterisation of CGD is needed to obtain an accurate diagnosis of the disease and to offer prenatal diagnosis and genetic counselling in future pregnancies (AU)

Prenatal diagnosis of chronic granulomatous disease in a male fetus.

Mutations in any of four known NADPH-oxidase components lead to CGD. X-linked CGD (X-CGD) is caused by defects in CYBB, the gene that encodes gp91-phox. Autosomal recessive (AR) CGD is caused by defects in the genes for p47 phox, p22-phox or p67-phox. The aim of this study was to screen the molecular defect in the fetus of an X-CGD carrier mother and postnatal confirmation of the results. In a family whose first-born child died from X-CGD, fetal DNA was obtained from an ongoing pregnancy by chorionic villus sampling (CVS). Direct sequencing was used to detect the previously identified CYBB gene mutation. The NADPH oxidase activity in the neutrophils from the carrier mother and from the newborn was analyzed by the DHR assay. Our studies predicted that the fetus in question was not affected by chronic granulomatous disease, which was demonstrated to be correct at birth. For prenatal screening in a pregnant X-CGD carrier, direct sequencing is a good method for detecting the mutation in the fetal DNA. Postnatal confirmation of results with the DHR assay is more practical than mutation screening to show whether the newborn have normal NADPH oxidase activity or does not.

Chronic granulomatous disease.

A 2(1/2)-year-old child presented with multiple discrete granulomatous lesions on the face and flexural regions since the age of 2 months along with lymphadenopathy. The patient also had recurrent bouts of pyodermas and respiratory tract infections. Biopsy of the lesion showed necrosis of tissue with suppuration and histiocytes but no evidence of tuberculosis, fungal infections or atypical mycobacteria. Lymph node biopsy also showed necrosis with suppuration but no infective organism. Nitroblue tetrazolium test was negative indicating that the neutrophils failed to oxidize the dye. We are reporting here a rare case of chronic granulomatous disease.

Congenital disorders of the function of polymorphonuclear neutrophils.

This review has concentrated on clinical syndromes for which a congenital basis of polymorphonuclear neutrophil dysfunction has been identified. The first clinical syndrome found to be associated with dysfunctional polymorphs was chronic granulomatous disease of childhood. Identification of a cellular defect in oxidative metabolism and microbicidal activity of polymorphonuclear neutrophils from patients with CGD stimulated intense investigation of the function of phagocytes in several clinical entities characterized by increased susceptibility to infection. Other diseases with a probable congenital basis for polymorph dysfunction include Chediak-Higashi syndrome, myeloperoxidase deficiency, severe glucose-6-phosphate dehydrogenase deficiency, and Down's syndrome. Functional defects have also been identified in neutrophils with morphologic abnormalities, such as the Pelger-Huet anomaly and the May-Hegglin anomaly, and in neutrophils without alkaline phosphatase or with a disorder of the glutathione system. The evidence for a relation between these cellular disorders and susceptibility to infection is tentative. Patients with congenital disorders of polymorphonuclear neutrophil microbicidal function frequently suffer prolonged infections in spite of appropriate antimicrobial therapy, and severe lesions recur with discouraging frequency. These lesions are usually soft tissue or bone abscesses, and the etiologic agents are typically staphylococci, gram-negative enteric species, or fungi. The infectious disease problems of patients with phagocytic cell disorders are usually quite distinct from the problems of patients without immunoglobulins or with complement deficiency. Patients with agammaglobulinemia, for example, suffer recurrent septicemia or meningitis due to Streptococcus pneumonia or H. influenzae. Septicemia, especially with the pyogenic bacterial species, is unusual in patients with polymorphoinuclear dysfunction. A major contribution of the currently intense investigation of cells from patients with congenital disorders of phagocyte function has been the greatly increased understanding of the molecular events necessary for the normal function of these cells. The role of the oxidative metabolic burst during phagocytosis has been clearly identified as essential to the microbicidal function of polymorphs and monocytes, and the glutathione system has been identified as essential to the regulation of these oxidative reactions. It is anticipated that these studies may lead to practical methods for "stimulating the phagocytes" in patients with increased susceptibility to infection.

Repeated staphylococcal pyoderma in two siblings with defective neutrophil bacterial killing.

2 children with undue susceptibility to skin infections and isolated defective neutrophil bacterial killing are described. Since the NBT-reducing capabilities of granulocytes were normal, a mild form of chronic granulomatous disease was excluded. Ascorbic acid was effective in delaying and eventually suppressing infectious episodes.

[Granulocyte dysfunction. I. Inborn defects (author's transl)]. / Granulocytendyfunktion. I. Angeborene Störungen

The insight in the function and dysfunction of granulocytes lately arouses more and more interest. This report summarises our present knowledge. In the first of two chapters the authors review the molecular basis of granulocyte function and the inborn defects of chemotaxis, opsonisation, phagocytosis and intracellular killing of bacteria and fungi.