21/409. The dermatosis of chronic granulomatous disease. A family with X-linked cytochrome-negative chronic granulomatous disease (CGD) involving three generations is reported. The diagnosis of CGD in both the latest male patient and the index male was confirmed by marked impairment in polymorphonuclear leucocyte oxidative burst activity in association with absence of both subunits of cytochrome b. The two female carriers have suffered from chronic inflammatory skin disorders characterized by slowly fluctuating erythematous plaques. The reported cases are discussed in the context of a literature review of the dermatosis of CGD. ( info) |
22/409. Visceral leishmaniasis and other severe infections in an adult patient with p47-phox-deficient chronic granulomatous disease. We report a rare case of a male patient without known immunodeficiency consecutively diagnosed with visceral leishmaniasis, brain abscess and cavitating pneumonia in the 3rd decade of life. Chronic granulomatous disease (CGD) was diagnosed by a nitroblue tetrazolium test. A p47-phox mutation of the nadph oxidase of the leukocytes was suspected by immunoblotting and confirmed by dna analysis. The patient was homozygous for this mutation while his mother and sister were heterozygous asymptomatic carriers. After the CGD diagnosis the patient started a chronic prophylactic regimen with subcutaneous interferon-gamma (0.05 mg/m2 of body surface/three times a week), and oral trimethoprim-sulfamethoxazole and itraconazole (both at 5 mg/kg/day) with no subsequent infections after 12 months of follow-up. ( info) |
23/409. CNS granulomatosis in a child with chronic granulomatous disease. Chronic granulomatous disease (CGD) is a disease in which a granulomatous process involves various organ systems and in which recurrent infections are seen. The basic defect is the absence of the granulocyte respiratory burst. CNS involvement is rare. We present a report of a child with CGD and CNS involvement, presenting with hydrocephalus. candida was identified in the granulomata. The patient responded well to a CSF shunt and antifungal therapy. ( info) |
24/409. Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22(phox). Chronic granulomatous disease is a rare inherited disorder caused by nonexistent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for generating the superoxide, nadph oxidase, involves at least 5 protein components. The absence of, or a defect in, any 1 of 4 of these proteins (p22(phox), p47(phox), p67(phox), or gp91(phox)) gives rise to the known types of chronic granulomatous disease. One of the rarest forms of the disease is due to defects in the CYBA gene encoding p22(phox), which together with gp91(phox) forms flavocytochrome b(558), the catalytic core of nadph oxidase. To date, only 9 kindreds with p22(phox) deficiency have been described in the literature comprising 10 mutant alleles. Four polymorphisms in the CYBA gene have also been reported. Here we describe 9 new, unrelated kindreds containing 12 mutations, 9 of which are novel. In addition, we report 3 new polymorphisms. The novel mutations are (a) deletion of exons 2 and 3, (b) a missense mutation in exon 3 (T155-->C), (c) a splice site mutation at the 5' end of intron 3, (d) a missense mutation in exon 2 (G74-->T), (e) a nonsense mutation in exon 1 (G26-->A), (f) a missense mutation in exon 4 (C268-->T), (g) a frameshift in exon 3 due to the insertion of C at C162, (h) a nonsense mutation in exon 2 (G107-->A), and (i) a missense mutation in exon 2 (G70-->A). ( info) |
25/409. A new exon created by intronic insertion of a rearranged LINE-1 element as the cause of chronic granulomatous disease. Long interspersed nuclear element-1 (LINE-1) or L1 elements are dna elements present in the genome in high copy number and capable of active retrotransposition. Here we present a patient with severe chronic granulomatous disease (CGD) caused by insertion of an L1 sequence into intron 5 of the X-lined gene CYBB. Due to internal rearrangements, the insert introduced new splice sites into the intron. This resulted in a highly heterogeneous splicing pattern with introduction of two L1 fragments as new exons into the transcripts and concomitant skipping of exonic coding sequence. Because no wild-type cDNA was found, this mechanism is probably responsible for the patient's phenotype. The L1 fragment, which belongs to the Ta subset of transcriptionally active LINEs, illustrates a new mechanism by which these elements can modify the transcribed coding sequence of genes. ( info) |
26/409. Failure to detect circulating aspergillus markers in a patient with chronic granulomatous disease and invasive aspergillosis. We report a patient with chronic granulomatous disease who developed invasive pulmonary aspergillosis and a subphrenic abscess. During treatment, high levels of aspergillus antigen were detected in the abscess, but circulating antigen and aspergillus dna were undetectable in the serum. ( info) |
27/409. Respiratory syncytial virus infection in patients with phagocyte defects. patients with phagocyte defects frequently develop bacterial or fungal pneumonias, but they are not considered to be at increased risk for viral infections. We describe 3 patients with known phagocyte immunodeficiencies who developed lower respiratory tract infections (LRTI) caused by respiratory syncytial virus (RSV). All 3 patients had dense pneumonias as indicated by computed tomography scan of the lungs and RSV was recovered. We conclude that RSV can present as a dense pneumonia in patients with phagocyte defects. Along with common pathogens causing LRTI, RSV should be considered in the differential diagnosis. Viral cultures as well as rapid antigen detection assays for respiratory viruses should be included in the evaluation of LRTI in patients with phagocyte defects. respiratory syncytial virus, phagocyte, immunodeficiency, pneumonia. ( info) |
28/409. First example of anti-Kx in a person with the McLeod phenotype and without chronic granulomatous disease. BACKGROUND: Kx is lacking in the RBCs of patients with the McLeod syndrome. This condition is sometimes associated with chronic granulomatous disease (CGD). If given allogeneic RBCs, CGD patients with the McLeod phenotype may produce anti-Kx and anti-Km, and only phenotypically matched McLeod blood would be compatible. McLeod phenotype persons without CGD have made anti-Km but not anti-Kx (2 examples), and thus both McLeod and K(O) blood would be compatible. CASE REPORT: RBCs from a transfused patient with the McLeod phenotype but not with CGD (non-CGD McLeod) were typed for the Kell blood group antigens, and the plasma was analyzed for the presence of antibody by agglutination. The molecular basis was determined by analyzing for XK protein on RBC membranes by Western immunoblotting, by sequencing the XK gene, and by RFLP. RESULTS: The RBCs did not react with anti-Kx anti-Km and showed weakening of Kell system antigens. The patient's plasma reacted moderately (2 ) with RBCs of common Kell type and strongly (4 ) with K(O) RBCs and RBCs of common Kell type treated with dithiothreitol, and did not react with McLeod RBCs. XK protein was absent from the RBC membranes. The XK gene had a point mutation in the donor splice site of intron 1 (G>C). CONCLUSION: This is the first report describing the molecular alteration in a non-CGD McLeod patient who has made anti-Kx. The immune response of people with the McLeod phenotype can vary, and K(O) blood may not always be compatible. ( info) |
29/409. Successful treatment of invasive aspergillosis in chronic granulomatous disease by granulocyte transfusions followed by peripheral blood stem cell transplantation. Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by impaired microbial killing and susceptibility to bacterial and fungal infections. Cure of the disease can be achieved by stem cell transplantation when performed early in its course, and before severe infections have developed. Invasive aspergillosis constitutes a very high risk for transplantation. We report a 4-year-old boy with X-linked CGD who underwent successful HLA-identical peripheral blood stem cell (PBSC) transplantation during invasive pulmonary aspergillosis and osteomyelitis of the left fourth rib, which was unresponsive to antifungal treatment. During the 2 months prior to the transplant he received G-CSF-mobilized granulocyte transfusions (GTX) from unrelated donors three times a week in addition to the antifungal treatment. This resulted in clinical improvement in his respiratory status. He also received GTX during the aplastic period after the conditioning regimen, until he had engrafted. Post-transplant superoxide generation test revealed that neutrophil function was within normal range. One year post transplant the CT scan showed almost complete clearance of the pulmonary infiltrates and a marked improvement in the osteomyelitic process. Based on other reports and our own experience, GTX can serve as important treatment in patients with CGD who have failed conventional anti-fungal treatment and for whom stem cell transplantation is the only chance for cure. ( info) |
30/409. colitis in chronic granulomatous disease. BACKGROUND: Involvement of the gut in chronic granulomatous disease (CGD) has been previously described and colitis highlighted. However, the nature and histopathology of the colitis are unclear and have been thought to be non-specific or similar to Crohn's disease. methods: Seven patients with CGD, suffering from gastrointestinal symptoms were prospectively studied. RESULTS: All patients had anaemia; other symptoms were failure to thrive (5/7) and diarrhoea (5/7). Most had microcytic anaemia (5/7), increased platelets (7/7), and increased erythrocyte sedimentation rate (6/6). Endoscopically there was a friable erythematous mucosa in 6/7. The histological features present in all patients consisted of a colitis with paucity of neutrophils, increased numbers of eosinophils, eosinophilic crypt abscesses, pigmented macrophages, and nuclear debris. In some granulomas were present (2/7). CONCLUSIONS: colitis is a common cause of gastrointestinal symptoms in CGD and is caused by a non-infective inflammatory process. The histology has specific features, which are distinctive from those seen in Crohn's disease. ( info) |