Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency

The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations. A myeloablative reduced toxicity HSCT was completed using an unrelated bone marrow donor. With the increasing cases of immune dysregulation being discovered with hypomorphic RAG variants, the use of HSCT may advance to the forefront of treatment. This case serves to discuss indications of HSCT, approaches to preparative therapy, and the potential complications in this growing cohort of patients with immune dysregulation and RAG deficiency.     

Hypersensitive Pneumonitis: an Initial Presentation of Chronic Granulomatous Disease in a Child

Hypersensitive pneumonitis (HP) is a rare initial presentation of chronic granulomatous disease (CGD), especially in children. CGD presenting as HP may result from exposure to inhaled environmental antigens and be induced by excessive production of inflammatory cytokines due to loss of reactive oxygen species production. We herein describe a 2-year-old boy with CGD caused by a mutation in CYBB gene, who initially presented with HP. The patient developed dry cough, progressive dyspnea, and fever after playing in dusty air in a factory that produced plastic materials containing isocyanates. The patient’s symptoms and radiological abnormalities did not improve after antigen avoidance, but disappeared after corticosteroid therapy. Because HP is uncommon in children, we should consider the possibility of CGD in children who present with HP. A prompt diagnosis of CGD is essential to enable initiation of prophylactic antibacterial and antifungal therapies.     

Disseminated Infection Due to Chrysosporium zonatum in a Patient with Chronic Granulomatous Disease and Review of Non-Aspergillus Fungal Infections in Patients with This Disease

We report the first case of Chrysosporium zonatum infection in a 15-year-old male with chronic granulomatous disease who developed a lobar pneumonia and tibia osteomyelitis while on prophylaxis with gamma interferon. The fungus was isolated from sputum and affected bone, and hyphae were observed in the bone by histopathology. Therapy with amphotericin B eradicated the osteomyelitis and pneumonia, but pneumonia recurred in association with pericarditis and pleuritis during therapy with itraconazole. These manifestations subsided, and no recurrences occurred with liposomal amphotericin B therapy. Infections caused by Chrysosporium species are very rare, and C. zonatum has not previously been reported to cause mycosis in humans. This species, the anamorph of the heterothallic ascomycete Uncinocarpus orissi (family Onygenaceae), is distinguished by its thermotolerance, by colonies which darken from yellowish white to buff, and by club-shaped terminal aleurioconidia borne at the ends of short, typically curved stalks. The case isolate produced fertile ascomata in mating tests with representative isolates. The median (range) MICs for our isolate as well as those for two other human isolates and a nonhuman isolate determined by the National Committee for Clinical Laboratory Standards method adapted for moulds were ≤0.06 μg/ml (≤0.06 to 0.25 μg/ml) for amphotericin B, 0.687 μg/ml (0.25 to 2 μg/ml) for itraconazole, >128 μg/ml (>128 μg/ml) for flucytosine, and 48 μg/ml (32 to >128 μg/ml) for fluconazole.     

Phellinus tropicalis Abscesses in a Patient with Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD), caused by genetic defects in components of the phagocyte NADPH oxidase pathway, leads to recurrent life-threatening bacterial and invasive fungal infections. While a number of unique pathogens have been associated with this disease, the causative organisms may be difficult to identify. Here, we present a 24 year old male with known X-linked CGD who concurrently developed a cervical abscess and an abscess in the subcutaneous tissues of the right hip, both of which were surgically drained. Cultures failed to identify any organisms. He was treated empirically with ertapenem but the hip abscess recurred at the original site and in contiguous dependent areas in the posterior thigh and knee. A filamentous organism was observed microscopically, initially considered a contaminant, but on culture yielded a mold growth, identified as Phellinus tropicalis (synonym: Inonotus tropicalis) based on phenotypic and molecular methods. This is the third case report of human infection with P. tropicalis, all in subjects with CGD. The patient was treated with voriconazole with resolution of his symptoms.     

Acidomonas Methanolica-Associated Necrotizing Lymphadenitis in a Patient with Chronic Granulomatous Disease

Purpose

Adenitis for which no causative organism can be isolated is a common occurrence in patients with chronic granulomatous disease (CGD). Here we identify Acidomonas methanolica as a pathogen associated with adenitis in a patient with CGD.

Methods

The causative pathogen was obtained after prolonged incubation of an excised lymph node in thioglycolate broth. Identification was carried out by sequencing the 16s rRNA. Immunoblots were prepared utilizing protein extracts from the case patient’s A. methanolica isolate, an ATCC type strain of A. methanolica and G. bethesdensis.

Results

Fastidious gram-negative rods grew after prolonged incubation of an excised lymph node in thioglycolate broth. Sequencing of the 16s rRNA identified the organism as A. methanolica. Immunoblot confirmed the pathogen’s role in the patient’s adenitis by showing the patient’s specific immune response to the organism.

Conclusions

A. methanolica is the second member of the family, Acetobacteaceae to be associated with adenitis in patients with CGD.     

Sporothrix schenckii Lymphadentitis in a Male with X-linked Chronic Granulomatous Disease

Sporothrix schenckii lymphadenitis was identified in a 33 month old male with X-linked chronic granulomatous disease (CGD). S. schenckii is a dimorphic catalase producing fungus found in the soil of temperate and tropical climates. Host defense against S. schenckii relies primarily on innate and cellular responses and gp91^phox?/? mice are susceptible to disseminated infection. This case represents the first report of susceptibility to sporotrichosis in a patient with CGD.     

Psychrobacter immobilis Septicemia in a Boy with X-linked Chronic Granulomatous Disease and Fulminant Hepatic Failure

A 16-year old boy with chronic granulomatous disease (CGD) developed Psychrobacter immobilis septicemia during a course of fulminant hepatic failure. The patient died despite aggressive management with antimicrobials and corticosteroids. While Psychrobacter immobilis rarely affects humans, it should be considered an organism that can cause sepsis in patients with CGD.     

Diagnostic Exome Sequencing Identifies a Novel Gene,EMILIN1, Associated with Autosomal‐Dominant Hereditary Connective Tissue Disease

Heritable connective tissue diseases are a highly heterogeneous family of over 200 disorders that affect the extracellular matrix. While the genetic basis of several disorders is established, the etiology has not been discovered for a large portion of patients, likely due to rare yet undiscovered disease genes. By performing trio‐exome sequencing of a 55‐year‐old male proband presenting with multiple symptoms indicative of a connective disorder, we identified a heterozygous missense alteration in exon 1 of the Elastin Microfibril Interfacer 1 (EMILIN1) gene, c.64G>A (p.A22T). The proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Sanger sequencing confirmed that the EMILIN1 alteration, which maps around the signal peptide cleavage site, segregated with disease in the affected proband, mother, and son. The impaired secretion of EMILIN‐1 in cells transfected with the mutant p.A22T coincided with abnormal protein accumulation within the endoplasmic reticulum. In skin biopsy of the proband, we detected less EMILIN‐1 with disorganized and abnormal coarse fibrils, aggregated deposits underneath the epidermis basal lamina, and dermal cells apoptosis. These findings collectively suggest that EMILIN1 may represent a new disease gene associated with an autosomal‐dominant connective tissue disorder.     

Clinical and Molecular Features of 38 Children with Chronic Granulomatous Disease in Mainland China

Purpose

Chronic granulomatous disease (CGD) is an inherited disorder, with phagocytes failing to produce antimicrobial superoxide due to deficient NADPH oxidase activity. Mutations in the gene encoding CYBB are responsible for the majority of the CGD cases. To date, there have been no reports on large samples of children with CGD in China. Therefore, in this study, we described the clinical and molecular features of 38 suspected CGD patients from 36 unrelated Chinese families.

Methods

Clinical diagnosis was performed using dihydrorhodamine assays detected by flow cytometry. Molecular analysis was used to identify underlying CGD-causative genes.

Results

The mean age of onset in our 38 patients was 3.4 months, while the mean age at diagnosis was 31.7 months. Apart from recurrent pneumonia and abscesses, tuberculosis (TB) and Bacille Calmette-Guerin (BCG) infections were notable features in our cohort. Overall, 17 cases died and patient 1 did not participate in the follow-up period . In total, we identified 29 different CYBB gene mutations in 31 patients. We found NCF1 and CYBA mutations in 3 and 2 patients, respectively. In addition, we identified 31 carriers and prenatally diagnosed 4 CGD and 4 healthy fetuses.

Conclusions

The results of our study demonstrate that children with BCG infections or recurrent TB infections should have immune function screening tests performed. Moreover, newborns with family histories of primary immunodeficiency diseases should avoid of BCG vaccination. Molecular analysis is an important tool for identifying patients, carriers, and high-risk CGD fetuses.     

Clinical, Functional and Genetic Analysis of Twenty-Four Patients with Chronic Granulomatous Disease - Identification of Eight Novel Mutations in CYBB and NCF2 Genes

Chronic granulomatous disease is an inherited disorder in which phagocytes lack a functional NADPH oxidase and cannot produce superoxide anions. The most common form is caused by mutations in CYBB encoding gp91phox. We investigated 24 CGD patients and their families. Twenty-one mutations in CYBB were classified as X91(0), X91(+) or X91(-) variants according to cytochrome b (558) expression. Point mutations in encoding regions represented 50?% of the mutations found in CYBB, splice site mutations 27?%, deletions and insertions 23?%. Eight mutations in CYBB were novel leading to X91(0)CGD cases. Two of these were point mutations: c493G>T and a double mutation c625C>G in exon 6 and c1510C>T in exon 12 leading to a premature stop codon at Gly165 in gp91phox and missense mutations His209Arg/Thr503Ile respectively. Two novel splice mutations in 5'intronic regions of introns 1 and 6 were found. A novel deletion/insertion c1024_1026delCTG/insT results in a frameshift introducing a stop codon at position 346 in gp91phox. The last novel mutation was the insertion of a T at c1373 leading to a frameshift and a premature stop codon at position 484 in gp91phox. For the first time the precise size of two large mutations in CYBB was determined by array-comparative genomic hybridization and carriers' status were evaluated by multiplex ligation-dependent probe amplification assay. No clear correlation between clinical severity and CYBB mutations could be established. Of three mutations in CYBA, NCF1 and NCF2 leading to rare autosomal recessive CGD, one nonsense mutation c29G>A in exon 1 of NCF2 was new.     

Septic Arthritis and Concern for Osteomyelitis in a Child with Rat Bite Fever

Rat bite fever is a rare infection usually caused by Streptobacillus moniliformis. A case of septic arthritis and possible osteomyelitis as sequelae of rat bite fever in a pediatric patient is described.     

Streptococcal Infections in Patients with Chronic Granulomatous Disease: Case Report and Review of the Literature

Streptococcus intermedius caused a liver abscess in a patient with chronic granulomatous disease (CGD). In contrast to typical staphylococcal abscesses in CGD, this abscess was liquid, easily drained, and resolved without surgery or steroids. This case and literature review provide insight into this organism's pathogenesis, including in CGD.     

Analysis of Chronic Granulomatous Disease in the Kavkazi Population in Israel Reveals Phenotypic Heterogeneity in Patients with the Same NCF1 mutation (c.579G>A)

Purpose

Chronic granulomatous disease (CGD) is an innate immune deficiency disorder of phagocytes, resulting from mutations in the components of the NADPH oxidase complex that impair the synthesis of oxygen radicals, thus rendering patients susceptible to recurrent infections and excessive hyperinflammatory responses. The most common autosomal recessive form of CGD is p47^phox deficiency, which is often clinically milder than the more common X-linked recessive form. Here, we report data on genetics, clinical and biochemical findings in 17 CGD patients of Kavkazi origin with the nonsense mutation c.579G>A in the NCF1 gene, leading to p47^phox deficiency.

Methods

Diagnosis was based on detailed clinical evaluation, respiratory burst activity by cytochrome c reduction and dihydrorhodamine-1,2,3 (DHR) assay by flow cytometry, expression of p47^phox by immunoblotting and molecular confirmation by DNA sequence analysis.

Results

Twelve male and five female patients with median age at onset of 2.5 years (range 1 day to 9 years) were included in the study. The present cohort displays an encouraging 88% overall long-term survival, with median follow-up of 17 years. Clinical manifestations varied from mild to severe expression of the disease. Correlation between genotype and phenotype is unpredictable, although the Kavkazi patients were more severely affected than other patients with p47^phox deficiency.

Conclusions

Kavkazi CGD patients harbor a common genetic mutation that is associated with a heterogeneous clinical phenotype. Early diagnosis and proper clinical management in an experienced phagocytic leukocyte center is imperative to ensure favorable patient outcome. New treatment strategies are ongoing, but results are not yet conclusive.