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Recognizing genetic disease: A key aspect of pediatric pulmonary care.

Pediatr Pulmonol. 2020 Jul;55(7):1794-1809

Authors: Yonker LM, Hawley MH, Moschovis PP, Lu M, Kinane TB

Abstract
Advancement in technology has improved recognition of genetic etiologies of disease, which has impacted diagnosis and management of rare disease patients in the pediatric pulmonary clinic. This review provides an overview of genetic conditions that are likely to present with pulmonary features and require extensive care by the pediatric pulmonologist. Increased familiarity with these conditions allows for improved care of these patients by reducing time to diagnosis, tailoring management, and prompting further investigation into these disorders.

PMID: 32533909 [PubMed – as supplied by publisher]

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Clinical, Immunologic, and Molecular Spectrum of Patients with Immunodeficiency, Centromeric instability, and Facial anomalies (ICF) syndrome: a Systematic Review.

Endocr Metab Immune Disord Drug Targets. 2020 Jun 13;:

Authors: Kiaee F, Zaki-Dizaji M, Hafezi N, Almasi-Hashiani A, Hamedifar H, Sabzevari A, Shirkani A, Zian Z, Jadidi-Niaragh F, Aghamahdi F, Goudarzvand M, Yazdani R, Abolhassani H, Aghamohammadi A, Azizi G

Abstract
BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism )ICF) syndrome is a rare autosomal recessive immune disorder presenting with hypogammaglobulinemia, developmental delay, and facial anomalies. The ICF type 1, type 2, type 3 and type 4 are characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS gene, respectively. This study aimed to present a comprehensive description of the clinical, immunologic and genetic features of patients with ICF syndrome.
METHODS: PubMed, Web of Science, and Scopus were searched systemically to find eligible studies.
RESULTS: Forty-eight studies with 118 ICF patients who met the inclusion criteria were included in our study. Among these patients, 60% reported with ICF-1, 30% with ICF-2, 4% with ICF-3, and 6% with ICF-4. The four most common symptoms reported in patients with ICF syndrome were: delay in motor development, low birth weight, chronic infections, and diarrhea. Intellectual disability and preterm birth among patients with ICF-2 and failure to thrive, sepsis and fungal infections among patients with ICF-1 were also more frequent. Moreover, the median levels of all three immunoglobulins (IgA, IgG, IgM) were markedly reduced within four types of ICF syndrome.
CONCLUSION: The frequency of diagnosed patients with ICF syndrome has increased. Early diagnosis of ICF is important since immunoglobulin supplementation or allogeneic stem cell transplantation can improve the disease-free survival rate.

PMID: 32533820 [PubMed – as supplied by publisher]

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Lentiviral gene therapy rescues p47phox chronic granulomatous disease and the ability to fight Salmonella infection in mice.

Gene Ther. 2020 Jun 12;:

Authors: Schejtman A, Aragão-Filho WC, Clare S, Zinicola M, Weisser M, Burns SO, Booth C, Gaspar HB, Thomas DC, Condino-Neto A, Thrasher AJ, Santilli G

Abstract
Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder characterised by recurrent and often life-threatening infections and hyperinflammation. It is caused by defects of the phagocytic NADPH oxidase, a multicomponent enzyme system responsible for effective pathogen killing. A phase I/II clinical trial of lentiviral gene therapy is underway for the most common form of CGD, X-linked, caused by mutations in the gp91phox subunit of the NADPH oxidase. We propose to use a similar strategy to tackle p47phox-deficient CGD, caused by mutations in NCF1, which encodes the p47phox cytosolic component of the enzymatic complex. We generated a pCCLCHIM-p47phox lentiviral vector, containing the chimeric Cathepsin G/FES myeloid promoter and a codon-optimised version of the human NCF1 cDNA. Here we show that transduction with the pCCLCHIM-p47phox vector efficiently restores p47phox expression and biochemical NADPH oxidase function in p47phox-deficient human and murine cells. We also tested the ability of our gene therapy approach to control infection by challenging p47phox-null mice with Salmonella Typhimurium, a leading cause of sepsis in CGD patients, and found that mice reconstituted with lentivirus-transduced hematopoietic stem cells had a reduced bacterial load compared with untreated mice. Overall, our results potentially support the clinical development of a gene therapy approach using the pCCLCHIM-p47phox vector.

PMID: 32533104 [PubMed – as supplied by publisher]

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Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing.

J Allergy Clin Immunol. 2020 Jun 09;:

Authors: Fusaro M, Rosain J, Grandin V, Lambert N, Hanein S, Fourrage C, Renaud N, Gil M, Chevalier S, Chahla WA, Bader-Meunier B, Barlogis V, Blanche S, Boutboul D, Castelle M, Comont T, Diana JS, Fieschi C, Galicier L, Hermine O, Lefevre-Utile A, Malphettes M, Merlin E, Oksenhendler E, Pasquet M, Suarez F, André I, Béziat V, De Saint Basile G, De Villartay JP, Kracker S, Lagresle-Peyrou C, Latour S, Rieux-Laucat F, Mahlaoui N, Bole C, Nitschke P, Hulier-Ammar E, Fischer A, Moshous D, Neven B, Alcais A, Vogt G, Bustamante J, Picard C

Abstract
This study aims to validate a targeted next-generation sequencing panel of 300 genes to diagnose a cohort of 129 patients with primary immunodeficiency with no prior molecular etiology.

PMID: 32531373 [PubMed – as supplied by publisher]

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Very early-onset inflammatory bowel disease in Japan: A nationwide survey.

J Gastroenterol Hepatol. 2020 Jun 12;:

Authors: Kudo T, Arai K, Uchida K, Tajiri H, Hokari R, Suzuki Y, Shimizu T

Abstract
BACKGROUND AND AIM: Very early-onset inflammatory bowel disease is defined as inflammatory bowel disease diagnosed before 6 years of age. Very early-onset inflammatory bowel disease has various differential diagnoses, including primary immunodeficiency disorders, and is known to be resistant to conventional treatment. Therefore, global attention is required to manage this challenging condition. We conducted a retrospective epidemiological survey of the number of patients, final diagnosis, and examinations performed to diagnose very early-onset inflammatory bowel disease in Japan.
METHODS: A primary questionnaire about the number of very early-onset bowel disease cases and its diagnosis was administered to 630 pediatric facilities nationwide in Japan. A secondary survey about the examinations performed to achieve diagnosis was sent to the facilities that responded to the first survey.
RESULTS: The answering rate was 92.2% (581/630 facilities); 81 facilities had 225 very early-onset bowel disease patients undergoing their care during the past 68 months. Twenty-six patients (11.6%) were diagnosed with immunodeficiency-associated inflammatory bowel disease. The answering rate of the secondary survey was 70.4% (57/81 facilities). Colonoscopy, esophagogastroduodenoscopy, and small bowel imaging were performed for 99.4%, 67.5%, and 28.8% of patients, respectively. Genetic analysis was performed for 26.9% (43/160 patients) of patients, and 51.2% (22/43) of patients were diagnosed with immunodeficiency-associated inflammatory bowel disease.
CONCLUSIONS: Approximately 40 patients are diagnosed yearly in Japan. Imaging studies, especially for small bowel lesions, can be challenging for this unique group of patients. However, a comprehensive approach including immunological and genetic analyses appears useful for diagnosing immunodeficiency-associated inflammatory bowel disease.

PMID: 32530546 [PubMed – as supplied by publisher]

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An unusual cause for rib osteomyelitis in the tropics: Cryptococcal osteomyelitis.

Trop Doct. 2020 Jun 11;:49475520929827

Authors: Ramesh V, Rao Polati V, Nimmala P, Anand M, Narreddy S, Saidulu G

Abstract
The more common manifestations of cryptococcal infections are restricted to the central nervous system and lungs. We report an unusual case of fungal osteomyelitis due to Cryptococcus. The patient was a young man who had been adequately treated for pulmonary tuberculosis three years prior. Three months before, he sustained a minor road-traffic accident with only minor abrasions. He presented with subacute chest pain of 15 days’ duration and was found to have radiological evidence of a lytic lesion of the fifth rib. Given prior tuberculosis, he was thought to have a relapse of disease with tuberculous osteomyelitis. Surprisingly, a biopsy revealed evidence of fungal osteomyelitis with Cryptococcus. An evaluation for primary immunodeficiency revealed low CD4 cell counts with undetectable serum IgA and IgM levels. Genetic sequencing proved a genetic mutation consistent with primary T-cell immunodeficiency. The patient responded well to treatment and is asymptomatic on follow-up.

PMID: 32525454 [PubMed – as supplied by publisher]

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Chronic Granulomatous Disease: a Comprehensive Review.

Clin Rev Allergy Immunol. 2020 Jun 10;:

Authors: Yu HH, Yang YH, Chiang BL

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency of phagocyte function due to defective NADPH oxidase (phox). Compared with the common types of CYBB/gp91phox, NCF1/p47phox, and CYBA/p22phox deficiency, NCF4/p40phox deficiency is a mild and atypical form of CGD without invasive bacterial or fungal infections. It can be diagnosed using serum-opsonized E.coli as a stimulus in dihydrorhodamine (DHR) assay. Patients with CYBC1/Eros deficiency, a new and rare form of CGD, present as loss of respiratory burst and gp91phox expression in phagocytes. Neutrophils from patients with CGD are deficient in neutrophil extracellular traps (NETosis), autophagy, and apoptosis. The hyper-activation of NF-ĸB and inflammasome in CGD phagocytes also lead to long-lasting production of pro-inflammatory cytokines and inflammatory manifestations, such as granuloma formation and inflammatory bowel disease-like colitis. Patients with CGD and X-linked female carriers also have a higher incidence of autoimmune diseases. The implementation of antimicrobial, anti-fungal, and interferon-γ prophylaxis has greatly improved overall survival. Residual NADPH oxidase activity is significantly associated with disease severity and the chance of survival of the patient. New therapeutic approaches using immunomodulators for CGD-related inflammatory manifestations are under investigation, including pioglitazone, tamoxifen, and rapamycin. Hematopoietic stem cell transplantation (HSCT) is the curative treatment. Outcomes of HSCT have improved substantially over the last decade with overall survival more than 84-90%, but there are debates about designing optimal conditioning protocols using myeloablative or reduced-intensity regimens. The gene therapy for X-linked CGD using hematopoietic stem and progenitor cells transduced ex vivo by lentiviral vector encoding the human gp91phox gene demonstrated persistence of adequate oxidase-positive neutrophils in a small number of patients. Gene therapy using genome-editing technology such as CRISPR/Cas9 nucleases is a promising approach for patients with CGD in the future.

PMID: 32524254 [PubMed – as supplied by publisher]

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