Research

The association between parental consanguinity and primary immunodeficiency diseases: a systematic review and meta-analysis.

Pediatr Allergy Immunol. 2016 Nov 28;:

Authors: Hadizadeh H, Salehi MM, Khoramnejad S, Vosoughi K, Rezaei N

Abstract
BACKGROUND: We aimed to establish the prevalence of parental consanguinity among patients with primary immunodeficiency diseases (PID), and compare the prevalence with the general population.
METHOD: We searched PubMed, EMBASE, and Scopus for studies mentioning parental consanguinity prevalence in PID patients and calculated the prevalence odds ratio (POR) of parental consanguinity in each study, compared to a matched healthy population.
RESULTS: We identified 21 eligible studies with a total population of 18091 accounting for sample overlap. The POR among studies on a sample of mixed PID patients ranged from 0.6 to 21.9 with the pooled POR of 3.0 (P<0.001; I(2) =89%, 95% CI 2.5-3.7).
CONCLUSION: PIDs with an autosomal recessive pattern of inheritance had significant odds of parental consanguinity compared to the healthy population; a phenomenon not observed in other inheritance patterns. Determining the extent of the impact that consanguinity impose upon the progeny paves the way for convincing healthcare policy makers in highly consanguineous communities to act more diligently in informing the masses about the consequences of practicing inbreeding. This article is protected by copyright. All rights reserved.

PMID: 27893166 [PubMed – as supplied by publisher]

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Novel mutation in DOCK8-HIES with severe phenotype and successful transplantation.

Clin Immunol. 2016 Nov 23;:

Authors: Al Shekaili L, Sheikh F, Al Gazlan S, Al Dhekri H, Al Mousa H, Al Ghonaium A, Al Saud B, Al Mohsen S, Rehan Khaliq AM, Al Sumayli S, Al Zahrani M, Dababo A, AlKawi A, Hawwari A, Arnaout R

Abstract
BACKGROUND: Hyper-IgE syndrome (HIES) due to DOCK8 deficiency is an autosomal recessive (AR) primary combined immunodeficiency which results in significant morbidity and mortality at a young age. Different mutations in the DOCK8 gene can lead to variable severity of the disease.
OBJECTIVE: We evaluated the genetic mutations in three related patients with severe clinical manifestations suggestive of AR HIES. We also explored whether treatment with stem cell transplantation could lead to complete disease resolution.
METHOD: We examined the clinical manifestations and immunological workup of these patients. Their DNA was also screened for causative mutation. Post transplantation, clinical and immunological data for the transplanted patient was also collected.
RESULTS: All patients had a severe course of the disease with rarely reported severe complications in HIES. One patient died with lymphoma while another died with progressive multifocal leukoencephalopathy (PML) due to a slow virus. All our patients had two novel mutations in the DOCK8 gene. One of these mutations was a novel pathogenic mutation and explains the severity of the disease (homozygous splice site mutation at position 5 after the end of exon 45), while the other mutation was mostly non-pathogenic. Hematopoietic stem cell transplantation (HSCT) was performed in the youngest patient with excellent engraftment and full reversibility of the clinical manifestations.
CONCLUSION: We report 3 patients from a consanguineous family diagnosed with AR-HIES due to a novel pathogenic mutation in DOCK8 gene leading to fatal outcome in 2 patients and complete resolution of the clinical and immunological features in the third patient by HSCT.

PMID: 27890707 [PubMed – as supplied by publisher]

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[Primary immunodeficiency and autoimmunity].

Rev Med Interne. 2016 Nov 23;:

Authors: Guffroy A, Gies V, Martin M, Korganow AS

Abstract
Many evidences highlight that immunodeficiency and autoimmunity are two sides of a same coin. Primary immune deficiencies (PIDs), which are rare mono- or multigenic defects of innate or adaptative immunity, frequently associate with autoimmunity. Analyses of single-gene defects in immune pathways of families with PIDs, by new tools of molecular biology (next genome sequencing technologies), allowed a better understanding of the ways that could both drive immune defect with immune deficiency and autoimmunity. Moreover, genes implicated in rare single-gene defects are now known to be also involved in polygenic conventional autoimmune diseases. Here, we describe the main autoimmune symptoms occurring in PIDs and the underlying mechanisms that lead to autoimmunity in immunodeficiency. We review the links between autoimmunity and immunodeficiency and purpose some principles of care for patients with PIDs and autoimmunity.

PMID: 27889323 [PubMed – as supplied by publisher]

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Adult Bronchiectasis Patients: A First Look at the United States Bronchiectasis Research Registry.

Chest. 2016 Nov 23;:

Authors: Aksamit TR, O’Donnell AE, Barker A, Olivier KN, Winthrop KL, Daniels ML, Johnson M, Eden E, Griffith D, Knowles M, Metersky M, Salathe M, Thomashow B, Tino G, Turino G, Carretta B, Daley CL, Bronchiectasis Research Registry Consortium

Abstract
OBJECTIVE: We sought to describe the characteristics of adult bronchiectasis patients enrolled in the United States Bronchiectasis Research Registry (BRR).
METHODS: The BRR is a database of non-cystic fibrosis bronchiectasis (NCFB) patients enrolled at 13 sites within the United States. Baseline demographic, spirometric, imaging, microbiologic, and therapeutic data were entered into a central web-based database. Patients were subsequently analyzed by the presence NTM.
RESULTS: We enrolled 1826 patients between 2008 and 2014. Patients were predominantly female (79%), white (89%), and never smokers (60%) with a mean age 64±14 years. Sixty-three percent of the patients had a history of NTM disease or NTM isolated at baseline evaluation into the BRR. NTM patients were older, predominantly female, and had bronchiectasis diagnosed at a later age than those without NTM. Gastroesophageal reflux (GERD) was more common in those with NTM whereas asthma, primary immunodeficiency and primary ciliary dyskinesia were more common in those without NTM. Fifty-one percent of patients had spirometric evidence of airflow obstruction. NTM patients were more likely to have diffusely dilated airways and tree-in-bud abnormalities. Pseudomonas and Staphylococcus aureus isolates were less commonly cultured among patients with NTM. Bronchial hygiene measures were used more often in those with NTM; whereas antibiotics used for exacerbations, rotating oral antibiotics, steroid use, and inhaled bronchodilators were more commonly used in those without NTM.
CONCLUSION: Adult bronchiectasis patients enrolled in the US BRR are described with differences noted in demographic, radiographic, microbiologic, and treatment variables based on stratification of the presence of NTM.

PMID: 27889361 [PubMed – as supplied by publisher]

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Genetic and Immune Dysregulation in Chronic Rhinosinusitis.

Otolaryngol Clin North Am. 2017 Feb;50(1):13-28

Authors: Halderman A, Lane AP

Abstract
Chronic rhinosinusitis (CRS) is a prevalent condition that is heterogeneous in disease characteristics and multifactorial in cause. Although sinonasal mucosal inflammation in CRS is often either reversible or well-managed medically and surgically, a significant proportion of patients has a refractory form of CRS despite maximal therapy. Two of the several described factors thought to contribute to disease recalcitrance are genetic influences and dysfunction of the host immune system. Current evidence for a genetic basis of CRS is reviewed, as it pertains to putative abnormalities in innate and adaptive immune function. The role of systemic immunodeficiencies in refractory CRS is discussed.

PMID: 27888910 [PubMed – in process]

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Primary Immunodeficiency Classification on Smartphone.

J Clin Immunol. 2016 Nov 25;

Authors: Jeddane L, Ouair H, Benhsaien I, Bakkouri JE, Bousfiha AA

PMID: 27888368 [PubMed – as supplied by publisher]

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Ataxia telangiectasia: a review.

Orphanet J Rare Dis. 2016 Nov 25;11(1):159

Authors: Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM

Abstract
DEFINITION OF THE DISEASE: Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome.
EPIDEMIOLOGY: The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.
CLINICAL DESCRIPTION: A-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations.
ETIOLOGY: A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.
DIAGNOSIS: The diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels). Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene.
DIFFERENTIAL DIAGNOSIS: There are several other neurologic and rare disorders that physicians must consider when diagnosing A-T and that can be confused with A-T. Differentiation of these various disorders is often possible with clinical features and selected laboratory tests, including gene sequencing.
ANTENATAL DIAGNOSIS: Antenatal diagnosis can be performed if the pathological ATM mutations in that family have been identified in an affected child. In the absence of identifying mutations, antenatal diagnosis can be made by haplotype analysis if an unambiguous diagnosis of the affected child has been made through clinical and laboratory findings and/or ATM protein analysis.
GENETIC COUNSELING: Genetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted.
MANAGEMENT AND PROGNOSIS: Treatment of the neurologic problems associated with A-T is symptomatic and supportive, as there are no treatments known to slow or stop the neurodegeneration. However, other manifestations of A-T, e.g. immunodeficiency, pulmonary disease, failure to thrive and diabetes can be treated effectively.

PMID: 27884168 [PubMed – in process]

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Haploidentical hematopoietic stem cell transplantation for a case with X-linked chronic granulomatous disease.

Pediatr Transplant. 2016 Nov 25;:

Authors: Zhou L, Dong LJ, Gao ZY, Yu XJ, Lu DP

Abstract
CGD is a rare primary immunodeficiency with high mortality rates when treated conventionally, especially for the X-chromosome-linked form. HSCT is the only curative therapy for CGD; however, haploidentical transplantation in CGD is rare. Here, we report a case of X-linked CGD treated successfully by haploidentical HSCT. The patient showed a positive result with full donor chimerism, good quality of life, and the absence of recurrent infectious diseases at follow-up (68 months). Thus, haploidentical HSCT may serve as an acceptable treatment approach for patients who have CGD, but no HLA-matched related or unrelated donor.

PMID: 27885760 [PubMed – as supplied by publisher]

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APRIL gene polymorphism and serum sAPRIL levels in children with systemic lupus erythematosus.

Clin Rheumatol. 2016 Nov 23;

Authors: Namazi S, Tajik N, Ziaee V, Sadr M, Soltani S, Rezaei A, Zoghi S, Rezaei N

Abstract
Systemic lupus erythematosus (SLE) is a multi-factor autoimmune disorder with diverse clinical manifestations and unclear pathogenesis. Genetic components play important roles in the incidence and development of SLE. Among these, APRIL as a cytokine has roles in the stimulation and antibody production in B cells. APRIL was hypothesized to be associated with SLE. The aim of this study was to assess the involvement of the APRIL gene in SLE susceptibility in Iranian patients. A single-nucleotide polymorphism (SNP) for rs11552708 of APRIL gene was analyzed by real-time PCR in 60 SLE Iranian children and 64 healthy controls. DNA samples of patients and healthy controls were extracted from peripheral blood leukocytes by phenol-chloroform. Serum samples obtained from 45 children with SLE and 45 healthy controls were assayed by enzyme-linked immunosorbent assay (ELISA). The G/G genotype (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.22-2.07; P = 0.68) and G allele (OR 0.81, 95% CI 0.25-2.56; P = 0.89) frequencies of polymorphism at codon 67 (67G) do not differ significantly in the SLE patients compared with those in the healthy controls. The serum APRIL levels in the SLE patients (mean ± SD = 29.27 ng/ml ± 20.77, range from 0 to 55.33 ng/ml) were significantly higher than those in the healthy controls (P = 0.02). Our results demonstrated that rs11552708 of the APRIL gene is not associated with SLE susceptibility in Iranian children. Likewise, these findings suggest that APRIL antagonist could be a potential therapeutic target to control SLE in children.

PMID: 27878683 [PubMed – as supplied by publisher]

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Visceral leishmaniasis in two patients with IL-12p40 and IL-12Rβ1 deficiencies.

Pediatr Blood Cancer. 2016 Nov 22;:

Authors: Parvaneh N, Barlogis V, Alborzi A, Deswarte C, Boisson-Dupuis S, Migaud M, Farnaria C, Markle J, Parvaneh L, Casanova JL, Bustamante J

Abstract
Mutations of the IL12B and IL12RB1 genes underlie the development of IL-12 p40 and IL-12Rβ1 deficiencies, respectively, both of which cause predisposition to infection with weakly virulent mycobacteria and Salmonella. Infections with other intramacrophagic organisms have only been rarely observed. We identified two patients with visceral leishmaniasis who had autosomal recessive IL-12 p40 and IL-12Rβ1 deficiencies, respectively. This finding demonstrates the importance of IFN-γ immunity in the control of leishmaniasis. We also searched the literature for similar reports in patients with these and other primary immunodeficiencies.

PMID: 27873456 [PubMed – as supplied by publisher]

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