-
Clinical Otolaryngology : Official... Feb 2018A cholesteatoma is a mass of keratinising epithelium in the middle ear. It is a rare disorder that is associated with significant morbidity, and its causative risk... (Review)
Review
OBJECTIVE
A cholesteatoma is a mass of keratinising epithelium in the middle ear. It is a rare disorder that is associated with significant morbidity, and its causative risk factors are poorly understood; on a global scale, up to a million people are affected by this each year. We have conducted a systematic literature review to identify reports about the heritability of cholesteatoma or any constitutional genetic factors that may be associated with its aetiology.
DATA SOURCES
A systematic search of MEDLINE (EBSCO) and two databases of curated genetic research (OMIM and Phenopedia) was conducted.
STUDY SELECTION
The participants and populations of interest for this review were people treated for cholesteatoma and their family members. The studies of interest reported evidence of heritability for the trait, or any association with congenital syndromes and particular genetic variants.
DATA EXTRACTION
The searches identified 449 unique studies, of which 35 were included in the final narrative synthesis.
DATA SYNTHESIS
A narrative synthesis was conducted, and data were tabulated to record characteristics, including study design, genetic data and author conclusions. Most of the studies identified in the literature search, and described here, are case reports and so represent the lowest level of evidence. In a few case reports, congenital and acquired cholesteatomas have been shown to segregate within families in the pattern typical of a monogenic or oligogenic disorder with incomplete penetrance. Evidence from syndromic cases could suggest that genes controlling ear morphology may be risk factors for cholesteatoma formation.
CONCLUSIONS
This is the first systematic review about the genetics of cholesteatoma, and we have identified a small body of relevant literature that provides evidence of a heritable component for its aetiology. Cholesteatoma is a complex and heterogeneous clinical phenotype, and it is often associated with chronic otitis media and with some rare congenital syndromes known to affect ear morphology and related pathologies.
Topics: Cholesteatoma, Middle Ear; Genetic Research; Humans
PubMed: 28485112
DOI: 10.1111/coa.12900 -
Allergy & Rhinology (Providence, R.I.) Mar 2017Inflammatory injury of nasal respiratory mucosa is a common feature of multisystem autoimmune disease. Certain autoimmune disorders are associated with nasal septum...
BACKGROUND
Inflammatory injury of nasal respiratory mucosa is a common feature of multisystem autoimmune disease. Certain autoimmune disorders are associated with nasal septum perforation (NSP). We performed a systematic review of the literature to better understand the association of NSP with specific autoimmune disorders. This is a case report of a 29-year-old woman with a history of arthralgia, autoreactive antibody titers, platelet dysfunction, and NSP. The constellation of symptoms and potential familial involvement indicated that the NSP in this patient was an early sign of an autoimmune disorder, an unknown autoimmune disorder, or a known disease with incomplete penetrance.
METHODS
A systematic review of the literature was performed by two independent reviewers. Relevant articles were reviewed, and data that pertained to autoimmune-related NSP were extracted and analyzed.
RESULTS
Overall, 140 cases of autoimmune-associated NSPs were reported. Granulomatosis with polyangiitis (48%), relapsing polychondritis (26%), and cocaine-induced midline lesions (15%) constituted 89.3% of the reported cases.
CONCLUSION
NSP is a potential sign of systemic disease. The identification of an NSP, especially in the context of other unexplained symptoms or workup suggestive of an autoimmune disorder, should prompt clinical evaluation for multisystem autoimmune disease with consideration of granulomatosis with polyangiitis, relapsing polychondritis, or cocaine-induced midline lesions.
PubMed: 28381327
DOI: 10.2500/ar.2017.8.0191 -
Pharmacogenomics and Personalized... 2017The emerging dual imperatives of personalized medicine and technologic advances make population screening for preventable conditions resulting from genetic alterations a... (Review)
Review
BACKGROUND
The emerging dual imperatives of personalized medicine and technologic advances make population screening for preventable conditions resulting from genetic alterations a realistic possibility. Lynch syndrome is a potential screening target due to its prevalence, penetrance, and the availability of well-established, preventive interventions. However, while population screening may lower incidence of preventable conditions, implementation without evidence may lead to unintentional harms. We examined the literature to determine whether evidence exists that screening for Lynch-associated mismatch repair (MMR) gene mutations leads to improved overall survival, cancer-specific survival, or quality of life. Documenting evidence and gaps is critical to implementing genomic approaches in public health and guiding future research.
MATERIALS AND METHODS
Our 2014-2015 systematic review identified studies comparing screening with no screening in the general population, and controlled studies assessing analytic validity of targeted next-generation sequencing, and benefits or harms of interventions or screening. We conducted meta-analyses for the association between early or more frequent colonoscopies and health outcomes.
RESULTS
Twelve studies met our eligibility criteria. No adequate evidence directly addressed the main question or the harms of screening in the general population. Meta-analyses found relative reductions of 68% for colorectal cancer incidence (relative risk: 0.32, 95% confidence interval: 0.23-0.43, three cohort studies, 590 participants) and 78% for all-cause mortality (relative risk: 0.22, 95% confidence interval: 0.09-0.56, three cohort studies, 590 participants) for early or more frequent colonoscopies among family members of people with cancer who also had an associated MMR gene mutation.
CONCLUSION
Inadequate evidence exists examining harms and benefits of population-based screening for Lynch syndrome. Lack of evidence highlights the need for data that directly compare benefits and harms.
PubMed: 28260941
DOI: 10.2147/PGPM.S123808 -
The Cochrane Database of Systematic... Dec 2016Various central nervous system-penetrant antibiotics are bactericidal in vitro and in vivo against the causative agent of Lyme neuroborreliosis (LNB), Borrelia... (Review)
Review
BACKGROUND
Various central nervous system-penetrant antibiotics are bactericidal in vitro and in vivo against the causative agent of Lyme neuroborreliosis (LNB), Borrelia burgdorferi. These antibiotics are routinely used clinically to treat LNB, but their relative efficacy is not clear.
OBJECTIVES
To assess the effects of antibiotics for the treatment of LNB.
SEARCH METHODS
On 25 October 2016 we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We searched clinical trial registers on 26 October 2016. We reviewed the bibliographies of the randomized trials identified and contacted the authors and known experts in the field to identify additional published or unpublished data. There were no language restrictions when searching for studies.
SELECTION CRITERIA
Randomized clinical trials of antibiotic treatment of LNB in adults and children that compared any antibiotic treatment, including combinations of treatments, versus any other treatment, placebo, or no treatment. We excluded studies of entities considered as post-Lyme syndrome.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We identified seven randomized studies involving 450 European participants with LNB for inclusion in this systematic review. We found no trials conducted in the United States. Marked heterogeneity among these studies prevented meta-analysis. None of the studies included a placebo control on the initial antibiotic treatment, and only one was blinded. None were delayed-start studies. All were active comparator studies, and most were not adequately powered for non-inferiority comparison. The trials investigated four antibiotics: penicillin G and ceftriaxone in four studies, doxycycline in three studies, and cefotaxime in two studies. One study tested a three-month course of oral amoxicillin versus placebo following initial treatment with intravenous ceftriaxone. One study was limited to children. The trials measured efficacy using heterogeneous physician- or patient-reported outcomes, or both. In some cases cerebrospinal fluid analysis was included as an indirect biomarker of disease and outcome. None of the studies reported on our proposed primary outcome, 'Improvement in a measure of overall disability in the long term (three or more months).' None of the trials revealed any between-group differences in symptom resolution in response to active treatment. In general, treatment was tolerated well. The quality of adverse event reporting, however, was low.
AUTHORS' CONCLUSIONS
There is mostly low- to very low-quality clinical evidence from a limited number of mostly small, heterogeneous trials with diverse outcome measures, comparing the relative efficacy of central nervous system-penetrant antibiotics for the treatment of LNB. The few existing randomized studies have limited power and lack consistent and well-defined entry criteria and efficacy endpoints. It is not possible to draw firm conclusions on the relative efficacy of accepted antibiotic drug regimens for the treatment of LNB. The majority of people are reported to have good outcomes, and symptoms resolve by 12 months regardless of the antibiotic used. A minority of participants did not improve sufficiently, and some were retreated. These randomized studies provide some evidence that doxycycline, penicillin G, ceftriaxone, and cefotaxime are efficacious in the treatment of European LNB. No evidence of additional efficacy was observed when, in one study, an initial antibiotic treatment with intravenous ceftriaxone was followed by additional longer treatment with oral amoxicillin. There is a lack of evidence identified through our high-quality search strategy on the efficacy of antibiotics for treatment of LNB in the United States.
Topics: Amoxicillin; Anti-Bacterial Agents; Borrelia burgdorferi; Cefotaxime; Ceftriaxone; Doxycycline; Humans; Lyme Disease; Lyme Neuroborreliosis; Penicillin G; Randomized Controlled Trials as Topic
PubMed: 27931077
DOI: 10.1002/14651858.CD006978.pub2 -
Hong Kong Medical Journal = Xianggang... Apr 2016Genetic risk factors and family history play an important role in breast cancer development. This review aimed to summarise the current genetic testing approach to... (Review)
Review
INTRODUCTION
Genetic risk factors and family history play an important role in breast cancer development. This review aimed to summarise the current genetic testing approach to hereditary breast/ovarian cancer.
METHODS
A systematic literature review was performed by searching the PubMed database. Publications available online until January 2015 that addressed issues related to hereditary breast/ovarian cancer genetic counselling/testing were selected. The search terms used were "familial breast/ovarian cancer", "susceptibility genes", "genetic counselling", and "genetic testing". The data extracted for this review were analysed by the authors, with a focus on genetic testing for hereditary breast/ovarian cancer.
RESULTS
Although a greater proportion of inherited breast/ovarian cancers are due to the BRCA1 and BRCA2 mutations, a number of new genes have emerged as susceptibility candidates, including rare germline mutations in high penetrance genes, such as TP53 and PTEN, and more frequent mutations in moderate/low penetrance genes, such as PALB2, CHEK2 and ATM. Multi-gene testing, if used appropriately, is generally a more cost- and time-effective method than single-gene testing, and may increase the number of patients who can be offered personal surveillance, risk-reduction options, and testing of high-risk family members.
CONCLUSIONS
Recent advances in molecular genetics testing have identified a number of susceptibility genes related to hereditary breast and/or ovarian cancers other than BRCA1 and BRCA2. The introduction of multi-gene testing for hereditary cancer has revolutionised the clinical management of high-risk patients and their families. Individuals with hereditary breast/ovarian cancer will benefit from genetic counselling/testing.
Topics: Breast Neoplasms; Female; Genetic Predisposition to Disease; Genetic Testing; Humans; Molecular Biology; Ovarian Neoplasms; Risk Factors
PubMed: 26980575
DOI: 10.12809/hkmj154634 -
International Journal of Epidemiology Feb 2016Low penetrance genetic variants, primarily single nucleotide polymorphisms, have substantial influence on colorectal cancer (CRC) susceptibility. Most CRCs develop from... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Low penetrance genetic variants, primarily single nucleotide polymorphisms, have substantial influence on colorectal cancer (CRC) susceptibility. Most CRCs develop from colorectal adenomas (CRA). Here we report the first comprehensive field synopsis that catalogues all genetic association studies on CRA, with a parallel online database [http://www.chs.med.ed.ac.uk/CRAgene/].
METHODS
We performed a systematic review, reviewing 9750 titles, and then extracted data from 130 publications reporting on 181 polymorphisms in 74 genes. We conducted meta-analyses to derive summary effect estimates for 37 polymorphisms in 26 genes. We applied the Venice criteria and Bayesian False Discovery Probability (BFDP) to assess the levels of the credibility of associations.
RESULTS
We considered the association with the rs6983267 variant at 8q24 as 'highly credible', reaching genome-wide statistical significance in at least one meta-analysis model. We identified 'less credible' associations (higher heterogeneity, lower statistical power, BFDP > 0.02) with a further four variants of four independent genes: MTHFR c.677C>T p.A222V (rs1801133), TP53 c.215C>G p.R72P (rs1042522), NQO1 c.559C>T p.P187S (rs1800566), and NAT1 alleles imputed as fast acetylator genotypes. For the remaining 32 variants of 22 genes for which positive associations with CRA risk have been previously reported, the meta-analyses revealed no credible evidence to support these as true associations.
CONCLUSIONS
The limited number of credible associations between low penetrance genetic variants and CRA reflects the lower volume of evidence and associated lack of statistical power to detect associations of the magnitude typically observed for genetic variants and chronic diseases. The CRA gene database provides context for CRA genetic association data and will help inform future research directions.
Topics: Adenoma; Alleles; Arylamine N-Acetyltransferase; Bayes Theorem; Colorectal Neoplasms; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Isoenzymes; Methylenetetrahydrofolate Reductase (NADPH2); NAD(P)H Dehydrogenase (Quinone); Polymorphism, Single Nucleotide; Risk Factors; Tumor Suppressor Protein p53
PubMed: 26451011
DOI: 10.1093/ije/dyv185 -
Cytogenetic and Genome Research 2014Breast cancer is the most common cancer and the second leading cause of death in women worldwide. The disease is caused by a combination of genetic, environmental,... (Review)
Review
Breast cancer is the most common cancer and the second leading cause of death in women worldwide. The disease is caused by a combination of genetic, environmental, lifestyle, and reproductive risk factors. Linkage and family-based studies have identified many pathological germline mutations, which account for around 20% of the genetic risk of familial breast cancer. In recent years, single nucleotide polymorphism-based genetic association studies, especially genome-wide association studies (GWASs), have been very successful in uncovering low-penetrance common variants associated with breast cancer risk. These common variants alone may explain up to an additional 30% of the familial risk of breast cancer. With the advent of available genetic resources and growing collaborations among researchers across the globe, the much needed large sample size to capture variants with small effect sizes and low population frequencies is being addressed, and hence many more common variants are expected to be discovered in the coming days. Here, major GWASs conducted for breast cancer predisposition and prognosis until 2013 are summarized. Few studies investigating other forms of genetic variations contributing to breast cancer predisposition and disease outcomes are also discussed. Finally, the potential utility of the GWAS-identified variants in disease risk models and some future perspectives are presented.
Topics: Breast Neoplasms; Female; Gene-Environment Interaction; Genetic Linkage; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Germ-Line Mutation; Humans; Penetrance; Polymorphism, Single Nucleotide; Prognosis; Risk Factors
PubMed: 25401968
DOI: 10.1159/000369045 -
Neuro-oncology Jun 2014Association studies of germline DNA repair single nucleotide polymorphisms (SNPs) and glioma risk have yielded inconclusive results. We therefore performed a systematic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Association studies of germline DNA repair single nucleotide polymorphisms (SNPs) and glioma risk have yielded inconclusive results. We therefore performed a systematic review and meta-analysis of studies investigating this association.
METHODS
We identified 27 eligible studies investigating 105 SNPs in 42 DNA repair genes. Of these, 10 SNPs in 7 genes were analyzed in at least 4 studies and were therefore included in our meta-analysis. The meta-analysis was performed for homozygote comparison, heterozygote comparison, and dominant and recessive models by applying a fixed- or random-effects model. The funnel and forest plots were created using RevMan software.
RESULTS
We found that SNPs rs3212986 (odds ratio [OR] = 1.35 (1.08-1.68), P = .008), rs13181 (OR = 1.18 (1.06-1.31), P = .002), and rs25487 (OR = 1.12 (1.03-1.22), P = .007) in DNA repair genes ERCC1, ERCC2 (XPD), and XRCC1 may increase the risk of glioma, while polymorphisms rs1136410 (OR = 0.78 (0.68-0.89), P = .0004) and rs12917 (OR = 0.84 (0.73-0.96), P = .01) in PARP1(ADPRT) and MGMT are associated with decreased susceptibility to glioma. No evidence of significant associations between ERCC2 rs1799793, OGG1 rs1052133, XRCC1 rs25489, XRCC1 rs1799782, or XRCC3 rs861539 and risk of glioma was observed.
CONCLUSION
This study provides evidence that DNA repair genes ERCC1, ERCC2, and XRCC1 might be low-penetrance glioma-risk genes, while MGMT and PARP1 polymorphisms may confer protection against glioma.
Topics: Brain Neoplasms; DNA Repair; Genetic Association Studies; Glioma; Humans; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 24500421
DOI: 10.1093/neuonc/nou003 -
The American Journal of Clinical... Aug 2013Hereditary hemochromatosis (HH) leads to iron loading because of a disturbance in the negative-feedback mechanism between dietary iron absorption and iron status. The... (Review)
Review
BACKGROUND
Hereditary hemochromatosis (HH) leads to iron loading because of a disturbance in the negative-feedback mechanism between dietary iron absorption and iron status. The management of HH is achieved by repeated phlebotomies.
OBJECTIVE
We investigated whether HH patients would benefit from a diet with low iron intake and bioavailability.
DESIGN
We performed a systematic review of studies that linked iron bioavailability and status with dietary factors in subjects with diagnosed HH. Studies on heterozygotes for the HFE mutation were excluded.
RESULTS
No prospective, randomized study was reported. Nine studies that directly measured iron bioavailability from test meals in HH patients have been described as well as 3 small, prospective, longitudinal studies in HH patients. Eight cross-sectional studies were identified that investigated the effect of dietary composition on iron status. Calculations of iron bioavailability in HH were made by extrapolating data on hepcidin concentrations and their association with iron bioavailability. The potential reduction in the yearly amount of blood to be phlebotomized when restricting dietary iron absorbed was estimated in the 3 longitudinal studies and ranged between 0.5 and 1.5 L. This amount would be dependent on individual disease penetrance as well as the dietary intervention.
CONCLUSIONS
Despite the limited quantitative evidence and the lack of randomized, prospective trials, dietary interventions that modify iron intake and bioavailability may affect iron accumulation in HH patients. Although this measure may be welcome in patients willing to contribute to their disease management, limited data exist on the clinical and quality-of-life benefit.
Topics: Absorption; Antimicrobial Cationic Peptides; Biological Availability; Diet; Hemochromatosis; Hepcidins; Heterozygote; Humans; Iron, Dietary; Mutation; Penetrance
PubMed: 23803887
DOI: 10.3945/ajcn.112.048264