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Familial Cancer Oct 2016Multiple endocrine neoplasia type 2A (MEN2A) may be rarely associated with cutaneous lichen amyloidosis (CLA), a skin lesion located in the interescapular region. Here,... (Review)
Review
Multiple endocrine neoplasia type 2A (MEN2A) may be rarely associated with cutaneous lichen amyloidosis (CLA), a skin lesion located in the interescapular region. Here, we describe 3 MEN2A-related CLA kindred and perform a systematic review (SR) of the literature on clinical, biochemical and molecular characteristics of MEN2A-related CLA patients. Thirty-eight patients with MEN2A-related CLA followed at our institution were evaluated. The median age at MEN2A diagnosis in our cohort was 25 (13-41) years, 68 % were women and all harbored codon 634 RET mutations. The literature search resulted in 20 publications that contributed with 25 MEN2A families and 214 individuals. The mean age of MEN2A diagnosis was 31 ± 17 years, with 77 % women. The mean age reported by patients to initial skin lesion suggestive to CLA was 20 ± 13 years. All but two kindred harbored mutations at codon 634: C634R 7 kindred (35 %), C634Y 5 kindred (25 %), C634W 3 kindred (15 %), C634G 1 kindred (5 %), V804M 1 kindred (5 %) and S891A 1 kindred (5 %). Most interesting, the standardized CLA prevalence was higher in women (2.3/1.0, P < 0.005). The overall reported prevalence of medullary thyroid carcinoma, CLA, pheochromocytoma and hyperparathyroidism was 94, 51, 30 and 16 %, respectively. SR of literature indicates that MEN2A-related CLA is more frequent in women and presents a high penetrance, being the second most frequent manifestation of the syndrome, preceded only by MTC.
Topics: Adolescent; Adult; Amyloidosis; Female; Humans; Male; Multiple Endocrine Neoplasia Type 2a; Pedigree; Proto-Oncogene Proteins c-ret; Skin Neoplasms; Young Adult
PubMed: 26920351
DOI: 10.1007/s10689-016-9892-6 -
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 -
Circulation. Genomic and Precision... Jun 2022Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a complex cardiomyopathy with autosomal dominant inheritance and age-related incomplete penetrance,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a complex cardiomyopathy with autosomal dominant inheritance and age-related incomplete penetrance, characterized by a high risk of sudden cardiac death. Recent professional consensus guidelines recommend clinical cardiac lifelong serial screening for at-risk family members refined only by age, but family genotype might influence necessary screening. Although numerous studies report prevalence of disease and arrhythmia in family members and explore predictors of penetrance and arrhythmic risk, a systematic review consolidating this evidence is lacking.
METHODS
We searched Medline (PubMed), Embase, The Cochrane Library, and Web of Science for studies that reported prevalence of (1) diagnosis of ARVC per 2010 Task Force Criteria and/or (2) sustained ventricular arrhythmias (VA) in at least 10 family members of definite patients with ARVC.
RESULTS
We identified 41 studies, including 36 that reported diagnosis by Task Force Criteria and 22 VA. Meta-analysis of 1359 family members, from 13 unique cohorts showed an average prevalence estimate of 25% for diagnosis as per Task Force Criteria (95% CI, 0.15-0.35, I96.44%). Overall prevalence of VA among gene-positive family members was 18% (95% CI, 0.13-0.23, I=33.25%) in 7 independent studies (n=597). Family genotype was a significant risk factor for diagnosis of both ARVC (odds ratio, 6.91 [95% CI, 1.27-37.70]; =0.0005) and VA (odds ratio, 13.62 [95% CI, 0.91-204.13]; =0.06). Male gender was not associated with disease prevalence (odds ratio, 1.18 [95% CI, 0.72-1.95]; =0.42) or VA (odds ratio, 0.81 [95% CI, 0.51-1.29]; =0.91).
CONCLUSIONS
The prevalence of ARVC and VA in at-risk family members differs significantly based on family genotype. Although recent recommendations provide a guideline based only on age, we propose screening every 1 to 2 years for gene-positive family members and every 3 to 5 years for first-degree relatives of gene-elusive cases, as long as they are asymptomatic and not athletes.
Topics: Arrhythmias, Cardiac; Arrhythmogenic Right Ventricular Dysplasia; Child, Preschool; Death, Sudden, Cardiac; Family; Humans; Infant; Male; Prevalence
PubMed: 35579515
DOI: 10.1161/CIRCGEN.121.003530 -
Clinical Genetics Jan 2019Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by germline TP53 mutations. Genetic testing is not routinely offered in... (Review)
Review
Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by germline TP53 mutations. Genetic testing is not routinely offered in asymptomatic children at risk of the condition as the benefits are debatable and the attitudes of families and health care professionals (HCPs) may vary. This review assessed the attitudes of families and HCPs towards offering genetic testing to children for LFS, with a focus on perceived advantages and disadvantages and involvement of children in the decision-making process. We searched three key databases (Medline, PsycINFO and EMBASE) to identify quantitative and qualitative studies. We screened 729 articles identifying eight studies for detailed review. Most parents perceived TP53 genetic testing to be beneficial in childhood, despite previous lack of surveillance guidelines. Parents raised some concerns, including decreased insurability and diminishing the child's autonomy. Most children tested reported no negative emotional concerns after testing, even if tested positive. Despite generally positive interest clinicians remain hesitant. Most families saw the value in involving children in decision-making. Families' acceptance of TP53 testing in childhood was high. This review highlights the need for research on the long-term psychosocial impacts of testing and the attitudes of families to be reflected in professional guidelines.
Topics: Attitude of Health Personnel; Decision Making; Genetic Predisposition to Disease; Genetic Testing; Genotype; Germ-Line Mutation; Health Personnel; Humans; Li-Fraumeni Syndrome; Parents
PubMed: 30191952
DOI: 10.1111/cge.13442 -
Frontiers in Genetics 2023To analyze the phenotypes, genotypes, and the relationship of phenotypes and genotypes for Chinese patients with Bardet-Biedl syndrome (BBS). The Chinese Wanfang and...
To analyze the phenotypes, genotypes, and the relationship of phenotypes and genotypes for Chinese patients with Bardet-Biedl syndrome (BBS). The Chinese Wanfang and Weipu data, and PubMed were searched up to December 2022. Patients with detailed clinical feature data were involved in the analysis. A total of 153 Chinese patients, including 87 males, 53 females, and 12 unknown, were enrolled. Their ages ranged from 1.2 to 44 years old with a mean of 16.70 ± 9.90 years old. Among these patients, 80 (52.29%) were reported by ophthalmologists, and only 24 (15.68%) reported by pediatricians. Most patients (132/137, 96.35%) had visual problems; 131/153 (85.62%) had polydactyly; 124/132 (93.93%) were overweight or obese; 63/114 (55.26%) had renal abnormalities; kidney dysfunction was found in 33 (21.57%); 83/104 (79.81%) had hypogonadism and/or genital hypoplasia; and 111/136 (81.62%) had mental retardation. In this series, genetic analysis was performed in 90 (58.82%) patients, including 22 (24.71%), 20 (22.73%), and 10 (11.24%) patients. Moreover, 11 fetuses were diagnosed prenatally in the last 4 years except for one patient in 2004 year. It was noted that had higher penetrance. had higher hearing impairment and lower renal abnormality penetrance. also had lower renal abnormality penetrance as well. Misdiagnosis or miss diagnosis of BBS may be common in China. In patients with polydactyly, visual impairment, obesity, renal abnormalities, hypogonadism, and mental retardation, or in fetuses with polydactyly and/or renal abnormalities, BBS should be considered in the differential diagnosis. Other deformities should be evaluated carefully and genetic analysis should be performed as early as possible.
PubMed: 38034494
DOI: 10.3389/fgene.2023.1247557 -
Gastroenterology Research and Practice 2017Environmental factors and genetic mutations have been increasingly recognized as risk factors for chronic pancreatitis (CP). The p.R122H mutation was the first... (Review)
Review
BACKGROUND
Environmental factors and genetic mutations have been increasingly recognized as risk factors for chronic pancreatitis (CP). The p.R122H mutation was the first discovered to affect hereditary CP, with 80% penetrance. We performed here a systematic review and meta-analysis to evaluate the associations of p.R122H mutation with CP of diverse etiology.
METHODS
The PubMed, EMBASE, and MEDLINE database were reviewed. The pooled odds ratio (OR) with 95% confidence intervals was used to evaluate the association of p.R122H mutation with CP. Initial analysis was conducted with all etiologies of CP, followed by a subgroup analysis for hereditary and nonhereditary CP, including alcoholic or idiopathic CP.
RESULTS
A total of eight case-control studies (1733 cases and 2415 controls) were identified and included. Overall, p.R122H mutation was significantly associated with an increased risk of CP (OR = 4.78[1.13-20.20]). Further analysis showed p.R122H mutation strongly associated with the increased risk of hereditary CP (OR = 65.52[9.09-472.48]) but not with nonhereditary CP, both alcoholic and idiopathic CP.
CONCLUSIONS
Our study showing the differential role of p.R122H mutation in various etiologies of CP indicates that this complex disorder is likely influenced by multiple genetic factors as well as environmental factors.
PubMed: 29118810
DOI: 10.1155/2017/9505460 -
Applied Health Economics and Health... Oct 2015Hereditary haemochromatosis (HH) is a common genetic condition amongst people of northern European heritage. HH is associated with increased iron absorption leading to... (Review)
Review
BACKGROUND
Hereditary haemochromatosis (HH) is a common genetic condition amongst people of northern European heritage. HH is associated with increased iron absorption leading to parenchymal organ damage and multiple arthropathies. Early diagnosis and treatment prevents complications. Population screening may increase early diagnosis, but no programmes have been introduced internationally: a paucity of health economic data is often cited as a barrier.
OBJECTIVE
To conduct a systematic review of all health economic studies in HH.
METHODS
Studies were identified through electronic searching of economic/biomedical databases. Any study on HH with original economic component was included. Study quality was formally assessed. Health economic data were extracted and analysed through narrative synthesis.
RESULTS
Thirty-eight studies met the inclusion criteria. The majority of papers reported on costs or cost effectiveness of screening programmes. Whilst most concluded screening was cost effective compared with no screening, methodological flaws limit the quality of these findings. Assumptions regarding clinical penetrance, effectiveness of screening, health-state utility values (HSUVs), exclusion of early symptomatology (such as fatigue, lethargy and multiple arthropathies) and quantification of costs associated with HH were identified as key limitations. Treatment studies concluded therapeutic venepuncture was the most cost-effective intervention.
CONCLUSIONS
There is a paucity of high-quality health economic studies relating to HH. The development of a comprehensive HH cost-effectiveness model utilising HSUVs is required to determine whether screening is worthwhile.
Topics: Cost-Benefit Analysis; Health Care Costs; Hemochromatosis; Humans; Mass Screening
PubMed: 26255179
DOI: 10.1007/s40258-015-0189-y -
Obesity Reviews : An Official Journal... May 2024The recent development of next-generation sequencing (NGS) technologies has led to an increase of mutation screening reports of monogenic obesity genes in diverse... (Review)
Review
Sequencing methods, functional characterization, prevalence, and penetrance of rare coding mutations in panels of monogenic obesity genes from the leptin-melanocortin pathway: A systematic review.
The recent development of next-generation sequencing (NGS) technologies has led to an increase of mutation screening reports of monogenic obesity genes in diverse experimental designs. However, no study to date has summarized their findings. Two reviewers independently conducted a systematic review of MEDLINE, Embase, and Web of Science Core Collection databases from inception to September 2022 to identify monogenic non-syndromic obesity gene screening studies. Of 1051 identified references, 31 were eligible after title and abstract screening and 28 after full-text reading and risk of bias and quality assessment. Most studies (82%) used NGS methods. The number of genes screened varied from 2 to 12 genes from the leptin-melanocortin pathway. While all the included studies used in silico tools to assess the functional status of mutations, only 2 performed in vitro tests. The prevalence of carriers of pathogenic/likely pathogenic monogenic mutations is 13.24% on average (heterozygous: 12.31%; homozygous/heterozygous composite: 0.93%). As no study reported the penetrance of pathogenic mutations on obesity, we estimated that homozygous carriers exhibited a complete penetrance (100%) and heterozygous carriers a variable penetrance (3-100%). The review provides an exhaustive description of sequencing methods, functional characterization, prevalence, and penetrance of rare coding mutations in monogenic non-syndromic obesity genes.
PubMed: 38779716
DOI: 10.1111/obr.13754 -
European Journal of Medical Genetics Feb 2022The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications... (Review)
Review
The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications encompass the LCR-A-to-D region but atypical duplications of various sizes have also been reported. These duplications are responsible for highly variable phenotypes with incomplete penetrance and expressivity, which is challenging for adequate genetic counselling, especially in the prenatal period. To better delineate prenatal phenotypes associated with these CNVs, we report here a clinical and molecular description of twelve cases (9 foetuses and 3 deceased new-borns babies) carrying recurrent 22q11 duplications (diagnosed via aCGH), along with a review of the existing literature. 22q11 duplications were inherited from an apparently healthy parent in almost 60% of the cases. Other CNVs were diagnosed for 8% of the cases. Increased nuchal translucency and cardiac anomalies (CHD) were the most prominent phenotypes observed, along with mild renal and skeletal anomalies. Duplications encompassing the LCR-C-to-D region (and the CRKL gene) seemed more likely to generate CHDs and renal malformations. Cleft lip/palate were observed in foetuses with duplications encompassing the LCR-A-to-B region or the SPECC1L gene, as previously suggested. However, genotype-phenotype correlations remain difficult to ascertain. Second-hit point variants, epigenetic or environmental variations could play a role in the phenotypic variability of 22q11 duplications, but remain a challenge for assessment in the short period of pregnancy.
Topics: Abnormalities, Multiple; Adaptor Proteins, Signal Transducing; Chromosome Duplication; Chromosomes, Human, Pair 22; DiGeorge Syndrome; Female; Fetus; Humans; Infant, Newborn; Male; Phenotype; Phosphoproteins
PubMed: 35026468
DOI: 10.1016/j.ejmg.2022.104422 -
Polymorphisms of progesterone receptor and ovarian cancer risk: a systemic review and meta-analysis.The Journal of Obstetrics and... Feb 2015Growing bodies of studies have investigated the associations between three progesterone receptor (PGR) polymorphisms, +331G/A, Alu insertion and Val660Leu, and... (Meta-Analysis)
Meta-Analysis Review
AIM
Growing bodies of studies have investigated the associations between three progesterone receptor (PGR) polymorphisms, +331G/A, Alu insertion and Val660Leu, and susceptibility to ovarian cancer, but the results remain controversial and inconclusive. Thus, we conducted a meta-analysis to derive a more precise estimation of the associations.
METHODS
A total of 21 case-control studies from 16 publications that included analyses of Alu insertion (981 cases, 2136 controls), Val660Leu (2205 cases, 3222 controls) and +331G/A (2842 cases, 4305 controls) polymorphisms were identified.
RESULTS
Significantly increased risks of ovarian cancer were found for Alu insertion (T2 T2 + T1 T2 vs T1 T1 ; odds ratio [OR], 1.504; 95% confidence interval [CI], 1.206-2.203) and Val660Leu (TT vs GT; OR, 1.524; 95% CI, 1.013-2.293). No significant association was found between +331G/A polymorphism and ovarian cancer.
CONCLUSION
This meta-analysis suggests that the two polymorphisms of PGR, Alu insertion and Val660Leu, may contribute to ovarian cancer susceptibility as low-penetrance risk factors.
Topics: Female; Genetic Predisposition to Disease; Humans; Ovarian Neoplasms; Penetrance; Polymorphism, Single Nucleotide; Receptors, Progesterone; Risk Factors
PubMed: 25228088
DOI: 10.1111/jog.12519