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Endocrine-related Cancer Mar 2021Pancreatic neuroendocrine tumors (pNETs) in Von Hippel-Lindau (VHL) disease have a relatively good prognosis. However, a subset of pNETs metastasize and significantly...
Pancreatic neuroendocrine tumors (pNETs) in Von Hippel-Lindau (VHL) disease have a relatively good prognosis. However, a subset of pNETs metastasize and significantly contribute to VHL-related mortality. Evidence-based guidelines are needed for timely detection, management and intervention of these tumors. However, the value of several diagnostic tools is controversial, and evidence-based management strategies are lacking. This systematic review aims to update current literature on diagnostic and management strategies of pNETs in VHL and proposes evidence-based recommendations. The databases of PubMed/Medline, Embase and Web of Science were systematically searched to identify relevant studies. Studies were screened independently and cross-checked by two authors to assess eligibility for inclusion. Eighty-four articles were eligible for full text reading, and thirteen were critically appraised using the modified Quality Assessment of Diagnostic Accuracy Studies or modified Quality in Prognostic Studies tool. Six studies assessed the diagnostic value of imaging modalities, five focused on the optimal timing for surgical intervention, and one article studied the growth rate of pNETs. Quality of the available evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluations tool. Studies recommended CT or MRI as the primary screening modalities for pNETs. For detection of metastases, 68Gallium-DOTATATE/TOC PET/CT is advised. For pNETs <2 cm a watch-and-wait approach is recommended, while for pNETs ≥2.5 cm surgical resection is advised. Due to limited data, no strong recommendations on surveillance could be proposed.
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radionuclide Imaging; von Hippel-Lindau Disease
PubMed: 33512331
DOI: 10.1530/ERC-20-0469 -
Journal of Neurochemistry Mar 2021The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization...
The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.
Topics: Amyloid; Amyloidosis, Familial; Animals; Gene Knockdown Techniques; Humans; Prealbumin
PubMed: 33155274
DOI: 10.1111/jnc.15233 -
Pancreatology : Official Journal of the... Oct 2020Since the description of the SPINK1 gene encoding the serine protease inhibitor Kazal type 1 and the CTRC gene encoding the Chymotrypsin C as being involved in chronic...
Since the description of the SPINK1 gene encoding the serine protease inhibitor Kazal type 1 and the CTRC gene encoding the Chymotrypsin C as being involved in chronic pancreatitis, more than 56 SPINK1 and 87 CTRC variants have been reported. Assessing the clinical relevance of SPINK1 and CTRC variants is often complicated in the absence of functional evidence and interpretation of rare variants is not very easy in clinical practice. The aim of this study was to review the different variants identified in these two genes and to classify them according to their degree of damaging effect. This classification was based on the results of in vitro experiments, in silico analysis using different prediction tools, and on population data, in comparing the allelic frequency of each variant in patients with pancreatitis and in unaffected control individuals. This review should help geneticists and clinicians in charge of patient's care and genetic counseling to interpret the results of genetic studies.
Topics: Chymotrypsin; Computer Simulation; Gene Frequency; Genetic Variation; Humans; Pancreatitis; Predictive Value of Tests; Trypsin Inhibitor, Kazal Pancreatic
PubMed: 32948427
DOI: 10.1016/j.pan.2020.09.001 -
Endocrine, Metabolic & Immune Disorders... 2021Multiple endocrine neoplasia type 2B (MEN 2B) is mainly caused by M918T RET germline mutation, and characterized by medullary thyroid carcinoma (MTC), pheochromocytoma...
BACKGROUND
Multiple endocrine neoplasia type 2B (MEN 2B) is mainly caused by M918T RET germline mutation, and characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and non-endocrine features. However, the diagnosis and treatment are usually delayed.
METHODS
This study reports 5 Chinese pedigrees with 5 individuals harboring germline RETM918T, and systematically reviewed previous Chinese literature reported.
RESULTS
All 5 patients initially presented MTC, but none had biochemically cured postoperatively. 2 also presented bilateral PHEO after adrenal-sparing surgery, 1 needed steroid replacement. Further, a total of 32 MEN 2B patients from literature were clustered with 28 available for analysis. 26 (92.8%) were diagnosed by endocrine-related symptoms; the remaining 2 (7.2%) due to RET testing and oral symptoms, respectively. 25 patients underwent thyroidectomy with/without neck lymph node dissection at the mean age of (23.3 ± 10.4) years. Histopathological examination revealed MTC (100%). Of them, 17 had definite TNM stage, with 1 in stage III and others in IV. Other information of MEN 2B-related symptoms included penetrance of PHEO (60.7%), constipation (32.1%), Hirschsprung disease (25%), alacrima (17.8%), mucosal ganglioneuroma (96.4%) and marfanoid habitus (71.4%). 19 patients were verified harboring RET-M918T (c.2753T>C), of whom 15 (78.9%) were de novo mutation. The other 9 were clinically diagnosed as MEN 2B.
DISCUSSION & CONCLUSION
The initial diagnosis of MEN 2B is relatively later, and diagnosed by non-endocrine components is extremely lower. Recognition of MEN 2B and its non-endocrine-related components is still the utmost requirement for a Chinese physician. Combined RET screening and serum calcitonin detection can facilitate early diagnosis.
Topics: Adolescent; Adult; Asian People; Biomarkers, Tumor; Calcitonin; Child; China; DNA Mutational Analysis; Early Detection of Cancer; Female; Genetic Predisposition to Disease; Heredity; Humans; Lymph Node Excision; Male; Middle Aged; Multiple Endocrine Neoplasia Type 2b; Mutation; Pedigree; Predictive Value of Tests; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Risk Factors; Thyroidectomy; Treatment Outcome; Young Adult
PubMed: 32914730
DOI: 10.2174/1871530320666200910112230 -
European Respiratory Review : An... Sep 2020The percentage of α-antitrypsin protease inhibitor ZZ (PiZZ) genotypes in patients with COPD is controversial, with large differences among various studies. We aimed to...
The percentage of α-antitrypsin protease inhibitor ZZ (PiZZ) genotypes in patients with COPD is controversial, with large differences among various studies. We aimed to estimate the prevalence of PiZZ in COPD patients from 20 European countries with available data, according to the number of PiZZ and COPD individuals in each country.A systematic review was conducted to select European countries with reliable data on the prevalence of PiZZ and COPD. We created a database with the following data: 1) total population and population aged ≥40 years according to the Eurostat database; 2) number and 95% CI of PiZZ patients aged ≥40 years; 3) application of a conversion factor of genetic penetrance of 60%; 4) number of COPD individuals, with 95% CI, aged ≥40 years; and 5) calculation of the PiZZ/COPD ratio. Finally, results were presented using an Inverse Distance Weighted Interpolation map.We found 36 298 (95% CI 23 643-56 594) PiZZ individuals at high risk and 30 849 709 (95% CI 21 411 293-40 344 496) COPD patients, with a PiZZ/COPD ratio of 0.12% (range 0.08-0.24%), and a prevalence of 1 out of 408 in Northern, 1 out of 944 in Western, 1 out of 1051 in Central, 1 out of 711 in Southern, and 1 out of 1274 in Eastern Europe.These data may be useful to plan strategies for future research and diagnosis, and to rationalise the available therapeutic resources.
Topics: Europe; Genotype; Humans; Prevalence; Pulmonary Disease, Chronic Obstructive; alpha 1-Antitrypsin Deficiency
PubMed: 32699024
DOI: 10.1183/16000617.0014-2020 -
Pediatric Surgery International Aug 2020Biliary atresia (BA) in twins is extremely rare reported in the literature, but twin studies are useful methods of examining the associated factors of a complex disease.... (Meta-Analysis)
Meta-Analysis
PURPOSE
Biliary atresia (BA) in twins is extremely rare reported in the literature, but twin studies are useful methods of examining the associated factors of a complex disease. The objective of this study was to analyze the characteristics and patterns of biliary atresia in twins from reviewing available articles.
METHODS
PubMed and EMBASE databases were reviewed for related articles using the keywords ''biliary atresia'', ''twins'', ''monozygotic (MZ)'', and ''dizygotic (DZ)'', including relevant papers in the reference lists.
RESULTS
This analysis was extracted from 12 articles, with a total of 35 twin pairs included. BA was found in 36 out of 70 twin subjects (51.4%), of which had an even gender split. 97.1% twins were discordant, among 55.9% of which were monozygotic twin sets, indicating that BA may be related to genetic phenotype or penetrance. Isolated BA was the largest group with 27 (75%) affected twins. Only one pair of dizygotic twins (2.9%) demonstrate concordance for BA, and have one affected family member.
CONCLUSION
BA was found in nearly half of twin subjects with an even gender split. Isolated BA was the largest group, in which the number of monozygotic twins was similar with dizygotic twins, so the onset of the disease may not associate with the zygosity of twins. Most of twin sets had discordant disease presentation, especially monozygotic twins therein, emphasizing the role of epigenetic factor in the pathogenesis of BA. Future studies should take genetic testing among any twin sets in BA, especially the disease-associated mutations, thus be useful to investigate the etiology of disease.
Topics: Adult; Biliary Atresia; Diseases in Twins; Female; Humans; Male; Twins
PubMed: 32504124
DOI: 10.1007/s00383-020-04690-4 -
European Journal of Human Genetics :... May 2020Family-based penetrance is frequently cited as a major challenge for translating penetrance estimates from familial populations to asymptomatic populations. A systematic...
Family-based penetrance is frequently cited as a major challenge for translating penetrance estimates from familial populations to asymptomatic populations. A systematic review was performed to assess the literature evidencing penetrance estimates in patients without a family history of disease, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. Initially 1592 papers were identified, which were filtered to a final nine, through application of inclusion and exclusion criteria. Fundamental differences in the identified papers prevented combination of papers using meta-analysis, so thematic analysis to produce a narrative synthesis was performed. Key themes included disease risk modifiers, evidence, study limitations and bias. A methodological appraisal too was used to assess quality of included studies. It is evident from the findings that the evidence base for penetrance estimates in individuals without a family history of disease is limited. Future work is needed to refine design of penetrance studies and the impact of incorrect estimates.
Topics: Genetic Diseases, Inborn; Genetic Testing; Humans; Medical History Taking; Pedigree; Penetrance
PubMed: 31937893
DOI: 10.1038/s41431-019-0556-5 -
Experimental Gerontology Jan 2020Collagens and elastin are 'building blocks' of tissues and extracellular matrix. Mutations in these proteins cause severe congenital syndromes. Adverse genetic...
Collagens and elastin are 'building blocks' of tissues and extracellular matrix. Mutations in these proteins cause severe congenital syndromes. Adverse genetic variations may accelerate the aging process in adults contributing to premature morbidity, disability and/or mortality. Favorable variants may contribute to longevity and/or healthy aging, but this is much less studied. We reviewed the association between variation in the genes of collagens and elastin and premature aging, accelerated aging, age-related diseases and/or frailty; and the association between genetic variation in those and longevity and/or healthy aging in humans. A systematic search was conducted in MEDLINE and other online databases (OMIM, Genetics Home Reference, Orphanet, ClinVar). Results suggest that genetic variants lead to aging phenotypes of known congenital disease, but also to association with common age-related diseases in adults without known congenital disease. This may be due to the variable penetrance and expressivity of many variants. Some collagen variants have been associated with longevity or healthy aging. A limitation is that most studies had <1000 participants and their criterion for statistical significance was p < 0.05. Results highlight the importance of adopting a lifecourse approach to the study of the genomics of aging. Gerontology can help with new methodologies that operationalize biological aging.
Topics: Aged; Aged, 80 and over; Aging; Collagen; Elastin; Frail Elderly; Frailty; Genetic Variation; Healthy Aging; Humans; Longevity; Phenotype
PubMed: 31740390
DOI: 10.1016/j.exger.2019.110781 -
European Journal of Ophthalmology Sep 2020Topical steroids may induce a rise in intraocular pressure. The risk may increase with prolonged use, high frequency of administration, young age, higher ocular...
Topical steroids may induce a rise in intraocular pressure. The risk may increase with prolonged use, high frequency of administration, young age, higher ocular penetrance and higher anti-inflammatory potency. We aimed to study this relationship by comparing published rates of intraocular pressure elevation following administration of topical steroids and compared the risk of higher versus lower dosage regimes, high- versus low-potency/penetration steroids and adults versus children. Data sources used were Ovid Embase, Ovid Medline, the Cochrane Central Register of Controlled Trials, Web of Science, Scopus, CINHAL Plus and LILACS. Eligible studies were randomised controlled trials of topical steroids versus any other topical steroid, nonsteroidal anti-inflammatory drugs, placebo or vehicle, or a different mode of administration administered for 7 days or longer that reported intraocular pressure elevation from baseline as >10, 6-15 or >15 mm Hg in adults or children. Risks of bias were reviewed using the GRADE quality approach. Data were extracted into the software package, RevMan, Version 5 (Cochrane Collaboration). In total, 43 studies were included. Meta-analysis was not possible. Topical steroids of lower anti-inflammatory potency, and with reduced intraocular penetration, are associated with reduced incidence of intraocular pressure elevation. A comparison of data in children and adults is limited by the use of different reporting systems. The principal obstacle to meta-analysis is the different reporting systems used to categorise intraocular pressure elevation. We recommend future studies should report intraocular pressure elevation >10 mm Hg from baseline to allow meta-analysis of data.
Topics: Administration, Ophthalmic; Adolescent; Adult; Child; Child, Preschool; Glaucoma; Glucocorticoids; Humans; Infant; Infant, Newborn; Intraocular Pressure; Ocular Hypertension; Ophthalmic Solutions; Risk Factors
PubMed: 31668084
DOI: 10.1177/1120672119885050 -
Advances in Therapy Dec 2019Leber's hereditary optic neuropathy (LHON) is a relatively common, rapidly progressing inherited optic neuropathy wherein LHON-affected eyes undergo optic nerve atrophy...
Leber's hereditary optic neuropathy (LHON) is a relatively common, rapidly progressing inherited optic neuropathy wherein LHON-affected eyes undergo optic nerve atrophy due to retinal ganglion cell (RGC) loss. It is a maternally inherited (or sporadic) mitochondrial disorder caused primarily by mutations in genes that encode components of respiratory complex (RC)1 in mitochondria. Mitochondrial deficiency of RC1 compromises ATP production and oxidative stress management in RGCs. The most common LHON-causing mutations are 11778G>A, 3460G>A, and 14484T>C point mutations in MT-ND4, MT-ND1, and MT-ND6. The unusually high mitochondrial load of RGCs makes them particularly sensitive to these mutations. Patients with LHON may be prescribed ubiquinone (a component of RC3) or idebenone, a ubiquinone analogue with enhanced bioavailability to act downstream of RC1. The challenge of accessing the inner mitochondrial membrane with gene therapy for LHON, and other mitochondrial diseases, may be overcome by incorporation of a specific mitochondrion-targeting sequence (MTS) that enables allotropic expression of a nucleus-transcribed ND4 transgene. Because LHON penetrance is incomplete among carriers of the aforementioned mutations, identification of environmental factors, such as heavy smoking, that interact with genetics in the phenotypic expression of LHON may be helpful toward preventing or delaying disease development. LHON has become a model for mitochondrial and neurogenerative diseases owing to it having a clearly identified genetic cause and its early onset and rapid progression characteristics. Hence, LHON studies and genetic treatment advances may inform research of other diseases.
Topics: DNA, Mitochondrial; Electron Transport Complex I; Genetic Therapy; Humans; Mutation; Optic Atrophy, Hereditary, Leber; Phenotype; Point Mutation
PubMed: 31605306
DOI: 10.1007/s12325-019-01113-2