-
Clinical and Experimental Hypertension... 2018Liddle syndrome is an autosomal dominant form of monogenic hypertension. Phenotypic variability makes it difficult to identify patients with Liddle syndrome, resulting... (Review)
Review
BACKGROUND
Liddle syndrome is an autosomal dominant form of monogenic hypertension. Phenotypic variability makes it difficult to identify patients with Liddle syndrome, resulting in misdiagnosis and severe complications at early age.
OBJECTIVES
To identify mutation in SCNN1B and SCNN1G genes in an adolescent with suspicious Liddle syndrome and his family members and to explore the screening target subjects of Liddle syndrome.
METHODS
Genetic analysis of the C-terminus of SCNN1B and SCNN1G genes was conducted in an adolescent, with treatment-resistant hypertension and hypokalemia, who was suspected of having Liddle syndrome, and his family members. A Medline research of the reported cases with Liddle syndrome was also performed.
RESULTS
A recurrent SCNN1B mutation, c.1853C>A (p.P618H), was detected in the 19-year-old male patient, and family screening identified five additional members who were heterozygous for the mutation. The diagnosis of Liddle syndrome was made in all affected individuals. Despite the phenotypic variability, a systematic review of 54 reported index cases revealed the early-onset hypertension, aged no more than 30 years, as a common feature.
CONCLUSIONS
Genetic screening for Liddle syndrome should be considered in hypertensive subjects with early penetrance, maybe no more than 30 years, after exclusion of common secondary causes of hypertension.
Topics: Age of Onset; Epithelial Sodium Channels; Genetic Testing; Heterozygote; Humans; Hypertension; Hypokalemia; Liddle Syndrome; Male; Mutation; Phenotype; Young Adult
PubMed: 28718682
DOI: 10.1080/10641963.2017.1334799 -
Cephalalgia : An International Journal... Feb 2018Objective We performed a systematic review on the comorbidities of familial/sporadic hemiplegic migraine (F/SHM) with seizure/epilepsy in patients with CACNA1A, ATP1A2... (Meta-Analysis)
Meta-Analysis
Objective We performed a systematic review on the comorbidities of familial/sporadic hemiplegic migraine (F/SHM) with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations, to identify the genotypes associated and investigate for the presence of mutational hot spots. Methods We performed a search in MEDLINE and in the Human Gene Mutation and Leiden Open Variation Databases for mutations in the CACNA1A, ATP1A2 and SCN1A genes. After having examined the clinical characteristics of the patients, we selected those having HM and seizures, febrile seizures or epilepsy. For each gene, we determined both the frequency and the positions at protein levels of these mutations, as well as the penetrance of epilepsy within families. Results Concerning F/SHM-Epilepsy1 (F/SHME1) and F/SHME2 endophenotypes, we observed a prevalent involvement of the transmembrane domains, and a strong correlation in F/SHME1 when the positively charged amino acids were involved. The penetrance of epilepsy within the families was highest for patients carrying mutation in the CACNA1A gene (60%), and lower in those having SCN1A (33.3%) and ATP1A2 (30.9%) mutations. Conclusion Among the HM cases with seizure/epilepsy, we observed mutational hot spots in the transmembrane domains of CACNA1A and ATP1A2 proteins. These findings could lead to a better understanding of the pathological mechanisms underlying migraine and epilepsy, therein guaranteeing the most appropriate therapeutic approach.
Topics: Epilepsy; Humans; Migraine with Aura; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Sodium-Potassium-Exchanging ATPase
PubMed: 28058944
DOI: 10.1177/0333102416686347 -
Radiotherapy and Oncology : Journal of... Nov 2022The diagnosis of hereditary or familial breast cancers influences the locoregional approach to breast cancer, with most patients undergoing mastectomy to avoid or...
The diagnosis of hereditary or familial breast cancers influences the locoregional approach to breast cancer, with most patients undergoing mastectomy to avoid or minimize the use of adjuvant radiation therapy. We evaluated the current literature about known high- and moderate-penetrance genes and studied their impact on local control, toxicities, and contralateral breast cancers after adjuvant radiation therapy. The aim is to encourage the safe use of adjuvant radiation therapy when indicated in concordance with the updated guidelines.
Topics: Humans; Female; Mastectomy; Breast Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Radiotherapy, Adjuvant; Neoplasm Recurrence, Local
PubMed: 36184999
DOI: 10.1016/j.radonc.2022.09.007 -
Journal of Crohn's & Colitis Jan 2023Inflammatory bowel diseases [IBD] have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Inflammatory bowel diseases [IBD] have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal aberrations and large structural abnormalities on IBD susceptibility is not clear. We aimed to comprehensively characterise the phenotype and prevalence of patients with IBD who possess rare numerical and structural chromosomal abnormalities.
METHODS
We performed a systematic literature search of databases PubMed and Embase; and analysed gnomAD, Clinvar, the 100 000 Genomes Project, and DECIPHER databases. Further, we analysed international paediatric IBD cohorts to investigate the role of IL2RA duplications in IBD susceptibility.
RESULTS
A meta-analysis suggests that monosomy X [Turner syndrome] is associated with increased expressivity of IBD that exceeds the population baseline (1.86%, 95% confidence interval [CI] 1.48 to 2.34%) and causes a younger age of IBD onset. There is little evidence that Klinefelter syndrome, Trisomy 21, Trisomy 18, mosaic Trisomy 9 and 16, or partial trisomies contribute to IBD susceptibility. Copy number analysis studies suggest inconsistent results. Monoallelic loss of X-linked or haploinsufficient genes is associated with IBD by hemizygous or heterozygous deletions, respectively. However, haploinsufficient gene deletions are detected in healthy reference populations, suggesting that the expressivity of IBD might be overestimated. One duplication that has previously been identified as potentially contributing to IBD risk involves the IL2RA/IL15R loci. Here we provide additional evidence that a microduplication of this locus may predispose to very-early-onset IBD by identifying a second case in a distinct kindred. However, the penetrance of intestinal inflammation in this genetic aberration is low [<2.6%].
CONCLUSIONS
Turner syndrome is associated with increased susceptibility to intestinal inflammation. Duplication of the IL2RA/IL15R loci may contribute to disease risk.
Topics: Humans; DNA Copy Number Variations; Turner Syndrome; Inflammatory Bowel Diseases; Chromosome Aberrations; Inflammation
PubMed: 35907265
DOI: 10.1093/ecco-jcc/jjac103 -
Heart (British Cardiac Society) Jun 2022Bicuspid aortic valve (BAV) affects 1% of the general population. was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed...
INTRODUCTION
Bicuspid aortic valve (BAV) affects 1% of the general population. was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to mutations has not been estimated.
AIM
The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to mutations.
METHODS
The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research-8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting sequencing in context of congenital heart disease.
RESULTS
sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic mutations was observed in almost half of reported pedigrees.
CONCLUSIONS
Pathogenic and likely pathogenic genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.
Topics: Aortic Valve; Bicuspid Aortic Valve Disease; Heart Valve Diseases; Humans; Mutation; Pedigree; Receptor, Notch1
PubMed: 35288444
DOI: 10.1136/heartjnl-2021-320428 -
World Neurosurgery Jan 2024Computeed tomography (CT) is a cornerstone of the identification and management of acute changes in neurosurgery patients. In addition to the monetary expense of CT...
BACKGROUND
Computeed tomography (CT) is a cornerstone of the identification and management of acute changes in neurosurgery patients. In addition to the monetary expense of CT scans, further costs are incurred due to the time of patient transport and radiation exposure. Ultrasounds (USs)offer a safe, inexpensive, and bedside alternative to CT but obstacles remain due to decreased penetrance in the adult skull. Sonolucent Cranial Implants (SCIs) offer a window for USs to view intracranial architectures.
METHODS
The authors performed a PRISMA guidelines-based systematic review of the literature. Information was extracted from included articles in regards to illness pathology, US imaging feasibility, comparison to standard imaging, infections, and revisions. Costs were collected in regards to price of implant and follow-up imaging.
RESULTS
A total of 226 articles resulted, of which 5 were included in the study. Ninety non-duplicate patients who received SCIs were analyzed. The pathologies of included patients is as follows: 51 patients were after extracranial-intracranial bypass, 37 after ventriculoperitoneal shunt placement for hydrocephalus, 1 after tumor resection, and 1 after cranioplasty following decompressive hemicraniectomy. All studies noted feasibility of US and comparability to standard imaging following SCI placement. Follow-up imaging with trans-sonolucent cranial implant ultrasound was estimated to save up to $4,000 per patient depending on the procedure.
CONCLUSIONS
Initial studies suggest that US imaging through SCIs is a safe and efficacious alternative to CT imaging in neurosurgical patients. Cost analysis suggests that SCI and subsequent US can offer a cost savings compared with current treatment.
Topics: Humans; Costs and Cost Analysis; Plastic Surgery Procedures; Prostheses and Implants; Skull; Ultrasonography
PubMed: 37931879
DOI: 10.1016/j.wneu.2023.10.145 -
American Journal of Rhinology & Allergy May 2024Orbital involvement of invasive fungal sinusitis (IFS) is an ominous prognostic marker that should prompt rapid intervention. Transcutaneous retrobulbar administration... (Review)
Review
BACKGROUND
Orbital involvement of invasive fungal sinusitis (IFS) is an ominous prognostic marker that should prompt rapid intervention. Transcutaneous retrobulbar administration of amphotericin B (TRAMB) is an off-label adjunctive treatment that can increase drug penetrance into diseased orbital tissue. To date, there is a lack of consensus regarding the use of TRAMB for treatment of IFS with orbital involvement.
OBJECTIVE
This systematic review aims to synthesize the indications, efficacy, and potential complications of TRAMB.
METHODS
PubMed, EMBASE, and Web of Science databases were probed for systematic review. Article search was conducted through June 2023 using the keywords "invasive fungal sinusitis," "invasive fungal rhinosinusitis," "rhino-orbital mucormycosis," "rhinosinusitis," "orbital," "retrobulbar," and "amphotericin."
RESULTS
In suitable cases as determined by radiologic and clinical evaluation, TRAMB administration has the potential to improve orbital salvage rates and improve versus stabilize visual acuity. Treatment complications are more likely with deoxycholate than with liposomal amphotericin formulations. The existing literature describing use of TRAMB is limited due to its retrospective nature, but the increase in IFS cases since 2020 due to the COVID pandemic has broadened the literature.
CONCLUSIONS
TRAMB is an effective adjunctive treatment in IFS with mild-to-moderate orbital involvement when used in combination with standard of care debridement, systemic antifungal therapy, and immunosuppression reversal. Prospective longitudinal studies and multi-institutional randomized trials are necessary to determine the definitive utility of TRAMB.
PubMed: 38772559
DOI: 10.1177/19458924241254422 -
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 -
International Journal of Cancer Aug 2011Arg72Pro is a common polymorphism in TP53, showing differences in its biological functions. Case-control studies have been performed to elucidate the role of Arg72Pro in... (Meta-Analysis)
Meta-Analysis
Arg72Pro is a common polymorphism in TP53, showing differences in its biological functions. Case-control studies have been performed to elucidate the role of Arg72Pro in cancer, although the results are conflicting and heterogeneous. Here, we analyzed pooled data from case-control studies to determine the role of Arg72Pro in different cancer sites. We performed a systematic review and meta-analysis of 302 case-control studies that analyzed Arg72Pro in cancer susceptibility. Odds ratios were estimated for different tumor sites using distinct genetic models, and the heterogeneity between studies was explored using I(2) values and meta-regression. We adopted quality criteria to classify the studies. Subgroup analyses were done for tumor sites according to ethnicity, histological, and anatomical sites. Results indicated that Arg72Pro is associated with higher susceptibility to cancer in some tumor sites, mainly hepatocarcinoma. For some tumor sites, quality of studies was associated with the size of genetic association, mainly in cervical, head and neck, gastric, and lung cancer. However, study quality did not explain the observed heterogeneity substantially. Meta-regression showed that ethnicity, allelic frequency and genotyping method were responsible for a substantial part of the heterogeneity observed. Our results suggest ethnicity and histological and anatomical sites may modulate the penetrance of Arg72Pro in cancer susceptibility. This meta-analysis denotes the importance for more studies with good quality and that the covariates responsible for heterogeneity should be controlled to obtain a more conclusive response about the function of Arg72Pro in cancer.
Topics: Case-Control Studies; Genetic Predisposition to Disease; Humans; Neoplasms; Penetrance; Polymorphism, Genetic; Prognosis; Risk Factors; Tumor Suppressor Protein p53
PubMed: 20886596
DOI: 10.1002/ijc.25710 -
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