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Clinical Journal of the American... May 2024Liddle syndrome was initially characterized by hypertension, hypokalemia, metabolic alkalosis, and suppressed plasma renin and aldosterone, resulting from...
BACKGROUND
Liddle syndrome was initially characterized by hypertension, hypokalemia, metabolic alkalosis, and suppressed plasma renin and aldosterone, resulting from gain-of-function variants in the epithelial Na + channel (ENaC). Efficient treatment with ENaC inhibitors is available, but the phenotypic spectrum of genetically confirmed Liddle syndrome is unknown, and some patients may remain undiagnosed and at risk of inefficient treatment. In this study, we used a reverse phenotyping approach to investigate the Liddle syndrome phenotypic spectrum and genotype-phenotype correlations.
METHODS
Pubmed, Embase, Scopus, and the Human Gene Mutation Database were searched for articles reporting Liddle syndrome variants. The genetic variants were systematically classified to identify patients with genetically confirmed Liddle syndrome. We identified 62 articles describing 45 unique variants within 86 Liddle syndrome families, and phenotypic data were pooled for 268 patients with confirmed Liddle syndrome.
RESULTS
The Liddle syndrome variants localized to exon 13 of SCNN1B and SCNN1G , disrupting the PPPxY motif critical for downregulating ENaC activity. Hypertension sensitive to ENaC inhibition was present in 97% of adults carrying Liddle syndrome variants while hypokalemia, metabolic alkalosis, and plasma renin and aldosterone suppression showed incomplete penetrance. In addition, 95% and 55% of patients had a family history of hypertension or cerebrovascular events, respectively. The genotype had minor phenotypic effects; however, probands compared with relatives showed significant phenotypic discrepancies consistent with selection bias for initial genetic screening.
CONCLUSIONS
Patients with genetically confirmed Liddle syndrome displayed a phenotypic spectrum, with ENaC-sensitive hypertension and family history of hypertension being the most common features. The phenotype seemed independent of the specific gene or variant type involved.
Topics: Humans; Liddle Syndrome; Epithelial Sodium Channels; Phenotype; Adult; Genetic Association Studies; Female; Male; Hypertension; Renin; Hypokalemia; Adolescent; Young Adult; Genetic Predisposition to Disease; Child; Mutation
PubMed: 38265765
DOI: 10.2215/CJN.0000000000000430 -
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 -
Ultrasound in Obstetrics & Gynecology :... Apr 2018To establish, based on a systematic literature review, the frequency of pathogenic submicroscopic chromosomal aberrations in fetuses that are not at increased risk for... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To establish, based on a systematic literature review, the frequency of pathogenic submicroscopic chromosomal aberrations in fetuses that are not at increased risk for unbalanced structural chromosomal aberrations, with the aim of determining whether high-resolution testing for submicroscopic aberrations is beneficial in a general pregnant population.
METHODS
EMBASE, PubMed, Web of Science and CENTRAL databases were searched systematically on 3 June 2016 for all relevant articles on the prevalence of pathogenic submicroscopic copy number variants (CNVs) in fetuses referred for prenatal invasive testing because of advanced maternal age (AMA) or parental anxiety (ANX). Relevant full-text articles were analyzed and the prevalence of submicroscopic CNVs was calculated based on the extracted data. Meta-analysis was conducted in a pooled cohort of 10 614 fetuses based on the 10 largest studies (n > 300) of a total of 19 that were relevant.
RESULTS
Pooled estimate analysis indicated that 0.84% (95% CI, 0.55-1.30%) of fetuses that had invasive testing because of AMA/ANX carried a pathogenic clinically significant submicroscopic aberration. The onset/penetrance of submicroscopic findings was studied in 10 314 fetuses reported in eight papers that presented aberrant cases with all necessary details to allow assessment of the findings. The pooled estimates resulting from meta-analysis of the data indicated that an early-onset syndromic disorder was detected in 0.37% (95% CI, 0.27-0.52%) of cases, a susceptibility CNV was found in 0.30% (95% CI, 0.14-0.67%) and late-onset diseases were reported in 0.11% (95% CI, 0.05%-0.21%). The prevalence of early-onset syndromic disorders caused by a submicroscopic aberration was calculated to be 1:270. When the risk for submicroscopic aberrations is added to the individual risk for microscopic chromosomal aberrations, all pregnant women have a risk of higher than 1 in 180 for a relevant chromosomal aberration, and pregnant women under 36 years of age have a higher risk for submicroscopic pathogenic aberrations than for Down syndrome.
CONCLUSION
This systematic review shows that a significant proportion of fetuses in a general pregnant population carry a submicroscopic pathogenic CNV. Based on these figures, all women should be informed on their individual risk for all pathogenic chromosomal aberrations and not only for common trisomies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Topics: Chromosome Aberrations; Cohort Studies; DNA Copy Number Variations; Down Syndrome; Female; Humans; Maternal Age; Oligonucleotide Array Sequence Analysis; Pregnancy; Risk; Ultrasonography, Prenatal
PubMed: 28556491
DOI: 10.1002/uog.17533 -
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 -
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 -
Alimentary Pharmacology & Therapeutics Apr 2018Alpha-1 antitrypsin deficiency (AATD) is estimated to affect three million people worldwide. It causes liver disease in a proportion of carriers of the PiS and PiZ...
BACKGROUND
Alpha-1 antitrypsin deficiency (AATD) is estimated to affect three million people worldwide. It causes liver disease in a proportion of carriers of the PiS and PiZ allele due to the formation and retention of polymers within the endoplasmic reticulum of hepatocytes. The reason for this selective penetrance is not known. Although clinical trials are underway, liver transplantation is the only effective treatment for liver disease due to AATD.
AIMS
To report the prevalence and natural history of liver disease among individuals with AATD, and assess the outcomes of liver transplantation through systematic review.
METHODS
A comprehensive search was conducted across multiple databases. Two independent authors selected the articles and assessed bias using the Newcastle-Ottawa Scale. Data were pooled for analysis, where comparable outcomes were reported.
RESULTS
Thirty-five studies were identified related to disease progression and 12 for the treatment of AATD. Seven per cent of children were reported to develop liver cirrhosis, with 16.5% of individuals presenting in childhood requiring liver transplantation. Of those surviving to adulthood, 10.5% had liver cirrhosis and 14.7% required transplantation. Liver transplantation was the only effective treatment reported and outcomes compare favourably to other indications, with 5-year survival reported as over 90% in children and over 80% in adults.
DISCUSSION
The clinical course of liver disease in individuals with AATD remains poorly understood, but affects about 10% of those with AATD. More research is required to identify those patients at risk of developing liver disease at an early stage, and to provide alternative treatments to liver transplantation.
Topics: Adult; Child; Disease Progression; Humans; Liver Cirrhosis; Liver Transplantation; Prevalence; Treatment Outcome; alpha 1-Antitrypsin Deficiency
PubMed: 29446109
DOI: 10.1111/apt.14537 -
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 -
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 -
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