A new family with an activating mutation (G431S) in the TSH receptor gene: a phenotype discussion and review of the literature.
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ABSTRACT:
SUBMITTER: Larsen CC
PROVIDER: S-EPMC4396564 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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Project description:BackgroundEpiphyseal, Vertebral, Ear, and Nose (EVEN)-PLUS syndrome is a rare condition characterized by the involvement of the Epiphyses, Vertebrae, Ears, and Nose, plus other associated findings, due to pathogenic variants in the HSPA9 gene. Due to the sparse number of patients, the clinical phenotypic spectrum is not clear.MethodsWe report two patients with pathogenic HSPA9 variants from a Chinese family. Besides the core clinical features of EVEN-PLUS syndrome, the two cases had seizures, developmental delay, and basal ganglia lesions in cerebral MRI. We also reviewed the previously published reports of patients with biallelic pathogenic HSPA9 variants.ResultsTogether with the presented cases, 12 cases (9 females) were identified from 6 relevant research items for analysis. All patients had synophrys or arched eyebrows, hypoplastic or dysplastic ears, hypoplastic nasal bone, and dysplastic femoral head. Other specific craniofacial features (such as triangular nares), abnormal skeletal presentations (such as bifid femur, dysplastic epiphyses at the knee, dysplastic acetabula, delayed ossification, short stature, vertebral clefting, scoliosis, and dislocated patellae), congenital heart defects, and renal alterations are common clinical features. Two patients had seizures and basal ganglia lesions in cerebral MRI. Infrequent features, such as aplasia cutis, short thorax and sternum, and widely spaced nipples, are also observed in the syndrome. Thirteen variants associated with EVEN-PLUS syndrome have been reported.ConclusionsHSPA9 gene mutations should be suspected in all cases with specific craniofacial features, abnormal skeletal presentations, congenital heart defects, and renal alterations. Seizures and basal ganglia lesions are a new phenotype of EVEN-PLUS syndrome.
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Project description:BackgroundSynchronous cancers are rarely detected when working-up a patient for a primary cancer. Neoadjuvant management of synchronous breast and pancreatic cancers, without a germline mutation, has yet to be discussed. Two patients were diagnosed with synchronous breast and pancreatic cancers at our institution over the last decade. A literature review was performed to evaluate the current evidence stance.ResultsThe first patient was 61-years old and diagnosed with a HER2+ breast cancer. The second patient was 77-years old and diagnosed with a Luminal B breast cancer. The inability to provide concurrent breast and pancreatic neoadjuvant therapy for the HER2+ patient, resulted in upfront surgery. The second patient was able to have both cancers treated simultaneously - neoadjuvant chemotherapy to the pancreas, and neoadjuvant endocrine therapy to the breast.DiscussThere is no single neoadjuvant regimen that treats both pancreatic and breast cancer. The differences in breast cancer sub-types impacted our neoadjuvant options. Our recent experience led us to the hypothesis that breast cancer care dictates treatment, while pancreatic cancer determines survival. There is a significant paucity in the literature regarding synchronous breast and pancreatic cancer.
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Project description:BACKGROUND:Glucocorticoid resistance is a rare, sporadic or familial condition caused by mutation of the gene encoding the glucocorticoid receptor (GR). Clinically it is characterized by symptoms developed due to local, tissue-specific, or generalized partial insensitivity to glucocorticoids. CASE PRESENTATION:A 31-year-old woman was evaluated because of infertility at the Endocrine Unit of the 2nd Department of Medicine, Semmelweis University. During her laboratory investigations, elevated serum and salivary cortisol were observed which failed to be suppressed after administration of 1 mg dexamethasone. 24 h urinary cortisol was increased, but a normal midnight serum cortisol was detected suggesting a maintained circadian rhythm. Plasma dehydroepiandrosterone-sulfate and androstendione levels were also elevated. Repeated plasma ACTH measurements indicated slightly elevated or normal values. Bone mineral density was normal. All laboratory results confirmed the diagnosis of glucocorticoid resistance. Genetic counseling followed by Sanger sequencing of the coding region of the gene encoding human glucocorticoid receptor was performed and a missense mutation (Arg714Gln, R714Q) in a heterozygous form was detected. Following family screening, the same mutation was found in her clinically-healthy 35-year-old sister who had no fertility problems.This variant was not detected in more than 60 patients and controls tested either for glucocorticoid resistance or Cushing's syndrome in our Laboratory and it was absent in Exome Variant Server, HumanGene Mutation Database and ExAC databases. CONCLUSIONS:Our case fulfils the diagnostic criteria of glucocorticoid resistance, also named Chrousos syndrome. The glucocorticoid receptor gene mutation detected in our patient has been already reported in a 2-year-old child with hypoglycaemia, hypokalaemia, hypertension and premature puberty. These distinct phenotypes may suggest that other factors may modify the functional consequences of the R714Q variant of GR.
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Project description:Large-scale transcriptome and methylome data analyses obtained by high-throughput technologies have been enabling the identification of novel imprinted genes. We investigated genome-wide DNA methylation patterns in multiple human tissues, using a high-resolution microarray to uncover hemimethylated CpGs located in promoters overlapping CpG islands, aiming to identify novel candidate imprinted genes. Using our approach, we recovered ~30% of the known human imprinted genes, further 168 candidates were identified, 61 of which with at least three hemimethylated CpGs shared by more than two tissue types. Thirty-four of these candidate genes are members of the protocadherins cluster on 5q31.3; in mice, protocadherin genes have non-imprinted monoallelic randomic expression, which might be the case in humans. Among the remaining 27 genes, ZNF331 was recently validated as an imprinted gene, and six of them have been reported as candidates, supporting our prediction. Five candidates (CCDC166, ARC, PLEC, TONSL and VPS28) map to 8q24.3, and might constitute a novel imprinted cluster. Additionally, we performed a comprehensive compilation of known human and mice imprinted genes from literature and databases, and a comparison among high-throughput imprinting studies in humans. The screening for hemimethylated CpGs shared by multiple human tissues, together with the extensive review, appears as a useful approach to reveal candidate imprinted genes.
2017-09-26 | GSE103413 | GEO
Project description:ContextCancer and its treatments cause fatigue in up to 90% of men with advanced prostate cancer. As men with prostate cancer are surviving longer, cancer-related fatigue is becoming increasingly important for clinicians to understand and proactively manage.ObjectiveThe aim of this work is to identify knowledge gaps that may support healthcare professionals to recommend personalised fatigue management strategies.Evidence acquisitionThis manuscript is based on a roundtable discussion held during the European Association of Urology 2022 Annual Symposium, combined with a review of the literature. Five core themes were generated from the roundtable: (1) meaning of fatigue in prostate cancer patients, (2) impact of fatigue, (3) association between fatigue and treatment selection, (4) benefits of managing fatigue, and (5) barriers to exercise.Evidence synthesisCancer-related fatigue has complex underlying aetiology and is a subjective experience that may be under-reported. Some studies have shown that techniques such as education, cognitive behavioural therapy, guided imagery, and progressive muscle relaxation can result in clinically meaningful improvements in fatigue. However, the largest body of evidence, and a theme echoed in the roundtable discussions, was the benefit of exercise on fatigue. Despite the benefits of exercise, for some men, objective barriers to exercise exist and knowledge of benefits does not automatically translate into implementation and adherence.ConclusionsUnderstanding the specific health needs of individual patients and their desired health outcomes is essential to identify personalised strategies for minimising fatigue. As an outcome of the roundtable meeting, we developed a quick reference guide for healthcare providers. A high-resolution copy can be downloaded from https://patients.uroweb.org/library/fatigue-in-prostate-cancer-patients-guide/.Patient summaryThis article is based on dialogue between a group of specialists, patients, and caregivers, which took place at a roundtable meeting during the European Association of Urology 2022 Annual Symposium. The group discussed how healthcare providers can best support their patients who experience fatigue. The group subsequently developed a guide to help healthcare providers during appointments.
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Project description:Mutations in the guanine nucleotide-binding protein (G protein), α activating activity polypeptide O (GNAO1) gene have recently been described in 6 patients with early infantile epileptic encephalopathies. In the present study, we report the phenotype and the clinical course of a 4-year-old female with an epileptic encephalopathy (Ohtahara syndrome) and profound intellectual disability due to a de novo GNAO1 mutation (c.692A>G; p.Tyr231Cys). Ohtahara syndrome is a devastating early infantile epileptic encephalopathy that can be caused by mutations in different genes, now also including GNAO1. The mutation was found using a targeted next generation sequencing gene panel and demonstrates targeted sequencing as a powerful tool for identifying mutations in genes where only a few de novo mutations have been identified.
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Project description:Studies on the TSH receptor (TSHR) have numerous practical applications in vitro and in vivo. For example human monoclonal autoantibodies (MAbs) to the TSHR are useful reagents for in vitro diagnostics. Measurement of TSHR autoantibodies (TRAbs) is helpful in diagnosis and management of autoimmune thyroid disease. Currently available highly sensitive and specific assays to measure TRAbs use the human TSHR MAb M22 instead of the TSH. Furthermore, preparations of the human TSHR MAb M22 are useful as the World Health Organisation International Standard for thyroid stimulating antibody and for calibration of the assays for measuring TRAbs. Preparations of thermostabilised TSHR extracellular domain have recently become available and this is likely to have an impact on improvements in specificity testing for TRAb assays. In addition the stable TSHR preparations have practical application for specific immunoadsorption of patient serum TRAbs. Human TSHR MAbs also have promising prospects as new therapeutics. Autoantibodies with TSHR antagonistic activities are "natural" inhibitors of TSHR stimulation and are expected to be helpful in controlling TSHR activity in patients with Graves' disease, Graves' ophthalmopathy and thyroid cancer.
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Project description:BackgroundMolybdenum cofactor deficiency (MoCD) is a rare autosomal-recessive disorder that results in the combined deficiency of molybdenum-dependent enzymes. Four different genes are involved in Molybdenum cofactor biosynthesis: MOCS1, MOCS2, MOCS3, and GEPH. The classical form manifests in the neonatal period with severe encephalopathy, including intractable seizures, MRI changes that resemble hypoxic-ischemic injury, microcephaly, and early death. To date, an atypical phenotype with late-onset has been reported in the literature in 13 patients.MethodsWe describe a late-onset and a relatively mild phenotype in a patient with MOCS2 homozygous mutation.ResultsPyramidal and extrapyramidal signs are recognized in those patients, often exacerbated by intercurrent illness. Expressive language is usually compromised. Neurological deterioration is possible even in adulthood, probably due to accumulation of sulfite with time.ConclusionSulfite inhibition of mitochondrial metabolism could be responsible for the ischemic lesions described in patients with MoCD or alternatively could predispose the brain to suffer an ischemic damage through the action of other insults, for instance intercurrent illness. It is possible that sulfite accumulation together with other external triggers, can lead to neurological deterioration even in adulthood. The role of other factors involved in clinical expression should be investigated to establish the reason for phenotypic variability in patients with the same mutation.
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