Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop met...Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.展开更多
BACKGROUND Rett syndrome is a monogenic X-linked dominant condition that affects 1/(10000-15000)girls due to de novo mutations in the methyl-CpG binding protein 2(MECP2)gene mapped to chromosome Xq28.The disease-causi...BACKGROUND Rett syndrome is a monogenic X-linked dominant condition that affects 1/(10000-15000)girls due to de novo mutations in the methyl-CpG binding protein 2(MECP2)gene mapped to chromosome Xq28.The disease-causing gene was identified as a mutation in the MECP2 gene,which is found in approximately 80%of patients diagnosed with Rett syndrome.Although chromosomal changes resulting in del(15)(q11q13)are usually associated with Angelman and Prader-Willi syndrome,very few cases,if any,of Rett syndrome with terminal 15q22-qter deletion have been published in English literature.CASE SUMMARY In this study,we report an unusual and rare clinical presentation of Rett syndrome in a 12-year-old Sudanese girl.The patient was brought in by her parents,complaining of gradual onset of abnormal walking,abnormal hand movement,loss of speech,and mental retardation for ten years.There was no reported history of convulsions or loss of consciousness.Clinical examination revealed microcephaly with no other apparent dysmorphic features,intact cranial nerves,and abnormal gait.She showed repetitive and stereotyped behaviors,including hand flapping,stimming,and chest pounding,which were concomitant with autism spectrum disorder.Magnetic resonance imaging and electroencephalography investigations were normal,and cytogenetic analysis showed 46,XX,del(15)(q22qter).Further molecular analysis using whole sequencing of MECP2 revealed an alteration cytosine>thymine at nucleotide 401,leading to phenylalanine replacing a serine at amino acid position 134.CONCLUSION This case,the first reported instance of Rett syndrome in Sudan,is of significant interest.The patient carries both the MECP2 gene mutation and the chromosome 15q22-qter deletion,which may explain the autistic behavior with atypical presentation of Rett syndrome.This report expands the genetic diversity of Rett syndrome,demonstrating how co-occurring 15q22-qter deletions can reshape MECP2-associated phenotypes in Rett syndrome.展开更多
Klinefelter syndrome （KS） （47, XXY） is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as on...Klinefelter syndrome （KS） （47, XXY） is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be difficult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of beth hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.展开更多
AIM:To investigate the associations between CDH1 gene polymorphisms and gastric cancer(GC) risk predisposition.METHODS:We analyzed four CDH1 polymorphisms(+54 T>C,-160 C>A,-616 G>C,-3159 T>C) in an Omani p...AIM:To investigate the associations between CDH1 gene polymorphisms and gastric cancer(GC) risk predisposition.METHODS:We analyzed four CDH1 polymorphisms(+54 T>C,-160 C>A,-616 G>C,-3159 T>C) in an Omani population,by extraction of genomic DNA from the peripheral blood of 192 patients with GC and 170 control participants and performed CDH1 genotyping using DNA sequencing.RESULTS:CDH1-160-AA genotype was associated with an increased risk of GC(OR = 3.6,95% CI:1.1-11.8)(P = 0.03).There was no significant association between the other polymorphisms and GC risk.The haplotype analysis of +54 T>C,-160 C>A,-616 G>C,-3159 T>C genotypes revealed that the OR of CCGC and CAGC haplotypes was 1.5(95% CI:0.7-3.5) and 1.5(95% CI:0.2-3.0),but did not reach statistical significance.CONCLUSION:The current study suggests that the-160 AA genotype was associated with an increased risk of GC in Oman.展开更多
Proximal symphalangism(SYM1B)(OMIM 615298) is an autosomal dominant developmental disorder affecting joint fusion. It is characterized by variable fusions of the proximal interphalangeal joints of the hands,typically ...Proximal symphalangism(SYM1B)(OMIM 615298) is an autosomal dominant developmental disorder affecting joint fusion. It is characterized by variable fusions of the proximal interphalangeal joints of the hands,typically of the ring and little finger,with the thumb typically being spared. SYM1 is frequently associated with coalition of tarsal bones and conductive hearing loss. Molecular studies have identified two possible genetic aetiologies for this syndrome,NOG and GDF5. We herein present a British caucasian family with SYM1 B caused by a mutation of the GDF5 gene. A mother and her three children presented to the orthopaedic outpatient department predominantly for feet related problems. All patients had multiple tarsal coalitions and hand involvement in the form of either brachydactyly or symphalangism of the proximal and middle phalanx of the little fingers. Genetic testing in the eldest child and his mother identified a heterozygous missense mutation in GDF5 c.1313G>T(p.R438L),thereby establishing SYM1 B as the cause of the orthopaedic problems in this family. There were no mutations identified in the NOG gene. This report highlights the importance of thorough history taking,including a three generation family history,and detailed clinical examination of children with fixed planovalgus feet and other family members to detect rare skeletal dysplasia conditions causing pain and deformity,and provides details of the spectrum of problems associated with SYM1 B.展开更多
Dear Editor,Persistent Müllerian duct syndrome(PMDS,MIM 261550)is an autosomal recessive inherent disorder of sex development in normally masculinized subjects with Müllerian duct derivatives,including the u...Dear Editor,Persistent Müllerian duct syndrome(PMDS,MIM 261550)is an autosomal recessive inherent disorder of sex development in normally masculinized subjects with Müllerian duct derivatives,including the uterus,fallopian tubes,and upper part of the vagina.1 PMDS is very rare with presentations of bilateral cryptorchidism(55%),unilateral cryptorchidism with contralateral hernia(20%),or transverse testicular ectopia(25%).展开更多
Genetic analyses of patients with transposition of the great arteries have identified rare copy number variations,suggesting that they may be significant to the aetiology of the disease.This paper reports the identifi...Genetic analyses of patients with transposition of the great arteries have identified rare copy number variations,suggesting that they may be significant to the aetiology of the disease.This paper reports the identification of a 16 p11.2 microduplication,a variation that has yet to be reported in association with transposition of the great arteries.The 16 p11.2 microduplication is associated with autism spectrum disorder and developmental delay,but with highly variable phenotypic effects.Autism and attention deficit disorders are observed more frequently in children with congenital heart disease than in the general population.Neonatal surgery is proposed as a risk factor,but as yet unidentified genetic abnormalities should also be taken into account.Thus,congenital heart abnormalities may constitute a part of the phenotypic spectrum associated with duplications at 16 p11.2.We suggest chromosomal microarray be considered part of the diagnostic work-up in patients with transposition of the great arteries.展开更多
An extract from ripe fruit of Vitex agnus-castus (Vitex) has been used to treat patients with various obstetric and gynecological disorders in Europe. We have demonstrated that Vitex showed cytocidal effects on variou...An extract from ripe fruit of Vitex agnus-castus (Vitex) has been used to treat patients with various obstetric and gynecological disorders in Europe. We have demonstrated that Vitex showed cytocidal effects on various types of cancer cell lines including a human colon carcinoma cell line, COLO 201. In this study, we extended our previous study to investigate the detailed mechanisms underlying cytocidal effects of Vi- tex on COLO 201. Furthermore, a possible clinical application of Vitex was also explored in vivo using nude mice xenografted with the cells. Treatment with Vitex induced apoptosis in COLO 201 in a time-dependent manner, accompanying with activa-tion of caspase-9 and -3, but not caspase-8. An inhibitor for c-Jun NH2-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK), significantly suppressed the apoptosis induction along with caspase-3 activation. Endoplasmic reticulum (ER) stress-related genes were also upregulated by Vitex treatment. Most importantly, the in vivo efficacy of Vitex evaluated by assessing the tumor growth revealed that the administration of Vitex significantly suppressed tumor growth in COLO 201 xenografted mice. Collectively, current results suggest that apoptosis induction by Vitex in COLO 201 is mediated through the activation of JNK and caspase-9, -3 resulted from ER stress. Based on the current clinical application of Vitex, these results thus provide a new insight into the clinical use of Vitex and leave open a possibility of a new regimen as an alternative medicine approach for such devastating colon cancer treatment.展开更多
BACKGROUND Early diagnosis of left ventricular diastolic dysfunction(LVDD)is essential for preventing heart failure.B-type natriuretic peptide(BNP)is a viable marker for predicting LVDD,as elevated BNP levels have bee...BACKGROUND Early diagnosis of left ventricular diastolic dysfunction(LVDD)is essential for preventing heart failure.B-type natriuretic peptide(BNP)is a viable marker for predicting LVDD,as elevated BNP levels have been associated with worsening LVDD in patients with diabetes over time.However,the utility of BNP as a diagnostic marker in diabetes is controversial,as BNP levels are often low in overweight individuals.AIM To examine the effectiveness of BNP levels and fragmented QRS(fQRS)on electrocardiography for diagnosing LVDD in patients with type 2 diabetes.METHODS This retrospective cohort study included 303 patients with type 2 diabetes(67.4±12.3 years old)with preserved ejection fraction(EF)≥50%admitted to Toyama University Hospital for glycemic management and comorbidity evaluation between November 2017 and April 2021.All participants underwent plasma BNP measurement,electrocardiography,and echocardiography.Cardiologists who were blinded to the BNP results assessed the electrocardiograms and echocardiograms.Subgroup analyses were conducted for overweight individuals.RESULTS Receiver operating characteristic(ROC)curve analysis determined optimal BNP cut-off values of 34.8 pg/mL and 7.2 pg/mL for diagnosing LVDD in non-overweight[area under the ROC curve(AUC):0.70]and overweight(AUC:0.55)groups,respectively(P=0.040).In the overweight subgroup,fQRS showed greater diagnostic accuracy for LVDD(AUC:0.67),indicating moderate diagnostic utility compared with the low performance of the BNP cutoff of 35 pg/mL(AUC:0.52)(P=0.010).Multivariate analyses confirmed that fQRS was superior to BNP for LVDD diagnosis regardless of the patient’s weight.CONCLUSION A BNP level≥35 pg/mL in non-overweight individuals may be a reliable LVDD marker.Additionally,fQRS was more effective than BNP in diagnosing LVDD irrespective of the patient’s weight.fQRS can complement BNP in the early detection of LVDD,especially in overweight patients,potentially improving early detection and mitigating progression to heart failure with preserved EF in patients with type 2 diabetes.展开更多
BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have bee...BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.展开更多
Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a fami...Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract. TFFs may be involved in IBD pathogenesis and are a potential treatment option. In the present review, we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression, possible function and pharmacological role in IBD.展开更多
Women gradually lose bone from the age of〜35 years,but around menopause,the rate of bone loss escalates due to increasing bone resorption and decreasing bone formation levels,rendering these individuals more prone to ...Women gradually lose bone from the age of〜35 years,but around menopause,the rate of bone loss escalates due to increasing bone resorption and decreasing bone formation levels,rendering these individuals more prone to developing osteoporosis.The increased osteoclast activity has been linked to a reduced estrogen level and other hormonal changes.However,it is unclear whether intrinsic changes in osteoclast precursors around menopause can also explain the increased osteoclast activity.Therefore,we set up a protocol in which CD14f blood monocytes were isolated from 49 female donors(40-66 years old).Cells were differentiated into osteoclasts,and data on differentiation and resorption activity were collected.Using multiple linear regression analyses combining in vitro and in vivo data,we found the following:(1)age and menopausal status correlate with aggressive osteoclastic bone resorption in vitro;(2)the type I procollagen N-terminal propeptide level in vivo inversely correlates with osteoclast resorption activity in vitro;(3)the protein level of mature cathepsin K in osteoclasts in vitro increases with age and menopause;and(4)the promoter of the gene encoding the dendritic cell-specific transmembrane protein is less methylated with age.We conclude that monocytes are"reprogrammed"in vivo,allowing them to"remember"age,the menopausal status,and the bone formation status in vitro,resulting in more aggressive osteoclasts.Our discovery suggests that this may be mediated through DNA methylation.We suggest that this may have clinical implications and could contribute to understanding individual differences in age-and menopause-induced bone loss.展开更多
AIM: To identify chromosomal translocations specific to gastric cancer (GC), spectral karyotyping (SKY) analysis was performed on established cell lines and cancerous ascitic fluids.METHODS: SKY analysis of 10 establi...AIM: To identify chromosomal translocations specific to gastric cancer (GC), spectral karyotyping (SKY) analysis was performed on established cell lines and cancerous ascitic fluids.METHODS: SKY analysis of 10 established cell lines and seven cancerous ascitic fluid samples identified recurrent chromosomal breakpoints and translocations in GC,several of which involved chromosomal loci of oncogenes or tumor suppressor genes.RESULTS: A total of 630 chromosomal breaks were identified. Chromosome no.8 was the most frequently involved in rearrangements (65 breaks), followed by chromosomes no. 11 (53), no. 1 (49), no. 7 (46), no. 13 (37), no. 3 (36), no. 17 (33), and no. 20 (29). Frequent breakpoints were detected in 8q24.1 (30 breaks), 11q13 (29), 13q14 (16), 20q11.2 (14), 7q32 (13), 17q11.2 (13),18q21 (12), 17q23 (9), 18q11.2 (9). SKY analysis identified a total of 242 chromosomal rearrangements including 190 reciprocal and non-reciprocal translocations. The recurrent combinations of chromosomal bands involved in translocations were 8q24.1 and 13q14 (3 cases), 8q24.1 and 11q13 (3), 11q13 and 17q11.2 (2), and 18q11.2 and 20q11.2 (2). Our study validated the ability of SKY to characterize in detail the chromosomal rearrangements in solid tumors and derived cell lines. Moreover,fluorescence in situ hybridization helped to identify the insertions, translocations, and homogeneously staining regions of MYCand CCND1 gene loci.CONCLUSION: The non-random co-localization of certain cytogenetic bands suggests the importance of chromosomal translocations in gastric carcinogenesis, by serving as landmarks for the cloning of GC causing genes.展开更多
Pseudomembranous colitis (PMC) usually manifests asfever and diarrhea in hospitalized patients treated withsystemic antibiotics. We described a case of PMC withintestinal obstruction but without diarrhea. A 60-yearold...Pseudomembranous colitis (PMC) usually manifests asfever and diarrhea in hospitalized patients treated withsystemic antibiotics. We described a case of PMC withintestinal obstruction but without diarrhea. A 60-yearold man was hospitalized for chemotherapy for the treatment of Burkitt lymphoma of the stomach. The patient became febrile and complained of crampy abdominal pain during the post-chemotherapy nadir. Plain abdominal radiography showed some intestinal gas and niveau. Because stool cytotoxin assay for clostridium difficile was positive and colon fiberscopic examination showed a pseudomembrane at the left side of the colon,and a diagnosis of PMC was made. Treatment with intracolonic vancomycin administration by colonoscopy and nasoileus tube was successful. Physicians should take into account the possibility of bowel obstruction due to PMC occurring in patients undergoing chemotherapy and perform emergency colonoscopy examination of suspected cases.展开更多
In this editorial we present an overview and insights of the management of hereditary polyposis syndromes.The primary focus was on familial adenomatous polyposis,juvenile polyposis syndrome and Peutz-Jegher syndrome.G...In this editorial we present an overview and insights of the management of hereditary polyposis syndromes.The primary focus was on familial adenomatous polyposis,juvenile polyposis syndrome and Peutz-Jegher syndrome.Genetic testing has become increasingly available and is easier than ever to integrate into clinical practice.Furthermore,several genes have been added to the expanding list of genes associated with hereditary polyposis syndromes,allowing for precise diagnostics and tailored follow-up.Endoscopic evaluation of patients with hereditary polyposis syndromes is paramount in the surveillance strategies.Current endoscopic procedures include both diagnostic procedures and surveillance as well as therapeutic interventions.Recommendations for endoscopic procedures in the upper and lower gastrointestinal canal were described.Surgery is still a key component in the management of patients with hereditary polyposis syndromes.The increased cancer risk in these patients often render prophylactic procedures or intended curative procedures in the case of cancer development.Surgical interventions in the upper and lower gastrointestinal canal were described with relevant considerations.Development of chemopreventive medications is ongoing.Few drugs have been investigated,including nonsteroidal anti-inflammatory drugs.It has been demonstrated that cyclooxygenase-2 inhibitors may lower the number of polyps.Other medications are currently under investigation,but none have,to date,consistently been able to prevent development of disease.展开更多
BACKGROUND Wilson's disease(WD)is a rare inherited disorder of copper metabolism.Treatment consists of chelating agents,but side effects are common.We describe a patient who developed colitis during trientine trea...BACKGROUND Wilson's disease(WD)is a rare inherited disorder of copper metabolism.Treatment consists of chelating agents,but side effects are common.We describe a patient who developed colitis during trientine treatment leading to decompensation of liver cirrhosis.CASE SUMMARY A healthy 51-year-old woman was diagnosed with liver cirrhosis due to decompensation with ascites.Etiologic evaluation raised suspicion of hereditary hemochromatosis because of compound heterozygosity HFE p.C282Y/p.H63D,and phlebotomy was started.Re-evaluation showed low ceruloplasmin,increased urinary copper excretion and the presence of Kayser-Fleischer rings.WD was confirmed by genetic analysis.Because of decompensated cirrhosis,she was referred for liver transplant evaluation.Simultaneously,treatment with trientine was initiated.Liver function initially stabilized,and the patient was not accepted for a liver transplant.Shortly after this,she developed severe hemorrhagic colitis,most probably a side effect of trientine.During that episode,she decompensated with hepatic encephalopathy.Because of a second decompensating event,she was accepted for liver transplantation,and an uneventful transplantation was carried out after clinical improvement of colitis.CONCLUSION Despite WD being a rare disorder,it is important to consider because it can present with a plethora of symptoms from childhood to an elderly age.Colitis should be recognized as a serious adverse drug reaction to trientine treatment that can result in decompensated liver disease.展开更多
LGMD type 21, caused by mutations in the fukutin-related protein, is a common form of LGMD. The phenotype resembles Duchenne/Becker muscular dystrophy. A point mutation, L276I has been found in all patients with LGMD2...LGMD type 21, caused by mutations in the fukutin-related protein, is a common form of LGMD. The phenotype resembles Duchenne/Becker muscular dystrophy. A point mutation, L276I has been found in all patients with LGMD2I studied so far. The authors screened for this mutation in 102 sporadic cases of Duchenne/Becker mutation-negative patients and found 13 patients with LGMD2I.展开更多
Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have be...Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. Methods: We performed Southern blot analysis in 112 patients from MLH1- , MSH2- , and MSH6- negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer,we performed immunohistochemistry using antibodies against MLH1,MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Results: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. Conclusions: We show that heterozygous truncatingmutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with Absent staining for the PMS2 protein.展开更多
PURPOSE: The aim of this research was to determine the molecular factors of influence on the clinical expression of Leber hereditary optic neuropathy (LHON), which might aid in counseling LHON patients and families. T...PURPOSE: The aim of this research was to determine the molecular factors of influence on the clinical expression of Leber hereditary optic neuropathy (LHON), which might aid in counseling LHON patients and families. The prevalence of LHON in the Dutch population was determined. DESIGN: Observational, retrospective population cohort study. METHODS: The clinical characteristics of LHON patients of 25 families, previously described in 1963, were reevaluated. The mutation and haplotype were determined in the DNA of one affected LHON patient per family. The genotype of their relatives could be deducted, enabling us to evaluate retrospectively the genotype-phenotype correlation. The prevalence of LHON was determined on the basis of anamnestic evaluation of patients in 1963 and by using population registers of that period. RESULTS: The LHON mutation does not influence disease penetrance (50% in male subjects; 10% to 20% in female subjects). More than half of the patients with the 14484 mutation exhibit a partial recovery of vision, regardless of the acuteness of disease onset (P=.001), whereas only 22% of the 11778 carriers and 15.4% of the 3460 carriers recovered. The recovery did not take place within the first year after onset and was uncommon after four years. The onset of LHON is in general very acute but might be more gradual in 11778 carriers and in children. The calculated prevalence of LHON in the Dutch population (1/39,000) is very likely an underestimation caused by a selection bias of familial cases in the original study. CONCLUSIONS: The LHON genotype influences the recovery of vision and disease onset but is unrelated to age, acuteness of onset, or gender. The genotype does not influence disease penetrance. Children might exhibit a slower onset of disease.展开更多
BACKGROUND Confined placental mosaicism(CPM)is one of the major reasons for discrepancies between the results of non-invasive prenatal testing(NIPT)and fetal karyotype analysis.CASE SUMMARY We encountered a primiparou...BACKGROUND Confined placental mosaicism(CPM)is one of the major reasons for discrepancies between the results of non-invasive prenatal testing(NIPT)and fetal karyotype analysis.CASE SUMMARY We encountered a primiparous singleton pregnant woman with a rare CPM consisting of 47,XY,+21;47,XXY;and 46,XY,who obtained a false-positive result on NIPT with a high risk for trisomy 21.Copy-number variation sequencing on amniotic fluid cells,fetal tissue,and placental biopsies showed that the fetal karyotype was 47,XXY,while the placenta was a rare mosaic of 47,XY,+21;47,XXY;and 46,XY.CONCLUSION The patient had a rare CPM consisting of 47,XY,+21;47,XXY;and 46,XY,which caused a discrepancy between the result of NIPT and the actual fetal karyotype.It is important to remember that NIPT is a screening test,not a diagnostic test.Any positive result should be confirmed with invasive testing,and routine ultrasound examination is still necessary after a negative result.展开更多
文摘Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.
文摘BACKGROUND Rett syndrome is a monogenic X-linked dominant condition that affects 1/(10000-15000)girls due to de novo mutations in the methyl-CpG binding protein 2(MECP2)gene mapped to chromosome Xq28.The disease-causing gene was identified as a mutation in the MECP2 gene,which is found in approximately 80%of patients diagnosed with Rett syndrome.Although chromosomal changes resulting in del(15)(q11q13)are usually associated with Angelman and Prader-Willi syndrome,very few cases,if any,of Rett syndrome with terminal 15q22-qter deletion have been published in English literature.CASE SUMMARY In this study,we report an unusual and rare clinical presentation of Rett syndrome in a 12-year-old Sudanese girl.The patient was brought in by her parents,complaining of gradual onset of abnormal walking,abnormal hand movement,loss of speech,and mental retardation for ten years.There was no reported history of convulsions or loss of consciousness.Clinical examination revealed microcephaly with no other apparent dysmorphic features,intact cranial nerves,and abnormal gait.She showed repetitive and stereotyped behaviors,including hand flapping,stimming,and chest pounding,which were concomitant with autism spectrum disorder.Magnetic resonance imaging and electroencephalography investigations were normal,and cytogenetic analysis showed 46,XX,del(15)(q22qter).Further molecular analysis using whole sequencing of MECP2 revealed an alteration cytosine>thymine at nucleotide 401,leading to phenylalanine replacing a serine at amino acid position 134.CONCLUSION This case,the first reported instance of Rett syndrome in Sudan,is of significant interest.The patient carries both the MECP2 gene mutation and the chromosome 15q22-qter deletion,which may explain the autistic behavior with atypical presentation of Rett syndrome.This report expands the genetic diversity of Rett syndrome,demonstrating how co-occurring 15q22-qter deletions can reshape MECP2-associated phenotypes in Rett syndrome.
文摘Klinefelter syndrome （KS） （47, XXY） is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be difficult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of beth hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.
文摘AIM:To investigate the associations between CDH1 gene polymorphisms and gastric cancer(GC) risk predisposition.METHODS:We analyzed four CDH1 polymorphisms(+54 T>C,-160 C>A,-616 G>C,-3159 T>C) in an Omani population,by extraction of genomic DNA from the peripheral blood of 192 patients with GC and 170 control participants and performed CDH1 genotyping using DNA sequencing.RESULTS:CDH1-160-AA genotype was associated with an increased risk of GC(OR = 3.6,95% CI:1.1-11.8)(P = 0.03).There was no significant association between the other polymorphisms and GC risk.The haplotype analysis of +54 T>C,-160 C>A,-616 G>C,-3159 T>C genotypes revealed that the OR of CCGC and CAGC haplotypes was 1.5(95% CI:0.7-3.5) and 1.5(95% CI:0.2-3.0),but did not reach statistical significance.CONCLUSION:The current study suggests that the-160 AA genotype was associated with an increased risk of GC in Oman.
文摘Proximal symphalangism(SYM1B)(OMIM 615298) is an autosomal dominant developmental disorder affecting joint fusion. It is characterized by variable fusions of the proximal interphalangeal joints of the hands,typically of the ring and little finger,with the thumb typically being spared. SYM1 is frequently associated with coalition of tarsal bones and conductive hearing loss. Molecular studies have identified two possible genetic aetiologies for this syndrome,NOG and GDF5. We herein present a British caucasian family with SYM1 B caused by a mutation of the GDF5 gene. A mother and her three children presented to the orthopaedic outpatient department predominantly for feet related problems. All patients had multiple tarsal coalitions and hand involvement in the form of either brachydactyly or symphalangism of the proximal and middle phalanx of the little fingers. Genetic testing in the eldest child and his mother identified a heterozygous missense mutation in GDF5 c.1313G>T(p.R438L),thereby establishing SYM1 B as the cause of the orthopaedic problems in this family. There were no mutations identified in the NOG gene. This report highlights the importance of thorough history taking,including a three generation family history,and detailed clinical examination of children with fixed planovalgus feet and other family members to detect rare skeletal dysplasia conditions causing pain and deformity,and provides details of the spectrum of problems associated with SYM1 B.
基金supported by grant from the National Key Research and Development Project(2021YFC1005300,2021YFC1005304,and 2018YFC1004202)the Natural Science Foundation of Liaoning Province(2022-MS-208)the 345 Talent of Shengjing Hospital of China Medical University(C0101).
文摘Dear Editor,Persistent Müllerian duct syndrome(PMDS,MIM 261550)is an autosomal recessive inherent disorder of sex development in normally masculinized subjects with Müllerian duct derivatives,including the uterus,fallopian tubes,and upper part of the vagina.1 PMDS is very rare with presentations of bilateral cryptorchidism(55%),unilateral cryptorchidism with contralateral hernia(20%),or transverse testicular ectopia(25%).
文摘Genetic analyses of patients with transposition of the great arteries have identified rare copy number variations,suggesting that they may be significant to the aetiology of the disease.This paper reports the identification of a 16 p11.2 microduplication,a variation that has yet to be reported in association with transposition of the great arteries.The 16 p11.2 microduplication is associated with autism spectrum disorder and developmental delay,but with highly variable phenotypic effects.Autism and attention deficit disorders are observed more frequently in children with congenital heart disease than in the general population.Neonatal surgery is proposed as a risk factor,but as yet unidentified genetic abnormalities should also be taken into account.Thus,congenital heart abnormalities may constitute a part of the phenotypic spectrum associated with duplications at 16 p11.2.We suggest chromosomal microarray be considered part of the diagnostic work-up in patients with transposition of the great arteries.
文摘An extract from ripe fruit of Vitex agnus-castus (Vitex) has been used to treat patients with various obstetric and gynecological disorders in Europe. We have demonstrated that Vitex showed cytocidal effects on various types of cancer cell lines including a human colon carcinoma cell line, COLO 201. In this study, we extended our previous study to investigate the detailed mechanisms underlying cytocidal effects of Vi- tex on COLO 201. Furthermore, a possible clinical application of Vitex was also explored in vivo using nude mice xenografted with the cells. Treatment with Vitex induced apoptosis in COLO 201 in a time-dependent manner, accompanying with activa-tion of caspase-9 and -3, but not caspase-8. An inhibitor for c-Jun NH2-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK), significantly suppressed the apoptosis induction along with caspase-3 activation. Endoplasmic reticulum (ER) stress-related genes were also upregulated by Vitex treatment. Most importantly, the in vivo efficacy of Vitex evaluated by assessing the tumor growth revealed that the administration of Vitex significantly suppressed tumor growth in COLO 201 xenografted mice. Collectively, current results suggest that apoptosis induction by Vitex in COLO 201 is mediated through the activation of JNK and caspase-9, -3 resulted from ER stress. Based on the current clinical application of Vitex, these results thus provide a new insight into the clinical use of Vitex and leave open a possibility of a new regimen as an alternative medicine approach for such devastating colon cancer treatment.
基金Supported by the JSPS KAKENHI,No.JP21K10300 and No.JP24K02714.
文摘BACKGROUND Early diagnosis of left ventricular diastolic dysfunction(LVDD)is essential for preventing heart failure.B-type natriuretic peptide(BNP)is a viable marker for predicting LVDD,as elevated BNP levels have been associated with worsening LVDD in patients with diabetes over time.However,the utility of BNP as a diagnostic marker in diabetes is controversial,as BNP levels are often low in overweight individuals.AIM To examine the effectiveness of BNP levels and fragmented QRS(fQRS)on electrocardiography for diagnosing LVDD in patients with type 2 diabetes.METHODS This retrospective cohort study included 303 patients with type 2 diabetes(67.4±12.3 years old)with preserved ejection fraction(EF)≥50%admitted to Toyama University Hospital for glycemic management and comorbidity evaluation between November 2017 and April 2021.All participants underwent plasma BNP measurement,electrocardiography,and echocardiography.Cardiologists who were blinded to the BNP results assessed the electrocardiograms and echocardiograms.Subgroup analyses were conducted for overweight individuals.RESULTS Receiver operating characteristic(ROC)curve analysis determined optimal BNP cut-off values of 34.8 pg/mL and 7.2 pg/mL for diagnosing LVDD in non-overweight[area under the ROC curve(AUC):0.70]and overweight(AUC:0.55)groups,respectively(P=0.040).In the overweight subgroup,fQRS showed greater diagnostic accuracy for LVDD(AUC:0.67),indicating moderate diagnostic utility compared with the low performance of the BNP cutoff of 35 pg/mL(AUC:0.52)(P=0.010).Multivariate analyses confirmed that fQRS was superior to BNP for LVDD diagnosis regardless of the patient’s weight.CONCLUSION A BNP level≥35 pg/mL in non-overweight individuals may be a reliable LVDD marker.Additionally,fQRS was more effective than BNP in diagnosing LVDD irrespective of the patient’s weight.fQRS can complement BNP in the early detection of LVDD,especially in overweight patients,potentially improving early detection and mitigating progression to heart failure with preserved EF in patients with type 2 diabetes.
基金Supported by Sanming Project of Medicine in Shenzhen of China,No.SZSM201612074
文摘BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.
文摘Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract. TFFs may be involved in IBD pathogenesis and are a potential treatment option. In the present review, we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression, possible function and pharmacological role in IBD.
基金This study was financed by the Research Counsel of Lillebaelt Hospitalthe Region of Southern Denmark(15/24819)+3 种基金the Institute of Regional Health Research,University of Southern Denmarkthe Aase Ejnar Danielsen foundation(10-001835)the Fru Astrid Thaysens foundation(ATL 16/02)We particularly wish to thank Annette Ulv for her hard work recruiting the blood donors,Merete Villumsen for her excellent technical assistance on CTX and PINP measurements,and Hellen Kuasne for her kind support in primer selection for pyrosequencing.
文摘Women gradually lose bone from the age of〜35 years,but around menopause,the rate of bone loss escalates due to increasing bone resorption and decreasing bone formation levels,rendering these individuals more prone to developing osteoporosis.The increased osteoclast activity has been linked to a reduced estrogen level and other hormonal changes.However,it is unclear whether intrinsic changes in osteoclast precursors around menopause can also explain the increased osteoclast activity.Therefore,we set up a protocol in which CD14f blood monocytes were isolated from 49 female donors(40-66 years old).Cells were differentiated into osteoclasts,and data on differentiation and resorption activity were collected.Using multiple linear regression analyses combining in vitro and in vivo data,we found the following:(1)age and menopausal status correlate with aggressive osteoclastic bone resorption in vitro;(2)the type I procollagen N-terminal propeptide level in vivo inversely correlates with osteoclast resorption activity in vitro;(3)the protein level of mature cathepsin K in osteoclasts in vitro increases with age and menopause;and(4)the promoter of the gene encoding the dendritic cell-specific transmembrane protein is less methylated with age.We conclude that monocytes are"reprogrammed"in vivo,allowing them to"remember"age,the menopausal status,and the bone formation status in vitro,resulting in more aggressive osteoclasts.Our discovery suggests that this may be mediated through DNA methylation.We suggest that this may have clinical implications and could contribute to understanding individual differences in age-and menopause-induced bone loss.
文摘AIM: To identify chromosomal translocations specific to gastric cancer (GC), spectral karyotyping (SKY) analysis was performed on established cell lines and cancerous ascitic fluids.METHODS: SKY analysis of 10 established cell lines and seven cancerous ascitic fluid samples identified recurrent chromosomal breakpoints and translocations in GC,several of which involved chromosomal loci of oncogenes or tumor suppressor genes.RESULTS: A total of 630 chromosomal breaks were identified. Chromosome no.8 was the most frequently involved in rearrangements (65 breaks), followed by chromosomes no. 11 (53), no. 1 (49), no. 7 (46), no. 13 (37), no. 3 (36), no. 17 (33), and no. 20 (29). Frequent breakpoints were detected in 8q24.1 (30 breaks), 11q13 (29), 13q14 (16), 20q11.2 (14), 7q32 (13), 17q11.2 (13),18q21 (12), 17q23 (9), 18q11.2 (9). SKY analysis identified a total of 242 chromosomal rearrangements including 190 reciprocal and non-reciprocal translocations. The recurrent combinations of chromosomal bands involved in translocations were 8q24.1 and 13q14 (3 cases), 8q24.1 and 11q13 (3), 11q13 and 17q11.2 (2), and 18q11.2 and 20q11.2 (2). Our study validated the ability of SKY to characterize in detail the chromosomal rearrangements in solid tumors and derived cell lines. Moreover,fluorescence in situ hybridization helped to identify the insertions, translocations, and homogeneously staining regions of MYCand CCND1 gene loci.CONCLUSION: The non-random co-localization of certain cytogenetic bands suggests the importance of chromosomal translocations in gastric carcinogenesis, by serving as landmarks for the cloning of GC causing genes.
文摘Pseudomembranous colitis (PMC) usually manifests asfever and diarrhea in hospitalized patients treated withsystemic antibiotics. We described a case of PMC withintestinal obstruction but without diarrhea. A 60-yearold man was hospitalized for chemotherapy for the treatment of Burkitt lymphoma of the stomach. The patient became febrile and complained of crampy abdominal pain during the post-chemotherapy nadir. Plain abdominal radiography showed some intestinal gas and niveau. Because stool cytotoxin assay for clostridium difficile was positive and colon fiberscopic examination showed a pseudomembrane at the left side of the colon,and a diagnosis of PMC was made. Treatment with intracolonic vancomycin administration by colonoscopy and nasoileus tube was successful. Physicians should take into account the possibility of bowel obstruction due to PMC occurring in patients undergoing chemotherapy and perform emergency colonoscopy examination of suspected cases.
文摘In this editorial we present an overview and insights of the management of hereditary polyposis syndromes.The primary focus was on familial adenomatous polyposis,juvenile polyposis syndrome and Peutz-Jegher syndrome.Genetic testing has become increasingly available and is easier than ever to integrate into clinical practice.Furthermore,several genes have been added to the expanding list of genes associated with hereditary polyposis syndromes,allowing for precise diagnostics and tailored follow-up.Endoscopic evaluation of patients with hereditary polyposis syndromes is paramount in the surveillance strategies.Current endoscopic procedures include both diagnostic procedures and surveillance as well as therapeutic interventions.Recommendations for endoscopic procedures in the upper and lower gastrointestinal canal were described.Surgery is still a key component in the management of patients with hereditary polyposis syndromes.The increased cancer risk in these patients often render prophylactic procedures or intended curative procedures in the case of cancer development.Surgical interventions in the upper and lower gastrointestinal canal were described with relevant considerations.Development of chemopreventive medications is ongoing.Few drugs have been investigated,including nonsteroidal anti-inflammatory drugs.It has been demonstrated that cyclooxygenase-2 inhibitors may lower the number of polyps.Other medications are currently under investigation,but none have,to date,consistently been able to prevent development of disease.
文摘BACKGROUND Wilson's disease(WD)is a rare inherited disorder of copper metabolism.Treatment consists of chelating agents,but side effects are common.We describe a patient who developed colitis during trientine treatment leading to decompensation of liver cirrhosis.CASE SUMMARY A healthy 51-year-old woman was diagnosed with liver cirrhosis due to decompensation with ascites.Etiologic evaluation raised suspicion of hereditary hemochromatosis because of compound heterozygosity HFE p.C282Y/p.H63D,and phlebotomy was started.Re-evaluation showed low ceruloplasmin,increased urinary copper excretion and the presence of Kayser-Fleischer rings.WD was confirmed by genetic analysis.Because of decompensated cirrhosis,she was referred for liver transplant evaluation.Simultaneously,treatment with trientine was initiated.Liver function initially stabilized,and the patient was not accepted for a liver transplant.Shortly after this,she developed severe hemorrhagic colitis,most probably a side effect of trientine.During that episode,she decompensated with hepatic encephalopathy.Because of a second decompensating event,she was accepted for liver transplantation,and an uneventful transplantation was carried out after clinical improvement of colitis.CONCLUSION Despite WD being a rare disorder,it is important to consider because it can present with a plethora of symptoms from childhood to an elderly age.Colitis should be recognized as a serious adverse drug reaction to trientine treatment that can result in decompensated liver disease.
文摘LGMD type 21, caused by mutations in the fukutin-related protein, is a common form of LGMD. The phenotype resembles Duchenne/Becker muscular dystrophy. A point mutation, L276I has been found in all patients with LGMD2I studied so far. The authors screened for this mutation in 102 sporadic cases of Duchenne/Becker mutation-negative patients and found 13 patients with LGMD2I.
文摘Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. Methods: We performed Southern blot analysis in 112 patients from MLH1- , MSH2- , and MSH6- negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer,we performed immunohistochemistry using antibodies against MLH1,MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Results: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. Conclusions: We show that heterozygous truncatingmutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with Absent staining for the PMS2 protein.
文摘PURPOSE: The aim of this research was to determine the molecular factors of influence on the clinical expression of Leber hereditary optic neuropathy (LHON), which might aid in counseling LHON patients and families. The prevalence of LHON in the Dutch population was determined. DESIGN: Observational, retrospective population cohort study. METHODS: The clinical characteristics of LHON patients of 25 families, previously described in 1963, were reevaluated. The mutation and haplotype were determined in the DNA of one affected LHON patient per family. The genotype of their relatives could be deducted, enabling us to evaluate retrospectively the genotype-phenotype correlation. The prevalence of LHON was determined on the basis of anamnestic evaluation of patients in 1963 and by using population registers of that period. RESULTS: The LHON mutation does not influence disease penetrance (50% in male subjects; 10% to 20% in female subjects). More than half of the patients with the 14484 mutation exhibit a partial recovery of vision, regardless of the acuteness of disease onset (P=.001), whereas only 22% of the 11778 carriers and 15.4% of the 3460 carriers recovered. The recovery did not take place within the first year after onset and was uncommon after four years. The onset of LHON is in general very acute but might be more gradual in 11778 carriers and in children. The calculated prevalence of LHON in the Dutch population (1/39,000) is very likely an underestimation caused by a selection bias of familial cases in the original study. CONCLUSIONS: The LHON genotype influences the recovery of vision and disease onset but is unrelated to age, acuteness of onset, or gender. The genotype does not influence disease penetrance. Children might exhibit a slower onset of disease.
基金Supported by the 345 Talent Project of Shengjing Hospital,No.M0298.
文摘BACKGROUND Confined placental mosaicism(CPM)is one of the major reasons for discrepancies between the results of non-invasive prenatal testing(NIPT)and fetal karyotype analysis.CASE SUMMARY We encountered a primiparous singleton pregnant woman with a rare CPM consisting of 47,XY,+21;47,XXY;and 46,XY,who obtained a false-positive result on NIPT with a high risk for trisomy 21.Copy-number variation sequencing on amniotic fluid cells,fetal tissue,and placental biopsies showed that the fetal karyotype was 47,XXY,while the placenta was a rare mosaic of 47,XY,+21;47,XXY;and 46,XY.CONCLUSION The patient had a rare CPM consisting of 47,XY,+21;47,XXY;and 46,XY,which caused a discrepancy between the result of NIPT and the actual fetal karyotype.It is important to remember that NIPT is a screening test,not a diagnostic test.Any positive result should be confirmed with invasive testing,and routine ultrasound examination is still necessary after a negative result.
