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International Journal of Gynecological... Dec 2023Endometrial cancers with more than one molecular feature- mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple...
BACKGROUND
Endometrial cancers with more than one molecular feature- mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple classifiers'.
OBJECTIVE
To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them.
METHODS
Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification.
RESULTS
Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. sequencing allowed the detection of additional 7 (18.9%) multiple classifiers with normal p53 immunostaining. The incidence of multiple classifiers ranged from 1.8% to 9.8% in 10 published studies including >100 patients. When only p53 immunohistochemistry was performed, the highest incidence was 3.9%.
CONCLUSIONS
The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and sequencing.
PubMed: 38135437
DOI: 10.1136/ijgc-2023-004864 -
Journal of the European Academy of... Jul 2024Vascular malformations (VMs) are clinically diverse with regard to the vessel type, anatomical location, tissue involvement and size. Consequently, symptoms and disease...
Vascular malformations (VMs) are clinically diverse with regard to the vessel type, anatomical location, tissue involvement and size. Consequently, symptoms and disease impact differ significantly. Diverse causative mutations in more and more genes are discovered and play a major role in the development of VMs. However, the relationship between the underlying causative mutations and the highly variable phenotype of VMs is not yet fully understood. In this systematic review, we aimed to provide an overview of known causative mutations in genes in VMs and discuss associations between the causative mutations and clinical phenotypes. PubMed and EMBASE libraries were systematically searched on November 9th, 2022 for randomized controlled trials and observational studies reporting causative mutations in at least five patients with peripheral venous, lymphatic, arteriovenous and combined malformations. Study quality was assessed with the Newcastle-Ottawa Scale. Data were extracted on patient and VM characteristics, molecular sequencing method and results of molecular analysis. In total, 5667 articles were found of which 69 studies were included, reporting molecular analysis in a total of 4261 patients and 1686 (40%) patients with peripheral VMs a causative mutation was detected. In conclusion, this systematic review provides a comprehensive overview of causative germline and somatic mutations in various genes and associated phenotypes in peripheral VMs. With these findings, we attempt to better understand how the underlying causative mutations in various genes contribute to the highly variable clinical characteristics of VMs. Our study shows that some causative mutations lead to a uniform phenotype, while other causal variants lead to more varying phenotypes. By contrast, distinct causative mutations may lead to similar phenotypes and result in almost indistinguishable VMs. VMs are currently classified based on clinical and histopathology features, however, the findings of this systematic review suggest a larger role for genotype in current diagnostics and classification.
Topics: Humans; Mutation; Phenotype; Vascular Malformations
PubMed: 38037869
DOI: 10.1111/jdv.19640 -
Ophthalmic Research 2024Although the p.C759F (c.2276G>T, p.Cys759Phe) variant in the USH2A gene has been identified in association with retinal degeneration by several authors, its... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although the p.C759F (c.2276G>T, p.Cys759Phe) variant in the USH2A gene has been identified in association with retinal degeneration by several authors, its pathogenicity has been questioned once by the publication of two unaffected homozygotes from a single family.
OBJECTIVES
The objective of the study was to ascertain the role of p.C759F in hereditary retinal disease.
METHODS
We examined 87 research articles reporting on patients carrying this variant and then used this information as primary data for a series of meta-analytical tests.
RESULTS
Independent statistical analyses showed that p.C759F (i) is highly enriched in patients with respect to healthy individuals, (ii) represents a clear-cut recessive allele causing disease when it is in trans with other mutations, (iii) is pathogenic in homozygotes.
CONCLUSIONS
Our results confirm that p.C759F is a bona fide mutation, leading to retinal blindness according to a recessive pattern of inheritance.
Topics: Humans; Retinitis Pigmentosa; Usher Syndromes; Mutation; Genotype; Extracellular Matrix Proteins; DNA Mutational Analysis
PubMed: 38016437
DOI: 10.1159/000535545 -
Child's Nervous System : ChNS :... Jan 2024Autosomal dominantly inherited neurofibromatosis type I (NF1) is a systemic disorder caused by a mutation of a gene on chromosome 17q11.2 and characterized by multiple... (Review)
Review
Autosomal dominantly inherited neurofibromatosis type I (NF1) is a systemic disorder caused by a mutation of a gene on chromosome 17q11.2 and characterized by multiple café-au-lait spots, lentiginous macules, Lisch nodules of the iris, and tumors of the nervous system. Bony manifestations such as scoliosis, dysplasia of the greater sphenoidal wing, tibial pseudoarthrosis, short stature, and macrocephaly have been reported in approximately 50% of patients. However, calvarial bone defects are rare. After screening 324 articles, 23 cases (12 adult and 11 pediatric patients) of occipital bone defects in NF1 patients were selected. All patients had a single/multiple bone defect over the lambdoid suture. Adjacent benign plexiform neurofibromas were observed in 14 patients (60.8%, 7 adults and 7 children); one adult patient was diagnosed with neurofibrosarcoma. Meningoencephalocele over the occipital defect was noted in 8 cases (34.78%, all adults). Cranioplasty was performed in only 17.39% of patients. Histologic examination was performed in 7 of the 15 patients with associated neurofibromas/neurofibrosarcomas. Biopsy of the bone margins surrounding the defect was performed in only one case. Pathologic examination of the herniated parieto-occipital or cerebellar tissue was not performed in any of the patients studied. We report the case of a 9-year-old girl with NF1 and a significant occipital bone defect and performed a systematic review of the relevant literature to highlight the challenges in treating this condition and to investigate the underlying mechanisms contributing to bone defects or dysplasia in NF1.
Topics: Adult; Female; Humans; Child; Neurofibromatosis 1; Cafe-au-Lait Spots; Mutation; Encephalocele; Occipital Bone
PubMed: 37993698
DOI: 10.1007/s00381-023-06232-4 -
Neurological Sciences : Official... Mar 2024
Review
Topics: Humans; Spastic Paraplegia, Hereditary; Mutation
PubMed: 37968432
DOI: 10.1007/s10072-023-07200-1 -
European Journal of Pediatrics Jan 2024Tessier clefts are skeletal and soft tissue abnormalities of a neonate's facial structures. They could be classified as syndromic and non-syndromic clefts, which can be... (Review)
Review
Tessier clefts are skeletal and soft tissue abnormalities of a neonate's facial structures. They could be classified as syndromic and non-syndromic clefts, which can be attributed to disruptions in fetal development and genetic mutations, respectively. Reported cases of these clefts typically document the presence of additional abnormalities associated with these clefts. In this systematic review, we analyzed reports of Tessier clefts accompanied by cardiovascular anomalies, as one of the commonly encountered anomalies. We systematically searched PubMed (MEDLINE), Scopus, Web of Science, Science Direct, and Google Scholar. We selected and included case reports, case series, and case reviews on patients with Tessier cleft and cardiovascular anomalies. The critical appraisal of the included studies was performed by two independent investigators using the Consensus-based Clinical Case Reporting Guideline Development (CARE) checklist. Overall, 20 reports (18 case reports and 2 case series) were eligible for inclusion in this review. Tessier clefts 3 and 30 were the most commonly observed. In addition, the most prevalent cardiovascular anomalies consisted of the ventricular septal defect (VSD), double-outlet right ventricle, and atrial septal defect (ASD). Most of the patients received cosmetic and cardiovascular surgeries. However, some were not proper candidates for cardiovascular surgery because of their unstable condition and therefore did not survive. Conclusion: Regardless of the focus placed on the cleft and subsequent plastic surgery procedures in these cases, it is important to prioritize other abnormalities that may be associated with mortality. A complete cardiovascular system and associated disorders assessment should be performed before facial cosmetic surgeries. What is Known: • Tessier clefts are congenital defects in the soft tissues and bones of the face and like many other congenital defects, they are accompanied by defects in other parts of the body. • In the current literature, the emphasis is on clefts and the cosmetic issues rather than the coinciding defects, particularly cardiovascular anomalies. What is New: • Review the cardiovascular anomalies that are commonly encountered in patients with Tessier clefts.
Topics: Infant, Newborn; Humans; Face; Cleft Palate; Cleft Lip; Plastic Surgery Procedures; Syndrome
PubMed: 37924347
DOI: 10.1007/s00431-023-05322-4 -
Cureus Sep 2023A specific type of neurodegeneration with brain iron accumulation (NBIA) falls under the omit phenotypic continuum-early childhood development of progressive... (Review)
Review
A specific type of neurodegeneration with brain iron accumulation (NBIA) falls under the omit phenotypic continuum-early childhood development of progressive pantothenate kinase-associated neurodegeneration (PKAN). Classic PKAN is distinguished from atypical PKAN by stiffness, dystonia, dysarthria, and choreoathetosis. Pigmentary retinal degeneration is a widespread cause of classic PKAN. Atypical PKAN is distinguished by a later onset (>10 years), noticeable speech abnormalities, psychological disorders, and slower disease development. Studies designed to support various PKAN therapeutic strategies have highlighted the intricacy of coenzyme A (CoA) metabolism and the limitations of our present understanding of disease causation. Therefore, improvements in our knowledge of the causes and therapy of PKAN may have ramifications for our comprehension of other, more prevalent diseases. They may also shed fresh light on the physiological significance of CoA, a cofactor essential for the operation of several cellular metabolic processes. The existence of low but considerable PANK2 expression, which can be elevated in some mutations, provides necessary information that can justify using a hefty dose of pantothenate as a treatment. A more effective therapeutic approach can be achieved by comparing the effects of various currently available pharmacological alternatives on the pathophysiological alterations in fibroblasts and neuronal cells obtained from PKAN patients. The objective of this study is to educate and inform people about PKAN disease conditions such as treatment, diagnosis, and complications. These cell models will also help evaluate the effectiveness of future medicinal innovations. This review discusses the neurodegeneration generated by pantothenate kinase in cellular models, iron/lipofuscin in pantothenate kinase-related neurodegeneration, and treatment and diagnosis of PKAN.
PubMed: 37900501
DOI: 10.7759/cureus.46135 -
Frontiers in Neurology 2023Spontaneous cervical artery dissection (sCeAD) is an important cause of stroke in young adults. The underlying pathophysiology remains unclear, without validated...
BACKGROUND
Spontaneous cervical artery dissection (sCeAD) is an important cause of stroke in young adults. The underlying pathophysiology remains unclear, without validated biomarkers to identify subjects at risk. Previous studies suggested the role of abnormalities in the connective component of the arterial wall.
PURPOSE
To assess dermal ultrastructural aberrations of connective tissue by skin biopsy and genetic variations in sCeAD patients.
METHOD
We searched the PubMed and Scopus databases until August 2023 with PRISMA guidelines. Original articles assessing skin biopsy in sCeAD patients were included. Two reviewers independently conducted the screening.
FINDINGS
We included 16 studies compromising 459 patients. Thirteen studies assessed ultrastructural changes and found aberrations of collagen and elastic fibers, described as irregular contours and calibers of collagen fibrils, composite flower-like fibrils, fragmented moth-eaten elastin, and microcalcifications, cumulatively in 50.5% of patients. Seven studies showed no causative mutations in collagen type I, III, V, or elastin genes. One study showed linkage between connective tissue alterations and mutation on chromosomes 15q2 and 10q26 using genome-wide linkage analysis, while another study found significant copy number variant enrichments in genes involved in extracellular matrix (COL5A2/COL3A1/SNTA1) and collagen fibril organizations (COL5A2/COL3A1). Finally, differential expression of extracellular proteins was linked to connective tissue disorder in patients with recurrent sCeAD using a quantitative proteomics approach.
CONCLUSION
Current literature supports the hypothesis that an underlying, subclinical connective tissue disorder, likely genetically determined, may predispose to arterial wall weakness and sCeAD. Further studies with larger sample sizes and robust methodology are needed to better define the role of connective tissue in sCeAD pathogenesis.
PubMed: 37885478
DOI: 10.3389/fneur.2023.1241084 -
Frontiers in Endocrinology 2023Preimplantation genetic testing for aneuploidy (PGT-A) is an emerging technology that aims to identify euploid embryos for transfer, reducing the risk of embryonic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Preimplantation genetic testing for aneuploidy (PGT-A) is an emerging technology that aims to identify euploid embryos for transfer, reducing the risk of embryonic chromosomal abnormalities. However, the clinical benefits of PGT-A in recurrent pregnancy failure (RPF) patients, particularly in young RPF patients, remains uncertain.
OBJECTIVE AND RATIONALE
This meta-analysis aimed to determine whether RPF patients undergoing PGT-A had better clinical outcomes compared to those not undergoing PGT-A, thus assessing the value of PGT-A in clinical practice.
SEARCH METHODS
We systematically searched PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Database for Chinese Technical Periodicals (VIP) from 2002 to 2022. Thirteen published studies involving 930 RPF patients screened using PGT-A and over 1,434 RPF patients screened without PGT-A were included in this meta-analysis. Clinical outcomes were evaluated based on embryo transfers after PGT-A (n=1,015) and without PGT-A (n=1,799).
CLINICAL OUTCOMES
The PGT-A group demonstrated superior clinical outcomes compared to the fertilization (IVF)/intracytoplasmic sperm injection (ICSI) group. The PGT-A group had a significantly higher implantation rate (IR) (RR=2.01, 95% CI: [1.73; 2.34]), clinical pregnancy rate (CPR) (RR=1.53, 95% CI: [1.36; 1.71]), ongoing pregnancy rate (OPR) (RR=1.76, 95% CI: [1.35; 2.29]), live birth rate (LBR) (RR=1.75, 95% CI: [1.51; 2.03]), and significantly lower clinical miscarriage rate (CMR) (RR=0.74, 95% CI: [0.54; 0.99]). Subgroup analysis based on patient age (under 35 years and 35 years or older) showed that both PGT-A subgroups had significantly better CPR (P<0.01) and LBR (P<0.05) values compared to the IVF/ICSI groups.
SUMMARY
This meta-analysis demonstrates that PGT-A in RPF patients, is associated with improved clinical outcomes, including higher IR, CPR, OPR, and LBR values, and lower CMR compared to the IVF/ICSI group. These findings support the positive clinical application of PGT-A in RPF patients.
SYSTEMATIC REVIEW REGISTRATION
http://INPLASY.com, identifier INPLASY 202320118.
Topics: Pregnancy; Female; Humans; Male; Adult; Preimplantation Diagnosis; Semen; Genetic Testing; Fertilization in Vitro; Abortion, Spontaneous; Aneuploidy
PubMed: 37850092
DOI: 10.3389/fendo.2023.1178294 -
Seizure Mar 2024To provide an updated list of epilepsy-associated genes based on clinical-genetic evidence.
PURPOSE
To provide an updated list of epilepsy-associated genes based on clinical-genetic evidence.
METHODS
Epilepsy-associated genes were systematically searched and cross-checked from the OMIM, HGMD, and PubMed databases up to July 2023. To facilitate the reference for the epilepsy-associated genes that are potentially common in clinical practice, the epilepsy-associated genes were ranked by the mutation number in the HGMD database and by case number in the China Epilepsy Gene 1.0 project, which targeted common epilepsy.
RESULTS
Based on the OMIM database, 1506 genes were identified to be associated with epilepsy and were classified into three categories according to their potential association with epilepsy or other abnormal phenotypes, including 168 epilepsy genes that were associated with epilepsies as pure or core symptoms, 364 genes that were associated with neurodevelopmental disorders as the main symptom and epilepsy, and 974 epilepsy-related genes that were associated with gross physical/systemic abnormalities accompanied by epilepsy/seizures. Among the epilepsy genes, 115 genes (68.5%) were associated with epileptic encephalopathy. After cross-checking with the HGMD and PubMed databases, an additional 1440 genes were listed as potential epilepsy-associated genes, of which 278 genes have been repeatedly identified variants in patients with epilepsy. The top 100 frequently reported/identified epilepsy-associated genes from the HGMD database and the China Epilepsy Gene 1.0 project were listed, among which 40 genes were identical in both sources.
SIGNIFICANCE
Recognition of epilepsy-associated genes will facilitate genetic screening strategies and be helpful for precise molecular diagnosis and treatment of epilepsy in clinical practice.
Topics: Humans; Epilepsy; Seizures; Genetic Testing; Mutation; Databases, Factual; Phenotype
PubMed: 37777370
DOI: 10.1016/j.seizure.2023.09.021