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When tumor doesn't read textbook. Third case of TTF1 and p40 co-expression in the same tumour cells in a non-small cell carcinoma. A potential new entity to consider?
Spinelli, M, Khorshad, J, Viola, P
Pathologica. 2019;(2):58-61
Abstract
INTRODUCTION The 2011 WHO Classification for lung adenocarcinoma enlightened the need for a wise use of immunohistochemistry to preserve tissue for both diagnosis and molecular studies. The current recommendation is to use a panel comprising TTF1 and p40 to classify tumors with no clear squamous or glandular differentiation as many studies have showed the higher specificity of p40 over p63 as marker of squamous differentiation. However, the co-expression of both markers opens a new scenario with subsequent classification and potentially treatment issues. MATERIALS AND METHODS We report a case of a non-small lung cell carcinoma (NSCLC) with coexistent expression of TTF1 and p40 in the same tumour cells. To our knowledge, this peculiar immunohistochemical profile is very rare, and thus a review of the clinical and molecular features including molecular variances of the tumour was performed. Review of the pertinent literature was also carried out. RESULTS Two additional articles describing unusual cases of NSCLC with coexistent expression of TTF1 and p40 were found and compared to our case. Interestingly, they all carried out aberrant mutation in TP53 oncogene and were of advance stage. CONCLUSION The positivity for both "squamous" and "adenocarcinomatous" markers and mutations of TP53 could be the expression of a not fully recognized variant of NSCLC with possible implications for classification, diagnosis and therapy.
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2.
Diseases caused by mutations in luteinizing hormone/chorionic gonadotropin receptor.
Qiao, J, Han, B
Progress in molecular biology and translational science. 2019;:69-89
Abstract
Accumulating evidence showed that the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) is an essential regulator of sexual development and reproduction from zebrafish to human. Activating and inactivating mutations of LHCGR gene have been identified from patients of different phenotypes. Familial male-limited precocious puberty, Leydig cell hypoplasia, and empty follicle syndrome are caused by LHCGR mutations. More than 50 mutations have been reported from subjects of different ethnic backgrounds. Functional analyses of the mutant LHCGR revealed multiple defects, including cell surface expression, ligand binding, and signaling. The difference of the two native ligands and signaling pathway activated by LHCGR are illustrated. Potential therapeutic implications from the analyses of the naturally occurring LHCGR mutations, such as pharmacological chaperones, are highlighted.
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3.
Irregularities in genetic variation and mutation rates with environmental stresses.
Ferenci, T
Environmental microbiology. 2019;(11):3979-3988
Abstract
The appearance of new mutations is determined by the equilibrium between DNA error formation and repair. In bacteria like Escherichia coli, stresses are thought shift this balance towards increased mutagenesis. Recent findings, however, suggest a very uneven relationship between stress and mutations. Only a subset of stressful environments increase the net rate of mutation and different forms of nutritional stress (such as oxygen, carbon or phosphorus limitations) result in markedly different mutation rates after similar reductions in growth rate. Moreover, different stresses result in altered mutational spectra, with some increasing transposition and others increasing indel formation. Single-base substitution rates are lower with some stresses than in unstressed bacteria. Indeed, changes to the mix of mutations with stress are more widespread than a marked increase in net mutation rate. Much remains to be learned on how environments have unique mutational signatures and why some stresses are more mutagenic than others. Even beyond stress-induced genetic variation, the fundamental unresolved question in the stress-mutation relationship is the adaptive value of different types of mutations and mutation rates; is transposition, for example, more advantageous under anaerobic conditions? It remains to be investigated whether stress-specific genetic variation impacts on evolvability differentially in distinct environments.
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4.
[Sitosterolemia (phytosterolemia)].
Lütjohann, D
Der Internist. 2019;(8):871-877
Abstract
Sitosterolemia or phytosterolemia is a rare autosomal recessive hereditary lipid storage disorder. It is caused by homozygous or compound heterozygous mutations in one of the two ABCG5 and ABCG8 genes encoding the intestinal and hepatic heterodimer ABCG5 (sterolin 1)/ABCG8 (sterolin 2) efflux transporters. These mutations lead to intestinal hyperabsorption and reduced hepatic secretion of cholesterol and plant sterols with subsequent accumulation of phytosterols and cholesterol in plasma and deposition in tissue (xanthoma). Phytosterols are found mainly in vegetable oils, margarine, nuts, grains, soybeans and avocados. Patients with sitosterolemia show extreme phenotypic heterogeneity from almost asymptomatic individuals to those with combined severe hypercholesterolemia at a young age, leading to increased atherosclerosis and premature cardiac death. Early abnormalities include hemolytic anemia with stomatocytosis, macrothrombocytopenia and splenomegaly. In addition to strict avoidance of phytosterol-containing foods, the use of the sterol absorption inhibitor ezetimibe, possibly in combination with the bile acid-binding resin cholestyramine, is the most effective treatment option.
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5.
Diseases associated with mutations in CNGA3: Genotype-phenotype correlation and diagnostic guideline.
Sun, W, Zhang, Q
Progress in molecular biology and translational science. 2019;:1-27
Abstract
Along with the molecular and functional characterization of CNGA3, knowledge about diseases associated with CNGA3 mutations has made great progress. So far, CNGA3 mutations are not only one of the most common causes of achromatopsia and cone dystrophy or cone-rod dystrophy but also one of the most commonly mutated genes among various forms of retinopathy. Understanding the clinical characteristics of CNGA3-associated retinal diseases may help clinical practice of infants or children with related diseases. Recognizing the importance of CNGA3 in inherited retinal diseases may enhance related research in searching for functional restoration or repair of CNGA3 defects.
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A CIB1 Splice-Site Founder Mutation in Families with Typical Epidermodysplasia Verruciformis.
Vahidnezhad, H, Youssefian, L, Saeidian, AH, Mansoori, B, Jazayeri, A, Azizpour, A, Hesari, KK, Yousefi, M, Zeinali, S, Jouanguy, E, et al
The Journal of investigative dermatology. 2019;(5):1195-1198
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7.
UMOD gene mutations in Chinese patients with autosomal dominant tubulointerstitial kidney disease: a pediatric case report and literature review.
Yang, J, Zhang, Y, Zhou, J
BMC pediatrics. 2019;(1):145
Abstract
BACKGROUND Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by UMOD gene mutation (ADTKD-UMOD) is rare in children, characterized by hyperuricemia, gout, and progressive chronic kidney disease. It usually leads to end-stage renal failure at fiftieth decades. Here, we report a 3-year-old Chinese boy in an ADTKD family caused by a novel UMOD gene mutation. CASE PRESENTATION A 3-year-old boy was admitted to our hospital because of persistent hematuria. Urinalysis showed BLD 2+ without proteinuria. The serum levels of uric acid, creatinine and electrolytes were normal. No renal cyst or calculus was found by ultrasonography. Renal biopsy was performed and focal and segmental glomerulosclerosis was found in 4 glomeruli among 35 glomeruli examined. His father was found with end-stage renal disease (ESRD) at the age of 29, and renal ultrasound showed several cysts in both kidneys. A novel heterozygous mutation (c.1648G > A,p.V550I) in exon 8 of UMOD gene was identified by whole exome sequencing in the family. SCBC Genome Browser alignment showed that V550 were highly conserved in uromodulin among different species. Software predicted that the mutation is suspected to be harmful. By literature review, there are 12 mutations of UMOD gene in 14 Chinese families including only one pediatric case(a 16-year-old girl). CONCLUSIONS A novel heterozygous mutation (c.1648G > A,p.V550I) in exon 8 of UMOD gene was found in in a Chinese child case with ADTKD-UMOD, which extends our understanding of UMOD gene mutation spectrum and phenotype of ADTKD-UMOD in children.
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8.
Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review.
Abi Farraj, L, Khatoun, WD, Abou Chebel, N, Wakim, V, Dawali, K, Ghassibe-Sabbagh, M
Diagnostic pathology. 2019;(1):123
Abstract
BACKGROUND Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population. CASE PRESENTATION Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis. CONCLUSION Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.
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9.
The glucose transporter type 1 (Glut1) syndromes.
Koch, H, Weber, YG
Epilepsy & behavior : E&B. 2019;:90-93
Abstract
The glucose transporter type 1 (Glut1) is the most important energy carrier of the brain across the blood-brain barrier. In the early nineties, the first genetic defect of Glut1 was described and known as the Glut1 deficiency syndrome (Glut1-DS). It is characterized by early infantile seizures, developmental delay, microcephaly, and ataxia. Recently, milder variants have also been described. The clinical picture of Glut1 defects and the understanding of the pathophysiology of this disease have significantly grown. A special form of transient movement disorders, the paroxysmal exertion-induced dyskinesia (PED), absence epilepsies particularly with an early onset absence epilepsy (EOAE) and childhood absence epilepsy (CAE), myoclonic astatic epilepsy (MAE), episodic choreoathetosis and spasticity (CSE), and focal epilepsy can be based on a Glut1 defect. Despite the rarity of these diseases, the Glut1 syndromes are of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms especially if it is started as early as possible. The present article summarizes the clinical features of Glut1 syndromes and discusses the underlying genetic mutations, including the available data on functional tests as well as the genotype-phenotype correlations. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond".
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10.
Review of SRD5A3 Disease-Causing Sequence Variants and Ocular Findings in Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation, and a Detailed New Case.
Kousal, B, Honzík, T, Hansíková, H, Ondrušková, N, Čechová, A, Tesařová, M, Stránecký, V, Meliška, M, Michaelides, M, Lišková, P
Folia biologica. 2019;(3):134-141
Abstract
Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a severe metabolic disease manifesting as muscle hypotonia, developmental delay, cerebellar ataxia and ocular symptoms; typically, nystagmus and optic disc pallor. Recently, early onset retinal dystrophy has been reported as an additional feature. In this study, we summarize ocular phenotypes and SRD5A3 variants reported to be associated with SRD5A3-CDG. We also describe in detail the ophthalmic findings in a 12-year-old Czech child harbouring a novel homozygous variant, c.436G>A, p.(Glu146Lys) in SRD5A3. The patient was reviewed for congenital nystagmus and bilateral optic neuropathy diagnosed at 13 months of age. Examination by spectral domain optical coherence tomography and fundus autofluorescence imaging showed clear signs of retinal dystrophy not recognized until our investigation. Best corrected visual acuity was decreased to 0.15 and 0.16 in the right and left eye, respectively, with a myopic refractive error of -3.0 dioptre sphere (DS) / -2.5 dioptre cylinder (DC) in the right and -3.0 DS / -3.0 DC in the left eye. The proband also had optic head nerve drusen, which have not been previously observed in this syndrome.