143 research outputs found
RB1 Germline Variant Predisposing to a Rare Ovarian Germ Cell Tumor: A Case Report
No full textMalignant ovarian germ cell tumors (MOGCTs) are neoplasms of the ovary, of which, due to their rarity and heterogeneity, few is reported about genetic background and development. Here, we report a 18-years old patient diagnosed with an ovarian mixed germ cell tumor, without any previous history of malignancies, who has been treated with surgery and chemotherapy and died 4 years later due to peritoneal metastasis complications. Patient's blood DNA was screened for a panel of 52 cancer-related genes in order to identify predisposing aberrations to this rare cancer. The analysis discovered the uncharacterized c.2393G>A variant in RB1, the retinoblastoma gene, leading both to a missense change and a splicing perturbation of the RB1 transcript. The variant was found to be hypomorphic, damaging the C-terminal domain with a partially impaired protein function. The variant is inherited from the unaffected mother. Due to an imprinting mechanism, the maternal allele is ~3-fold more expressed than the paternal one. The parent-of-origin effect combined with the hypomorphic impact of the variant determines a rescue of sufficient tumor-suppressor activity to prevent retinoblastoma development but can predispose to other cancers in the adult age. In order to understand the somatic events acting on the germline predisposition we used the NGS-liquid biopsy covering 77 cancer driver genes. Using this approach, we detected deleterious mutations in TP53, SMAD4, FGFR3, and MSH2, indicative of a dis-regulation of cell cycle and DNA repair mechanisms pathways. In conclusion, we have pinpointed for the first time that an RB1 leaky variant, not leading to retinoblastoma because of its maternal origin, can predispose in adults to a very rare form of ovarian cancer and that the somatic disruption of few genes contributes to the tumor progression and aggressiveness. © 2020 Gelli, Fallerini, Valentino, Giliberti, Castiglione, Laschi, Palmieri, Fabbiani, Tita, Mencarelli, Renieri and Ariani
Prognostic Value of Glomerular Collagen IV Immunofluorescence Studies in Male Patients with X-Linked Alport Syndrome
No full textBackground and objectives X-linked Alport syndrome (X-AS) is caused by mutations of the COL4A5 gene, which encodes for the collagen IV a5 chain (a5[COLIV]), resulting in structural and functional abnormalities of the glomerular basement membrane (GBM) and leading to CKD. The aim of the present study was to evaluate the prognostic value of residual collagen IV chain expression in the GBM of patients with X-AS. Design, setting, participants, & measurements The medical records of 22 patients with X-AS from 21 unrelated families collected between 1987 and 2009 were reviewed (median age at last follow-up, 19.9 years; range, 5.4-35.1 years); GBM expression of a1, a3, and a5(COLIV) chains was assessed by immunofluorescence microscopy. Results GBM distribution of the a5(COLIV) chain was diffuse in 1 and segmental or absent in 21 of the 22 patients; the expression of the a3(COLIV) chain was diffuse in 5 of 22 patients and segmental or absent in 17 of 22 patients. Patients with diffuse staining for the a3(COLIV) chain presented with proteinuria significantly later (median age, 16.9 versus 6.1 years; P=0.02) and reached an estimated GFR < 90 ml/min per 1.73 m2 at an older age (median age, 27.0 versus 14.9 years; P=0.01) compared with patients with segmental or absent staining. Two thirds of patients with abnormal a3(COLIV) expression by immunofluorescence studies had null or truncating COL4A5 mutations, as opposed to none of the 4 tested patients with diffuse a3(COLIV) chain glomerular distribution. © 2013 by the American Society of Nephrology
A Unique Patient Presenting with Concomitant Klinefelter Syndrome, Alport Syndrome and Craniopharyngioma.
No full textA 31 years old Caucasian male was referred for panhypopituitarism resulting from an operated craniopharyngioma. The patient had been previously submitted to kidney transplantation for end-stage-renal-disease due to X-linked Alport syndrome (ATS). Subsequent Quantitative-Fluorescent-Polymerase-Chain-Reaction-analysis indicated a 47,XXY-karyotype, consistent with Klinefelter syndrome (KS). The relevance of this unique case stems from several issues: i) KS was an unexpected finding due to a previous diagnosis of hypogonadotropic hypogonadism resulting from craniopharyngioma; ii) the discovery of a de novo p.G406S substitution causing ATS; iii) the multifactor origin of severe sexual dysfunction. This is the first description of the co-occurrence of KS, ATS and craniopharyngioma
A Unique Patient Presenting with Concomitant Klinefelter Syndrome, Alport Syndrome and Craniopharyngioma.
No full textSpondyloocular Syndrome: a novel XYLT2 variant with description of the neonatal phenotype
No full textSpondyloocular syndrome (SOS) is a skeletal disorder caused by pathogenic variants in XYLT2 gene encoding a xylotransferase involved in the biosynthesis of proteoglycans. This condition, with autosomal recessive inheritance, has a high phenotypic variability. It is characterized by bone abnormalities (osteoporosis, fractures), eye and cardiac defects, hearing impairment, and varying degrees of developmental delay. Until now only 20 mutated individuals have been reported worldwide. Here, we describe two siblings from consanguineous healthy parents in which a novel homozygous frameshift variant c.1586dup p(Thr530Hisfs*) in the XYLT2 gene was detected by exome sequencing (ES). The first patient (9 years) presented short stature with skeletal defects, long face, hearing loss and cataract. The second patient, evaluated at a few days of life, showed macrosomia, diffuse hypertrichosis on the back, overabundant skin in the retronucal area, flattened facial profile with drooping cheeks, elongated eyelid rims, wide and flattened nasal bridge and turned down corners of the mouth. During the prenatal period, high nuchal translucency and intestinal hyperechogenicity were observed at ultrasound. In conclusion, these two siblings with a novel pathogenic variant in XYLT2 further expand the clinical and mutational spectrum of SOS
Prognostic value of glomerular collagen IV immunofluorescence studies in male patients with X-linked Alport syndrome.
No full textIndagine di correlazioni anatomo cliniche in 22 pazienti con sindrome di alport x-linked per valutare il significato prognostico della espressione del collagene di tipo IV nella membrana basale dei glomerul
A Unique Patient Presenting with Concomitant Klinefelter Syndrome, Alport Syndrome and Craniopharyngioma.
No full textA 31 years old Caucasian male was referred for panhypopituitarism resulting from an operated craniopharyngioma. The patient had been previously submitted to kidney transplantation for end-stage-renal-disease due to X-linked Alport syndrome (ATS). Subsequent Quantitative-Fluorescent-Polymerase-Chain-Reaction-analysis indicated a 47,XXY-karyotype, consistent with Klinefelter syndrome (KS). The relevance of this unique case stems from several issues: i) KS was an unexpected finding due to a previous diagnosis of hypogonadotropic hypogonadism resulting from craniopharyngioma; ii) the discovery of a de novo p.G406S substitution causing ATS; iii) the multifactor origin of severe sexual dysfunction. This is the first description of the co-occurrence of KS, ATS and craniopharyngioma
Non-collagen genes role in digenic Alport syndrome
No full textAbstract Background Alport syndrome is a clinically heterogeneous nephropathy characterized by severe symptomatology at kidney level due to ultrastructural lesions of the glomerular basement membrane (GBM) as consequence of mutations in COL4 genes. The disease has been linked to COL4A3/COL4A4/COL4A5 mutations, which impair GBM functionality and can be inherited in a dominant, recessive or X-linked transmission. Although a targeted Next Generation Sequencing approach has allowed identifying families with pathogenic mutations in more than one COL4 α3-α4-α5 heterotrimer encoding genes, leading to conclude for a digenic pattern of inheritance, the role of non-collagen genes in digenic Alport syndrome has not yet been established. Methods We employed a whole-exome sequencing approach on three families in whom a digenic pattern of transmission could be suspected because of a likely biparental contribution or an unexplained phenotype in the proband. Results We identified in the three probands hypomorphic LAMA5 mutations co-inherited with pathogenic COL4 α4-α5 chains mutations. Segregation analysis revealed that the combination of LAMA5/COL4 variants co-segregate with a fully penetrant phenotype in line with a digenic inheritance. In one of the three probands an hypomorphic variant in NPHS2 was also found, suggesting that role of other kidney disease related-genes as modifiers. Conclusion These findings validate the impact of LAMA5 mutations in digenic ATS and highlight the role of extracellular matrix’s genes, basement membrane, slit diaphragm and podocyte cytoskeleton in ATS. This underline the need for a more extensive panel approach in the presence of a digenic ATS, in order to better define clinical severity and recurrence risk for family members
Development Activities on an Advanced Propellant Flow Control Unit
No full textA new generation of propellant control equipment for
electric propulsion systems is needed in order to
improve performance and operating ranges, symplify
h/w configuration, reduce mass and dimensions,
eliminate mass flow ripple, reduce time response. In
this frame, the development of key components, their
assembly and experimental investigation/ validation is
on-going at Alenia Spazio-Laben/Business Unit Proel
Tecnologie ( Proel in the following ) in the frame of an
ESA GSTP program.
The new components shall support different EP
technologies, future EP multi-tasking capability and
wide operating ranges.
This paper reports about the development effort, its
achievements and perspectives
X-Linked Alport Syndrome in Women : Genotype and Clinical Course in 24 Cases
No full textObjectives: X-linked Alport syndrome (XLAS) females are at risk of developing proteinuria and chronic kidney damage (CKD). The aim of this study is to evaluate the genotype-phenotype correlation in this rare population. Materials and Methods: This is a prospective, observational study of XLAS females, confirmed by a pathogenic mutation in COL4A5 and renal ultrastructural evaluation. Proteinuria, renal function and extrarenal involvement were monitored during follow-up. Patients were divided in 2 groups, according to mutations in COL4A5: missense (Group 1) and non-missense variants (Group 2). Results: Twenty-four XLAS females, aged 10.6 ± 10.4 years at clinical onset (mean follow-up: 13.1 ± 12.6 years) were recruited between 2000 and 2017 at a single center. In group 1 there were 10 patients and in group 2, 14 (mean age at the end of follow-up: 24.9 ± 13.6 and 23.2 ± 13.8 years, respectively). One patient in Group 1 and 9 in Group 2 (p = 0.013) developed proteinuria during follow-up. Mean eGFR at last follow-up was lower in Group 2 (p = 0.027), where two patients developed CKD. No differences in hearing loss were documented among the two groups. Two patients in Group 2 carried one mutation in both COL4A5 and COL4A3 (digenic inheritance) and were proteinuric. In one family, the mother presented only hematuria while the daughter was proteinuric and presented a greater inactivation of the X chromosome carrying the wild-type allele. Conclusions: The appearance of proteinuria and CKD is more frequent in patients with severe variants. Carrying digenic inheritance and skewed XCI seem to be additional risk factors for proteinuria in XLAS females
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