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de Souza MA, Hartmann JK, Zottis LFF, Gama TKK, Rosa EBD, Zen PRG, Rosa RFM. Laryngotracheomalacia in a Patient with Mosaic Trisomy 8. J Pediatr Genet 2024; 13:57-61. [PMID: 38567174 PMCID: PMC10984713 DOI: 10.1055/s-0041-1736609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 09/20/2021] [Indexed: 10/19/2022]
Abstract
Mosaic trisomy 8 is a condition characterized by a great phenotypic and cytogenetic variability whose incidence ranges around 1 in 25,000 to 50,000 live births. Here, we report a mosaic trisomy 8 patient presenting laryngotracheomalacia, an uncommon finding, analyzing its possible role over morbidity, and mortality. The patient was a boy who, after birth, had tachypnea and paleness. He presented periods of respiratory dysfunction with need of ventilatory support. Respiratory syncytial virus test was positive. Naso fibrobronchoscopy showed moderate laryngotracheomalacia. He also had recurrent episodes of pneumonia and difficulty in withdrawing continuous positive airway pressure. The patient also presented leucoma, abnormal and low-set ears, pectus excavatum, clenched fists with overlapping fingers, cryptorchidism, clubfeet, and deep longitudinal plantar creases. G-bands by Trypsin using giemsa (GTG-banding) karyotype from a peripheral blood sample revealed a mosaic trisomy 8: mos 47,XY, + 8[15]/46,XY[7]. At 4 months, the patient developed respiratory failure, and a chest computed tomography scan showed areas of atelectasis and gross fibroatelectatic striae. He ended up presenting clinical worsening and died at 4 months and 8 days. In our literature review, we found some reports describing patients with mosaic trisomy 8 and laryngotracheomalacia. However, we cannot rule out the possibility that this association could be casual, since laryngotracheomalacia is a relatively common finding in children. Therefore, more studies are still necessary to understand the possible relation between both conditions and the role of laryngotracheomalacia over morbidity and prognosis of mosaic trisomy 8 patients.
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Affiliation(s)
- Mateus A. de Souza
- Department of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Jéssica K. Hartmann
- Department of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Laira F. F. Zottis
- Department of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Thiago K. K. Gama
- Department of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Ernani B. da Rosa
- Postgraduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Paulo R. G. Zen
- Postgraduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
- Department of Clinical Medicine, Clinical Genetics Service, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
- Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Rafael F. M. Rosa
- Postgraduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
- Department of Clinical Medicine, Clinical Genetics Service, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
- Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
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Blyth U, Craciunas L, Hudson G, Choudhary M. Maternal germline factors associated with aneuploid pregnancy loss: a systematic review. Hum Reprod Update 2021; 27:866-884. [PMID: 33969392 DOI: 10.1093/humupd/dmab010] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 03/02/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Miscarriage describes the spontaneous loss of pregnancy before the threshold of viability; the vast majority occur before 12 weeks of gestation. Miscarriage affects one in four couples and is the most common complication of pregnancy. Chromosomal abnormalities of the embryo are identified in ∼50% of first trimester miscarriages; aneuploidy accounts for 86% of these cases. The majority of trisomic miscarriages are of maternal origin with errors occurring during meiotic division of the oocytes. Chromosome segregation errors in oocytes may be sporadic events secondary to advancing maternal age; however, there is increasing evidence to suggest possible maternal germline contributions to this. OBJECTIVE AND RATIONALE The objective of this review was to appraise critically the existing evidence relating to maternal germline factors associated with pregnancy loss secondary to embryo aneuploidy, identify limitations in the current evidence base and establish areas requiring further research. SEARCH METHODS The initial literature search was performed in September 2019 and updated in January 2021 using the electronic databases OVID MEDLINE, EMBASE and the Cochrane Library. No time or language restrictions were applied to the searches and only primary research was included. Participants were women who had suffered pregnancy loss secondary to numerical chromosomal abnormalities of the embryo. Study identification and subsequent data extraction were performed by two authors independently. The Newcastle-Ottawa Scale was used to judge the quality of the included studies. The results were synthesized narratively. OUTCOMES The literature search identified 2198 titles once duplicates were removed, of which 21 were eligible for inclusion in this systematic review. They reported on maternal germline factors having variable degrees of association with pregnancy loss of aneuploid origin. The Online Mendelian Inheritance in Man (OMIM) gene ontology database was used as a reference to establish the functional role currently attributed to the genes reported. The majority of the cases reported and included were secondary to the inheritance of maternal structural factors such as Robertsonian translocations, deletions and insertions. Germline factors with a plausible role in aneuploid pregnancy loss of maternal origin included skewed X-inactivation and CGG repeats in the fragile X mental retardation (FMR1) gene. Studies that reported the association of single gene mutations with aneuploid pregnancy loss were conflicting. Single gene mutations with an uncertain or no role in aneuploid pregnancy loss included mutations in synaptonemal complex protein 3 (SYCP3), mitotic polo-like kinase 4 (PLK4) and meiotic stromal antigen 3 (STAG3) spindle integrity variants and 5,10-methylenetetrahydrofolate reductase (MTHFR). WIDER IMPLICATIONS Identifying maternal genetic factors associated with an increased risk of aneuploidy will expand our understanding of cell division, non-disjunction and miscarriage secondary to embryo aneuploidy. The candidate germline factors identified may be incorporated in a screening panel for women suffering miscarriage of aneuploidy aetiology to facilitate counselling for subsequent pregnancies.
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Affiliation(s)
- Ursula Blyth
- Newcastle Fertility Centre at Life, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Laurentiu Craciunas
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Gavin Hudson
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Meenakshi Choudhary
- Newcastle Fertility Centre at Life, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Thomsen SH, Lund ICB, Fagerberg C, Bache I, Becher N, Vogel I. Trisomy 8 mosaicism in the placenta: A Danish cohort study of 37 cases and a literature review. Prenat Diagn 2020; 41:409-421. [PMID: 33251614 DOI: 10.1002/pd.5875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/15/2020] [Accepted: 11/23/2020] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To evaluate the risk of fetal involvement when trisomy 8 mosaicism (T8M) is detected in chorionic villus samples (CVS). METHODS A retrospective descriptive study of registered pregnancies in Denmark with T8M in CVS identified through a database search and a review of published cases of T8M found through a systematic literature search and inclusion of cross references. Pregnancies with T8M in CVS and no additional numerical chromosomal aberrations were included. RESULTS A total of 37 Danish cases and 60 published cases were included. T8M detected in a CVS was associated with fetal involvement in 18 out of 97 pregnancies (18.6% [95%CI: 11.4-27.7]). Eight out of 70 (11.4% [95%CI: 5.1-21.3]) interpreted prenatally to be confined placental mosaicism (CPM) were subsequently found to be true fetal mosaicisms (TFM). CONCLUSION T8M detected in CVS poses a significant risk of fetal involvement, and examination of amniotic fluid (AF) and/or fetal tissue should be offered. However, a normal result of AF still has a considerable residual risk of fetal involvement. Genetic counselling at an early gestational age is essential, and follow-up ultrasonography should be performed to predict fetal involvement if possible.
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Affiliation(s)
- Simon Horsholt Thomsen
- Center for Fetal Diagnostics, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Ida Charlotte Bay Lund
- Center for Fetal Diagnostics, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
| | - Christina Fagerberg
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Iben Bache
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Naja Becher
- Center for Fetal Diagnostics, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
| | - Ida Vogel
- Center for Fetal Diagnostics, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
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Kato T, Kawai M, Miyai S, Suzuki F, Tsutsumi M, Mizuno S, Ikeda T, Kurahashi H. Analysis of the Origin of Double Mosaic Aneuploidy in Two Cases. Cytogenet Genome Res 2020; 160:118-123. [PMID: 32248198 DOI: 10.1159/000507177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2020] [Indexed: 11/19/2022] Open
Abstract
We present 2 cases of double mosaic aneuploidy harboring 2 or more different aneuploid cell lines, but no line with a normal chromosome constitution. One of these cases presented mosaicism of sex chromosome aneuploid cell lines (47,XXX/45,X) along with another line containing an autosomal trisomy (47,XX,+8), while the other case showed mosaicism of 2 different autosomal trisomy cell lines (47,XY,+5 and 47,XY,+8). To elucidate the mechanisms underlying these mosaicisms, we conducted molecular cytogenetic analyses. Genotyping data from the SNP microarray indicated that 2 sequential meiotic or early postzygotic segregation errors likely had occurred followed by natural selection. These cases suggest that frequent segregation errors and selection events in the meiotic and early postzygotic stages lead to this condition.
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Pertile MD, Halks-Miller M, Flowers N, Barbacioru C, Kinnings SL, Vavrek D, Seltzer WK, Bianchi DW. Rare autosomal trisomies, revealed by maternal plasma DNA sequencing, suggest increased risk of feto-placental disease. Sci Transl Med 2018; 9:9/405/eaan1240. [PMID: 28855395 PMCID: PMC10040211 DOI: 10.1126/scitranslmed.aan1240] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 06/22/2017] [Accepted: 08/10/2017] [Indexed: 12/13/2022]
Abstract
Whole-genome sequencing (WGS) of maternal plasma cell-free DNA (cfDNA) can potentially evaluate all 24 chromosomes to identify abnormalities of the placenta, fetus, or pregnant woman. Current bioinformatics algorithms typically only report on chromosomes 21, 18, 13, X, and Y; sequencing results from other chromosomes may be masked. We hypothesized that by systematically analyzing WGS data from all chromosomes, we could identify rare autosomal trisomies (RATs) to improve understanding of feto-placental biology. We analyzed two independent cohorts from clinical laboratories, both of which used a similar quality control parameter, normalized chromosome denominator quality. The entire data set included 89,817 samples. Samples flagged for analysis and classified as abnormal were 328 of 72,932 (0.45%) and 71 of 16,885 (0.42%) in cohorts 1 and 2, respectively. Clinical outcome data were available for 57 of 71 (80%) of abnormal cases in cohort 2. Visual analysis of WGS data demonstrated RATs, copy number variants, and extensive genome-wide imbalances. Trisomies 7, 15, 16, and 22 were the most frequently observed RATs in both cohorts. Cytogenetic or pregnancy outcome data were available in 52 of 60 (87%) of cases with RATs in cohort 2. Cases with RATs detected were associated with miscarriage, true fetal mosaicism, and confirmed or suspected uniparental disomy. Comparing the trisomic fraction with the fetal fraction allowed estimation of possible mosaicism. Analysis and reporting of aneuploidies in all chromosomes can clarify cases in which cfDNA findings on selected "target" chromosomes (21, 18, and 13) are discordant with the fetal karyotype and may identify pregnancies at risk of miscarriage and other complications.
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Affiliation(s)
- Mark D Pertile
- Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Melbourne, Victoria 3052, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Victoria 3010, Australia
| | | | - Nicola Flowers
- Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Melbourne, Victoria 3052, Australia
| | | | | | | | | | - Diana W Bianchi
- Tufts Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA. .,National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Tsai MC, Cheng HY, Su MT, Chen M, Kuo PL. Partial trisomy 8 mosaicism not detected by cultured amniotic-fluid cells. Taiwan J Obstet Gynecol 2014; 53:598-601. [DOI: 10.1016/j.tjog.2014.06.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2014] [Indexed: 12/31/2022] Open
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Davidsson J. The epigenetic landscape of aneuploidy: constitutional mosaicism leading the way? Epigenomics 2014; 6:45-58. [PMID: 24579946 DOI: 10.2217/epi.13.78] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The role of structural genetic changes in human disease has received substantial attention in recent decades, but surprisingly little is known about numerical chromosomal abnormalities, even though they have been recognized since the days of Boveri as partaking in different cellular pathophysiological processes such as cancer and genomic disorders. The current knowledge of the genetic and epigenetic consequences of aneuploidy is reviewed herein, with a special focus on using mosaic genetic syndromes to study the DNA methylation footprints and expressional effects associated with whole-chromosomal gains. Recent progress in understanding the debated role of aneuploidy as a driver or passenger in malignant transformation, as well as how the cell responds to and regulates excess genetic material in experimental settings, is also discussed in detail.
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Affiliation(s)
- Josef Davidsson
- Division of Molecular Medicine & Gene Therapy, Lund Stem Cell Center, Lund University, SE-221 84 Lund, Sweden
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8
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Sood V, Khanna R, Alam S, Rawat D, Bhatnagar S, Rastogi A. Ductal paucity and Warkany syndrome in a patient with congenital extrahepatic portocaval shunt. World J Hepatol 2014; 6:358-362. [PMID: 24868329 PMCID: PMC4033293 DOI: 10.4254/wjh.v6.i5.358] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 01/09/2014] [Accepted: 03/18/2014] [Indexed: 02/06/2023] Open
Abstract
An eleven-year-old clinically dysmorphic and developmentally retarded male child presenting with complaints of 5 episodes of recurrent cholestatic jaundice since 3 years of age was evaluated. Imaging revealed features consistent with congenital extrahepatic portocaval shunt (Abernethy type 1b), multiple regenerative liver nodules and intrahepatic biliary radical dilatation. The presence of ductal paucity and trisomy 8 were confirmed on liver biopsy and karyotyping. The explanation for unusual and previously unreported features in the present case has been proposed.
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Valind A, Pal N, Asmundsson J, Gisselsson D, Holmquist Mengelbier L. Confined trisomy 8 mosaicism of meiotic origin: A rare cause of aneuploidy in childhood cancer. Genes Chromosomes Cancer 2014; 53:634-8. [DOI: 10.1002/gcc.22173] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 03/28/2014] [Indexed: 11/12/2022] Open
Affiliation(s)
- Anders Valind
- Department of Clinical Genetics; Lund University, University and Regional Laboratories; Lund Sweden
| | - Niklas Pal
- Department of Pediatric Oncology; Astrid Lindgren Children's Hospital, Karolinska University Hospital; Stockholm Sweden
| | - Jurate Asmundsson
- Department of Pathology; Karolinska University Hospital; Stockholm Sweden
| | - David Gisselsson
- Department of Clinical Genetics; Lund University, University and Regional Laboratories; Lund Sweden
- Department of Pathology; Skåne Regional and University Laboratories, Lund University; Lund Sweden
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Davidsson J, Veerla S, Johansson B. Constitutional trisomy 8 mosaicism as a model for epigenetic studies of aneuploidy. Epigenetics Chromatin 2013; 6:18. [PMID: 23816241 PMCID: PMC3704342 DOI: 10.1186/1756-8935-6-18] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2013] [Accepted: 05/30/2013] [Indexed: 12/21/2022] Open
Abstract
Background To investigate epigenetic patterns associated with aneuploidy we used constitutional trisomy 8 mosaicism (CT8M) as a model, enabling analyses of single cell clones, harboring either trisomy or disomy 8, from the same patient; this circumvents any bias introduced by using cells from unrelated, healthy individuals as controls. We profiled gene and miRNA expression as well as genome-wide and promoter specific DNA methylation and hydroxymethylation patterns in trisomic and disomic fibroblasts, using microarrays and methylated DNA immunoprecipitation. Results Trisomy 8-positive fibroblasts displayed a characteristic expression and methylation phenotype distinct from disomic fibroblasts, with the majority (65%) of chromosome 8 genes in the trisomic cells being overexpressed. However, 69% of all deregulated genes and non-coding RNAs were not located on this chromosome. Pathway analysis of the deregulated genes revealed that cancer, genetic disorder, and hematopoiesis were top ranked. The trisomy 8-positive cells displayed depletion of 5-hydroxymethylcytosine and global hypomethylation of gene-poor regions on chromosome 8, thus partly mimicking the inactivated X chromosome in females. Conclusions Trisomy 8 affects genes situated also on other chromosomes which, in cooperation with the observed chromosome 8 gene dosage effect, has an impact on the clinical features of CT8M, as demonstrated by the pathway analysis revealing key features that might explain the increased incidence of hematologic malignancies in CT8M patients. Furthermore, we hypothesize that the general depletion of hydroxymethylation and global hypomethylation of chromosome 8 may be unrelated to gene expression regulation, instead being associated with a general mechanism of chromatin processing and compartmentalization of additional chromosomes.
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Affiliation(s)
- Josef Davidsson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, SE 221 85, Lund, Sweden.
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Chen CP, Su YN, Chern SR, Chen YT, Su JW, Pan CW, Wang W. Prenatal diagnosis of trisomy 8 mosaicism. Taiwan J Obstet Gynecol 2013; 51:666-8. [PMID: 23276580 DOI: 10.1016/j.tjog.2012.09.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2012] [Indexed: 10/27/2022] Open
Affiliation(s)
- Chih-Ping Chen
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
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Abu-Amero KK, Kondkar AA, Salih MA, Al-Husain M, Al Shammari M, Zeidan G, Oystreck DT, Hellani AM, Kentab AY, Bosley TM. Ophthalmologic Observations in a Patient with Partial Mosaic Trisomy 8. Ophthalmic Genet 2013; 34:249-53. [DOI: 10.3109/13816810.2012.762933] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Mosaiktrisomie 8p11.21q11.21 als Prädisposition für myeloische Leukämien. MED GENET-BERLIN 2012. [DOI: 10.1007/s11825-012-0316-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Zusammenfassung
Bei der juvenilen myelomonozytären Leukämie (JMML) handelt es sich um eine myeloproliferative Erkrankung der frühen Kindheit. Bei vielen Patienten lassen sich zugrunde liegende somatische, aber auch konstitutionelle Mutationen in NRAS, KRAS, PTPN11, NF1 und CBL nachweisen. Zur Identifizierung submikroskopischer Veränderungen, die für die leukämische Transformation von Bedeutung sein können, wurden 20 JMML-Proben mittels hochauflösender Oligo-Microarray-basierter komparativer genomischer Hybridisierung (aCGH) untersucht. Bei 2 von 10 Patienten mit submikroskopischen Aberrationen konnte ein nahezu identischer Zugewinn von Chromosom 8 gezeigt werden, der sich in weiteren Untersuchungen als konstitutionelles Mosaik darstellte. Eine Übersicht von 27 Patienten mit einem konstitutionellen Trisomie-8-Mosaik (cT8M) und maligner Neoplasie zeigte, dass es sich meist um myeloische Neoplasien, auch JMML, handelt. Durch unsere Untersuchungen konnte die kritische Region auf Chromosom 8, deren Loci mutmaßlich an der Leukämieentstehung und/oder Progression beteiligt sein können, dramatisch reduziert werden: 8p11.21q11.21. Es bleibt zu klären in welcher Form das partielle Trisomie-8-Mosaik an der Leukämieentstehung beteiligt ist und in welcher Weise dies für verschiedenen Mutationssubtypen der JMML eine Rolle spielt.
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Chen CP, Chen M, Pan YJ, Su YN, Chern SR, Tsai FJ, Chen YT, Wang W. Prenatal diagnosis of mosaic trisomy 8: Clinical report and literature review. Taiwan J Obstet Gynecol 2011; 50:331-8. [DOI: 10.1016/j.tjog.2011.07.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2011] [Indexed: 10/15/2022] Open
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Ripperger T, Tauscher M, Praulich I, Pabst B, Teigler-Schlegel A, Yeoh A, Göhring G, Schlegelberger B, Flotho C, Niemeyer CM, Steinemann D. Constitutional trisomy 8p11.21-q11.21 mosaicism: a germline alteration predisposing to myeloid leukaemia. Br J Haematol 2011; 155:209-17. [PMID: 21848520 DOI: 10.1111/j.1365-2141.2011.08817.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Juvenile myelomonocytic leukaemia (JMML) is a unique myeloproliferative disorder of early childhood. Frequently, mutations in NRAS, KRAS, PTPN11, NF1 or CBL are found in these patients. Monosomy 7 is the most common cytogenetic aberration. To identify submicroscopic genomic copy number alterations, 20 JMML samples were analysed by comparative genomic hybridization. Ten out of 20 samples displayed additional submicroscopic alterations. In two patients, an almost identical gain of chromosome 8 was identified. In both patients, fluorescence in situ hybridization confirmed a constitutional partial trisomy 8 mosaic (cT8M). A survey on 27 cT8M patients with neoplasms showed that 21 had myeloid malignancies, and five of these had a JMML. Notably, the region gained in our cases is the smallest gain of chromosome 8 reported in cT8M cases with malignancies so far. Our results dramatically reduce the critical region to 8p11.21q11.21 harbouring 31 protein coding genes and two non-coding RNAs, e.g. MYST3, IKBKB, UBE2V2, GOLGA7, FNTA and MIR486--a finding with potential implications for the role of somatic trisomy 8 in myeloid malignancies. Further investigations are required to more comprehensively determine how constitutional partial trisomy 8 mosaicisms may contribute to leukaemogenesis in different mutational subtypes of JMML and other myeloid malignancies.
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Affiliation(s)
- Tim Ripperger
- Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany
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Datta A, Picker J, Rotenberg A. Trisomy 8 mosaicism and favorable outcome after treatment of infantile spasms: case report. J Child Neurol 2010; 25:1275-7. [PMID: 20489041 DOI: 10.1177/0883073809357361] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Constitutional mosaic trisomy 8 syndrome occurs in approximately 1 of 35 000 live births. Clinically, it has a variable presentation. Some patients are asymptomatic, while others have multisystemic involvement. The overall incidence of neurological abnormalities has not been reported, but seizures are among the neurological symptoms associated with this condition. Previous reports describe astatic seizures, complex partial seizures, generalized tonic-clonic seizures, and absence seizures with the age of onset varying from 3 months to early childhood. However, instances of infantile spasms and the patients' response to treatment have not been reported to our knowledge. Accordingly, we report a case of a patient with constitutional mosaic trisomy 8 syndrome and infantile spasms, who became seizure free after treatment with adrencorticotropic hormone and clonazepam.
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Affiliation(s)
- Anita Datta
- Division of Epilepsy, Department of Neurology, Children's Hospital Boston, Boston, Massachusetts, USA
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Conlin LK, Thiel BD, Bonnemann CG, Medne L, Ernst LM, Zackai EH, Deardorff MA, Krantz ID, Hakonarson H, Spinner NB. Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet 2010; 19:1263-75. [PMID: 20053666 DOI: 10.1093/hmg/ddq003] [Citation(s) in RCA: 326] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic development; (ii) co-occurrence of mosaic trisomy and UPD and (iii) potential recurrence risks. We used a genome-wide single nucleotide polymorphism (SNP) array to study patients with chromosome aneuploidy mosaicism, UPD and one individual with XX/XY chimerism to gain insight into the developmental mechanism and timing of these events. Sixteen cases of mosaic aneuploidy originated mitotically, and these included four rare trisomies and all of the monosomies, consistent with the influence of selective factors. Five trisomies arose meiotically, and three of the five had UPD in the disomic cells, confirming increased risk for UPD in the case of meiotic non-disjunction. Evidence for the meiotic origin of aneuploidy and UPD was seen in the patterns of recombination visible during analysis with 1-3 crossovers per chromosome. The mechanisms of formation of the UPD included trisomy rescue, with and without concomitant trisomy, monosomy rescue, and mitotic formation of a mosaic segmental UPD. UPD was also identified in an XX/XY chimeric individual, with one cell line having complete maternal UPD consistent with a parthenogenetic origin. Utilization of SNP arrays allows simultaneous evaluation of genomic alterations and insights into aneuploidy and UPD mechanisms. Differentiation of mitotic and meiotic origins for aneuploidy and UPD supports existence of selective factors against full trisomy of some chromosomes in the early embryo and provides data for estimation of recurrence and disease mechanisms.
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Affiliation(s)
- Laura K Conlin
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
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Houge G, Lybaek H, Gulati S. Mosaicism for combined tetrasomy of chromosomes 8 and 18 in a dysmorphic child: a result of failed tetraploidy correction? BMC MEDICAL GENETICS 2009; 10:42. [PMID: 19445731 PMCID: PMC2691399 DOI: 10.1186/1471-2350-10-42] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2008] [Accepted: 05/18/2009] [Indexed: 11/30/2022]
Abstract
Background Mosaic whole-chromosome tetrasomy has not previously been described as a cause of fetal malformations. Case presentation In a markedly dysmorphic child with heart malformations and developmental delay, CGH analysis of newborn blood DNA suggested a 50% dose increase of chromosomes 8 and 18, despite a normal standard karyotype investigation. Subsequent FISH analysis revealed leukocytes with four chromosomes 8 and four chromosomes 18. The child's phenotype had resemblance to both mosaic trisomy 8 and mosaic trisomy 18. The double tetrasomy was caused by mitotic malsegregation of all four chromatids of both chromosome pairs. A possible origin of such an error is incomplete correction of a tetraploid state resulting from failed cytokinesis or mitotic slippage during early embryonic development. Conclusion This unique case suggests that embryonic cells may have a mechanism for tetraploidy correction that involves mitotic pairing of homologous chromosomes.
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Affiliation(s)
- Gunnar Houge
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
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20
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Marti S, Galan FM, Casero JM, Merino J, Rubio G. Characterization of trisomic natural killer cell abnormalities in a patient with constitutional trisomy 8 mosaicism. Pediatr Hematol Oncol 2008; 25:135-46. [PMID: 18363181 DOI: 10.1080/08880010801890135] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Malignancies found in children and adults with constitutional trisomy 8 mosaicism (CT8M) could be in part the consequence of dysfunction of trisomic immune cells. An adult patient exhibiting trisomy in the entire natural killer (NK) cell population has made possible the characterization of trisomy 8-positive NK cells. The study showed normal cytotoxic activity but predominance of an immunosenescent phenotype (CD56(dim)CD94/NKG2(bright)) characterized by a weak response to IL-2, increased upregulation of CD95/Fas, and impaired TNF-alpha production. As these defects may contribute to the escape and expansion of neoplastic cells, the authors hypothesize that cancer predisposition in CT8M may be partly a result of altered immunosurveillance.
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Affiliation(s)
- Salvador Marti
- Area of Immunology, Miguel Hernandez University, Sant Joan, Alicante, Spain
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21
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Hall HE, Surti U, Hoffner L, Shirley S, Feingold E, Hassold T. The origin of trisomy 22: evidence for acrocentric chromosome-specific patterns of nondisjunction. Am J Med Genet A 2008; 143A:2249-55. [PMID: 17705154 DOI: 10.1002/ajmg.a.31918] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Trisomy 22 is one of the most common trisomies in clinically recognized pregnancies, yet relatively little is known about the origin of nondisjunction for chromosome 22. Accordingly, we initiated studies to investigate the origin of the extra chromosome in 130 trisomy 22 cases. Our results indicate that the majority of trisomy 22 errors (>96%) arise during oogenesis with most of these errors ( approximately 90%) occurring during the first meiotic division. As with other trisomies, failure to recombine contributed to nondisjunction of chromosome 22. Taken together with data available for other trisomies, our results suggest patterns of nondisjunction that are shared among the acrocentric, but not all nonacrocentric, chromosomes.
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Affiliation(s)
- Heather E Hall
- Center for Reproductive Biology and School of Molecular Biosciences, Washington State University, Pullman, Washington 99164-4660, USA
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22
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Maserati E, Pressato B, Valli R, Patitucci F, Lo Curto F, Pasquali F, Minelli A, Danesino C, Marchetti M, Barosi G. Constitutional trisomy 8 mosaicism in primary myelofibrosis: relevance to clinical practice and warning for trisomy 8 studies. ACTA ACUST UNITED AC 2008; 179:79-81. [PMID: 17981220 DOI: 10.1016/j.cancergencyto.2007.08.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2007] [Accepted: 08/14/2007] [Indexed: 10/22/2022]
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23
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Voigt R, Gburek-Augustat J, Seidel A, Gillessen-Kaesbach G. Hemihyperplasia and discordant bone age in a patient with trisomy 8 mosaicism. Am J Med Genet A 2008; 146A:132-5. [PMID: 18074372 DOI: 10.1002/ajmg.a.32049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- R Voigt
- Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
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24
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Golzio C, Guirchoun J, Ozilou C, Thomas S, Goudefroye G, Morichon-Delvallez N, Vekemans M, Attié-Bitach T, Etchevers HC. Cytogenetic and histological features of a human embryo with homogeneous chromosome 8 trisomy. Prenat Diagn 2007; 26:1201-5. [PMID: 17075794 DOI: 10.1002/pd.1588] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Homogeneous and complete trisomy 8 is extremely rare. With one recent neonatal exception, all reported cases have been mosaic, due to mitotic non-disjunction during early zygotic development. We report a case of chromosome 8 trisomy in a human embryo examined at Carnegie stage 11 (25 days post-fertilization). It presented severe cardiovascular and central nervous system malformations. METHODS The unusual bifid heart in this embryo spurred a detailed histological examination, karyotyping of a chorionic villus sample and subsequent FISH on inter-phase nuclei of intra-embryonic sections. RESULTS Trophoblast cells had a karyotype of 47,XX, +8. Within the embryo proper, FISH demonstrated that the trisomy 8 was homogeneous in embryonic as well as extra-embryonic tissues. FQ-PCR supports a meiosis I origin of non-disjunction. In sections, the pharyngeal arches (including cardiac outflow tract), forebrain, mesonephros and liver were absent. Somites and yolk sac blood vessels were irregularly shaped. CONCLUSION We show that homogeneous, intra-embryonic trisomy 8 is compatible with implantation and early human development. Molecular pathways that may be compromised and their impact on organogenesis are discussed.
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Affiliation(s)
- Christelle Golzio
- INSERM U781, Hôpital Necker - Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France
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25
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Paulsson K, Johansson B. Trisomy 8 as the sole chromosomal aberration in acute myeloid leukemia and myelodysplastic syndromes. ACTA ACUST UNITED AC 2007; 55:37-48. [PMID: 16697122 DOI: 10.1016/j.patbio.2006.04.007] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2006] [Accepted: 04/05/2006] [Indexed: 10/24/2022]
Abstract
Trisomy 8 as the sole abnormality is the most common karyotypic finding in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), occurring in approximately 5% and 10% of the cytogenetically abnormal cases, respectively. However, despite the high frequency of +8, much remains to be elucidated as regards its epidemiology, etiology, clinical impact, association with other chromosomal abnormalities, cell of origin, and functional and pathogenetic consequences. Here, we summarize and review these various aspects of trisomy 8, focusing on AMLs and MDS harboring this abnormality as a single change.
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Affiliation(s)
- K Paulsson
- Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden.
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26
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Gradek GA, Kvistad PH, Houge G. Monosomy 8 rescue gave cells with a normal karyotype in a mildly affected man with 46,XY,r(8) mosaicism. Eur J Med Genet 2006; 49:292-7. [PMID: 16829350 DOI: 10.1016/j.ejmg.2005.08.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2005] [Accepted: 08/29/2005] [Indexed: 10/25/2022]
Abstract
The psychomotor and somatic development from early childhood into adult life is described in a man with 46,XY,r(8)/46,XY mosaicism. The ring chromosome 8 appeared to be of normal length on G-banding, but terminal deletions on 8q and 8p were detected with FISH and CGH. By STR marker analysis the 8p deletion proved to be quite large, at least 6.74 Mb, while the 8q deletion was small, around 2.5 Mb. The haplotype analysis also demonstrated that the r(8) originated from a maternal chromosome 8, and that cells with normal male karyotype resulted from monosomy 8 rescue after loss of the ring 8, i.e. a mitotic duplication of the paternal chromosome 8. The patient has a mild phenotype with no malformations and mild mental retardation, also compared to other ring chromosome 8 patients. His clinical condition has remained stable for the last 20 years.
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Affiliation(s)
- Gyri Aasland Gradek
- Centre for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen, Norway
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27
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Ando S, Maemori M, Sakai H, Ando S, Shiraishi H, Sakai K, Ruhnke GW. Constitutional trisomy 8 mosaicism with myelodysplastic syndrome complicated by intestinal Behcet disease and antithrombin III deficiency. ACTA ACUST UNITED AC 2005; 162:172-5. [PMID: 16213367 DOI: 10.1016/j.cancergencyto.2005.01.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2004] [Accepted: 01/13/2005] [Indexed: 11/18/2022]
Abstract
Trisomy 8 is the most common acquired chromosomal abnormality associated with myeloid malignancy. As a constitutional trisomy 8 mosaicism (T8M), it exhibits an extremely variable phenotype. In addition, Behcet disease (BD) has been reported as an unusual complication of myelodysplastic syndrome (MDS). To our knowledge, 12 case reports of various hematologic malignancies in patients with T8M and 18 case reports of MDS with acquired trisomy 8 complicated by BD have been published to date. We report a case of constitutional T8M with MDS complicated by intestinal BD and antithrombin III deficiency.
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Affiliation(s)
- Sachiko Ando
- Department of Hematology, Teine Keijinkai Hospital, Hokkaido, Japan.
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28
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Belloso JM, Caballín MR, Gabau E, Baena N, Vidal R, Villatoro S, Guitart M. Characterization of six marker chromosomes by comparative genomic hybridization. Am J Med Genet A 2005; 136:169-74. [PMID: 15948187 DOI: 10.1002/ajmg.a.30788] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
We applied comparative genomic hybridization (CGH) in six patients with de novo prenatal or postnatal extra marker chromosomes (MC). In four cases, MCs were mosaic and in one of them, the MC was detected in less than 50% of the cells. In three cases, CGH identified the origin of the extra MCs. In the other three, two prenatal cases and one child with an abnormal phenotype, CGH showed normal profiles. Among these cases, a normal profile and entirely C-band positive was identified suggesting that MC did not contain euchromatin. Genetic imbalances detected by CGH were as follow: a gain of 8p10-p12 in a boy with facial dysmorphism, hyperactivity and speech delay, a gain of 8q10-q12 in a healthy man with a history of spontaneous abortions, and a gain of 15q11-q13 in a girl with speech delay, and motor skill and object manipulation difficulties. Clinical data of these patients were compared with those reported in the literature. We conclude that CGH is a very useful and powerful tool for characterizing prenatal or postnatal MCs, even when the mosaicism is present and the MCs are present in less than 50% of the cells.
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Affiliation(s)
- J M Belloso
- Laboratori de Genètica, UDIAT-Centre Diagnòstic, Servei de Pediatria, Hospital de Sabadell, Corporació Sanitària Parc Taulí, Fundació Parc Taulí Institut Universitari UAB, Sabadell, Spain
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29
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Alkuraya FS, Harris DJ. Trisomy 8 mosaicism in a patient with heterotaxia. BIRTH DEFECTS RESEARCH. PART A, CLINICAL AND MOLECULAR TERATOLOGY 2004; 73:58-60. [PMID: 15578648 DOI: 10.1002/bdra.20091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Constitutional trisomy 8 mosaicism (CT8M) is a relatively rare trisomy in humans with a characteristic phenotype. We report an infant with the characteristic CT8M phenotype in addition to heterotaxia. A number of chromosomal abnormalities have been reported in association with laterality defects but this is the first time heterotaxia is reported in CT8M. In addition to expanding CT8M phenotype, our report may provide insight into the mechanism of heterotaxia.
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Affiliation(s)
- Fowzan S Alkuraya
- Division of Genetics and Metabolism, Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
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30
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Baidas S, Chen TJ, Kolev V, Wong LJ, Imholte J, Qin N, Meck J. Constitutional trisomy 8 mosaicism due to meiosis II non-disjunction in a phenotypically normal woman with hematologic abnormalities. Am J Med Genet A 2004; 124A:383-7. [PMID: 14735586 DOI: 10.1002/ajmg.a.20390] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Constitutional trisomy 8 mosaicism (CT8M) in liveborns is typically caused by mitotic non-disjunction and exhibits wide phenotypic variability. By contrast, CT8M due to meiotic errors usually results in miscarriage. We describe a case of CT8M due to a paternal meiosis II non-disjunction error. The patient, a 32-year-old woman, was phenotypically normal except for a history of recurrent aphthous ulcers since childhood and a 4-year history of macrocytosis. The ulcers were refractory to steroids, but responded well to thalidomide. To the best of our knowledge, this is the first report of CT8M due to meiotic non-disjunction in a phenotypically normal individual.
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Affiliation(s)
- Said Baidas
- Departments of Medicine and Oncology, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
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31
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Le Bris MJ, Marcorelles P, Audrézet MP, Parent P, Heren P, Le Guern H, Herry A, Morel F, Collet M, Férec C, De Braekeleer M. Prenatal diagnosis of mosaic tetrasomy 8p. Am J Med Genet A 2003; 120A:44-8. [PMID: 12794691 DOI: 10.1002/ajmg.a.20199] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Tetrasomy 8p is a rare chromosomal disorder that has only been detected in a mosaic form. At the present time, 11 cases have been reported; their phenotype included agenesis of the corpus callosum, enlarged ventricles, minor facial dysmorphism, rib and vertebral anomalies, and mild to moderate developmental delay. To the best of our knowledge, tetrasomy 8p has never been prenatally diagnosed. This 43-year-old woman was referred for amniocentesis at 20 weeks' gestation because of advanced maternal age. Amniotic fluid cells were cultured according to standard techniques by the in situ method. A supernumerary chromosomal marker was detected in a single clone of cultured amniotic cells and interpreted by RHG banding as an isochromosome of the short arm of chromosome 8 (i(8p)). The ultrasound investigation at 27 weeks gestation revealed enlarged ventricles and agenesis of the corpus callosum, which were confirmed at fetal autopsy after medical termination of the pregnancy. Chromosomal analyses, including RHG banding and FISH, of several tissues showed different levels of i(8p) mosaicism. Whereas no i(8p) was detected on cytotrophoblast nor additional amniotic fluid cells, 97% and 30% of cells from long-term cultures of placenta and lymphocytes, respectively, had the i(8p). Using DNA markers, the isochromosome 8p was interpreted as the result of a prezygotic event during maternal meiosis. Our findings suggest that the i(8p) is the subject of tissue selection. Tetrasomy 8p might be underdiagnosed during pregnancy; therefore, karyotyping on a fetal blood sample following detection of agenesis of the corpus callosum when no chromosomal abnormality has been found on the amniotic fluid cell cultures should be discussed with the parents.
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Affiliation(s)
- Marie-Josée Le Bris
- Service de Cytogénétique, Cytologie et Biologie de la Reproduction, CHU Morvan, Université de Bretagne Occidentale, 22 avenue Camille Desmoulins, F-29285 Brest cedex, France.
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32
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Nucaro AL, Cao A, Faedda A, Crisponi G. Trisomy 8 mosaicism in a patient born to a mother with 47,XXX. Am J Med Genet A 2003; 119A:85-6. [PMID: 12707966 DOI: 10.1002/ajmg.a.20086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Hulley BJ, Hummel M, Cook LL, Boyd BK, Wenger SL. Trisomy 8 mosaicism: selective growth advantage of normal cells vs. growth disadvantage of trisomy 8 cells. Am J Med Genet A 2003; 116A:144-6. [PMID: 12494432 DOI: 10.1002/ajmg.a.10651] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
A fetus with trisomy 8 mosaicism was identified prenatally due to an abnormal maternal serum triple screen. Tissue samples were taken at birth to determine the level of trisomy 8 mosaicism found within embryonic and extra-embryonic tissues, rates of cell division for the two cell lines, and the effect of mosaicism on the phenotype. The level of trisomy 8 cells in blood and fibroblasts was higher than in placental tissue. Cell cycle kinetics, by incorporation of bromodeoxyuridine for 48 hr, was not significantly different between the trisomy 8 and normal cells for blood or amnion. Fluorescent in situ hybridization (FISH) using centromeric probe for chromosome 8 showed significantly more trisomy 8 in interphase vs. metaphase in lymphoblasts, umbilical cord fibroblasts, and chorion. The loss of trisomy 8 cells is not due to anaphase lag, as determined by micronuclei analysis. The similarity of cell cycle kinetics between trisomy 8 cells and normal diploid cells suggests some trisomy 8 cells are exiting the cell cycle prematurely. This growth disadvantage of trisomy 8 cells results in the appearance of growth advantage for diploid cells.
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Affiliation(s)
- Bonnie J Hulley
- Genetics and Developmental Biology Program, West Virginia University, Morgantown, West Virginia 26506-9203, USA
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34
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Velissariou V, Antoniadi T, Gyftodimou J, Bakou K, Grigoriadou M, Christopoulou S, Hatzipouliou A, Donoghue J, Karatzis P, Katsarou E, Petersen MB. Maternal uniparental isodisomy 20 in a foetus with trisomy 20 mosaicism: clinical, cytogenetic and molecular analysis. Eur J Hum Genet 2002; 10:694-8. [PMID: 12404100 DOI: 10.1038/sj.ejhg.5200867] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2002] [Revised: 06/24/2002] [Accepted: 06/28/2002] [Indexed: 11/09/2022] Open
Abstract
The clinical significance of trisomy 20 mosaicism detected prenatally remains uncertain due to the rarity of liveborn cases with inconsistent clinical findings, and lack of long-term follow-up and outcome. We describe a case of true trisomy 20 mosaicism in a liveborn girl with maternal uniparental isodisomy of chromosome 20 in the diploid blood cells. Trisomy 20 mosaicism was originally detected in amniotic fluid (98%) and was confirmed in the term placenta (100%), as well as in the blood (10%) and urine sediment (100%) of the neonate. There was intrauterine and postnatal growth retardation, but otherwise the newborn manifested no gross abnormalities. At 9 months of age moderate psychomotor retardation, central hypotonia with peripheral hypertonia, numerous minor morphogenetic variants, marked kyphosis, and extensive Mongolian spot were observed. To our knowledge this represents the first case of trisomy 20 mosaicism detected prenatally and confirmed in different tissues of the newborn, where uniparental disomy was demonstrated in the diploid cell line. The clinical and laboratory findings in our patient are compared with those of five previously reported cases of UPD20, suggesting that maternal UPD20 might be associated with a characteristic phenotype.
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Affiliation(s)
- Voula Velissariou
- Cytogenetics Laboratory, Department of Genetics and Molecular Biology, Mitera Maternity and Surgical Center, Athens, Greece
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35
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Abstract
Somatic mosaicism -- the presence of genetically distinct populations of somatic cells in a given organism -- is frequently masked, but it can also result in major phenotypic changes and reveal the expression of otherwise lethal genetic mutations. Mosaicism can be caused by DNA mutations, epigenetic alterations of DNA, chromosomal abnormalities and the spontaneous reversion of inherited mutations. In this review, we discuss the human disorders that result from somatic mosaicism, as well as the molecular genetic mechanisms by which they arise. Specifically, we emphasize the role of selection in the phenotypic manifestations of mosaicism.
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Affiliation(s)
- Hagop Youssoufian
- Department of Clinical Discovery, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, USA.
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36
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van Haelst MM, Van Opstal D, Lindhout D, Los FJ. Management of prenatally detected trisomy 8 mosaicism. Prenat Diagn 2001; 21:1075-8. [PMID: 11746167 DOI: 10.1002/pd.215] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
We report on ten pregnancies with trisomy 8 mosaicism. Nine cases were prenatally detected in chorionic villi (n=6), amniotic fluid (AF) cells (n=2) or fetal blood (FB) lymphocytes (n=1). Follow-up laboratory investigations showed confined placental mosaicism (CPM) or pseudomosaicism in eight cases. In one case with ultrasound abnormalities, trisomy 8 mosaicism was detected in FB cells although cultured AF cells showed normal cells only. Another case of mosaic trisomy 8 was prenatally missed; cytogenetic analysis of short-term cultured villi revealed a normal male karyotype, while postnatally, trisomy 8 mosaicism was detected in peripheral blood lymphocytes and skin fibroblasts of the affected child. These findings indicate the difficulties in the prenatal diagnosis of trisomy 8 mosaicism. When found in chorionic villi, it mostly represented CPM, while in a case of true fetal trisomy 8 mosaicism, the cytotrophoblast cells showed a normal karyotype. So, the cytotrophoblast compartment of chorionic villi is a poor indicator of the presence or absence of fetal trisomy 8 mosaicism. Follow-up investigations including amniocentesis and especially fetal blood sampling are required to come to a definite prenatal diagnosis of trisomy 8 mosaicism.
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Affiliation(s)
- M M van Haelst
- Department of Clinical Genetics, Erasmus University Rotterdam, Rotterdam, The Netherlands.
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Eggermann T, Marg W, Mergenthaler S, Eggermann K, Schemmel V, Stoffers U, Zerres K, Spranger S. Origin of uniparental disomy 6: presentation of a new case and review on the literature. ANNALES DE GENETIQUE 2001; 44:41-5. [PMID: 11334617 DOI: 10.1016/s0003-3995(01)01035-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Paternal uniparental disomy (UPD) of chromosome 6 has been reported several times in patients with (transient) neonatal diabetes mellitus ((T)NDM). Here we present our short tandem repeat typing results in a new patient with NDM, revealing a paternal isodisomy (UPiD). Summarising these data with those published previously on complete paternal (n=13) and maternal (n=2) UPD6, all cases show isodisomy. In general, several modes of UPD formation have been suggested: While a meiotic origin of UPD mainly results in a uniparental heterodisomy (UPhD), UPiD is probably the result of a post-zygotic mitotic error. This mode of formation consists of a mitotic nondisjunction in a disomic zygote, followed by either a trisomic rescue or a reduplication. Endoduplication in a monosomic zygote is another possible but less probable mechanism, taking into consideration that monosomic zygotes are not viable. The exclusive finding of isodisomy in case of chromosome 6 therefore gives strong evidence that segregational errors of this chromosome are mainly influenced by postzygotic factors. This hypothesis is supported by the observation of two cases with partial paternal UPiD6 originating from mitotic recombination events. The influence of mitotic segregational errors in UPD6 formation is in agreement with the results in trisomy/UPD of other chromosomes of the C group (7 and 8), and is in remarkable contrast to the findings in studies on the origin of the frequent aneuploidies. Multiple factors ensure normal segregation and we speculate that they vary in importance for each chromosome.
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Affiliation(s)
- T Eggermann
- Institut für Humangenetik, RWTH, Aachen, Germany
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Abstract
Constitutional chromosomal mosaicism is the result of postfertilization mitotic error, the mechanism of which is not fully understood. The distribution of mosaicism in the conceptus depends on the timing, cell lineage(s) involved, cell viability, and chromosome involved. The developmental consequences of mosaicism also are related to its meiotic or somatic type. Meiotic mosaicism often is associated with a more severely adverse effect on the conceptus (see trisomy zygote rescue) due to the presence of uniparental disomy in the embryo/fetus and/or to dysfunction of a trisomic placenta. As mosaicism can be tissue specific, the result of a normal karyotype in cultured lymphocytes does not exclude the presence of mosaicism elsewhere in the conceptus. Mosaicism can best be detected by a combination of traditional cytogenetic analysis with molecular cytogenetic techniques such as comparative genomic hybridization and fluorescence in situ hybridization.
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Affiliation(s)
- D K Kalousek
- Cytogenetics Laboratory, Children's and Women's Health Centre, Vancouver, British Columbia, Canada.
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Mergenthaler S, Wollmann HA, Burger B, Eggermann K, Kaiser P, Ranke MB, Schwanitz G, Eggermann T. Formation of uniparental disomy 7 delineated from new cases and a UPD7 case after trisomy 7 rescue. Presentation of own results and review of the literature. ANNALES DE GENETIQUE 2000; 43:15-21. [PMID: 10818216 DOI: 10.1016/s0003-3995(00)00010-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Maternal uniparental disomy for the entire chromosome 7 (matUPD7) has been reported several times in Silver-Russell syndrome (SRS) and growth-restricted patients. Here we present our results from the analysis of an abortion with confined placental mosaicism (CPM) for trisomy 7 which showed a maternal meiotic origin of the trisomy in the placenta and rescue to maternal UPD7 in foetal membrane. Furthermore, two newly detected SRS cases with maternal UPD7 revealed isodisomy and partial heterodisomy, respectively. Summarising these results with those published previously on the origin of UPD7, similar numbers of isodisomy (n=11) and cases with complete or partial heterodisomy (n=12) have been reported. In respect to the different formation mechanisms of UPD, complete isodisomy should be the result of a post-zygotic mitotic segregation error, whereas heterodisomic UPDs should be caused by trisomic rescue after meiotic non-disjunction events. In maternal UPD7, 50% of cases seem to be caused by post-zygotic mitotic segregation errors, which is similar to the situation in trisomy 7. This result corresponds to the situation in trisomy 8 but is in contrast to observations in the frequent aneuploidies. Thus, the different findings in these aberrations reflect the presence of multiple factors that act to ensure normal segregation, varying in importance for each chromosome.
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Affiliation(s)
- S Mergenthaler
- Institute of Human Genetics, Technical University of Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
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