Trisomy Disorders

Archive for February 2012

Molecular and Clinicopathologic Characterization of AML With Isolated Trisomy 4.

Mar 2012


Dept of Hematopathology, Unit 72, 1515 Holcombe Blvd, Houston, TX 77030.


Acute myeloid leukemia (AML) with isolated trisomy 4 is rare. Associations with KIT mutations on chromosome 4q12 have been documented. The clinicopathologic features and mutational status of KIT, FLT3, NPM1, CEBPA, and RAS were assessed in 13 AML cases with isolated trisomy 4. There were 9 men and 4 women with a median age of 54 years. Median blast count was 84% (range, 24%-93%). Morphologic features varied across five 2008 World Health Organization categories. FLT3 (5/10) and NPM1 (4/10) mutations were observed at a frequency similar to normal-karyotype AML cases. KIT D816V (1/10), RAS (1/11; NRAS), and CEBPA (0/9) mutations were rare or absent. In 11 of 13 cases, complete remission was achieved. In 8 cases, relapse occurred, with median relapse-free survival of 11 months. Median overall survival was 28 months. AML with isolated trisomy 4 is rare and associated with high bone marrow blast counts and an intermediate to poor prognosis. KIT mutations are uncommon.



A Human Stem Cell Model of Early Alzheimer’s Disease Pathology in Down Syndrome.

Feb 2012


Gurdon Institute and Department of Biochemistry, University of Cambridge,Tennis Court Road, Cambridge, CB2 1QN.


Human cellular models of Alzheimer’s disease (AD) pathogenesis would enable the investigation of candidate pathogenic mechanisms in AD and the testing and developing of new therapeutic strategies. We report the development of AD pathologies in cortical neurons generated from human induced pluripotent stem (iPS) cells derived from patients with Down syndrome. Adults with Down syndrome (caused by trisomy of chromosome 21) develop early-onset Alzheimer’s disease, probably due to increased expression of a gene on chromosome 21 that encodes the amyloid precursor protein (APP). We found that cortical neurons generated from iPS cells and embryonic stem (ES) cells from Down syndrome patients developed AD pathologies over months in culture, rather than years in vivo. These cortical neurons processed the transmembrane APP protein resulting in secretion of the pathogenic peptide fragment amyloid-β42 (Aβ42), which formed insoluble intracellular and extracellular amyloid aggregates. Production of Aβ peptides was blocked by a gamma-secretase inhibitor. Finally, hyperphosphorylated tau protein, a pathological hallmark of AD, was found to be localized to cell bodies and dendrites in iPS cell-derived cortical neurons from Down syndrome patients, recapitulating later stages of the AD pathogenic process.


Auditory function in the tc1 mouse model of down syndrome suggests a limited region of human chromosome 21 involved in otitis media.



Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.


Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomyof chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K(+) currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca(2+) activated K(+) current (I(K,f)), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active.


Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome.

Feb 2012


Individuals with Down syndrome (DS; also known as trisomy 21) have a markedly increased risk of leukemia in childhood but a decreased risk of solid tumors in adulthood. Acquired mutations in the transcription factor-encoding GATA1 gene are observed in nearly all individuals with DS who are born with transient myeloproliferative disorder (TMD), a clonal preleukemia, and/or who develop acute megakaryoblastic leukemia (AMKL). Individuals who do not have DS but bear germline GATA1 mutations analogous to those detected in individuals with TMD and DS-AMKL are not predisposed to leukemia. To better understand the functional contribution of trisomy 21 to leukemogenesis, we used mouse and human cell models of DS to reproduce the multistep pathogenesis of DS-AMKL and to identify chromosome 21 genes that promote megakaryoblastic leukemia in children with DS. Our results revealed that trisomy for only 33 orthologs of human chromosome 21 (Hsa21) genes was sufficient to cooperate with GATA1 mutations to initiate megakaryoblastic leukemia in vivo. Furthermore, through a functional screening of the trisomic genes, we demonstrated that DYRK1A, which encodes dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A, was a potent megakaryoblastic tumor-promoting gene that contributed to leukemogenesis through dysregulation of nuclear factor of activated T cells (NFAT) activation. Given that calcineurin/NFAT pathway inhibition has been implicated in the decreased tumor incidence in adults with DS, our results show that the same pathway can be both proleukemic in children and antitumorigenic in adults.

Journal of Clinical Investigation

Clinical ocular manifestation of Patau’s syndrom (trisomy 13)–own observations


Kanigowska KGrałek MSeroczyńska M.


Z Kliniki Okulistyki Instytutu “Pomnik – Centrum Zdrowia Dziecka” w Warszawie.



The purpose of the article is to present the clinical abnormalities of Patau’s syndrome (trisomy13).


Examination was performed on 18 months old girl with trisomy13 in which we noted characteristic malformations in ocular system. The patient underwent cataract surgery and intraocular lens implantation in right eye. In this case the diagnosis of trisomy 13 was confirmed by karyotype.


Inferonasal iris colobomas, anterior-posterior form of persistent hyperplastic primary vitreus (PHPV), persistent tunica vasculosa lentis (PTVL), coloboma of the lens and cataract in right eye were found. Cataract surgery was performed with good results. Systemic abnormalities included heart defect, brain defect, cleft palate, small head, dysplastic ears, mental retardation, epilepsy and increased muscle tone.


The child with the presence of inferonosal iris colobomas and cataract and with other systemic and dysmorfic findings, should have kariotype examination to look for trisomy 13.


New report of two patients with mosaic trisomy 9 presenting unusual features and longer survival.

Dec 2011

Zen PRRosa RFRosa RCGraziadio CPaskulin GA.


Program and Clinical Geneticist, Universidade Federal de Ciências da Saúde de Porto Alegre.


Key words: Mosaicism. Chromosomes, human, pair 9. Chromosome aberrations. Goldenhar syndrome. Survivorship (Public health).

CONTEXT: Mosaic trisomy 9 is considered to be a rare chromosomal abnormality with limited survival. Our objective was to report on two patients with mosaic trisomy 9 presenting unusual findings and prolonged survival.


The first patient was a boy aged six years and five months presenting weight of 14.5 kg (< P3), height of 112 cm (P10), head circumference of 49 cm (P2), prominent forehead, triangular and asymmetric face, thin lips, right microtia with overfolded helix, small hands, micropenis (< P10), small testes and hallux valgus. His lymphocyte karyotype was mos 47,XY,+9 [4 ]/46,XY [50 ]. Additional cytogenetic assessment of the skin showed normal results. The second patient was a two-year-old girl who was initially assessed at five months of age, when she presented weight of 5.3 kg (< P3), height of 61.5 cm (P2-P10), head circumference of 40.5 cm (P25), sparse hair, micrognathia, right ear with overfolded helix and preauricular pit, triphalangeal thumbs and sacral dimple. She also had a history of congenital heart disease, hearing loss, hypotonia, delayed neuropsychomotor development and swallowing disorder. Her lymphocyte karyotype was mos 47,XX,+9 [3 ]/46,XX [69 ]. Both patients had unusual clinical findings (the first, hemifacial hypoplasia associated with microtia, with a phenotype of oculo-auriculo-vertebral spectrum, and the second, triphalangeal thumbs and hearing loss) and survival greater than what is usually described in the literature (< 1 year). Further reports will be critical for delineating the clinical features and determining the evolution of patients with mosaic trisomy 9.

SciElo Sao Paulo Medical Journal

Detection of 9p partial trisomy using array-based comparative genomic hybridization.

Feb 2012

[Article in Chinese]


Center of Prenatal Diagnosis, Nanjing Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210004, P. R. China.;



To detect chromosomal aberrations in a child with developmental delay and speech and language disorders in order to explore the underlying genetic causes of congenital malformation, and to investigate the feasibility of array-based comparative genomic hybridization (array-CGH) for molecular genetic diagnosis.


G-banding and array-CGH were applied to characterize the genetic abnormality in the three family members.


G-banding analysis revealed the affected child and the healthy mother are both carriers of inv(9)(p13q13), while the child has carried a chromosome fragment derived from chromosome 13. Array-CGH analysis indicated the derivative chromosome fragment has originated from 9p with breakpoints at around 9p13.1-p24.3.


Trisomy 9p13.1-p24.3 may be the cause of congenital malformation in the child. For its high resolution and high accuracy, array-CGH is a powerful tool for genetic analysis.



February 2012
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