Phenotypic Features Of Down Syndrome Research Articles

Double Autosomal Aneuploidy: A Case of Trisomy 18 and 21 Mosaicism in A Neonate with Clinical Down Syndrome

Background: Double aneuploidy is the phenomenon where two aneuploidies co-exist in the same individual, usually involving one autosomal chromosome and one sex chromosome. Double autosomal aneuploidy is rare and usually results in spontaneous abortions. There are only six published case reports of liveborn with trisomy 18 and trisomy 21 and all of which involve mosaicism. Case Presentation: This case report documents an infant born at 35 weeks with phenotypic features of Down Syndrome. However, cytogenetic analysis showed a mosaic of both trisomy 18 and 21. The patient initially had patent ductus arteriosus requiring operative closure and has congenital hypothyroidism. Conclusion: We describe five possible pathways leading to this phenomenon, including error during meiosis, meiotic nondisjunction, mitotic nondisjunction, sequential mitotic segregation and chimerism. This case report reiterates the significance of traditional cytogenetic analysis in children with features of Down Syndrome to detect any further abnormalities.

Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 21q11.2-q21.1 and a literature review

ObjectiveWe present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome (sSMC) derived from chromosome 21q11.2-q21.1, and we review the literature of an sSMC(21) with a duplication of 21q11.2-q21.1. Case reportA 40-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+mar [18]/46,XX [4]. The parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. aCGH analysis of cultured amniocytes revealed a 2.855-Mb duplication of 21q11.2-q21.1 encompassing the genes of LIPI, ABCC13 and NRIP1. Metaphase fluorescence in situ hybridization analysis on cultured amniocytes revealed a result of 47,XX,+mar .ish der(13/21) (D13/21Z1+) [10]. Spectral karyotyping analysis determined the origin of chromosome 21 in the sSMC. A female fetus was delivered with no phenotypic features of Down syndrome and no structural abnormalities. We discuss the genotype–phenotype correlation of LIPI, ABCC13 and NRIP1, and review the literature of an sSMC(21) associated with dup(21)(q11.2q21.1). ConclusionaCGH is useful for identification of the nature and genetic component of a prenatally detected sSMC.

Obstructive sleep apnoea/hypopnoea syndrome in adults with Down syndrome.

Key pointsAdults with Down syndrome are predisposed to obstructive sleep apnoea/hypopnoea syndrome (OSAHS) due to overlap between the Down syndrome phenotype and OSAHS risk factors.The prevalence of OSAHS in adults with Down syndrome is estimated at 35–42%. This is up to ten-times higher than in the general adult population.Symptoms of OSAHS, including behavioural and emotional disturbances as well as standard symptoms such as sleepiness, should be monitored as part of regular health surveillance in adults with Down syndrome.There is evidence that the use of continuous positive airway pressure (CPAP) therapy in adults with Down syndrome and comorbid OSAHS can lead to significant improvements in subjective sleepiness, behaviour and cognitive function, though further large-scale trials are required.Educational aimsTo discuss the relationship between the phenotypic features of Down syndrome and the risk factors for obstructive sleep apnoea/hypopnoea syndrome (OSAHS).To examine the prevalence of OSAHS in adults with Down syndrome.To review recent research into the effectiveness of treatment of OSAHS in adults with Down syndrome using continuous positive airway pressure (CPAP) therapy.Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is characterised by repeated cycles of upper airway obstruction during sleep, leading to diurnal symptoms. Individuals with Down syndrome are predisposed to OSAHS due to overlap between the Down syndrome phenotype and OSAHS risk factors. Recent large studies using subjective and objective measures estimate that OSAHS affects around 40% of adults with Down syndrome, in contrast to 2–4% of the general adult population. The “double-hit” of comorbid Down syndrome and OSAHS may accelerate cognitive decline in adults with Down syndrome. However, with the appropriate care and support, OSAHS can be treated effectively in this group using continuous positive airway pressure (CPAP) therapy, improving daytime function and behaviour. Symptoms of OSAHS should be routinely monitored in this population, with testing and treatment available to all adults with Down syndrome; however, this is not currently commonplace, and health inequalities are evident.

Self-concept in children with Down syndrome.

Self-concept is a critical indicator of quality of life but few studies have examined this subject in children with Down syndrome (DS). In this study, we propose a novel methodology to assess the self-concept of children with DS by analyzing their responses towards two dolls, one with a "typically developing" (TD) appearance and one with the phenotypic features of DS. Fifty-four children with DS participated in play sessions with both dolls and were then interviewed to assess doll preference, resemblance, and attribution of positive qualities. We observed that children with DS: (i) exhibited a preference for the TD doll regardless of age, gender, IQ or self-awareness; (ii) attributed more positive qualities to the TD doll than the DS doll; and (iii) believed that they resembled the TD doll, rather than the more phenotypically accurate representation of themselves. Older participants were more likely to exhibit self-recognition by this technique. These findings contribute to current understandings of how people with DS view themselves and their disability.

Premature Menarche Associated with Hashimoto Thyroiditis at 2 years 9 months: Case Report

Primary hypothyroidism is frequently associated with delayed puberty. However, precocious puberty is known to occur in some rare cases of hypothyroidism untreated for a long time. A female patient with Down syndrome aged 2 years and 9 months was referred with the symptom of vaginal bleeding continuing for 1 week. In her history, there were no symptoms suggesting trauma, foreign body, urinary tract infection or intracranial mass. The patient exhibited the phenotypic features of Down syndrome and her height and weight were within 5%-25% percentiles and 25%-50% percentiles, respectively, regarding the growth curves generated for children with Down syndrome. Breast development was at Tanner stage 3 bilaterally, and she had no axillary or pubic hairs. Suprapubic ultrasonography revealed cystic lesions in the right lower quadrant and left adnexial region. She was diagnosed with Hashimoto thyroiditis as result of the tests and was started on Na lthyroxine replacement therapy, and all examination findings relevant to precocious puberty and laboratory parameters returned to normal in the 6th month of the treatment.

Risk Factors for Early Death in Transient Myeloproliferative Disorder Without Phenotypic Features of Down Syndrome

Not only in newborns with Down syndrome, but newborns without phenotypic features of Down syndrome also develop transient myeloproliferative disorder (TMD). In these cases, trisomy 21 and related chromosomal abnormalities are either constitutionally mosaic or limited to blood cells. Risk factors for early death of these patients are unknown so far. We here report a fatal case of TMD without phenotypic features of Down syndrome and review literature to identify risk factors associated with early death. Not only are gestational age and white blood cell count risk factors for early death in TMD with Down syndrome, but they also appear to be risk factors in TMD without Down syndrome.

Skin involvement in Down syndrome transient abnormal myelopoiesis

A new-born baby girl with phenotypic features of Down syndrome presented with hepatosplenomegaly and a haemoglobin concentration (Hb) of 146 g/l, platelet count 73 9 10/l and white blood cell (WBC) count 39·1 9 10/l. Blood cytomorphology and immunophenotyping showed 50% circulating blasts. Constitutional trisomy 21 was confirmed by karyotyping and a diagnosis of transient abnormal myelopoiesis (TAM) associated with Down syndrome was made. GATA1 mutation screening using WAVE and direct sequencing of polymerase chain reaction products failed to show any of the known common mutations. During hospitalization she developed a generalized papular skin rash, the histology of which showed a superficial perivascular infiltrate of predominantly mononuclear cells with round to reniform nuclei and variable quantities of pale cytoplasm. No mitotic figures were identified but there was conspicuous apoptosis. Immunohistochemical stains were strongly positive for CD117 in the perivascular cell population, which showed patchy CD68 positivity. CD34, CD3, CD7, CD56, CD61 and toluidine blue stain were negative. The morphological and immunophenotypic features were consistent with involvement of skin by TAM. During follow up, she became progressively pancytopenic with her Hb dropping to 60 g/l and her platelet count falling to 20 9 10/l, requiring supportive transfusion. By the second month of life she continued to be thrombocytopenic, but her WBC count normalized, her bone marrow showed no excess of blasts and her liver returned to normal size. Her skin rash subsided over the same time period with no specific intervention. In the third month of life she developed rapidly progressive hepatic dysfunction and subsequently died despite intensive management. Limited post mortem examination showed no evidence of TAM in the liver but identified extensive hepatocellular necrosis including bridging necrosis and venoocclusive disease – features previously reported in TAM. Skin involvement in TAM is rare, as is the absence of a detectable mutation in haematopoietic gene GATA1. The failure in this case to detect a mutation in GATA1, especially with the high blast count at presentation, suggests an uncommon mutation may have been driving the TAM and be responsible for the atypical phenotype.

Embryonic Stem Cells from a Mouse Down Syndrome Model Have Impaired Proliferation and Increased Oxidative Stress.

Despite the fact that Down syndrome is the most common chromosomal birth defect, the pathogenesis of this disorder is still poorly understood. To develop a model for studying both the effects of this trisomy in pluripotent cells and the pathogenesis of this disorder in vitro, we recently established mouse embryonic stem cell (mESC) lines from a mouse Down syndrome model that carries the complex chromosomal rearrangement Rb(12.Ts171665Dn)2Cje. This chromosomal abnormality results in triplication of at least 6 Mb of proximal chromosome 17 and 13.9 Mb of distal chromosome 16. The triplicated region of 16 is syntenic with human chromosome 21 and confers many of the phenotypic features of Down syndrome. For mESC derivation, 50 blastocysts generated from trisomic females, which transmit this chromosomal abnormality to roughly half of their oocytes, were subjected to a standard derivation protocol using mESC culture medium supplemented with the MAP kinase/ERK kinase inhibitor PD98059. There was a significantly reduced derivation efficiency for trisomic relative to disomic lines (94% were disomic, n=17). Spectral karyotyping and chromosomal counts of the one trisomic and 2 disomic lines revealed over 60% of nuclei were diploid, and there were no unexpected structural chromosomal aberrations. Evaluation of the transcriptomes of these 3 lines using Illumina Mouse WG-6 arrays revealed that 69% of 115 evaluated genes from triplicated regions were overexpressed in the trisomic line relative to disomic lines with an average fold increase of 1.12. The trisomic line was also found to have a significantly slower rate of proliferation, larger average cell size and increased intracellular oxidative stress. Of note, superoxide dismutase-1 (Sod1), a gene in the triplicated region and implicated in the increased oxidative stress in Down syndrome individuals, was overexpressed by 1.54 fold in trisomic cells. This report describes the first trisomic embryonic stem cell line to be generated from this particular mouse model for Down syndrome. Furthermore, it reveals that many of the triplicated genes are overexpressed in trisomic cells at this early developmental stage, and these perturbations in gene expression have profound effects on cellular physiology. This research was supported by NCRR grant 3 P40 RR001183-32S1. (platform)

Double Trisomy 48,XXY,+21 in a Child With Phenotypic Features of Down Syndrome

Patient One-month-old male infant History of Present Illness The infant presented with dysmorphic features suggestive of Down syndrome and was referred for chromosomal analysis. Family History Patient was the fourth child of a consanguineous marriage and a product of normal gestation (39 weeks) and delivery. The mother’s and father’s ages were 43 and 45, respectively. The couple has 3 healthy sons. Physical Examination The proband delivered with body weight of 2.83 kg and length of 48 cm. He showed widely open fontanelle, microcephaly, flat occiput, slanting palpebral fissures, low set and malformed ears, protruding tongue, open mouth, hypotonia, short broad hand, clinodactyly, gap between first and second toes, and plantar furrow—all typical features of Down syndrome. The child was born also with cryptorchidism but normal penis size. Laboratory Findings Chromosomal analysis of proband revealed 48,XXY,+21 by karotyping and FISH technique ( Figures 1 and 2 ) with no evidence of mosaicism. Parental karyotypes were normal. 1. What are this patient’s most striking clinical and laboratory findings? 2. What is the frequency of double aneuploidy according to the literature? 3. What is the etiology and molecular basis of this patient’s syndrome? 4. What are the benefits in presenting such a case study? 1. A 1-month-old male infant with dysmorphic features suggestive of Down syndrome was referred for chromosomal analysis. This case …

Clinical profile of children with down syndrome treated in a genetics outpatient service in the southeast of Brazil

Considering that studies about the frequencies of phenotypic features of Down syndrome (DS) in the Brazilian population with large ethnic variability are scarce in literature, this study analyzed clinical and demographic characteristics of DS children from the Southeastern region of Brazil. Sixty-two DS children with free trisomy 21 were evaluated by physical examination using reference values that considered the children s gender and age at their presentation. Data about clinical complications were collected by retrospective analysis of the children's medical records and/or information supplied by their mothers. Statistical analysis was performed using Likelihood Ratio Test, with significance level less or equal to 5%. Clinical features observed in more than 90% of the individuals were flat facial profile, brachycephaly, slanted palpebral fissures, hypotonia at birth and flat nasal bridge. Congenital heart disease was present in 56.5% of the cases, verbal language acquisition disorder in 87%, and global delayed development in 77.8%. The comparison between our data and related literature showed a great variability of the phenotype features frequencies of DS among studies. Besides environmental factors, this can reflect individual as well as population characteristics.

The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase.

The Down syndrome critical region (DSCR) on Chromosome 21 contains many genes whose duplication may lead to the major phenotypic features of Down syndrome and especially the associated mental retardation. However, the functions of DSCR genes are mostly unknown and their possible involvement in key brain developmental events still largely unexplored. In this report we show that the protein TTC3, encoded by one of the main DSCR candidate genes, physically interacts with Citron kinase (CIT-K) and Citron N (CIT-N), two effectors of the RhoA small GTPase that have previously been involved in neuronal proliferation and differentiation. More importantly, we found that TTC3 levels can strongly affect the NGF-induced differentiation of PC12 cells, by a CIT-K-dependent mechanism. Indeed, TTC3 overexpression leads to strong inhibition of neurite extension, which can be reverted by CIT-K RNAi. Conversely, TTC3 knockdown stimulates neurite extension in the same cells. Finally, we find that Rho, but not Rho kinase, is required for TTC3 differentiation-inhibiting activity. Our results suggest that the TTC3-RhoA-CIT-K pathway could be a crucial determinant of in vivo neuronal development, whose hyperactivity may result in detrimental effects on the normal differentiation program.

GATA1 Mutations in Clonal Disorders of Children with and without Down Syndrome.

Down Syndrome (DS) children are 10–20 times folder likely to develop acute leukemia (AL) within the first four years of life compared to general pediatric population. Recently acquired somatic mutations in GATA1 gene on chromosome X have been described in most cases of DS AML and congenital TMD of DS carry the same type of mutations in exon 2 of GATA1. Here we report the preliminary results of GATA1 mutation in AL with and without DS children. The aim of this study is to provide insights in the relationships of GATA1 mutations and trisomy 21 in leukemogenesis process. GATA1 mutations were assayed in genomic DNA in 34 children with DS and AL, 2 with transient myeloproliferative disorder (TMD), 3 with myelodisplastic syndrome. Sequential sample including 2 pre-diagnosis in neonate period and 1 year before diagnosis were available in two children and 40 randomly selected DS children without known hematological disorder. A rare case of a non-DS neonate with TMD and clonal trisomy 21 were also examined. Genomic DNA was extracted and the exon 2 of GATA1 was PCR amplified as described by Wechsler et al. PCR products were sequenced in both directions and analyzed in a MegaBACE 1000 automated sequencer. Presently, GATA 1 mutations were found in 7 cases of AL, in all TMD cases with DS and none MDS case of DS. Interesting, a neonate girl with no phenotypic features of DS, but TMD features whose karyotype revealed 47, XX, +21/46, XX mosaics. A G-to-T transversion was detected which is predicted to result in a premature stop codon (c.119G>T; p.Glu67X) at the time of onset of TMD. However this same mutation was not detcted at 5 years of age.To our knowledge, this is the first reported case of TMD without DS with a detected GATA1 mutation. The presence of both somatically acquired abnormalities probably confers a proliferative advantage to the cell, resulting in TMD. We postulated in this case that both genetic abnormalities were temporary because of the non self-renewing nature of the progenitor that first had a non-disjunction event and this progenitor and the proliferative clone eventually disappeared. Therefore, even the proliferative advantage that the combination of trisomy 21 and GATA1 mutation confer, maintenance of these genetic changes are necessary for full leukemic transformation and persistence.

Down syndrome:: Clinical profile from India

Background Our objective was to study demographic features, clinical features, and karyotype analyses of patients with Down syndrome (DS). Our study design was a retrospective analysis, while the study was conducted in the Genetic Clinic of a tertiary-care teaching hospital. Methods Retrospective analysis of cases referred to the Genetic Clinic was performed. Case proformas of the patients presenting with phenotypic features of DS were analyzed. The following information was recorded from the proformas: age at presentation; sex; maternal age; craniofacial and other physical features; presence and type of congenital heart disease; gastrointestinal abnormalities, and results of cytogenetic evaluation. Clinical features in neonates with DS were separately analyzed. Results Analysis included cases of DS presenting over a period of 7.5 years; a total of 524 patients were studied (303 males and 221 females; M:F ratio 1.37:1). Average age at presentation was 19.4 months (range: 1 day–26 years). Average maternal age at birth of the affected child was 26.8 years (range: 16–45 years). Craniofacial features noted in >50% of the cases included mongoloid slant (83.9%), ear abnormalities (66.9%), epicanthic folds (56.9%), and flat facial profile (50.9%). A total of 76.3% cases had hypotonia. Characteristic limb and dermatoglyphic anomalies were seen in less than one half of cases. These included sandle sign (46.2%), unilateral or bilateral simian crease (33.2%), clinodactyly (36.1%), and brachydactyly (11.1%). Ophthalmologic abnormalities included hypertelorism (33.9%), nystagmus (3.2%), Brushfield spots (3.2%), squint (2.7%), and cataracts (1.9%). Congenital heart disease was clinically diagnosed in 96 cases (18.3%). The nature of the cardiac defect was ascertained by color Doppler examination and/or 2D-echocardiography in 58 cases. The most common cardiac anomalies were ventricular septal defect (25.8%), tetralogy of Fallot (15.5%), and atrial septal defect (12.1%). Gastrointestinal anomalies were noted in seven cases and included three cases with imperforate anus, two with Hirschsprung disease, and one each with duodenal atresia and Morgagni hernia. Results of cytogenetic abnormalities were available in 42.2%. Free trisomy (non-dysjunction) was present in 95%, 3.2% had translocation, and 1.8% were mosaics. In neonates, common features noted were mongoloid slant, ear abnormalities, flat facial profile, hypotonia, sandle sign, and clinodactyly±brachydactyly. Conclusions All characteristic craniofacial and physical features of DS need not be present in every case. Major features noted in the present study were mongoloid slant, ear abnormalities, epicanthic folds, flat facies, and hypotonia. Congenital heart disease was present in 18.3% of cases, with ventricular septal defect being the most common type of defect. Non-dysjunction was the most common cause of the chromosomal anomaly.

Regional and cellular specificity of the expression of TPRD, the tetratricopeptide Down syndrome gene, during human embryonic development

The TPRD gene (tetratricopeptide (TPR) containing Down syndrome gene) is one of the candidate genes in the Down syndrome chromosomal region-1. Duplication of this gene may be the cause of major phenotypic features of Down syndrome. Here we show that the TPRD expression is developmentally regulated during human embryogenesis. At the earliest stages of development (Carnegie 8–12) TPRD expression is ubiquitous. At later developmental stages (Carnegie stages 14, 16 and 18), it becomes restricted to the nervous system, as is the case for the mtprd gene during mouse development. We extended our analysis of TPRD expression during fetal development of the human nervous system (13, 22 and 24 weeks). A new oblique illumination technique was used to compare signal intensity and cell density. Some regions of the nervous system such as the external cortical layers of the brain, and the inner neuroblastic layer of the eye, strongly express the TPRD gene.

An Integrated Map with Cosmid/PAC Contigs of a 4-Mb Down Syndrome Critical Region

The major phenotypic features of Down syndrome have been correlated with partial trisomies of chromosome 21, allowing us to define the candidate gene region to a 4-Mb segment on the 21q22.2 band. We present here a high-resolution physical map with megabase-sized cosmid/PAC contigs. This ordered clone library has provided unique material for the integration of a variety of mappable objects, including exons, cDNAs, restriction sites, etc. Furthermore, our results have exemplified a strategy for the completion of the chromosome 21 map to sequencing.

Isolation and regional mapping of NotI and EagI clones from human chromosome 21

NotI and EagI boundary libraries were constructed for human chromosome 21. One hundred forty-seven clones were isolated from the somatic cell hybrid 72532X-6 and localized using a hybrid mapping panel. After identification of those clones, which were isolated more than once, as well as those probes derived from a previously unrecognized integrated non-chromosome-21 fragment, 58 individual boundary clones (plus 2 additional NotI- EcoRI clones isolated from a flow-sorted library) were localized to 11 separate regions. The distribution of these probes is highly nonrandom, with 50% of the clones located in the distal band 21q22.3. Two probes, Not50 and Eag101, map to regions in the very proximal long arm which may contain the gene responsible for familial Alzheimer's disease (AD1), and Not50 would appear to be more proximal than D21S16 (E9). Twenty-eight probes map to the region between superoxide dismutase (SOD1) and the ETS2 oncogene, which appears to contain genes responsible for many of the phenotypic features of Down syndrome. Twenty clones contain (GT) n repeats, as determined by hybridization to a CA polymer, and should provide additional highly polymorphic probes. Closure of gaps in the physical linkage map of chromosome 21 should be facilitated by the isolation of these probes, as they identify many of the unmethylated CpG-rich islands that have hindered pulsed-field gel analysis. They will also be useful in identifying a set of genes in proximity to NotI and EagI restriction sites, as well as conserved DNA sequences for comparative mapping studies.

The Alzheimer amyloid precursor protein maps to human chromosome 21 bands q21.105–q21.05

The Alzheimer amyloid protein precursor (APP) has previously been localized to human chromosome 21q11.2–q21. We have refined the regional localization to a small region including chromosome bands 21q21.105–q21.05 by using quantitative Southern blot analysis of cell lines aneuploid for parts of chromosome 21. Our findings exclude the APP gene from the minimal region producing the classical phenotypic features of Down syndrome. This further narrowing of the APP location will help in identifying the physical location of the gene causing familial Alzheimer disease.