Trisomy 21

This project investigates different aspects of craniofacial phenotypes exhibited in individuals with Down syndrome (DS), siblings of individuals with DS, and typically developing sibling pairs. A human sample (4-12 yrs.) consisting of 3D facial surface images (n = 55 for four separate samples: i.e. n = 220 overall) was used to explore developmental instability of the face and patterns of facial covariation between individuals with DS, their siblings, and typically developing sibling pairs. Morphometric analyses were used to infer how gene-dosage imbalance, caused by trisomy 21, is affecting DS craniofacial development. Overall we found increased fluctuating asymmetry in the faces of individuals with DS, which provides evidence for the "amplified developmental instability" model put forth by Shapiro (1975, 1983). However, the patterns of differences that we found suggest specific disruptions to regions of the face during craniofacial development rather than the generalized disruptions described by Shapiro under the amplified developmental instability model. Additionally, the results of our investigation found that covariation of facial metrics is different in DS individuals and in DS siblings relative to typically developing siblings. Based on differences in the pattern and strength of integration within and between facial regions in the DS and DS sibling samples, we put forth an "aneuploid conception model" to explain why facial integration is lowest in DS siblings and strengthened in DS relative to DS siblings.

In addition to the human-based analyses, micro-computed tomography (µCT) scans and morphometric analysis were employed to evaluate a complete genetic mouse model for DS - the Ts1Yey mouse. Morphometric comparison of craniofacial measures for Ts1Yey mice and euploid littermates (n = 12 for each sample) was done to determine if this model exhibits craniofacial differences similar to differences seen in humans with DS and in previously established DS mouse models. Overall, our results validate this mouse model for use in craniofacial DS investigations.

Leukemia Group B (CALGB 8461) : Presented in part at the 43rd annual patients with de novo acute myeloid leukemia: results from Cancer and success, cumulative incidence of relapse, and overall survival in adult Pretreatment cytogenetic abnormalities are predictive of induction http://bloodjournal.hematologylibrary.org/content/100/13/4325.full.html Updated information and services can be found at: (3716 articles) Clinical Trials and Observations Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests

We developed a bedside scoring system for diagnosis of trisomy 18 in the immediate neonatal period. Points are assigned for the presence of features known to occur in trisomy t8: five points for the presence of features previously reported in 500 or more of affected infants; three points for features reported to occur in between 10% and 50% of affected individuals; and one point for features known to occur in less than 10% of infants with the disorder. Using the scoring system, we evaluated two cohorts of patients: those in whom a diagnosis of trisomy 18 was previously established (retrospective group) and those in whom the diagnosis was suspected but not yet proved (prospective group). The average score in the retrospective series (n = 25) was 96.7, and no patient scored less than 70. Twenty,two patients were evaluated prospectively; in all cases the presence or absence of trisomy 18 was correctly predicted. The average score in the 11 patients without trisomy 18 was 4t.4, and all patients scored 60 or less. In the 11 patients confirmed to have trisomy 18, the average score was 94.3, with a range of 70 to 1t3. This scoring system is an accurate, reproducible method for predicting trisomy 18 in neonates with multiple congenital malformations. (J PEDIATR 1988;1t3:45-8)

| A considerable and unanticipated plasticity of the human genome, manifested as inter-individual copy number variation, has been discovered. These structural changes constitute a major source of inter-individual genetic variation that could explain variable penetrance of inherited (Mendelian and polygenic) diseases and variation in the phenotypic expression of aneuploidies and sporadic traits, and might represent a major factor in the aetiology of complex, multifactorial traits. For these reasons, an effort should be made to discover all common and rare copy number variants (CNVs) in the human population. This will also enable systematic exploration of both SNPs and CNVs in association studies to identify the genomic contributors to the common disorders and complex traits.

Periodontal disease is highly prevalent in Down syndrome (DS) individuals and is a significant cause of tooth loss in these individuals. Alterations in the immune system associated with poor oral hygiene, normally observed in these patients, are important contributing factors for the increased susceptibility to periodontal disease. The etiology of periodontal disease in DS is complex and more recently much focus has been placed in understanding the immune response alterations resulting from this genetic disorder. The purpose of this paper is to review the literature on the immunological alterations observed in Down syndrome patients and their relationship to periodontal disease. The increased incidence of periodontal disease in DS subjects relates to its genetic background. The reduced ability of the immune system to properly eliminate periodontal pathogens may be the main reason behind the increased susceptibility to periodontitis. Evaluation, treatment and monitoring of these patients as early as during the primary dentition can reduce the morbidity associated with periodontal disease.

Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by delays in social interactions and communication as well as displays of restrictive/repetitive interests. DNA copy number variants have been identified as a genomic susceptibility factor in ASDs and imply significant genetic heterogeneity. We report a 7-year-old female with ADOS-G and ADI-R confirmed autistic disorder harbouring a de novo 4 Mb duplication (18q12.1). Our subject displays severely deficient expressive language, stereotypic and repetitive behaviours, mild intellectual disability (ID), focal epilepsy, short stature and absence of significant dysmorphic features. Search of the PubMed literature and DECIPHER database identified 4 additional cases involving 18q12.1 associated with autism and/or ID that overlap our case: one duplication, two deletions and one balanced translocation. Notably, autism and ID are seen with genomic gain or loss at 18q12.1, plus epilepsy and short stature in duplication cases, and hypotonia and tall stature in deletion cases. No consistent dysmorphic features were noted amongst the reviewed cases. We review prospective ASD/ID candidate genes integral to 18q12.1, including those coding for the desmocollin/desmoglein cluster, ring finger proteins 125 and 138, trafficking protein particle complex 8 and dystrobrevin-alpha. The collective clinical and molecular features common to microduplication 18q12.1 suggest that dosage-sensitive, position or contiguous gene effects may be associated in the etiopathogenesis of this autism-ID-epilepsy syndrome.

Chromosome 11 abnormalities are found in many hematological malignancies. In acute myeloid leukemia (AML), a protooncogene MLL (11q23.3) is frequently altered. However, rearrangements involving other regions of chromosome 11 have been reported. Therefore, we have characterized the chromosome 11 breakpoints and common deleted and amplified areas in the bone marrow or peripheral blood cells of newly diagnosed patients with AML. Using molecular-cytogenetic methods (multicolor fluorescence in situ hybridization (mFISH), multicolor banding (mBAND), microarrays, and FISH with bacterial artificial chromosome (BAC) probes, chromosome 11 abnormalities were delineated in 54 out of 300 (18%) newly diagnosed AML patients. At least 36 different chromosome 11 breakpoints were identified; two were recurrent (11p15.4 in the NUP98 gene and 11q23.3 in the MLL gene), and three were possibly nonrandom: 11p13 (ch11:29.31-31.80 Mb), 11p12 (ch11:36.75-37.49 Mb) and 11q13.2 (68.31-68.52 Mb). One new MLL gene rearrangement is also described. No commonly deleted region of chromosome 11 was identified. However, some regions were affected more often: 11pter-11p15.5 (n ¼ 4; ch11:0-3.52 Mb), 11p14.1-11p13 (n ¼ 4; ch11:28.00-31.00 Mb) and 11p13 (n ¼ 4; ch11:31.00-31.50 Mb). One commonly duplicated (3 copies) region was identified in chromosomal band 11q23.3-11q24 (n ¼ 9; ch11:118.35-125.00 Mb). In all eight cases of 11q amplification (>3 copies), only the 5 0 part of the MLL gene was affected. This study highlights several chromosome 11 loci that might be important for the leukemogeneic process in AML.

Survival of cases of trisomy 13 (Patau's syndrome) into adulthood is a rare phenomenon. The purpose of this paper is to report one such survivor who has had the typical clinical features of trisomy 13 confirmed by chromosome analysis of both blood and skin, and to speculate on some of the factors that may have contributed to his unusually long survival.

cutoff of 1: 100, the estimated detection rate (DR) was 87.0% for trisomy 21 and 91.8% for trisomies 18 and 13, at a falsepositive rate (FPR) of 2.2%. Addition of PLGF, AFP and DV PIV increased the DR to 93.3% for trisomy 21 and 95.4% for trisomies 18 and 13 and reduced the FPR to 1.3%. Conclusions: Effective screening for trisomies can be achieved using specific algorithms based on NT, FHR, DV PIV, β-hCG, PAPP-A, PLGF and AFP.

Down syndrome was first medically described as a separate condition from other forms of cognitive impairment in 1866. Because it took so long for Down syndrome to be recognized as a clinical entity deserving its own status, several investigators have questioned whether or not Down syndrome was ever recognized before 1866. Few cases of ancient skeletal remains have been documented to have Down syndrome-like characteristics. However, several forms of material culture may depict this condition. Within this paper the history of our understanding of Down syndrome is discussed. Both skeletal remains and different forms of material culture that may depict Down syndrome are described, and where relevant, debates within the literature about how likely such qualitative diagnoses are to be correct are also discussed. Suggestions are then made for ways in which a quantitative diagnosis can be made to either strengthen or weaken qualitative arguments for or against the diagnosis of Down syndrome in different forms of historic material culture.

Recommended Citation
Starbuck, John M. (2011) "On the Antiquity of Trisomy 21: Moving Towards a Quantitative Diagnosis of Down Syndrome in Historic Material Culture," Journal of Contemporary Anthropology: Vol. 2: Iss. 1, Article 2.
Available at: http://docs.lib.purdue.edu/jca/vol2/iss1/2

Developmental data were abstracted from medical records on 50 trisomy 18 individuals ranging in age from 1 to 232 months and 12 trisomy 13 individuals ranging in age from 1 to 130 months. Data on the age when trisomy 18 and trisomy 13 children achieved developmental skills were collected from a larger group of 62 trisomy 18 individuals and 14 trisomy 13 individuals whose families filled out parent questionnaires. Developmental quotient (DQ), defined as developmental age divided by chronological age, averaged 0.18 for trisomy 18 and 0.25 for trisomy 13. There was a dramatic drop in DQ from infancy to later childhood. The highest DQs and the greatest variation in DQs were in the first 2-3 years of life. Developmental ages in 7 skill areas were significantly different, with daily living and receptive language having the highest values and motor and communication skills having the lowest. When chronological age was taken into account, there was no significant difference in DQs in the same 7 skill areas, although there was a trend that was similar to the pattern of differences with developmental age. Older children could use a walker, understand words and phrases, use a few words and/or signs, crawl, follow simple commands, recognize and interact with others, and play independently. Walking and some toileting skills were also reported for trisomy 13. Although individuals with trisomy 18 and trisomy 13 were clearly functioning in the severe to profound developmentally handicapped range, they did achieve some psychomotor maturation and always continued to learn.

Trisomy of 15q26-qter is frequently associated with tall stature and mental retardation. Here we describe a patient with such trisomy, without a partial monosomy of another chromosome. The tall stature in this patient is most probably caused by duplication of the IGF1R gene. A duplication of the IGF1R gene is not a frequent finding in patients with tall stature. In 38 patients with features of Sotos syndrome without NSD1 alterations, a duplication was found only once. This patient was already known to have an unbalanced 2;15 translocation. Looking for a duplication of the 15qter region is still worth consideration in patients with tall stature and features of Sotos syndrome without an NSD1 alteration, especially when there is craniosynostosis or marked speech delay.

Clinical and cytogenetic data of two related patients, both trisomic for the segment 4q27→qter, are reported. Familial studies determined that the mothers of the two probands were carriers of the same balanced translocation between chromosomes 4 and 18. Altogether, two partial trisomies 4q, five balanced karyotypes, and one 45,XO karyotype were found in the family. The 18 cases reported to date are reviewed with respect ot the karyotype-phenotype correlation.

Partial trisomy 16 is rare and most of the reported cases are secondary to chromosome rearrangements resulting in concurrent monosomies or trisomies of a second chromosome. Only a few patients survive the neonatal period and the duplication of the long arm seems to be mainly responsible for the prenatal lethality of the full trisomy 16. The reported patients with a partial 16q trisomy have a wide spectrum of congenital anomalies that include dysmorphic features, central nervous system malformations, failure to thrive, and club feet. The patients with duplications of proximal 16q frequently have short stature, developmental delay, speech delay, learning difficulties, and mild to severe behavioral problems. Here we describe a patient with an inverted de novo tandem duplication of 16q with breakpoints evaluated in detail by molecular-cytogenetic techniques. Main clinical features include postural, motor and speech delay with severe learning difficulties and behavioral problems, obesity, microcephaly, and mild dysmorphic features. In the report we attempt to classify the few reported patients with pure partial duplications of 16q in more narrow and homogeneous groups: proximal, proximal-intermediate, intermediate, and intermediate-distal duplications. Moreover, we emphasize the importance of proper cytogenetic investigation and complete molecular cytogenetic refinement in all cases with a suspected chromosomal anomaly.

K E Y W O R D S: aneuploidy; ductus venosus; first trimester; genetic sonogram; nasal bone; nuchal fold; second trimester; tricuspid regurgitation; trisomy 21 ABSTRACT Objective To investigate the performance of nuchal fold thickness, nasal bone hypoplasia, reversed flow in the ductus venosus and tricuspid valve regurgitation in the prediction of fetal aneuploidies in the early second trimester. Methods This was a prospective study of 870 fetuses at 14 + 0 to 17 + 6 weeks of gestation, performed from 2005 to 2007. In all cases we assessed classical structural anomalies, second-trimester markers of aneuploidy including nuchal fold thickness and nasal bone length, as well as ductus venosus blood flow pattern and tricuspid valve regurgitation. Results The study group included 37 fetuses with trisomy 21, eight with trisomy 18 and four with trisomy 13. Nasal bone hypoplasia was the single most sensitive parameter to identify fetuses with trisomy 21. Independent from maternal age, screening by assessment of nuchal fold and nasal bone identified 64.9% of cases with trisomy 21 and 66.7% of cases with trisomy 18/13 (false-positive rate (FPR), 5.8%). By including ductus venosus and tricuspid flow evaluation, the detection rate increased to 75.7% for trisomy 21 and 83.3% for trisomy 18/13 (FPR, 10.8%). Identification of fetuses with structural abnormalities combined with assessment of all four markers under investigation raised the detection rate of trisomy 21 to 83.9% and that of trisomy 18/13 to 100%. The sensitivity of classical second-trimester markers was 62.2% for trisomy 21 and 70.6% for other autosomal aneuploidies (FPR, 11.3%).

Partial duplication of 11q is related to several malformations like growth retardation, intellectual disability, hypoplasia of corpus callosum, short nose, palate defects, cardiac, urinary tract abnormalities and neural tube defects. We have studied the clinical and molecular characteristics of a patient with severe intellectual disabilities, dysmorphic features, congenital inguinal hernia and congenital cerebral malformation which is referred to as cytogenetic exploration. We have used FISH and array CGH analysis for a better understanding of the double chromosomic aberration involving a 7p microdeletion along with a partial duplication of 11q due to adjacent segregation of a paternal reciprocal translocation t(7;11)(p22;q21) revealed after banding analysis. The patient's karyotype formula was: 46,XY,der(7)t(7;11)(p22;q21)pat. FISH study confirmed these rearrangement and array CGH technique showed precisely the loss of at least 140 Kb on chromosome7p22.3pter and 33.4 Mb on chromosome11q22.1q25. Dysmorphic features, severe intellectual disability and brain malformations could result from the 11q22.1q25 trisomy. Our study provides an additional case for better understanding and delineating the partial duplication 11q.

Background. Although the Spitz classification is the most widely used prognostic classification for esophageal atresia and/or tracheoesophageal fistula (EA), its discrimination ability remains unclear. We sought to develop a more accurate prognostic classification for EA. Methods. The records of 121 consecutive infants with EA (1980EA ( --2005 were reviewed. The independent variables included 6 clinical characteristics, and the dependent variables were survival and mortality.

We report on the case of a male child with autistic disorder, postnatal overgrowth, and a minor brain malformation. Karyotyping and fluorescent in situ hybridization (FISH) analysis showed the presence of an extra copy of the distal portion of chromosome 15q (15q25.2-qter) transposed to chromosome 15p leading to 15q25.2-qter pure trisomy. This karyotype-phenotype study further supports the evidence for a specific phenotype related to trisomy 15q25 or 26-qter and suggests that distal chromosome 15q may be implicated in specific behavioral phenotypes.