Down syndrome—A narrative review with a focus on anatomical features

Down syndrome (DS) is the most common aneuploidy of chromosome 21, characterized by the presence of an extra copy of that chromosome (trisomy 21). Children with DS present with an abnormal phenotype, which is attributed to a loss of genetic balance or an excess dose of chromosome 21 genes. In recent years, advances in prenatal screening and diagnostic tests have aided in the early diagnosis and appropriate management of fetuses with DS. A myriad of clinical symptoms resulting from cognitive, physical, and physiological impairments caused by aberrations in various systems of the body occur in DS. However, despite these impairments, which range from trivial to fatal manifestations, the survival rate of individuals with DS has increased dramatically from less than 50% during the mid‐1990s to 95% in the early 2000s, with a median life expectancy of 60 years reported recently. The aim of this narrative review is to review and summarize the etiopathology, prenatal screening and diagnostic tests, prognosis, clinical manifestations in various body systems, and comorbidities associated with DS. Clin. Anat. 29:568–577, 2016. © 2015 Wiley Periodicals, Inc.     

Trisomy 18/trisomy 13 mosaicism in an adult with profound mental retardation and multiple malformations

We report on an adult woman with profound mental retardation and multiple anomalies who consists of 3 cell lines: one with trisomy 18, one with trisomy 13, and a normal cell line. Her phenotype includes manifestations of both trisomy syndromes. The origin of these cell lines could have been a doubly aneuploid (48,XX+ 13, + 18) or singly aneuploid (47,XX + 18 or 47,XX, + 13) zygote with subsequent mitotic nondisjunctions, or a normal zygote with multiple mitotic nondisjunctions. There have been four previous reports of mosaicism involving both trisomy D and trisomy E; all died in the first six months of life. Two of these cases had a doubly aneuploid (48,XX, + D + E) cell line. Our patient illustrates the need for study of several tissues in patients with complex aneuploidy syndromes or atypical manifestations of a given syndrome (such as prolonged survival), as well as the need for caution in counseling families about prognosis for survival in autosomal trisomies which usually are lethal.     

Double aneuploidy involving trisomy 7 with Potter sequence

We report a prenatal case of double aneuploidy (consisting of chromosome 7 and X) with the features of Potter sequence. Of the stillborn fetus, skin fibroblast cultures were performed and fluorescence in situ hybridization (FISH) technique was also used for further investigation. On physical examination; the fetus was found to have malformed ears, micrognatia, hypertelorism, abnormal extremities, rocker-bottom feet and abnormal external genitalia and polycystic right kidney was seen after an extensive autopsy. As amniocentesis and cordocentesis materials revealed X chromosome mosaicism, trisomy 7 was detected in the skin fibroblast culture of the ex fetus and karyotype evaluated as composite; 46~47,X,+7,-X[cp18]. FISH results confirmed the double aneuploidy and also revealed XX and XXXX cell lines. Comparison with the previously reported cases of trisomy 7 with Potter syndrome suggests a possible link (if not coincidental) between trisomy 7 and Potter syndrome in our case. This is the first reported case of double aneuploidy involving trisomy 7 with the features of Potter syndrome.     

Population-based study of congenital heart defects in Down syndrome

Mental retardation and hypotonia are found in virtually all Down syndrome (DS) individuals, whereas congenital heart defects (CHDs) are only present in a subset of cases. Although there have been numerous reports of the frequency of CHDs in DS, few of the studies have had complete ascertainment of DS in a defined geographic area. The Atlanta Down Syndrome Project, a population-based study of infants born with trisomy 21, provides such a resource. In the first 6.5 years of the study, 243 trisomy 21 livebirths were identified in the five-county Atlanta area (birth prevalence: 9.6/10,000). Cardiac diagnoses were available on 227 (93%) of the cases and 89% of these evaluations were made by echocardiography, cardiac catheterization, surgery, or autopsy. Of the 227 DS infants, 44% had CHDs including 45% atrioventricular septal defect (with or without other CHDs), 35% ventricular septal defect (with or without other CHDs), 8% isolated secundum atrial septal defect, 7% isolated persistent patent ductus arteriosus, 4% isolated tetralogy of Fallot, and 1% other. This report is unique in that it contains the largest number of trisomy 21 infants ascertained in a population-based study where modern techniques for diagnosing cardiac abnormalities predominate. Am. J. Med. Genet. 80:213–217, 1998. © 1998 Wiley-Liss, Inc.     

Mosaic trisomy 22: A case presentation and literature review of trisomy 22 phenotypes

In a case of mosaic trisomy 22 the trisomic cells were detected primarily in fibroblasts. Results of initial lymphocyte chromosome analysis were normal. However, mosaicism was suspected because the patient had hypomelanosis of Ito, hemiatrophy, failure to thrive, and mental retardation. Mosaicism was confirmed in cultured fibroblasts. Repeat cytogenetic analysis of peripheral blood demonstrated a low level of trisomic metaphase cells, which was confirmed by interphase fluorescent in situ hybridization (FISH) analysis. Molecular studies supported maternal disomy in the child's disomic cells. The phenotype of this condition overlaps that of non-mosaic trisomy 22 chromosome mosaicism in general and to some extent the Ullrich-Turner syndrome phenotype. Improved cytogenetic and molecular techniques now allow better delineation of aneuploidy syndromes. Molecular and FISH studies added information about this case (mosaicism and uniparental disomy) not appreciated by routine cytogenetic analysis of lymphocytes. The detection of low-level mosaicism and/or uniparental disomy in such cases may change the clinical classification and our understanding of pathogenesis and recurrence risk of these disorders. Am. J. Med. Genet. 71:406–413, 1997. © 1997 Wiley-Liss, Inc.     

Two cases with partial trisomy 9p: Molecular cytogenetic characterization and clinical follow‐up

This paper describes two patients with partial trisomy 9p and partial trisomy 14q due to 3:1 segregation from de novo maternal reciprocal translocations. The breakpoints are different from previously described 9;14 translocations and their 3:1 segregation products. The clinical phenotype of both cases is compatible with the partial trisomy 9p syndrome. We present the follow‐up of both patients from birth up to age 7 years. Partial trisomy 9p is a frequently described chromosome abnormality. This does not appear to be related to a breakage sensitive locus on chromosome 9p, since the trisomic fragments of the published cases are heterogeneous. In the two cases described here, GTG‐banded karyotyping suggested that the 9p breakpoints were similar; DNA marker analysis, however, showed them to be different. Such DNA studies will be necessary to define the genotype‐phenotype relation in partial trisomy 9p syndrome. © 2002 Wiley‐Liss, Inc.     

Pure and complete 12p trisomy due to a maternal centric fission of chromosome 12

Pure and complete 12p trisomy are rare. Here, we report on a unique patient with trisomy 12p syndrome due to centric fission of maternal chromosome 12. Conventional cytogenetic and fluorescence in situ hybridization (FISH) techniques revealed the proposita's karyotype to be 47,XX,+fis(12)(p10)mat whereas the maternal one was 47,XX,-12,+fis(12)(p10),+fis(12) (q10). This is the first report on centric fission of chromosome 12 leading to stable telocentrics, each with a fully functional centromere. Our observation shows that the centric fission of chromosome 12 can be a new mechanism for generation of a partial centromere and trisomy 12p syndrome.     

Anatomy of trisomy 12

Trisomy 12 is a rare aneuploidy and fetuses with this defect tend to spontaneously abort. However, mosaicism allows this anomaly to manifest itself in live births. Due to the fact that mosaicism represents a common genetic abnormality, trisomy 12 is encountered more frequently than expected at a rate of 1 in 500 live births. Thus, it is imperative that medical practitioners are aware of this aneuploidy. Moreover, this genetic disorder may result from a complete or partial duplication of chromosome 12. A partial duplication may refer to a specific segment on the chromosome, or one of the arms. On the other hand, a complete duplication refers to duplication of both arms of chromosome 12. The combination of mosaicism and the variable duplication sites has led to variable phenotypes ranging from normal phenotype to Potter sequence to gross physical defects of the various organ systems. This article provides a review of the common anatomical variation of the different types of trisomy 12. This review revealed that further documentation is needed for trisomy 12q and complete trisomy 12 to clearly delineate the constellation of anomalies that characterize each genetic defect. Clin. Anat. 29:633–637, 2016. © 2016 Wiley Periodicals, Inc.     

Chromosome abnormalities in infants with prune belly anomaly: Association with trisomy 18

Two infants are described with “prune belly anomaly” (PBA) and concomitant trisomy 18. Severe abdominal distention was detected prenatally in one by ultrasonographic study, and in the second child at birth. Other chromosome abnormalities previously associated with PBA also are reviewed. The prune belly anomaly constitutes a malformation sequence that is causally nonspecific and which may occur in diverse aneuploidy syndromes. Aneuploidy is important to detect in prenatally diagnosed cases in which intrauterine fetal treatment is being considered.     

Microstructure of trabecular bone in a mouse model for down syndrome

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21) and results in a suite of dysmorphic phenotypes, including effects on the postcranial skeleton and the skull. We have previously demonstrated parallels in the patterns of craniofacial dysmorphology in DS and in the Ts65Dn mouse model for DS. The specific mechanisms underlying the production of these changes in craniofacial shape remain unknown. High‐resolution computed tomography scan data were collected for the presphenoid bone of euploid and aneuploid mice. Three‐dimensional morphometric parameters of trabecular bone were quantified and compared between euploid and aneuploid mice using nonparametric statistical tests. Aneuploid presphenoid bones were smaller than those of their euploid littermates and had lower bone volume fraction and fewer, more rod‐like trabeculae. The differences in cancellous bone structure suggest that bone development, perhaps including bone modeling and remodeling, is affected by aneuploidy. These differences may contribute to the observed dysmorphology of skull and postcranial skeletal phenotypes in DS. Anat Rec, 2007. © 2007 Wiley‐Liss, Inc.     

Seizures in trisomy 18: Prevalence,description, and treatment

Changes in medical intervention over the last decade have improved outcomes for individuals with trisomy 18, the second most common human aneuploidy syndrome at birth. As children with trisomy 18 live longer, a shared concern of medical experts and parents is the occurrence and treatment of seizures. Previously published surveillance guidelines for this condition have not addressed seizure management. Using parent-reported data collected as part of the Tracking Rare Incidence Syndromes project, we report on the prevalence, course, and management of seizures in individuals with trisomy 18. Twenty-eight percent (52/186) of individuals diagnosed with trisomy 18 in our retrospective cohort experienced generalized, focal, or mixed seizures at some point in their lifetime. For many individuals, seizures were effectively managed by broad-spectrum anti-seizure medications. Correlation analysis showed that focal and generalized seizures were more likely to occur in individuals who had previously experienced infantile spasms or central apnea. Electroencephalogram testing should be considered as part of a standard screening approach in individuals with trisomy 18 to enable early diagnosis and treatment of seizures. An international registry that incorporates parent-reported and clinical data for patients with trisomy 18 may facilitate ongoing research and recruitment into clinical trials for seizure management.     

Down syndrome with partial duplication and del (21) syndrome: study protocol and call for collaboration. Study I: clinical assessment

We report on the clinical and cytogenetic assessment of five cases of Down syndrome phenotype with either a partial duplication of chromosome 21 or a normal karyotype, and we quote a case of del (21q) syndrome. Down syndromes with a partial duplication of chromosome 21 (as well as cases of del (21q), which are partly the phenotypic countertype of trisomy 21) are of paramount importance in the understanding of genes involved in the phenotype of Down syndrome. The goal is to find the relevant genes implicated in the main traits of Down syndrome (i.e. mental retardation, Alzheimer disease, and serious visceral malformations). Such a goal, in our opinion, cannot be reached just by publishing the genotype and the phenotype of a small cohort of patients: 1. a sufficient number of accurate cases is needed, and 2. data have to be computerized for definite conclusions to be reached. The main aims of this report are to present our study protocol and to invite colleagues to participate in a collaborative study in order to collect a maximum of these (rare) cases.     

Molecular characterisation of partial chromosome 21 aneuploidies by fluorescent PCR

Although trisomy of chromosome 21 is the most prevalent human genetic disorder, data from partial 21 aneuploidies are very scanty. Eight different partial aneuploidies for chromosome 21 were characterised by fluorescence quantitative PCR. Allelic dosage analysis was performed for each patient using 25 CHLC STRs covering the entire q arm. The length of the corresponding trisomies and monosomies was ascertained for five partial trisomics and three partial monosomics. All trisomic patients carried unbalanced translocations involving chromosome 21, whereas one of the monosomic patients bore a ring chromosome 21 and another showed an interstitial deletion of chromosome 21. The chromosomal breakpoints of two partial trisomy patients could be clearly delimited. However, the other three trisomies involved most of the 21 q arm as three allelic doses were detected for each marker. Although these latter patients do not show all the features of Down syndrome, genotype/phenotype correlations agree with previously reported data. The chromosomal breakpoints observed in two partially monosomic patients helped further to define the region involved in different phenotypic features associated with chromosome 21 monosomy. Telomeric material loss was also detected in a patient bearing a ring 21 chromosome. The parental origin of the aneuploidy was assigned for each case, which allowed us to conclude that two of the monosomic cases originated from de novo chromosomal rearrangements. There was no correlation with parental sex in contrast to trisomic patients originating from meiotic nondisjunction.     

Maternal origin of a unique extra chromosome,der(9)(pter→q13::q13→q12:) in a girl with typical trisomy 9p syndrome

We report on a girl with the typical trisomy 9p syndrome who had an additional E‐sized metacentric chromosome. On the basis of GTG‐ and CBG‐banding, her karyotype was considered to be 47,XX,+der(9)(pter→q13::q13→q12:) de novo. Results of a fluorescence in situ hybridization study using a chromosome 9‐specific painting probe were compatible with this cytogenetic interpretation. Molecular analyses of six highly polymorphic dinucleotide repeat loci on the short arm and the proximal long arm of chromosome 9 demonstrated that the girl inherited one allele from her father and two identical or different alleles from the mother. We speculated that the extra chromosome may have resulted from either nondisjunction of chromosome 9 followed by a U‐type exchange and a crossing‐over between different sister chromatids during maternal meiosis I and subsequent breakage and malsegregation during meiosis II, or nondisjunction during meiosis II followed by isochromosome formation in one of the two maternal chromosomes 9 and subsequent breakage. © 2001 Wiley‐Liss, Inc.     

Partial trisomy 8 mosaicism due to a pseudoisodicentric chromosome 8

Chromosome 8 is the largest autosome in which mosaic trisomy is compatible with life. Constitutional trisomy 8 (T8) is estimated to occur in approximately 0.1% of all recognized pregnancies. The estimated frequency of trisomy 8 mosaicism (T8M), also known as Warkany syndrome, is about 1/25,000 to 50,000 liveborns, and is found to be more prevalent in males than females, 5:1. T8M is known to demonstrate extreme clinical variability affecting multiple systems including central nervous, ocular, cardiac, gastrointestinal, genitourinary, and musculoskeletal. There appears to be little correlation between the level of mosaicism and the extent of the clinical phenotype. Additionally, the exact mechanism that causes the severity of phenotype in patients with T8M remains unknown. We report on a mildly dysmorphic male patient with partial low-level T8M due to a pseudoisodicentric chromosome 8 with normal 6.0 SNP microarray and high resolution chromosome analyses in lymphocytes. The aneuploidy was detected in fibroblasts and confirmed by FISH in lymphocytes. This report elaborates further the clinical variability seen in trisomy 8 mosaicism.     

Mosaicism for a chromosome 8-derived minute marker chromosome in a patient with manifestations of trisomy 8 mosaicism

We describe a patient with manifestations of the mosaic trisomy 8 syndrome and mo-saicism for a minute marker chromosome. Fluorescence in situ hybridization (FISH) with a chromosome 8 probe confirmed that the marker was derived from chromosome 8. This is the smallest piece of chromosome 8 to be reported in a patient with mosaic trisomy 8 syndrome. When the clinical picture is strongly suggestive of trisomy for a specific chromosome region, we believe that FISH can be used to test markers in a guided, rather than random, fashion. © 1995 Wiley-Liss, Inc.     

Goldenhar sequence and mosaic trisomy 22

We describe a term infant with facioauriculo-vertebral “dysplasia” (Goldenhar sequence), hypertelorism, and mosaic trisomy 22: peripheral blood, 46, XY/47, XY, +22 (72%/28%); skin fibroblasts, 47, XY, +22 (100%). This is the second report of Goldenhar anomaly with epibulbar dermoids in a live-born infant with aneuploidy. Hypertelorism is rare in Goldenhar sequence, but typical of trisomy 22. We recommend chromosome analysis in all patients with Goldenhar sequence. Those with hypertelorism may be more likely to have aneuploidy as well. © 1995 Wiley-Liss, Inc.     

Features of trisomy 18 and 18p-syndromes in an infant with 46, XY, i(18q)

An isochromosome for the long arm of chromosome number 18 - 46,XY,i(18q) - was found in an infant who had features of both trisomy 18 and 18p- syndromes. Findings compatible with trisomy 18 included postmature delivery, prominent occiput, severe congenital heart disease, overlapping fingers, and rocker-bottom feet. Those of 18p- syndrome, which frequently resembles Turner syndrome, were downward obliquity to the palpebral fissures, short, webbed neck, low posterior hairline, and widely-spaced nipples. The infant died of heart failure at 3.5 months of age. Parental karyotypes were normal.     

无创性产前基因测序技术在染色体非整倍体中的应用

目的探讨高通量并行测序技术在胎儿染色体非整倍体检测中的应用价值。方法2012年10月至2013年4月,生化血清学筛查唐氏高危或高龄孕妇,采用高通量测序技术对胎儿染色体非整倍体进行无创性产前检测,评估患病风险率,提示高危孕妇进行核型分析确诊。结果813例无创检测高危孕妇,13例提示异常高危,异常率为1．59％,其中4例21三体,3例18三体,6例性染色体。核型确诊4例均为21三体,准确度100％;2例18三体;1例47,XXY和1例47,XXX。结论基于高通量测序技术的方法能快速、准确、无创检测唐氏综合征,相对18三体和性染色体检测准确度和稳定性有待优化与提高。     

Trisomy 4p in four relatives: variability and lack of distinctive features in phenotypic expression

We report two brothers and two second cousins with 4p trisomy secondary to a familial translocation t(4;7) (p12;q36). A comparison of their physical features demonstrates the variability of clinical manifestations associated with this chromosome abnormality. While previous authors have emphasized the distinctiveness of the 4p trisomy syndrome, the variability seen in the affected relatives in this family suggests that trisomy 4p is one of the less distinctive chromosomal syndromes. Further comparison of our patients with the previously reported cases of 4p trisomy and with two cases whose chromosomal breakpoints were similar confirms this variability. Studies of phenotype/karyotype correlations in affected relatives provides the best opportunity to determine the phenotypic consequences of a specific (that is, identical) translocation. Studies of unrelated persons are complicated by the effects of different breakpoints and of possible partial deletions.