DOWN SYNDROME CRITICAL REGION, INCLUDED
TRANSIENT MYELOPROLIFERATIVE DISORDER OF DOWN SYNDROME, INCLUDED
DCR, INCLUDED
LEUKEMIA, MEGAKARYOBLASTIC, OF DOWN SYNDROME, INCLUDED
DOWN SYNDROME CHROMOSOME REGION, INCLUDED
DSCR, INCLUDED
Trisomy 21
Down syndrome, the most frequent form of mental retardation caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history. It is caused by triplicate state (trisomy) of all or a ... Down syndrome, the most frequent form of mental retardation caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history. It is caused by triplicate state (trisomy) of all or a critical portion of chromosome 21.
During the second trimester of pregnancy, serum alpha-feto protein (AFP; 104150) is commonly used for evaluating the risk of Down syndrome. Decreased levels of AFP are indicative of Down syndrome. However, Petit et al. (2009) noted that a ... During the second trimester of pregnancy, serum alpha-feto protein (AFP; 104150) is commonly used for evaluating the risk of Down syndrome. Decreased levels of AFP are indicative of Down syndrome. However, Petit et al. (2009) noted that a congenital deficiency of AFP may result in decreased AFP in the maternal serum and amniotic fluid. They reported a male fetus with congenital absence of AFP, due to a truncating mutation (104150.0003), who showed normal growth and development. Tsui et al. (2010) showed that analysis of PLAC4 (613770) can aid in the noninvasive prenatal detection of trisomy 21 using maternal plasma samples. PLAC4 is transcribed from chromosome 21 in the placenta and is specific for the fetus in maternal plasma. One analytic method, termed the RNA-SNP approach, measures the ratio of alleles for a SNP in placenta-derived mRNA molecules in maternal plasma. The RNA-SNP approach detected the deviated RNA-SNP allelic ratio in PLAC4 mRNA caused by an imbalance in chromosome 21 dosage. In a study of 153 pregnant women, the diagnostic sensitivity and specificity using this method was 100% and 89.7%, respectively. In fetuses homozygous for the SNP, a second analytic approach was used, which quantifies circulating PLAC4 mRNA concentrations. Trisomy 21 pregnancies showed significantly increased plasma PLAC mRNA compared to unaffected pregnancies. The sensitivity and specificity of this method were 91.7% and 81.0% using real-time PCR, and 83.3% and 83.5% using digital PCR. The overall findings suggested that the synergistic use of these 2 methods will increase the yield of correct diagnosis of trisomy 21 using noninvasive methods.
Down syndrome (Down, 1866), a particular combination of phenotypic features that includes mental retardation and characteristic facies, is caused by trisomy 21 (Lejeune et al., 1959), one of the most common chromosomal abnormalities in liveborn children.
... Down syndrome (Down, 1866), a particular combination of phenotypic features that includes mental retardation and characteristic facies, is caused by trisomy 21 (Lejeune et al., 1959), one of the most common chromosomal abnormalities in liveborn children. It has long been recognized that the risk of having a child with trisomy 21 increases with maternal age (Penrose, 1933). For example, the risk of having a liveborn with Down syndrome at maternal age 30 is 1 in 1,000 and at maternal age 40 is 9 in 1,000 (Hook, 1982; Hook et al., 1983). Individuals with Down syndrome often have specific major congenital malformations such as those of the heart (30-40% in some studies), particularly atrioventricular septal defect (AVSD), and of the gastrointestinal tract, such as duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease (142623). Some of these clinical features have been incorporated into the preliminary phenotypic maps of chromosome 21 developed by Korenberg (1993), Korenberg et al. (1992), and Delabar et al. (1993). Leukemia (both ALL and AML) and leukemoid reactions show increased incidence in Down syndrome (Fong and Brodeur, 1987; Robinson, 1992). Estimates of the relative risk have ranged from 10 to 20 times higher than the normal population; in particular, acute megakaryocytic leukemia occurs 200 to 400 times more frequently in the Down syndrome than in the chromosomally normal population (Zipursky et al., 1987). Transient leukemoid reactions have been reported repeatedly in the neonatal period, and this phenotype has been tentatively mapped to the proximal long arm of chromosome 21 (Niikawa et al., 1991). Ninety percent of all Down syndrome patients have a significant hearing loss, usually of the conductive type (Mazzoni et al., 1994). For additional defects and phenotypic characteristics, see Epstein (1989). Patients with Down syndrome develop the neuropathologic hallmarks of Alzheimer disease at a much earlier age than individuals with Alzheimer disease without trisomy 21 (Wisniewski et al., 1985). Characteristic senile plaques and neurofibrillary tangles are present in the brain of all individuals with Down syndrome over the age of 40 years (Wisniewski et al., 1985). The triplication of the amyloid precursor protein gene (APP; 104760) may be the cause of this phenomenon. Several mutations in the APP gene have been described in families with early-onset Alzheimer disease without trisomy 21 (e.g., Goate et al., 1991). Castilla et al. (1998) performed an epidemiologic analysis of the association of polydactyly with other congenital anomalies in 5,927 consecutively born polydactyly cases. Trisomy 13, Meckel syndrome (249000), and Down syndrome explained 255 of the 338 syndromic polydactyly cases. Down syndrome was strongly associated with first-digit duplication, and negatively associated with postaxial polydactyly. In a retrospective study of high-altitude pulmonary edema performed at Children's Hospital in Denver, Durmowicz (2001) identified 6 of 52 patients as having Down syndrome. Five of the 6 children had preexisting illnesses including chronic pulmonary hypertension, existing cardiac defects with left-to-right shunt, or previous defects of left-to-right shunt that had been repaired. One child had Eisenmenger syndrome. Durmowicz (2001) suggested caution in traveling to even moderate altitudes with children with Down syndrome. To determine whether newborns with DS have decreased blood T4 (thyroxine; tetraiodothyronine) concentrations at the time of the neonatal screening, van Trotsenburg et al. (2003) conducted an observational study in a large and representative cohort of Dutch children with DS born in 1996 and 1997. Results of congenital hypothyroidism (CH) screening measuring T4, TSH (see 188540), and T4-binding globulin (314200) concentrations were analyzed in comparison with clinical information obtained by interviewing the parents and data from the general newborn population and a large control group. The mean T4 concentration of the 284 studied children with DS was significantly decreased. The individual T4 concentrations were normally (Gaussian) distributed but shifted to lower concentrations. Mean TSH and T4-binding globulin concentrations were significantly increased and normal, respectively. The decreased T4 concentration, left-shifted normal distribution, and mildly elevated TSH concentrations pointed to a mild hypothyroid state in newborns with DS and supported the existence of a DS-specific thyroid (regulation) disorder. In a case-control study, Tyler et al. (2004) found that the rate of symptomatic gallbladder disease was 25% among 28 index cases of adults with Down syndrome compared to 4.5% among sex-matched controls (p = 0.002). The adjusted relative risk for gallbladder disease among individuals with Down syndrome was 3.52. Henry et al. (2007) examined complete blood counts obtained in the first week of life from 158 consecutive neonates with Down syndrome and found that neutrophilia, thrombocytopenia, and polycythemia were the most common hematologic abnormalities, occurring in 80%, 66%, and 33% of patients, respectively. - Survival Zhu et al. (2013) studied survival among individuals with Down syndrome from the Danish population using a national cohort of 3,530 persons with Down syndrome identified from the Danish Cytogenetic Register and a reference cohort of persons without Down syndrome randomly selected from the general population followed from 1 April 1968 to 15 January 2009 by linkages to the Register of Causes of Death and the Civil Registration System. Overall, persons with Down syndrome had higher mortality than the reference cohort but to a lesser degree for persons with mosaic trisomy 21 than for persons with standard trisomy 21 or with Robertsonian translocations (hazard ratio 4.98 (95% CI 3.52-7.08), 8.94 (8.32-9.60) and 10.23 (7.50-13.97), respectively). Among persons with Down syndrome born after April 1968, more recent birth cohorts had lower mortality rates than older birth cohorts, which was largely due to declining mortality among persons with Down syndrome who also had congenital heart defects.
Lyle et al. (2009) used array comparative genomic hybridization to analyze 30 patients with anomalies of chromosome 21, including 19 with partial trisomy 21 and 11 with partial monosomy 21, all for different segments of the chromosome. They ... Lyle et al. (2009) used array comparative genomic hybridization to analyze 30 patients with anomalies of chromosome 21, including 19 with partial trisomy 21 and 11 with partial monosomy 21, all for different segments of the chromosome. They also examined the phenotypes of 5 patients with a Down syndrome-like phenotype with a normal karyotype and 6 with complete trisomy 21. The majority of the phenotypes mapped to distal 21; averaging the phenotype score indicated a region approximately 37 to 44 Mb, which was involved in most Down syndrome phenotypes. These results were not surprising, as this is the most gene-rich region of chromosome 21. Five patients were trisomic for proximal 21 and did not include the so-called Down syndrome critical region (DSCR), thus excluding the possibility there is a single DSCR responsible for all aspects of the phenotype.
Fuentes et al. (1995) cloned a gene (RCAN1; 602917), which they designated DSCR1, from the Down syndrome critical region that is highly expressed in brain and heart, and ... - Genes Within the Down Syndrome Critical Region Fuentes et al. (1995) cloned a gene (RCAN1; 602917), which they designated DSCR1, from the Down syndrome critical region that is highly expressed in brain and heart, and suggested it as a candidate for involvement in the pathogenesis of DS, in particular mental retardation and/or cardiac defects. Nakamura et al. (1997) identified DSCR4 (604829) as 2 ESTs that map to the 1.6-Mb Down syndrome critical region. DSCR4 is predominantly expressed in placenta. Vidal-Taboada et al. (1998) identified DSCR2 (605296) within the Down syndrome critical region 2 between DNA marker D21S55 and MX1. Nakamura et al. (1997) identified DSCR3 (605298) within the Down syndrome critical region. Using indexing-based differential display PCR on neuronal precursor cells to study gene expression in Down syndrome, Bahn et al. (2002) found that genes regulated by the REST (600571) transcription factor were selectively repressed. One of these genes, SCG10 (600621), which encodes a neuron-specific growth-associated protein, was almost undetectable. The REST factor itself was also downregulated by 49% compared to controls. In cell culture, the Down syndrome cells showed a reduction of neurogenesis, as well as decreased neurite length and abnormal changes in neuron morphology. The authors noted that REST-regulated genes play an important part in brain development, plasticity, and synapse formation, and they suggested a link between dysregulation of REST and some of the neurologic deficits seen in Down syndrome. Eggermann et al. (2010) reported a patient with a paternally inherited 0.46-Mb duplication of chromosome 21q22, including the KCNE1 (176261) and RCAN1 genes, who did not have typical facial or cardiac features of Down syndrome. The patient had a clinical phenotype resembling Silver-Russell syndrome (SRS; 180860), which is characterized by poor growth, but typical epigenetic changes associated with SRS were excluded. The duplication was inherited from the unaffected father. Eggermann et al. (2010) concluded that the RCAN1 gene is not sufficient for generating the phenotypic features associated with Down syndrome. - Acute Megakaryoblastic Leukemia of Down Syndrome Children with Down syndrome have a 10- to 20-fold elevated risk of developing leukemia, particularly acute megakaryoblastic leukemia (AMKL). Wechsler et al. (2002) showed that leukemic cells from individuals with Down syndrome-related AMKL had mutations in the GATA1 gene (305371). Look (2002) reviewed the mechanism by which GATA1 mutations might interact with trisomy 21 to result in AMKL. He pointed out that several lines of evidence indicated that at least 2 classes of mutations are needed to transform a normal hematopoietic stem cell into a clonal acute myeloid leukemia. One class imparts a myeloproliferative or survival advantage, as illustrated by activating mutations in FLT3 (136351), encoding a receptor tyrosine kinase, or the increased dosage of genes in chromosome 21 in persons with Down syndrome. To generate overt leukemia, a second class of genetic alterations must produce lineage-specific blocks in differentiation. The mutations responsible for this step have been demonstrated mainly in genes encoding chimeric transcription factors produced by chromosomal translocation. GATA1 is a transcription factor that plays a pivotal role in myeloid lineage commitment. - Transient Myeloproliferative Disorder of Down Syndrome As many as 10% of infants with Down syndrome present with transient myeloproliferative disorder (TMD) at or shortly after birth. TMD is characterized by an abundance of blasts within peripheral blood and liver, and undergoes spontaneous remission in a majority of cases. TMD may be a precursor to AMKL, with an estimated 30% of TMD patients developing AMKL within 3 years. Mutations in GATA1 are associated with AMKL of Down syndrome. To determine whether the acquisition of GATA1 mutations is a late event restricted to acute leukemia, Mundschau et al. (2003) analyzed GATA1 in DNA from TMD patients. They found that GATA1 was mutated in the TMD blasts from every infant examined. These results demonstrated that GATA1 is likely to play a critical role in the etiology of TMD, and mutagenesis of GATA1 represents a very early event in myeloid leukemogenesis in Down syndrome. Hitzler et al. (2003) likewise presented evidence that GATA1 mutations are an early event, and that AMKL arises from latent transient leukemia clones following initial apparent remission. All 7 patients reported by Mundschau et al. (2003) and almost all of the patients studied by Hitzler et al. (2003) had deletions or insertions in the GATA1 gene rather than nucleotide substitutions. Taketani et al. (2002) screened the RUNX1 gene (151385) in 46 Down syndrome patients with hematologic malignancies. They identified a heterozygous missense mutation (H58N; 151385.0008) in 1 patient diagnosed with TMD 5 days after birth. The patient died suddenly 12 months after birth; it was not known whether she developed acute myeloid leukemia. - Atrioventricular Septal Defects of Down Syndrome Given that mutations in the CRELD1 gene (607170) appear to be a risk factor for atrioventricular septal defect (AVSD) in the euploid population, and the fact that trisomy 21 is by far the most common finding associated with AVSD, Maslen et al. (2006) analyzed the CRELD1 gene in 39 individuals with Down syndrome and complete AVSD. They identified heterozygosity for missense mutations in 2 infants (607170.0001 and 607170.0005, respectively), and suggested that defects in CRELD1 may contribute to the pathogenesis of AVSD in the context of trisomy 21. Ackerman et al. (2012) used a candidate gene approach among individuals with Down syndrome and complete AVSD (141 cases) and Down syndrome with no congenital heart defect (141 controls) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. Ackerman et al. (2012) found a significant excess (p less than 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, they found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in 6 genes: COL6A1 (120220), COL6A2 (120240), CRELD1 (mutations in which have already been identified as a cause of AVSD; see 606217), FBLN2 (135821), FRZB (605083), and GATA5 (611496). Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGFA (192240) pathway, suggesting to Ackerman et al. (2012) that rare variants in this pathway might contribute to the genetic underpinnings of AVSD in humans. - Acute Lymphoblastic Leukemia of Down Syndrome Bercovich et al. (2008) identified somatic mutations in the JAK2 gene (147796) in 16 (18%) of 88 patients with Down syndrome-associated acute lymphoblastic leukemia. Only 1 of 109 patients with non-Down syndrome-associated leukemia had the mutation, but this child was also found to have an isochromosome 21q. All the JAK2-associated leukemias were of the B-cell precursor type. Children with a JAK2 mutation were younger (mean age 4.5 years) compared to patients without JAK2 mutations (8.6 years) at diagnosis. Five mutant JAK2 alleles were identified, each affecting a highly conserved residue: arg683 (i.e., R683G, R683S, R683K). In vitro functional expression studies in mouse hematopoietic progenitor cells showed that the mutations caused constitutive Jak/Stat activation and cytokine-independent growth, consistent with a gain of function. This growth was sensitive to pharmacologic inhibition with a JAK inhibitor. Modeling studies showed that arg683 is located in an exposed conserved region of the JAK2 pseudokinase domain in a region different from that implicated in myeloproliferative disorders. Bercovich et al. (2008) concluded that there is a specific association between constitutional trisomy 21 and arg683 JAK2 mutations that predispose to the development of B-cell ALL in patients with Down syndrome.