Children With Down Syndrome Can Learn
Figure 17.35 Down syndrome, weight, North American females, birth to three years. Adapted from Cronk et al. (1988) and http www.growthcharts.com . Figure 17.36 Down syndrome, weight, North American females, 2 to 18 years. Adapted from Cronk et al. (1988) and http www.growthcharts.com . Figure 17.36 Down syndrome, weight, North American females, 2 to 18 years. Adapted from Cronk et al. (1988) and http www.growthcharts.com . Figure 17.37 Down syndrome, head circumference, North American males, birth to three years. Adapted from Palmer et al. (1992) and http www.growthcharts.com . Figure 17.37 Down syndrome, head circumference, North American males, birth to three years. Adapted from Palmer et al. (1992) and http www.growthcharts.com . Figure 17.38 Down syndrome, head circumference, North American females, birth to three years. Adapted from Palmer et al. (1992) and http www.growthcharts.com . Figure 17.38 Down syndrome, head circumference, North American females, birth to three years....
Most affected children have 47 chromosomes with an extra chromosome 21.194 About 5 have 46 chromosomes with a translocation involving chromosome 13, 14, or 15, with 14 being most frequent, or a Robertsonian translocation involving either chromosome 21 or 22 (G group), with 21 being most frequent. The translocation may be inherited from a phenotypically normal parent with 45 chromosomes. There are no clinical differences between children with Down's syndrome caused by trisomy 21 or by a translocation. The overall incidence of Down's syndrome is 1 in 700 live births and is age dependent. The risk increases with increasing maternal age. The recurrence risk for parents of a child with Down's syndrome is about 1 if both parents have normal chromosomes. In the event of a parental translocation, the risk is higher if the mother is the carrier in the rare case of a 21 21 translocation in a parent, all the offspring will have Down's syndrome (see Fig. 3-7). Mosaicism for trisomy 21 is common....
Over 90 of these cases, the extra chromosome is of maternal origin, due to nondisjunction during meiosis (Hassold, Chiu, & Yamane, 1984 Sherman et al., 1991 Stewart et al., 1988). Translocation of chromosome 21 material to another chromosome (usually 13 or 18) and mosaicism (transmission of a cryptic trisomy 21 cell line from an unaffected parent) are rare causes of DS (Hook, 1982 Staples, Sutherland, Haan, & Clisby, 1991).
Remarks The posterior fontanelle is usually closed in neonates and only 3 percent of normal newborn infants have a posterior fontanelle that measures more than 2 cm. A third (or parietal) fontanelle may be found in about 5 percent of normal infants about 2 cm anterior to the posterior fontanelle. It occurs with greater frequency in Down syndrome and in congenital rubella syndrome. Fig. 7.30 shows normal values for posterior fontanelle size in African American and Caucasian American children at birth.
Triple screen (multiple marker screening). In women under age 35 years, screening for fetal Down syndrome is accomplished with a triple screen. Maternal serum alpha-fetoprotein is elevated in 2025 of all cases of Down syndrome, and it is elevated in fetal neural tube deficits. Levels of hCG are higher in Down syndrome and levels of unconjugated estriol are lower in Down syndrome. 2. If levels are abnormal, an ultrasound examination is performed and genetic amniocentesis is offered. The triple screen identifies 60 of Down syndrome cases. Low levels of all three serum analytes identifies 60-75 of all cases of fetal trisomy 18.
Table 11.2 lists the conditions that have been documented as predisposing to development of AML. The high incidence of individuals having congenital defects such as Down syndrome and bone marrow failure syndromes such as Fanconi's anemia has demonstrated that these factors are often implicated in the pathogenesis of Down syndrome
Hair directional slope is secondary to the plane of stretch exerted on the skin by the growth of underlying tissues during the period of down-growth of the hair follicles at around 10-12 weeks gestation. The posterior parietal hair whorl is interpreted as the focal point from which the growth stretch is exerted by the dome-like out-growth of the brain during the time of hair follicle development. Malformations that antedate hair follicle development, such as encephalocele, produce aberrations in scalp patterning. Eighty-five percent of patients with primary microcephaly have altered scalp hair patterning, indicating an early onset of abnormal brain development. Aberrant scalp patterning is also found frequently in association with established syndromes including Down syndrome. Thus, aberrant scalp hair patterning may be utilized as an indicator of altered size and or shape of the brain prior to 12 weeks gestation. Early anomalies in development of the eye and of the face can...
ANEUPLOIDY is the addition of one chromosome (trisomy) or loss of one chromosome (monosomy). Trisomy usually results in spontaneous abortion of the conceptus however, trisomy 13 (Patau's syndrome), trisomy 18 (Edwards' syndrome), trisomy 21 (Down syndrome), and Klinefelter's syndrome (47, XYY) are found in the liveborn population. Monosomy usually results in spontaneous abortion of the conceptus however, monosomy X chromosome (45, X Turner's syndrome) is found in the liveborn population. Aneu-ploidy occurs as a result of nondisjunction during meiosis (Figure 22-1). C. Trisomy 21, or Down syndrome (Figure 22-2 A-C), is characterized by moderate mental retardation, microcephaly, microphthalmia, colobomata, cataracts and glaucoma, flat nasal bridge, epicanthic folds, protruding tongue, simian crease in the hand, and congenital heart defects. Alzheimer's neurofibrillary tangles and plaques are found in Down syndrome patients who are older than 30 years. Acute megakaryocyte leukemia...
Thenar, hypothenar, and hallucal patterns Patterns may be present in the thenar and hypothenar areas of the palm. Unusual patterns may be helpful in making a specific diagnosis. A lack of ridges in the hypothenar region of the palm can be seen in Cornelia de Lange syndrome. On the soles of the feet, in the hallucal area, a pattern (loop or whorl) is usually seen. If no pattern is present (i.e., there is an arch), the hallucal area is said to have an open field. Open hallucal fields are very rarely found in normal individuals, but are present in about 50 percent of patients with Down syndrome. Radial loops on the fourth and fifth finger are unusual in normal individuals (1.5 percent) but are common in individuals with Down syndrome (12.4 percent).
A woman aged forty receives genetic counseling before having an amniocentesis performed. She understands that her risk of carrying a fetus that has trisomy 21 Down syndrome is 1 in 106, but she is confused when the counselor explains that the risk of any aneuploid is 1 in 66. What does this mean
Brushfield spot Mottled, marbled, or speckled elevation of the iris due to increased density of the anterior border layer of the iris white or light yellow iris nodule caused by deposition or aggregation of stromal fibrocytes observed in 85 percent of patients with Down syndrome. Can be noted in the normal population (about 25 percent). buphthalmos Congenital glaucoma keratoglobus, or enlargement of the eye.
A single palmar crease (fusion of FFC and TFC) can be found unilaterally in 4 percent of the normal population and bilaterally in 1 percent of normal individuals. It is twice as common in males as in females. Single palmar creases are seen with increased frequency in Down syndrome.
Cronk, C., Crocker, A.C., Pueschel, S.M., Shea, A.M., Zackai, E., Pickens, G., and Reed, R.B. (1988). Growth charts for children with Down syndrome 1 month to 18 years of age. (1988). Pediatrics, 81, 102-110. Palmer, C.G., Cronk, C., Pureschel, S.M., Wisniewski, K.E., Laxova, R., Crocker, A.C., and Pauli, R.M. (1992). Head circumference of children with Down syndrome (0-36 months). American Journal of Medical Genetics, 42, 61-67. Richards, G. Growth charts for children with Down syndrome. Available at http www.growthcharts.com . Accessed March 30, 2006.
In the study of syndromes with dysmorphic features, we are looking for recognizable signs that help to define and delineate the specific condition. Those recognizable features may be quite different during different life periods. Using Down syndrome as an example, from embryofetal pathology we have learned that manifestation of the Down syndrome phenotype in a fetus depends on the gestational week, and often very few features are present until near birth. Similarly, there is a changing phenotype during childhood and into adulthood, with the typical phenotype of Down syndrome sometimes becoming hard to recognize in the adult.
Moreover, the brain of primates contains specific astroglial cells, which are absent in other vertebrates (Figure 4.2). Most notable of these are the interlaminar astrocytes, which reside in layer I of the cortex this layer is densely populated by synapses but almost completely devoid of neuronal cell bodies. These interlaminar astrocytes have a small cell body ( 10 m), several short and one or two very long processes the latter penetrate through the cortex, and end in layers III and IV these processes can be up to 1 mm long. The endings of the long processes create a rather unusual terminal structure, known as the 'terminal mass' or 'end bulb', which are composed of multilaminal structures, containing mitochondria. Most amazingly, the processes of interlaminar astrocytes and size of 'terminal masses' were particularly large in the brain of Albert Einstein although whether these features were responsible for his genius is not really proven. The function of these interlaminar...
The etiology of ALL is unknown in the vast majority of cases. Environmental agents, such as ionizing radiation and chemical mutagens, have been implicated, and there is evidence to suggest a genetic factor in some patients. Children with Down syndrome have an increased risk of leukemia, particularly precursor B lymphoblastic leukemia. There is a higher frequency of childhood ALL in industrialized countries compared with in developing countries. It has also been postulated that some cases of childhood leukemia stem from an adverse cellular response to common infections that occur at a later time than was typically experienced in past centuries.45,46 These delayed exposures are believed to increase the risk of genetic mutations in the lymphoid precursors, leading to the development of leukemia.
We are all products of a sperm fertilizing an egg. Humans have twenty-two pairs of chromosomes, plus the sex chromosomes. After meiosis, the sperm should have twenty-two chromosomes plus either the X or Y chromosome, and the egg should have twenty-two chromosomes plus an X chromosome (see figure 7.1). But sometimes, errors occur in the process of meiosis, and a given gamete is either missing a chromosome or has more than one copy of a particular chromosome. . When this happens, and the egg or sperm that has an aberrant number of chromosomes is involved in making a new individual, of course, that individual will have a wrong number of chromosomes. Because there are so many genes on each chromosome, such errors would be expected to be very deadly. A great majority of fetuses with abnormal chromosome numbers do not survive to birth. Thus, chromosomal abnormalities explain some cases of infertility and pregnancy loss. Indeed, up to 50 percent of first-trimester spontaneous abortions are...
Down syndrome disease Transient abnormal myelopoiesis (TAM) Myeloid leukemia of Down syndrome MDS does not reflect the hematological and clinical picture of MDS in childhood. To account for the special features of MDS in children, an international consensus on a pediatric modification of the WHO classification has been proposed (Table 7.1) (Hasle et al. 2003). Myelodysplastic and myeloproliferative disorders in children are separated into three main groups JMML, MDS, and Down syndrome. JMML is a unique disorder of infancy characterized by a hyperactive RAS signaling pathway due to molecular aberrations in the genes encoding for SHP-2, RAS, or neurofibromatosis type 1. MDS in Down syndrome in the first 5 years of life is not biologically different from AML in these patients. The unifying term myeloid leukemia of Down Syndrome is proposed for this disorder, and patients should be excluded from MDS series.
Chromosomal anomalies may be numerical or structural. Structural changes result from the breakage and rearrangement of chromosome parts, and animal experiments have shown that they can be induced by a variety of exposures, including ionizing radiation and certain viral infections and toxic substances. They occur as duplications, deletions, translocations, insertions, or inversions of chromosome parts or as rings on selected chromosomes. Numerical anomalies arise through nondisjunction during meiosis or mitosis, through lagging of chromosomes at anaphase of cell division, or through fertilization by two sperm (i.e., triploidy). Chromosomal anomalies as a whole contribute more to fetal loss than to live births and MR. Kline, Stein, and Susser (1989) estimated that from 8 weeks after the last menstrual period, the proportion of chromosomal aberrations lost by miscarriage exceeds 90 for all but trisomy 21 (DS), XXX, XXY (Klinefelter syndrome), and XYY. In survivors after birth in...
There not only are differences between children with cultural-familial MR and those with organic MR, but among the different genetic disorders that produce cognitive impairment as well. Hodapp et al. (63) found that individuals with fragile X syndrome (FXS) exhibit sequential processing deficits on the K-ABC, while individuals with Down syndrome (DS) do not. Children with Williams syndrome (WS) seem to show remarkable expressive language skills given their typical level of MR (64), although other researchers have found similar cognitive-behavioral profiles between children with WS and age-matched children with FXS, despite the obvious phe-notypic differences between the two genetic disorders (65).
Most cases of early-onset AD arise sporadically, but others are inherited, usually in polygenic fashion, although in a few families there is a dominant gene. Mutations in the amyloid precursor protein (APP) gene on chromosome 21 have been found in a few affected families. APP is implicated in the formation of senile plaques, one of the key neuropathological findings in AD. The role of APP ties in with the well-known increased rate of AD in trisomy 21 (Down's syndrome) patients.
Down's syndrome is caused by one of two conditions, trisomy 21 or translocation of chromosome 21. It is the most common specific cause of LD, occurring in 1 per 650 pregnancies. Trisomy 21 does not generally run in families, but becomes more frequent with increasing maternal age, as shown in the following table Frequency of trisomy 21 (per 1000 births)
The earliest days of cancer genetics began with the analysis of metaphase chromosomes by light microscopy for gross chromosomal abnormalities. With the exception of point mutations, most of the alterations listed above could be detected this way. Aneuploidy is the loss or gain of chromosome number. In its simplest form, this involves loss or gain of a single chromosome (e.g., trisomy 21 or monosomy 7) (Fig. 1a). More complex chromosome anomalies, such as amplifications, deletions, and translocations have been characterized in greater detail by cytogenetic analysis of the banding patterns of metaphase chromosomes. For example, in a translocation, a new chromosome is formed by the fusion of fragments of two different chromosomes, which may be clearly demonstrated by comparing the banding pattern of the new chromosome with that observed in the contributing normal chromosomes (Fig. 1b).
Since one of the most common causes of maternal UPD15 is trisomy 15 rescue, the possibility of advanced maternal age, similar to that of trisomy 21 (Antonarakis et al., 1993), has been examined in these cases. Nondisjoined chromosomes 15 from 115 cases of maternal UPD15 (ascertained through Prader-Willi syndrome) and 13 cases of trisomy of maternal origin were densely genotyped for microsatellite loci
Animal models of human diseases can enhance our understanding of the etiology and progression of a particular disorder and enhance the design of therapeutic strategies. With technical advances in the manipulation of the mouse genome, several transgenic models of human diseases have emerged (see Bedell et al., 1997, for a recent review). These include animal models of cancer (Adams and Cory, 1991 Kappel et al., 1994 Lovejoy et al., 1997), neurodegenerative disorders (Aguzzi et al., 1996 Brown, 1995), atherosclerosis (Bres-low, 1996 Chien, 1996), diabetes (Tisch and McDevitt, 1996), cardiovascular disease (Chien, 1996), Down syndrome (Cabin et al., 1995 Groner, 1995 Mirochnitchenko and Inouye, 1996 Sumar-sono et al., 1996), and others.
A recent multimethod study provides a clear example of the utility of the narrative approach. Parents of children with Down syndrome were contacted through a support group mailing list as well as through area hospitals (King, Scollon, Ramsey, & Williams, 2000). The parents were initially asked self-report questions concerning well-being, administered a projective test of ego development, and asked to write a story about when they were first told that their child had Down syndrome. Two years after the initial assessment, parents again responded to self-report measures of well-being and a projective measure of ego development. The narratives were assessed by three independent raters for themes of accommodation (exploration, shifts in perspective, activity) and closed (denial, negative affect). Parents who were low in ego development at Time 1 who wrote in an accommodative manner demonstrated increased ego development 2 years later. Parents who wrote narratives in both an accommodative...
Down Syndrome As a result of its relatively high prevalence and distinct cranio-facial features, Down syndrome (DS) is perhaps the most widely recognized genetic syndrome (1). DS is almost always caused by a complete trisomy of chromosome 21 that results from a non-disjunction event, usually with a maternal origin (2). Occurring once in approx 800 live births, DS is the most common genetic cause of mental retardation. In addition to low IQ scores, problems related to memory, language, speech, and motor coordination are frequently reported (3-6).There is now a renewed interest in DS because persons with this condition are at an increased risk for developing Alzheimer-like dementia beginning at a young age.
Although increasing maternal age has long been known to be associated with an increased incidence of birth defects, new data show that the age of the male does matter and the genetic quality of sperm does decline with age. Several studies have demonstrated that older men are at higher risk of fathering a child with various genetic diseases such as schizophrenia and Down Syndrome, to name a few. Additionally, there has been an increased risk of miscarriage with increasing paternal age. in 1974. A trend toward advanced parental age is simultaneously occurring in American men. The birth rate among men 25 to 44 years has been steadily increasing since the 1970s, whereas the birth rate of men less than 25 years has been decreasing (Hamilton et al., 2003). An improved understanding of the effects of increased parental age on the developing fetus and newborn is imperative for counseling older couples preparing for childbearing. Advanced paternal age has been suggested to result in increased...
Fig. 1. a, Aneuploidy monosomy 7 and trisomy 21. b, Interchromosomal translocation t(9 22)(qq). c, Interstitial deletion (1p33). d, Homogeneous staining region (HSR). e, Inversion 14(q11.2, q32). Fig. 1. a, Aneuploidy monosomy 7 and trisomy 21. b, Interchromosomal translocation t(9 22)(qq). c, Interstitial deletion (1p33). d, Homogeneous staining region (HSR). e, Inversion 14(q11.2, q32).
Figs. 7.22 and 7.23 outline the constant and accessory fontanelles present at birth. The most common accessory fontanelle is the parietal (sagittal) fontanelle, otherwise known as a third fontanelle, which is found in 6.3 percent of infants and may be more common in infants with Down syndrome. The metopic fontanelle represents the extremely long anterior arm of the anterior fontanelle which, in the process of closure, becomes separated from the anterior fontanelle. A metopic fontanelle has been reported in association with craniofacial dysostosis, cleidocranial dysostosis, spina bifida occulta, and meningomyelocoele. It can also occur as an isolated finding. An increased incidence of open metopic fontanelles is found in infants with congenital rubella syndrome, Down syndrome, cleft lip with or without cleft palate, and widened sutures. The metopic fontanelle is easy to palpate, and the discovery of its presence during the examination of the newborn infant may be important clinically.
Aneuploidy usually causes drastic phenotypic effects because it leads to unbalanced gene dosage. In humans, sex-chromosome aneuploids are less detrimental than autosomal aneuploids because X-chromosomeinactivation reduces the problems of unbalanced gene dosage. The most common autosomal aneuploid in living humans is trisomy 21, which results in Down syndrome. Primary Down syndrome is caused by the presence of three full copies of chromosome 21, whereas familial Down syndrome is caused by the presence of two normal copies of chromosome 21 and a third copy that is attached to another chromosome through a translocation.
Remarks Ear defects are important in syndrome diagnosis, particularly in the newborn infant. Small ears have been found to be a consistent clinical characteristic of Down syndrome and are the most clinically apparent malformation in Treacher Collins syndrome and hemifacial microsomia. External ear abnormalities are common in the 22q11.2 microdeletion syndrome. Ears are often protuberant in the presence of a myopathy. The ear is one of the few organs that continue to grow during adulthood. It is
That is characterized by a small oral cavity as in Beckwith-Wiedemann or Down syndrome. The tongue may be large if it is the site of a congenital vascular malformation. Acquired forms of macroglossia include trauma and allergic reactions, for example, angioneurotic edema. When considering the tongue in facial diagnosis, one should remember that largeness is not necessarily the same as protrusion.
Disseminated intravascular coagulation (DIC), 43, 273 acute, mechanism of, 273-274 conditions precipitating, 273f events triggering, 274t laboratory profile in, 275t treatment, 276 DNA synthesis, 87 Dohle bodies, 146f, 148, 148f, 308 Donath-Landsteiner test, 108 Down syndrome, 161, 175 Duckert, F., 230 Dysfibrinogenemia, 271
Extra genetic material is apparently less dangerous than missing material, and this is why most children born with the wrong number of chromosomes have an extra one, called a trisomy, rather than a missing one, called a monosomy. Aneuploid conditions have historically been named for the researchers or clinicians who identified them, but today chromosome designations are preferred because they are more precise. Down syndrome, for example, refers to a distinct set of symptoms that are usually caused by trisomy 21. However, the syndrome may also arise from one copy of chromosome 21 exchanging parts with a different chromosome, which is a type of aberration called a translocation. Knowing whether a child with these symptoms has trisomy 21 or translocation Down syndrome is very important in a practical sense, because the probability of trisomy 21 recurring in a sibling is about 1 in 100, but the chance of translocation Down syndrome recurring is considerably greater. Clinical Application...
Both strategies are now being actively pursued, and examples of each are presented both in this volume and in a recent volume on neurodevelopmental disorders (Tager-Flusberg, 1999). Examples of the first strategy are neurodevelopmental studies of Down syndrome, A solution for both these problems is the use of animal models, in which the genetic alteration is randomly assigned and the genetic and environmental backgrounds are controlled. Complementary studies of humans and animals with the same genetic (or metabolic) alteration offer a powerful strategy, one that has been very usefully applied to PKU (Diamond, this volume) and is now being applied to fragile X (Willems, Rey-niers, and Oostra, 1995) and Down syndrome (Crnic and Pennington, 2000). As another important advantage, these animal models permit a clearer test of which brain correlates associated with a syndrome are directly caused by the genetic alteration in question. In contrast, neuroimaging findings from humans with a...
Inv dup chromosomes derived from chromosome 15 account for approx 35 of SMCs (4), and, after trisomy 21, are the most common autosomal chromosomal aberration (16). Although the phenotype associated with the inv dup(15) itself can be variable, uniparental disomy or deletion of the normal chromosome 15 can accompany the inv dup chromosome with additional clinical consequences (17,18). The presence of abnormalities on the normal chromosomes 15, the size of the inv dup(15), and the parental origin of the chromosomal abnormalities all affect the severity of the outcome. This information is critical in the context of genetic counseling, particularly in the setting of prenatal ascertainment of a de novo inv dup(15).
IN NEONATES, INFANTS, AND CHILDREN Chromosome analysis should be done when the malformations correspond to well-established chromosome syndromes, especially when the diagnosis is doubtful. The syndromes associated with aneup-loidy are the most common and easily recognized at autopsy. Three of the more frequently encountered conditions in autopsies of newborns are the Down (trisomy 21) (10), Patau (trisomy 13), and Edwards (trisomy 18) syndrome (11). Presence of ambiguous genitalia is also a common indication of a genetic problem and may be a clue to gonadal dysgenesis, true herm-
The prevalence of mental retardation in North America is a subject of heated debate. It is thought to be between 1 -3 depending upon the population, methods of assessment, and criteria of assessment that are used. Many people believe that the actual prevalence is probably closer to 1 , and that the 3 figure is based on misleading mortality rates cases that are diagnosed in early infancy and the instability of the diagnosis across the age span. If the 1 figure is accepted, however, it means that 2.5 million mentally retarded people reside in the United States. The three most common causes of mental retardation, accounting for about 30 of cases, are Down syndrome, fragile X, and fetal alcohol syndrome. Males are more likely than females to have MR in a 1.5 1 ratio.
Several types of tests performed on pregnant women can identify increased risk of carrying a fetus with a chromosomal problem or actually detect the abnormal chromosomes (fig. 24.15) A blood test performed during the fifteenth week of pregnancy detects levels of maternal serum markers (specifically, alpha fetoprotein, a form of estrogen, and human chorionic gonadotropin) that can indicate the underdeveloped liver that is a symptom of certain trisomies, including Down syndrome. Often called the triple test or AFP test, screening maternal serum markers is routine in the management of pregnancy. Down Syndrome The most common autosomal aneuploid is trisomy 21, an extra chromosome 21. The characteristic slanted eyes and flat face of affected individuals prompted Sir John Langdon Haydon Down to coin the inaccurate term mongolism when he described the syndrome in 1886. As the medical superintendent of a facility for the profoundly mentally retarded, Down noted that about 10 of his patients...