The most immediately apparent, if not the most serious, manifestations of Down syndrome are the minor dysmorphic features, which collectively constitute its distinctive physical phenotype (Fig. 63-1). A list of these features is presented in Table 63-1. Detailed descriptions of the minor anomalies are contained in Smith and Berg5 and Pueschel et al.18 Quantitative cephalometric analyses have been used to describe the craniofacial anomalies in persons with DS.19,20 Not mentioned in Table 63-1, but worthy of note, are two abnormalities of the eye which appear later in life, cataracts and keratoconus.21
Eight-month-old child with Down syndrome.
Table 63-1: Physical Characteristics of Down Syndrome |Favorite Table|Download (.pdf) Table 63-1: Physical Characteristics of Down Syndrome
|Feature ||Frequency, %* |
|Oblique (upslanting) palpebral fissures ||82 |
|Loose skin on nape of neck ||81 |
|Narrow palate ||76 |
|Brachycephaly ||75 |
|Hyperflexibility ||73 |
|Flat nasal bridge ||68 |
|Gap between first and second toes ||68 |
|Short, broad hands ||64 |
|Short neck ||61 |
|Abnormal teeth ||61 |
|Epicanthic folds ||59 |
|Short fifth finger ||58 |
|Open mouth ||58 |
|Incurved fifth finger ||57 |
|Brushfield spots ||56 |
|Furrowed tongue ||55 |
|Transverse palmar crease ||53 |
|Folded or dysplastic ear ||50 |
|Protruding tongue ||47 |
Although any single individual will have many of the characteristic features and be easily recognized as having DS, none of these features is present in all persons with DS. Conversely, it is very rare for any single individual with DS to have all the features contained in the list. It should also be remembered that none of the features in the list is unique either to DS or to chromosome abnormalities in general. Accordingly, the presence of one or a few minor dysmorphic features in an otherwise normal individual does not, in itself, signify the existence of a chromosomal abnormality.
In addition to the features listed in Table 63-1, there is a series of dermatoglyphic features that are quite characteristic of DS.22 These used to play a much greater role in clinical diagnosis than they now do, but they represent, nevertheless, distinctive aspects of the phenotype of DS. Particularly characteristic are the arch tibial pattern on the hallucal area of the foot, ulnar loops on the second fingers, and a distal axial palmar triradius. These features, along with ear length (short), the distance between the first and second toes (wide), the internipple distance (<−1 standard deviation [SD]), the presence of Brushfield spots of the iris, and the excessive skinfolds or a fat pad on the neck, can be used to construct an index capable of permitting the diagnosis of 95 percent of patients suspected of having DS with an accuracy of 99.9 percent.23 In this regard, it is of interest that about 75 to 85 percent of infants clinically suspected of having DS actually have trisomy 21.23
Mental Retardation and Neurologic Abnormalities
While the dysmorphic features just discussed are of clinical significance, the condition of overriding clinical importance in DS is, of course, mental retardation. The brain, insofar as it is involved in cognition and other highly integrated mental functions, seems to be the organ most vulnerable to the deleterious effects of autosomal aneuploidy, whichever chromosome is involved. Although structural anomalies of the brain often occur in aneuploid states other than DS, they do not, in themselves, provide a complete explanation for the very severe functional abnormalities that are almost invariably present.
In addition to the effects on intelligence and control of muscle tone early and throughout life, trisomy 21 is also associated with a process of neuronal degeneration during the adult years. This process, which is pathologically identical to Alzheimer disease (AD) (presenile and/or senile dementia), results in significant pathologic changes in the brain and may further compromise the already impaired mental functioning.
Although newborns with DS may, with the exception of the profound hypotonia (see “Muscle Tone” below), appear reasonably normal behaviorally, developmental retardation generally becomes obvious during the first several months of life. The attainment of developmental landmarks becomes, on the mean, increasingly more delayed as time goes on. Thus, whereas the average delay may be on the order of 2 months for the very early landmarks (e.g., rolling over, transferring objects), it gradually lengthens and reaches 1 to 2 years for functions that normally appear at about 2 years of age (Fig. 63-2).24 However, because of the great variability in attainment of landmarks (Fig. 63-3),25 this delay may or may not be obvious for any single child with DS. For institutionalized individuals, progress continues during the first decade of life, following which there is usually a plateau in mental age.26 Some individuals may continue to progress mentally for another 5 years or so. There is then a second plateau and ultimately a decline (see “Alzheimer Disease” below).26
Median time of appearance of developmental landmarks in children with Down syndrome (*) as compared with a normal population (∣). (Data from Share and Veale.24 )
Mean and range of time of appearance of developmental landmarks in children with Down syndrome. The vertical marks to the left of the dashed lines indicate the upper limits for 95 percent of the Down syndrome group. For sitting, standing, walking, and speaking the first word, the figures given are for boys. (Data from Melyn and White.25 )
The conclusions just cited concerning intellectual development in DS were developed based on studies carried out during the 1960s and 1970s. They may be somewhat different now because of changes in social attitudes and education. Nevertheless, many studies of development during the first decade of life indicate that even with DS children reared at home, there is a progressive, virtually linear decline in developmental quotient (DQ) or intelligence quotient (IQ) starting within the first year25,27 (Fig. 63-4). The same appears to be true of social quotients (SQ).27 Once again, the wide range of IQs and SQs should be noted. In contrast to these results are the results from a prospective study of infants with DS over the first 3 years of life.28 In this group, mean DQs, based on the mental scale of the Bayley Scales of Infant Development, remained constant at 55 to 58, although the mean on the motor scale dropped from 67 at 6 months to 53 at 3 years. Cardiac status did not significantly influence mental development, but it did influence motor development.28 Both mental and motor development appeared to correlate with muscle tone.28,29
Mean and observed range of intelligence quotient (IQ) of children with Down syndrome as a function of age. (Data from Morgan.27 )
Genetic and Environmental Effects.
In rare instances, children with DS without known mosaicism have attained IQs above 80 and have performed in the low average range.30 Young men with DS have even written books,31,32 and another, a well-known television actor, has coauthored one.33 Although these instances must be considered unusual, they do point out the variability of the syndrome and raise the question of what factors do or could influence mental development. One possible factor is, of course, the intrinsic genetic differences among individuals. An approach to looking at this has been to examine the relationship between parental education levels or IQs and the IQs of their children with DS. Despite evidence against the existence of such correlations,34 two studies have affirmed the association. In one group of children reared at home and followed longitudinally, the mean DQ or IQ at a mean age of about 6 years was 74.6±12 for children of mothers with ≥16 years of schooling and 58.8±12 for children of mothers with <12 years of schooling.35 In another group with a mean age of 5.2 years, the IQs were 70.3 and 28.8, respectively, when the fathers’ schooling was similarly scored.36
The results just cited are consistent with a genetic basis for the differences in the IQs of persons with DS, and there is no reason to believe that such genetic influences should not be operating. However, some authors have argued to the contrary,26 and it is also possible, of course, that social and educational practices relating to the child are influenced by parental IQ and/or education, and that these environmental factors also play a role. Evidence for the potential impact of environmental factors on intellectual development stems principally from two sources: studies of the outcomes of home-reared versus institutionalized persons with DS, and the results of early intervention programs.
A study of children reared at home showed a positive benefit, with an increase in IQ of ≥17 points at 9 to 10 years of age.37 Similarly, early intervention with intellectual and motor stimulation starting in infancy has also been described as having a positive effect on development.34,37,38 Both short-term39 and long-term37,38 gains have been claimed, although these conclusions are not always based on carefully controlled investigations and the performance of such controlled studies poses problems of its own.40 In one study in which a control group was used, early intervention and preschool stimulation resulted in a mean increase in IQ of 6.3 points above control levels at 9 to 10 years of age; but the early intervention and preschool stimulation did not significantly alter the gradual decline in IQ when the subjects were followed longitudinally over a 10-year period.37 The long-term effects of early intervention programs remain to be proven. While it does appear that evidence exists that early intervention can have a positive effect on early development,41,42 particularly in the domains of fine coordination, self-help skills, and DQ/IQ scores,43 research in this area is difficult for a variety of reasons,40 and definitive conclusions are difficult to obtain. However, one evaluation of 21 early intervention demonstration studies indicated that IQ gains receded over time to the levels of the control group or comparison database and that, although primary school performance is critically lacking in many subjects, social acceptance in school is relatively good.43
A considerable literature on the nature of the cognitive impairment in DS has developed and is critically reviewed in detail by Gibson.26 Unfortunately, much of this literature has been criticized as being characterized by “the relatively poor quality of research design and data management… . It has been possible to reach conclusions, on a tentative basis, by assuming that consensus has power and methodological error is randomly distributed. Both arguments are subject to dispute.”26 Personality stereotypes attributed to individuals with DS have also been seriously questioned and probably have little validity.24,44 Nevertheless, it was recently asserted that adults with DS show less maladaptive behaviors than do other adults with similar chronological ages and DQs.45
Despite the questions about stereotypes, the present state of affairs seems to be well summarized as follows:46
Although delays app26 already in young DS infants in all areas, it seems that, given the appropriate stimulating environment, it is not really until the DS child reaches school age that the delays start to cause problems serious enough to require very intensive and specialized training. The major problem seems to be the lack of ability to handle more advanced cognitive strategies and processes. Thus, in whichever area of development one may look at, the inability to comprehend instructions, to plan alternative approaches to the problem, to attend to several variables at one time, or to express oneself clearly to another to be able to receive help, for example, are all deficiencies which are serious enough to be a major hindrance in pursuing a “normal” life.
Relative to other mentally retarded individuals, persons with Down syndrome are reported to have greater difficulty in recalling sequences of verbal information presented aurally, particularly when there is no supporting extralinguistic context.47 Specific deficits in linguistic structure, both syntax and phonology, are also present,48 and these are impaired relative to other verbal abilities such as communicative function and vocabulary knowledge.49,50 Anomalous dominance (lateralization) of language has been observed in young adults with DS,51 and altered interregional correlations of rates of glucose utilization are believed to reflect the abnormalities of language function.52
Nadel53 characterizes the situation with Down syndrome as follows: “Cognitive development in Down syndrome individuals appears slower than normal, with some qualitative quirks that suggest rather selective deficits in rule-based systems, such as number and grammar.” The identification of these selective deficits is of considerable importance in understanding the nature of the cognitive impairment produced by trisomy 21. With new methods of psychological investigation being applied to DS, an understanding of the specific nature of the intellectual deficits in DS and their neurologic and biochemical bases should ultimately be obtained.
Perhaps the single most characteristic feature of DS in newborns and infants is hypotonia, and several investigators regard it as a universal finding.54 In a longitudinal study, the muscle tone of DS newborns was rated as 1.6 ± 0.84 (SD) and 1.5 ± 0.70 for males and females, respectively, increasing to 2.8 ± 0.28 and 2.7 ± 0.33, respectively, at 2 years of age (with 0 = extremely, 1 = moderately, and 2 = mildly hypotonic; 3 = normal).55 During the first year of life, tone was significantly less in infants with moderate to severe congenital heart disease.55 Tone was also rated as decreased in older children, aged 4 to 17 years, with a mean of 2.74 versus a control mean of 3.14.56 Patellar reflexes, a stretch reflex response considered to be related to the involuntary reflex responses that are the genesis of muscle tone, were also less smooth and less brisk (2.32 cm versus 6.06 cm in controls) in the DS group.56 Grip strength was also decreased at all ages between 4 and 17 years, and there was a positive and significant correlation between strength and tone (r = 0.65, p < 0.01).56
The basis for the decreased muscle tone is unknown. It is not the result of a decrease in the concentration of 5-hydroxytryptamine (serotonin) in the peripheral blood;57 5-hydroxytryptophan was found to induce infantile spasms in 14 percent of infants receiving the drug.58 Similarly, vitamin B6 administration, which also elevates blood serotonin, had no beneficial effects on tone or development.57,59 It has been reported, however, that dietary manipulations intended to increase central serotonin levels did reduce self-injurious behavior in an adult with DS.60
Other Neurologic Abnormalities.
In infancy, there is, in addition to the hypotonia, delayed dissolution of early reflexes and automatisms—grasp reflexes, the Moro response, and automatic stepping.54 Abnormal or deficient responses have been noted in the traction response, position in ventral suspension, and the patellar jerk. In later years, atlantoaxial/atlanto-occipital instability presents a risk to about 15 to 20 percent of children with DS, although symptomatic manifestations appear to be rare.61,62
Seizures have been reported in 1 to 17 percent of persons with Down syndrome.63–65 In one study,64 with 8.1 percent of a cohort of 405 persons with DS having seizures, 40 percent of these, usually infantile spasms and tonic-clonic seizures with myoclonus, began during the first year of life. Seizures in another 40 percent, usually tonic-clonic, partial simple, or partial complex, began in the third decade. Seizures beginning after 35 years of age are considered indicative of the development of AD, as is the loss of the ability to identify odors.66 In this study, febrile seizures were very rare. However, another study reported febrile seizures in 5.3 percent of persons with DS and afebrile seizures in 7.9 percent.67
In addition to the unsuccessful trials with 5-hydroxytryptophan, numerous other agents have been used in an attempt to improve the development of children with DS.68 Prominent among these are the so-called orthomolecular approaches based on the administration of mixtures of vitamins, minerals, thyroid hormone, and other substances.69–70 Despite claims for remarkable successes—with IQ reported to increase between 10 and 25 points over a 4- to 8-month period69 −these results have not been duplicated in carefully controlled trials.71,72 Another approach has been sicca-cell therapy in which lyophilized embryonic animal cells are injected at frequent intervals. Again, contrary to the claims of its proponents,73 controlled trials have not shown this form of therapy to have any efficacy.74 There is, in fact, considerable concern that it may be dangerous.
It was recently suggested that the administration of piracetam, a nootropic agent,75,76 might be of benefit, but, at present, no form of pharmacologic therapy is known to have a reproducibly beneficial effect on the signs or symptoms of DS.
Like so many aspects of DS, there has been considerable disagreement about the frequency and nature of anatomic abnormalities of the brain. However, the present consensus is that in the majority of patients with Down syndrome the results of neuropathologic study are normal.77,78 Although histologic findings have been inconsistent, brain weight is in the low-normal range, and the size of the cerebellum and brainstem may be reduced to an even greater extent.79 The relative volume of the cerebellum does not decrease significantly with age.80 Frontal-occipital length is shortened, secondary to reduced frontal lobe growth, and there is narrowing of the superior temporal gyri in about a third of cases.81 Among the semispecific findings in DS are nerve cell heterotopias in the white layers of the cerebellum and vermis, which are found in 16 percent of infantile and fetal DS brains.77 These heterotopias are attributed to a disturbance or retardation of embryonal cell migration. The anterior commissure in adults with Down syndrome is reduced in cross-sectional area.82
Detailed neuronal architecture, studied with Golgi-type preparations, has been analyzed in a handful of cases. Because of the limitations in numbers, all reports must be viewed with caution. There appears to be a diminution and/or abnormality of dendritic spines in infants and children with DS, including atrophy rather than expansion of the dendritic tree of the visual cortex.83 This dendritic atrophy continues into adulthood, and becomes even more pronounced when AD develops.84,85 These abnormalities of spine morphology and number are probably nonspecific, and can probably be interpreted as representing secondary changes in neurons that are metabolically or otherwise affected by the trisomic state.
Other evidence for defects in brain histogenesis has also been reported. This includes a poverty of granular cells, possibly the aspinous stellate cells, throughout the cortex and, in individuals ranging in age from newborn to 14 years, of decreased neuronal densities in layers II and IV of the occipital cortex (area 17).86 This decrease averaged 30 percent during the first year and 20 to 25 percent thereafter. In young infants, the cell layers of the visual cortex are poorly defined,83 and diminution in the number of hypothalamic neurons has also been observed.87 Synaptic density in the neocortex has been reported as normal, although presynaptic and postsynaptic width and length may be reduced.83 Similarly, the surface area of synaptic contact may be lower than normal in the occipital cortex.86 A reduction in the number of inferior olivary neurons has been reported.88
In fetal DS cortex, the activity of choline acetyltransferase and concentration of N-CAM were normal.89 Although cholinergic muscarinic receptors were found reduced in the superior colliculus and substantia nigra of two stillborns with DS,90 the activities of cholinergic markers were found to be normal in several regions of brains from infants with DS.91 However, there appears to be a doubling of the number of S100 protein immunoreactive cells, presumably astroglia, in the hippocampus.83
From the above, it is obvious that a clear picture of the state of the “wiring” of the brain in DS does not emerge. Although there is accumulating evidence for abnormalities of neuronal differentiation and migration in fetal and infant brains, it is not certain, if the developmental plasticity of the young brain is taken into account, how many of the changes are permanent or functionally significant.
It has been reported that all the phospholipids of myelin contain reduced amounts of monounsaturated fatty acids but do not have unequivocally abnormal amounts of polyunsaturated fatty acids (PUFA).92 The opposite, however, seems to be true of synaptosomal phospholipids, with reduced proportions of PUFA and normal amounts of monounsaturated fatty acids being found. Monounsaturated fatty acids are reduced in sphingomyelin. The basis for these abnormalities, which are also found in phenylketonuria, is unknown, and it is unclear whether they result in92 or from93 other developmental and functional abnormalities of the nervous system. Abnormal ratios of phosphoglycerides were also noted in fetal DS brains, and it was speculated that these alterations could result in membrane abnormalities, and consequently in functional disturbances.94
Biochemical analyses, while providing valuable information about the chemical structure of elements of the nervous system, do not directly speak to the question of alterations in function. Unfortunately, there are few data that really bear on this issue, and they principally involve electrophysiological studies of one type or another. There are no specific EEG patterns associated with DS, and the observed abnormalities are not well correlated with specific behavioral or neurologic signs and symptoms.95 It has been suggested, however, that there is an incomplete postnatal development of neuronal interconnections or an immaturity of cerebral development.96,97 These conclusions were considered to be consistent with the independently described histologic findings of dendritic abnormalities mentioned earlier. Although some of the physiological observations that underlie them are in question,98 some supportive evidence has come from work on the spectral analysis of EEG, which showed that the most important deviation from normal was a reduction in relative α power.99
Somewhat closer to the issue of neuronal function in DS are the studies of visual- and auditory-evoked potentials. Significant differences in patterns are found between DS and other retarded and nonretarded subjects, which differences have been interpreted as indicating that there is abnormal neural activity in numerous neural systems ranging from sensory to cognitive in DS.100 As summarized by Courchesne,100 the evoked-response potential (ERP) evidence relating to DS indicates reduced inhibitory control, reduced selectivity and specificity of responsiveness, increased neural responsiveness, abnormalities in the timing of neural responses, and abnormal mechanisms involved in temporal integration and information storage. ERP and reaction time results from children with DS have indicated slower processing of certain types of auditory information and an altered scalp distribution of amplitudes of some ERP components in comparison to both chronological and mental age controls.101 In young adults with DS, auditory brain stem response detection levels were elevated, response amplitude was reduced, and latency intensity functions were significantly steeper than in a matched nonretarded control group.102 The meaning of these differences remains to be established, but they do not appear to be attributable to the presence of hearing deficits, even though mild to moderate high-frequency loss or abnormal impedance are found in as many as 73 percent of adults with DS.102,103 The abnormal responses have been attributed to both structural and neurochemical alterations.104 Following median-nerve stimulation, interpeak latencies were significantly prolonged in DS, and impaired impulse conduction in the proximal part of the brachial plexus, posterior roots and/or posterior column-medial lemniscal pathway was inferred.105 Sensory conduction from the upper cervical cord to the sensory cortex appeared normal.
In addition to the in vivo studies of neuronal function, functional studies of DS neurons have been done on fetal and infant dorsal root ganglia neurons cultured in vitro, and it was found that several physiological parameters were altered. It was postulated that the greater rate of depolarization of trisomic neurons observed at resting potentials was the result of activation of residual fast-sodium channels that also have a faster course of activation.106 Although there is no evidence to prove it, it has been speculated that similar abnormalities may also occur in central nervous system neurons and could be the neurologic basis of the mental retardation in DS.107 These inferences are, of course, speculative.
Fetal DS cortical neurons cultured in vitro were found to degenerate spontaneously and to undergo apoptosis under conditions in which diploid control neurons did not.108 Free radical scavengers or catalase could prevent this degeneration, which was associated with increased lipid peroxidation and intracellular reactive oxygen species, but SOD or an NO synthase inhibitor could not prevent it.
Considerable interest has focused on peripheral neurotransmitter function in DS. Hypersensitivity to the mydriatic effect of atropine has been repeatedly confirmed.109 There is still debate, however, about its cardioacceleratory effect, and both increased110 and normal111 sensitivity have been reported. The activity of the enzyme dopamine-β-hydroxylase, which converts dopamine to norepinephrine, is significantly decreased in the plasma of individuals with DS.112 Nevertheless, the plasma concentration of norepinephrine is normal or increased.112 Studies of cerebrospinal fluid (CSF) monoamine metabolism in young adults with DS that showed increased concentrations of CSF 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine were interpreted as indicating an increased turnover of monoamines. However, this alteration was not believed to be related to cognitive decline with age.113,114
A considerable literature has accumulated on abnormalities of tryptophan metabolism and platelet serotonin (5-hydroxytryptamine) in DS, with the latter being of particular interest because of its possible relevance to understanding central nervous system neurotransmitter function. The principal observation is that the concentration of serotonin is decreased in whole blood to about 65 percent of normal, a decrease that is attributable to a reduction in the level of platelet serotonin to levels as low as 35 to 40 percent of normal.115 Studies of serotonin uptake by platelets demonstrate a reduced rate of influx,115 which has been attributed to a reduction in Na+/K+-ATPase activity with concomitant abnormalities of sodium, potassium, and/or calcium fluxes.116 On the basis of observations made on transgenic mice with elevated activities of CuZn-superoxide dismutase (CuZnSOD), in which similar decreases in platelet uptake were found, the DS platelet abnormality has been attributed to the 50 percent increase in CuZnSOD activity found in all DS cells.117
It has been suggested that the platelet, with its uptake and storage of amines, can serve as a model for synaptosomes in the central nervous system.118 However, although direct studies of serotonin concentration and uptake in central nervous system neurons have not been conducted, the CSF concentration of 5-HIAA, the principal catabolite of serotonin, is not significantly reduced in DS.119 Furthermore, the content of serotonin in the striatum of CuZnSOD transgenic mice with threefold elevated CuZnSOD activity is normal.120 Therefore, it remains to be shown whether the platelet abnormalities have any relevance for central nervous system function.
Response to β-Adrenergic Agonists and Other Fibroblast Abnormalities.
When skin fibroblasts obtained from a variety of sources were treated with 1 μM isoproterenol, the cyclic adenosine monophosphate (cAMP) content of trisomy 21 cells increased to 29 times the initial level in 10 min, in comparison with the 2.5 to 3.2 times increase observed in diploid cells and in cells trisomic for chromosomes other than 21—a ninefold difference.121 Epinephrine had a similar although less pronounced effect, and epinephrine-induced platelet aggregation (supposedly an α-adrenergic function in platelets) was produced at a considerably lower concentration with trisomy 21 than with control platelets.122 These alterations in response could not be attributed to increased adenylate cyclase or decreased phosphodiesterase activity, nor to a gene dosage effect at the receptor level. These observations suggest the existence of some type of alteration in the function of a membrane receptor-controlled system, which could have important implications for a variety of physiological and developmental processes in which catecholamines and cAMP are involved. Unfortunately, related work has not yet been done in cells other than fibroblasts, so it is difficult to know how generalizable the results are.
The uptake and incorporation into lipid of inositol by trisomy 21 fibroblasts is increased to about three times normal.123 By contrast, trisomic fibroblasts are deficient (by 50 percent) in the release of prostaglandin E2 (PGE2).124 As was postulated to explain the decreased uptake of serotonin by trisomic platelets, the defect in PGE2 release has been attributed to the elevated level of CuZnSOD in the cells which is presumed to affect arachidonic acid metabolism.
The possibility of a relationship between DS and dementia has been recognized for over 100 years125 and between DS and AD (as defined pathologically) for over 50 years.126 This relationship is now well-established.127–130 The consensus of a large number of reports is that the brains of adults with DS possess all the pathological and neurochemical hallmarks of AD. Detailed morphometric analyses suggest that the pathological changes found in adult DS brains may differ quantitatively in some areas from those found in AD,129,131 but the order of progression of involved areas appears to be the same in DS as in AD.132 It has also been reported that the astrocytic reaction is more marked in DS than AD.133
The time of appearance and the frequency of the lesions of AD in DS have been matter of particular concern, because the interest in the relationship between the two conditions has been as much a function of the early and generalized appearance of the lesions as of the nature of the lesions themselves. In an extensive autopsy series, which included 347 cases of DS, 5 of 312 (1.6 percent) brains from individuals dying under the age of 40 (20 to 38 years) and 35 of 35 (100 percent) from individuals over the age of 40 (42 to 69 years) had the gross pathologic changes of AD.134 Of the latter, 60 percent were described as severe and comparable to the most advanced cases of AD, and 40 percent were mild to moderate. In a study of 100 brains of institutionalized individuals with DS, senile plaques and tangles were found in all cases over 30 years of age, and brain weights were generally below the mean −2 SD from the second decade on.135 It is, therefore, generally believed that the neuropathologic changes of AD are almost universal over the age of 35 years.136 Based on immunocytochemical analyses, it is claimed that the deposition of the β/A4 amyloid protein in the brains of persons with DS begins 50 years earlier than it does in normal brains, possibly as the result of overexpression of the amyloid precursor protein (APP) gene.137 However, ubiquitin-immunoreactive dystrophic neurites have been observed in the gray matter of brains of persons with DS as young as 6 years of age, prior to the time of amyloid deposition, as compared with 29 years of age in control brains.138
Although the pathology may be virtually invariant in its occurrence, a significant proportion of adults with DS do not appear to have dementia by any criteria. Furthermore, some persons with DS who are thought to be demented are instead suffering from major depression.139 It has been estimated that only about 25 percent of adults with DS are demented;140 however, frequencies ranging from 45 percent to 100 percent (after age 60 years), depending on age, have also been reported.141–144 In one prospective study involving both institutionalized and noninstitutionalized adults with DS, 84 percent of demented individuals had seizures, 20 percent had parkinsonian features, and all showed loss of brain tissue by computerized tomography (CT), especially in the temporal lobes.144 In two institutionalized populations, the mean age of onset of dementia was between 51 and 54 years, and the mean duration of dementia in the patients who died was about 5 years.145,146
The relationship between numbers of tangles and plaques and the degree of dementia in DS is not known. However, it has been proposed that the number of these abnormalities must exceed a threshold value before symptoms and signs appear—a threshold which for some reason is higher in DS than in non-DS individuals.146 Alternatively, as suggested by Mann et al.,147 although senile plaques and neurofibrillary tangles are reliable semiquantitative markers for the presence of AD, “there is no compelling evidence that they, by themselves, actually cause dementia, though they obviously make a contribution to it through the damaging effect they inflict….”
CT has demonstrated increased CSF volume and accelerated rates of lateral ventricle and suprasellar cistern dilatation in demented adults with DS.148–150 Likewise, dementia is associated with reductions of glucose metabolic rates, as measured by positron emission tomography, in the parietal and temporal motor areas, which are not seen in nondemented adults with DS151 and with an increase in the latency of the auditory P300 event-related potential.152 On routine magnetic resonance imaging, persons with DS had a higher prevalence and severity of atrophy and white matter lesions, both of which increased with age, and of T2 hypointensity of the basal ganglia, which did not.153
Irrespective of whether frank dementia occurs, there appears to be a progressive loss of a variety of intellectual functions and receptive language not attributable simply to mental retardation in many, if not all, older individuals with DS.141,154–156 Furthermore, nondemented older adults with DS appear to manifest a selective pattern of neuropsychologic reductions as compared with young adults with DS.157 These reductions include a diminished ability to form long-term memories and impaired visuospatial construction. Intermediate memory span and language seem to be spared, although language function was already significantly impaired. The consistent impairment of visuospatial construction with sparing of language is thought to distinguish the findings in the nondemented adults with DS from those characteristic of early to intermediate Alzheimer-type dementia.157
The belief that intellectual decline is inevitable in adults with DS has been challenged.158 Based both on cross-sectional and relatively short-term longitudinal studies, it is claimed that only a third of persons with DS over 35 years of age show intellectual deterioration. Another study has claimed that only 4 of 91 persons with mild and moderate mental retardation between 31 and 63 years of age could be considered as being demented.159
A study of over 100 adults with DS has shown that males are three times more likely than females to develop clinical AD.160 However, another study indicated that females are affected earlier and have higher densities of neurofibrillary tangles. Because of the discovery that the presence of the apolipoprotein E allele ϵ4 is a risk factor for the development of both sporadic and familial AD unrelated to DS, numerous studies have been done to determine whether the same is true in DS. Presence of the ϵ4 allele has been reported to be associated with a higher frequency of clinical AD,160 a tendency to an earlier age of onset of dementia,161 poorer language ability,162 more rapid cognitive decline,163 and earlier age of death.164 A meta-analysis that reviewed several studies indicated that there was little evidence for reduced survival to adulthood of persons with the homozygous ϵ4ϵ4 genotype.165
For a discussion of the pathogenesis of AD in DS, see “Pathogenesis of Specific Features of Down Syndrome” below.
Major Congenital Malformations
Despite the presence of many dysmorphic features in DS, relatively few major malformations are produced by trisomy 21. Those that do occur are quite specific and principally involve two systems—the heart and the gastrointestinal tract.
Congenital Heart Disease.
The most frequent major congenital abnormality in DS is congenital heart disease, and 16 to 62 percent of children have been reported as being affected.166 The most unbiased estimates for living children range from 29 to 39 percent.167,168 In unselected DS abortuses, 45 percent were found to have forms of congenital heart disease that would not be expected to close after birth,77 and an overall estimate of 40 percent appears to be reasonable. A variety of estimates also exist for the frequencies of specific cardiac lesions in affected children: atrioventricular canal, 18 to 54 percent (mean: 39 percent); ventricular septal defect, 27 to 43 percent (mean: 31 percent); atrial septal defect, 2 to 17 percent (mean: 9 percent); tetralogy of Fallot, 1 to 15 percent (mean: 6 percent); patent ductus arteriosus, 2 to 24 percent (mean: 9 percent).190 In the fetal cases, 73 percent of those with cardiac anomalies were judged to have an atrioventricular canal.168 Despite the variety of lesions described, it is believed that most represent variations of a common problem in the formation of the venous inflow tract of the heart, although other lesions, such as aortic arch anomalies, can also occur.77 In a survey of institutionalized adults with mental retardation, unsuspected aortic regurgitation or mitral valve prolapse was detected in 20 percent of DS persons as compared to 6 percent of controls.169
Survival of children with congenital heart disease is better than was formerly believed, and 80 percent survival to 15 years of age with atrioventricular canal defects has been reported.170 Development of pulmonary hypertension is generally considered to occur earlier and more severely in children with DS with congenital heart disease,171 although this conclusion has been disputed.172 Abnormal development of the lung parenchyma and of the pulmonary vasculature, which could contribute to the development of pulmonary hypertension, may also be present. Pulmonary hypoplasia characterized by a diminished number (<50 percent of normal) of alveoli in relation to acini and a reduction in total alveolar surface area has been reported to be independent of the presence of heart disease.173 Reduction of airway branching and a thinning of the medial layer of the small pulmonary arteries have also been described.174,175
Gastrointestinal Tract Abnormalities.
Although much less common than congenital heart disease, there is nevertheless an increased frequency of specific intestinal anomalies in DS. In an aggregate of five series, the most characteristic lesion was duodenal stenosis or atresia, sometimes with annular pancreas, with a frequency of 2.5 percent, followed by imperforate anus (1 percent), Hirschsprung disease (0.56 percent), and tracheoesophageal fistula or esophageal atresia (0.43 percent).176 Conversely, 5.9 percent of infants with Hirschsprung disease had DS,177 as did 28 percent of patients with duodenal atresia or stenosis176 and 20 percent with annular pancreas.178
Leukemia and Leukemoid Reactions
An increased incidence of leukemia has long been recognized in DS. Estimates of the relative risk have ranged from 10 to 18 times normal in children up to 16 years of age,179,180 and adults over 20 years also have an excessive rate of mortality from leukemia.181 The distribution of leukemia by type is shown in Table 63-2. Congenital and newborn cases (<1 year of age) are predominantly acute nonlymphoblastic leukemia (ANLL), but from age 3 years and up, the distribution of types is the same for both DS and non-DS subjects.182,183 The age of onset of ANLL is younger in DS than in diploid patients, but the ages are the same for acute lymphoblastic leukemia (ALL).184 The length of survival of DS individuals after diagnosis of ALL is shorter than that of diploid individuals.
Table 63-2: Types of Leukemia in Down Syndrome |Favorite Table|Download (.pdf) Table 63-2: Types of Leukemia in Down Syndrome
| || || ||Proportion of Types (%) |
| || || || |
|Sources of Cases ||Age ||Total Cases ||ALL ||ANLL ||AUL |
|Acute leukemia group B182 ||< 1 month ||5 ||20.0 ||80.0 ||— |
| ||1 month–19 years ||41 ||69.8 ||30.2 ||— |
|Rosner and Lee182 ||< 1 month ||47 ||42.1 ||57.9 ||— |
| ||1 month–19 years ||229 ||69.1 ||30.9 ||— |
|Oxford study of childhood cancer183 ||< 1 year ||10 ||10.0 ||80.0 ||10.0 |
| ||1–2 years ||25 ||44.4 (82.2)* ||52.0 (13.7) ||4.0 (4.1) |
| ||3–14 ||35 ||80.0 (79.2) ||17.1 (18.2) ||2.9 (2.6) |
Acute Megakaryoblastic Leukemia.
Although major emphasis has been placed on ALL and ANLL, it should be noted that the latter may include other forms of leukemia, such as acute megakaryoblastic leukemia, in addition to acute myelocytic leukemia.185 It has been suggested that acute megakaryoblastic leukemia may be much more common in DS than previously suspected. Of 24 cases of leukemia in DS seen over a 10-year period at a single hospital, 4 (17 percent) originally diagnosed as having ALL were believed to have this form of leukemia. It has been estimated that 20 to 40 percent of all cases of acute leukemia and leukemoid reactions or transient leukemia are of this type.186 Conversely, most cases of acute megakaryoblastic leukemia in young children are thought to occur in individuals with trisomy 21 or trisomy 21/2n mosaicism, and the overall incidence of this form of leukemia may be 200 to 400 times greater in the DS than in the chromosomally normal population.186
The response of children with DS to therapy differs from that of chromosomally normal patients.187 For so-called ALL, which could include misdiagnosed, and hence inappropriately treated, acute megakaryoblastic leukemia,186 remission induction is reduced (80 percent vs 94 percent in non-DS cases) and mortality is higher (14 percent vs 3 percent), with death resulting principally from infection.187 The 5-year survival is also decreased (50 percent vs 65 percent), but this is mainly attributable to the initial failure to induce a remission. In contrast, children with DS with acute myelogenous leukemia have a very high rate of event-free survival after chemotherapy. Their myeloblasts have a greatly enhanced sensitivity to 1-β-D-arabinofuranosylcytosine, which has been attributed to enhanced metabolism of this drug.188 Severe methotrexate toxicity at standard therapeutic doses has also been demonstrated.189 This toxicity was postulated to result from increased tetrahydrofolic acid demand, and hence greater sensitivity to an antifolate agent, because of a presumed increased rate of purine synthesis. It has also been suggested that a decreased rate of methotrexate clearance may be responsible.190
A high frequency of “transient” acute leukemia, transient myeloproliferative syndrome, or leukemoid reaction has been reported to be present in newborns with DS.182 In these cases, there is apparently a complete remission, and it is believed by most investigators that the affected individuals never had true leukemia at all. Rather, they appear to have had what has been termed ineffective regulation of granulopoiesis masquerading as congenital leukemia.191 Unlike true acute leukemia, there are normal numbers of granulocytes and macrophage stem cells (CFU-GM) in the bone marrow,192–194 there are ultrastructural differences between leukemoid and true leukemic blast cells,195 and the mean maternal age is lower.196 However, as in true leukemia, the abnormal cellular proliferation appears to be clonal in nature.197,198 That the presence of an extra chromosome 21 is of importance in this condition is borne out by several cases of such leukemoid reactions described in phenotypically normal trisomy 21/2n mosaics, in which the abnormally proliferating cell population was always trisomic for chromosome 21.192,199 It has been proposed that disomic homozygosity for a locus on the long arm of chromosome 21 proximal to the centromere, arising from meiosis II nondisjunction, may be involved in the genesis of leukemoid reactions.196,200
The relationship between leukemoid reactions and true leukemia still remains to be defined. While it is, of course, possible that they are unrelated, it is tempting to try to visualize some significant relationship between two such infrequent aberrations affecting leukocyte proliferation. Furthermore, the finding of other hematologic abnormalities in trisomic newborns, especially an increased hematocrit, but also including either thrombocytosis or thrombocytopenia,201,202 is compatible with the notion of a generalized abnormality in stem-cell regulation. It has been suggested, although not shown, that there is an extensive congenital defect of bone marrow function in DS newborns, possibly due to the presence of a marrow-stimulating humoral substance.203
A view dissenting from the prevailing one—that the leukemoid reactions and true leukemia are distinct entities—has been published.186,204 This dissenting view holds that leukemoid reactions are transient but true leukemia, which most often is acute megakaryoblastic leukemia. In most cases, this leukemia regresses spontaneously, but in about 25 percent it recurs during the first 3 years of life, again as acute megakaryoblastic leukemia.
The immunologic status of individuals with DS has been the subject of intensive investigation for many years, primarily because of clinical observations suggesting that they are more susceptible to a variety of infectious diseases205 and, as was just discussed, to the development of leukemia. Infection still constitutes the leading cause of death of trisomic individuals (see “Life Expectancy and Causes of Death” below). In general, the literature (summarized in references5,7, and 206) has been characterized by considerable disagreement and contradiction stemming, in large part, from differences in subject selection (age, institutionalized vs noninstitutionalized), choice of control subjects, and the methods used. Nevertheless, a picture of immunologic impairment associated with DS still emerges.
The consensus is that serum IgG is elevated, particularly in older subjects. However, there are reports of normal IgG levels and, in newborns, of decreased concentrations.7,206 The situation with regard to IgM and IgA is less clear. Serum concentrations of IgM have been reported as decreased, normal, and even increased, and the differences do not appear to be age-related. Similarly, IgA has been reported to be decreased, normal, and increased. A transition from normal levels in children to elevated levels in adults may explain some of the discrepancy.206
Quantitative studies of peripheral blood T lymphocytes reveal a reduction, often quite small, in the proportion or absolute number of T lymphocytes,206 although normal proportions or numbers of T and B lymphocytes in DS children have also been seen.207 The proportion of T-helper cells (CD4+) is decreased, resulting in a decreased, perhaps reversed (<1.0) ratio of helper to suppressor (CD8+) cells,208 Furthermore, peripheral blood T cells have a decreased number of cells expressing the T-cell receptor-α,β (TCRα,β) complex, elevated numbers expressing TCRγ,δ, and a decreased proportion of CD4+, CD45RA+ naive T cells, suggesting that the DS thymus is inefficient in the release of functionally mature T cells.209 There appears to be an age dependence in the proliferative response to phytohemagglutinin (PHA) of DS lymphocytes, but not of normal lymphocytes.206 Allogeneic mixed lymphocyte proliferative responses are decreased, as are PHA-induced interleukin-2 production and cytotoxic T-lymphocyte activity.206,210
Studies of the in vitro response of DS T lymphocytes to specific antigens demonstrate normal responses to purified protein derivative (PPD) and to staphylococcal, streptococcal, and Sendai virus antigens.211,212 In contrast, significantly reduced responses, as measured by proliferation, interleukin-2 production, and in vitro antibody production, to tetanus toxoid and to influenza virus antigens have been found.208,213 Further dissection of this system has shown that the depressed proliferative response to influenza virus antigen results from a diminished responsiveness of T-helper cells rather than from an increased T-suppressor activity.213 An intrinsic defect in B-cell antibody production has also been noted, as has a defect in the enhancement of B-cell antibody production by T-helper cells. The in vitro observations on tetanus toxoid and influenza antigens are compatible with reports of diminished in vivo responses to tetanus toxoid and typhoid vaccine214 (although normal responses were found by other investigators),215 influenza vaccine,216 bacteriophage ΦX174,217 pneumococcal polysaccharide,218 recombinant hepatitis B vaccine,219 and exposure to hepatitis infection.220 Decreased natural antibody titers have also been found.221
Further evidence implicating abnormalities of the T-lymphocyte system in the immunologic defects of DS derives from anatomic and functional abnormalities of the thymus.206 In comparison to age-matched controls, thymuses from infants with DS from 1 day to 15 months of age have marked lymphoid depletion, with a thin cortex and poor corticomedullary demarcation.222 The Hassall corpuscles are increased in size and frequently cystic.222 The presence of lower proportions of cells bearing high levels of the TCRα,β complex and of CD3, a signal-transducing complex for the T-cell receptor, in thymuses of children with DS and the increase in the proportions of cells with these markers with age are indicative of delayed maturation of T cells within the thymus.223 In addition, DS thymuses contain elevated levels of IFN-γ and TNF-α mRNA expressing cells, and there is mast cell hyperplasia and overexpression of class I MHC, CD18, and ICAM-1.224 DS thymocytes also have a greater than normal sensitivity to inhibition of IL-4-induced proliferation by IFN-γ and TNF-α.225 Taken together, these findings are indicative of abnormal thymocyte maturation and cytokine dysregulation in the DS thymus, possibly initiated by gene dose-related increased sensitivity to IFN-γ and to overexpression of CD18 (LFA-1β).224
In addition to the neonatal hematologic abnormalities just cited, several other erythrocyte and leukocyte alterations are found in DS. Macrocytosis is commonly observed, with the mean corpuscular volume increased 11 to 14 percent above control values.225 The enzymes, glutamic oxalacetic transaminase (AST), glucose-6-phosphate dehydrogenase (G-6-PD), 6-phosphogluconate dehydrogenase, adenosine deaminase, and catechol-O-methyltransferase, are increased 15 to 60 percent,226–228 but membrane ATPase activity (total, Mg2 +, and Na+, K+) is decreased by 60 to 70 percent.229 The red cell adenine nucleotides have been variously reported as increased, decreased, or unchanged,227,230,231 and it is not clear why there has been such variability in the results obtained.
Several enzymes are increased in activity in leukocytes, including alkaline phosphatase, acid phosphatase, galactose-1-phosphate uridyltransferase, and G-6-PD.226 The increases in acid and alkaline phosphatases, and in G-6-PD, are found in both granulocytes and lymphocytes. A variety of abnormalities in leukocyte function, of unknown physiological significance, have been reported.232–234 No satisfactory explanation has been provided for the numerous alterations in the activities of enzymes, none of which are coded for by chromosome 21, in DS erythrocytes and leukocytes, or for the increased size of the DS erythrocytes. However, these observations do highlight the difficulty in attempting to infer the locations of genes for enzymes based on putative dosage effects on their activities in erythrocytes and leukocytes. The same nongene dosage-related increases in enzyme activity are not observed in cultured fibroblasts or other nucleated cells.235
Increases in serum uric acid levels have been reported by several investigators,236 with the increases ranging from 16 to 44 percent. A particularly thorough study found a mean increase of 44 percent in trisomic individuals, with significant differences from normal being found in all age groups.237 Because urinary uric acid excretion was, if anything, increased, it was inferred that the hyperuricemia was the result of purine overproduction. Other suggestions regarding the etiology of the hyperuricemia have been made, including increased degradation of purines resulting from enhanced leukocyte turnover238 or associated with an increased adenosine deaminase activity.227,239 The increased enzyme activity could also be an effect of increased synthesis, rather than a cause of increased degradation. Furthermore, the issue of overproduction (or increased purine degradation) versus diminished excretion has still not been fully resolved, and the role of increased purine biosynthetic enzyme activity (see “Secondary Effects” below) remains to be determined. At issue with regard to the latter is whether the cellular concentrations of these enzymes control the flux of metabolites through the purine biosynthetic pathway.
Thyroid Dysfunction and Autoimmunity.
Both hypothyroidism and hyperthyroidism have been reported in individuals with DS. In newborn infants studied in a statewide newborn screening program, 1.1 percent with DS had congenital hypothyroidism. This was persistent in 8, an incidence 28 times that of the general population.240 An increase in thyroid antibodies was not detected. In children aged 4 months to 3 years studied retrospectively, 3 of 49 (6.1 percent) had congenital hypothyroidism, 1 had acquired hypothyroidism, and 1 had acquired hyperthyroidism; 13 had mildly elevated thyroid-stimulating hormone (TSH) but normal thyroxine levels.241 Only the two patients with acquired disease had thyroid antibodies. Mean TSH levels were increased and mean reverse triiodothyronine (T3) levels were decreased in children with DS.242 In institutionalized adults with DS, hypothyroidism was found in 17 percent, hyperthyroidism in 2.5 percent, and goiter in 18 percent.243 Although these results would suggest a progressive age-dependent increase in thyroid antibodies and disease in DS, contradictory results were obtained in a study that demonstrated a high frequency of antibodies against thyroglobulin in DS subjects of all ages from 1 to 50 years.244 T3 levels were reported to be lower in DS persons with AD than in those without.245 However, an age-dependent increase in hepatitis B surface antigen (HBsAg) was observed, and the frequency of HBsAg carriers was higher in individuals with thyroid antibodies (mean = 41.8 percent vs control mean = 19.7 percent) than in those without.244 The etiology of the thyroid abnormalities is not known, but it has been speculated that they are related in part to the abnormalities of the immune function described above. Although it is often stated that persons with DS have a propensity to developing autoimmune disorders, this is not well documented except for thyroid autoantibodies.
The prevalence of type 1 diabetes mellitus appears to be greater than in the non-DS population, but glycemic control was as good as was observed in the control population.246
Newborns with DS are slightly smaller, on the mean, than chromosomally normal infants, with length being reduced by about 0.5 SD of the mean.247 The mean head circumference at birth is reduced about 1 SD from the normal, but the growth velocity of the head parallels the normal until age 5 to 6 months, after which it levels off just below 2 SD below the normal mean.248 After correcting for potential confounding influences, the mean reduction of weight, in comparison with the birthweight of sibs, was found to be 0.24 kg, about 7 percent.249 In a Swedish group, mean length was reduced at birth by 1.5 SD in females and 0.5 SD in males, and mean height was reduced by 3 SD at age 3 years.250 This reduction in stature persists throughout life, with the difference from normal individuals becoming greater with increasing age. Similarly, in a longitudinally studied home-reared Japanese group, mean stature was reduced >1 SD up to 24 months of age and ≥3 SD after 30 months.251 The lower limbs were disproportionately short, and incremental growth rates for both total stature and lower limb length were significantly decreased at all ages up to 4 years. A similar decrease in growth velocity was also observed in home-reared American children with DS, and mean bone age was reduced and had greater variance than normal at 24 and 30 months.247
In a longitudinal 12-year study of institutionalized children and adolescents with DS, standing and sitting mean heights were both reduced >2 SD in comparison with a normal noninstitutionalized control population.252 Because bone age was retarded in the DS subjects, these differences were less in the prepubertal years. The stability of the growth pattern between 10 and 18 years of age was the same in both the DS and control groups, and final adult heights were considered to be equally predictable from the heights at 10 years of age in both groups. It was concluded, therefore, that the biologic mechanisms that regulate growth in this age range are not appreciably altered in DS.252
Growth charts for children with DS have been developed.252 A diminished growth rate is most apparent in infancy and in adolescence, and children with congenital heart disease are smaller in stature and weight than those without. In addition to shortness of stature, children and adults with DS tend to be overweight.253,254 In the latter, an increase in the proportion of body fat on the order of 50 percent or more has been noted in both males and females, and it has been suggested that both environmental (poor diet, lack of activity) and genetic factors may be involved.254
In an attempt to define a specific mechanism for the reduction in growth, measurements of growth hormone and somatomedins have been carried out. Plasma growth hormone levels do not appear to be reduced in children with DS,255 and serum insulin-like growth factor 1 (IGF-1) is increased during the first 2 years of life.250 However, rather than undergoing the normal twofold increase in concentration between early childhood and adult life, IGF-1 remains constant throughout life. In contrast, the serum concentration of IGF-2 is normal, as are the levels of insulin and somatomedin receptors in the brains of fetuses with DS.256,257 Treatment of DS children between 3.5 and 6.5 years of age with growth hormone resulted in increases in the levels of both immunoreactive IGF-1 and IGF-2, the former to normal range, and 50 to 200 percent increases in growth velocity.255 Similarly, treatment of 13 children with recombinant human growth hormone increased mean growth velocity to 2.25 times pretreatment values.258 The significance of these findings is presently unclear, but they do suggest that the growth impairment in DS may result from specific growth regulatory defects rather than being a general or nonspecific effect of the aneuploid condition.
There is only one documented case of reproduction by a male with trisomy 21,259 although males with mosaic trisomy 21 have fathered both normal and trisomic offspring.260 The principal defect in reproduction appears to be in spermatogenesis, with all degrees of impairment—from mild reduction to total arrest—having been reported for males with DS between 16 and 52 years of age.261 In a few cases, the impairment was so mild as to be compatible with fertility, at least as judged histologically.262 Sperm counts in nine cases were reported as greatly reduced in five and as zero in four.263 Penile and testicular size have been described as normal in adolescents,264 although diminished testicular size approaching that found in Klinefelter syndrome was reported for 17 individuals with a mean age of 30.7 years.265 In the latter group, significantly elevated levels of FSH (about 3 times control levels) were observed in both young and old individuals and of LH (increased about 1.5 times) only in individuals over 30 years of age.265 Although a control group was not studied, apparently normal levels of FSH, LH, and testosterone were reported in adolescents reared at home;264 normal plasma testosterone levels were found in other studies as well.266
The cause of the spermatogenic arrest in males with DS is unknown. It has been suggested that it is the result of a direct interference by the extra autosome with meiosis, possibly because the extra chromosome 21 associates with the sex vesicle.261 A similar impairment of spermatogenesis has been observed in mice heterozygous for robertsonian fusion translocations, albeit in a balanced state.267 It is also possible, although untested, that the trisomic state is itself, by a dosage effect, deleterious to spermatogenesis. While failure of spermatogenesis may be a sufficient explanation of fertility in males, other factors probably also play a role. These may include a decrease in libido and a diminished opportunity for sexual intercourse.
In contrast to the apparent total sterility of males, reproduction has been documented in females. At least 24 women with DS have had children, including a stillborn pair of twins, of which 10 of 25 had trisomy 21.260 Although equal numbers of disomic and euploid gametes might be expected, a proportion of less than 0.5 for trisomic offspring at term is consistent with the high fetal mortality of trisomy 21. Histologic examination of the ovaries of females with DS between birth and 14.5 years of age revealed an absence or retardation of follicle growth, with a reduced number of antral follicles,268 and there was no evidence for ovulation in 4 of 13 (31 percent) institutionalized women with DS.269
Life Expectancy and Causes of Death
With the changing patterns of institutionalization and of the utilization and methods of medical and surgical therapy provided to persons with DS, it is difficult to obtain accurate current figures for life expectancy. Comprehensive reviews of earlier studies270,271 indicate that mean life expectancy has improved dramatically in the last half-century since the estimate of 9 years in 1929.272 This increase in life expectancy is presumed to be the result of improved medical and social care of persons with DS at all ages. This conclusion is supported by the finding that, within a single country, survival rates during the first 5 years of life were reduced from 0.80 in the region with good pediatric care to 0.59 in the region with inferior care.273
The major determinant of survival during the first decade of life, and especially the first 4 to 5 years, is the presence or absence of congenital heart disease. Recent results from Japanese,274 Danish,275 and Canadian276,277 studies are presented in Table 63-3. Long-term survival rates and life expectancy are not calculated with regard to the presence of congenital heart disease, but its impact is, in part, revealed by comparison of the survival rates of the total DS population with those alive at age 10 and by the increase in total life expectancy during the first 5 years of life (Table 63-3).276 When compared with the background (whole) population, the life expectancy of an individual with DS at any point in time is 10 to 20 years less, with the difference being greater for females than for males.276 Furthermore, the absolute fractional survival rates for institutionalized individuals are 0.10 to 0.15 lower than for persons with DS living outside of institutions.270 When compared with other mentally retarded persons, whether institutionalized or not, one study reported that the survival rates of individuals with DS were not significantly different until age 30, but then became lower thereafter.277 In another study, however, the DS survival rates were lower at all ages than in a control mentally retarded population.277
Table 63-3: Survival Rates and Life Expectancy in Down Syndrome |Favorite Table|Download (.pdf) Table 63-3: Survival Rates and Life Expectancy in Down Syndrome
| ||Rate of Survival in Japanese Study ||Rate of Survival in Danish Study || || || |
| || || || || || |
| ||Without CHD ||With CHD ||Total Population ||Population Alive at Age 10 Years ||Estimated Life Expectancy, Years ||Rate of Survival in Canadian Study |
| || || || |
|Age ||Male ||Female ||Male ||Female ||Without CHD || ||With CHD |
|0 || || || || || || ||46.5 || || || |
|1 ||0.98 ||1.00 ||0.85 ||0.89 ||0.92 || ||49.5 ||0.91 || ||0.67 |
|5 ||0.96 ||0.97 ||0.72 ||0.77 ||0.84 || ||50.0 ||0.87 || ||0.62 |
|10 ||0.96 ||0.95 ||0.70 ||0.77 ||0.83 || ||45.9 ||0.85 || ||0.57 |
|20 || || || || ||0.80 ||0.97 ||37.1 || || || |
|30 || || || || ||0.75 ||0.92 ||29.2 ||0.79 || ||0.50 |
|40 || || || || ||0.71 ||0.86 ||20.8 || ||0.70 || |
|50 || || || || ||0.64 ||0.77 ||12.4 || ||0.61 || |
|60 || || || || ||0.40 ||0.49 ||6.3 || ||0.44 || |
|68 || || || || || || || || ||0.14 || |
|70 || || || || ||0.10 ||0.12 ||5.1 || || || |
Earlier studies recorded the major causes of death in DS as respiratory disease, including pneumonia (23 to 41 percent), congenital heart disease (30 to 35 percent), other infectious diseases (2 to 15 percent), malignancy (2 to 9 percent), and “senility” and stroke (0 to 9 percent).270,278–280 In an analysis of the causes of death of persons with DS who died in 1976, it was found that age-corrected rates for deaths from pneumonia were increased 5.6 times and constituted 16 percent of the total deaths observed.278 For congenital anomalies (83 percent of which were congenital heart disease), the increase was 4.7 times with 38 percent of the total; for leukemia and lymphatic neoplasms, 1.7 and 1.30 times and 3.0 percent and 1.1 percent, respectively. Increased rates for other types of infectious diseases, including kidney infections, influenza, enteritis, and meningitis, were also found. Congenital defects (mainly heart disease) were the leading cause of death up to age 35 years. The increased mortality from pneumonia and congenital anomalies (heart disease) was found over all age groups, while that for leukemia was increased at ages 1 to 4 and 20 to 34 years and for lymphatic neoplasms for 20 to 34 years. Mortality rates for cancers at other sites were greatly diminished (to 0.32, or less than expected), as were the rates for ischemic heart disease (0.57) and cirrhosis of the liver (0.44).
Alterations in Cultured Cells
Several aspects of the DS phenotype have been defined in cultured cells which represent an enhanced responsiveness to external stimuli. Although in many instances the differences between trisomic and diploid cells are relatively small, in some cases they are quite marked. One such difference, in the responsiveness of cultured fibroblasts to β-adrenergic agonists, is discussed in “Neuropharmacology” above.
Because of the location of the gene for the interferon-α/β receptor (IFNAR1) on chromosome 21, the responsiveness of DS cells to interferon has been examined in detail. The results indicate that trisomic cells have an enhanced sensitivity to several biologic actions of IFN-α.281–285 Subsequently, it was determined that a second component of this receptor, coded for by IFNAR2, is also located on chromosome 21. The enhanced functional and biochemical responses to IFN-α have, therefore, been attributed to the presence of an increased copy of each of these IFN-α receptor genes (see below). Although the IFN-γ receptor gene is not located on chromosome 21, enhanced responses of DS cells to IFN-γ have also been observed,282,283 and these appear to be due to the fact that a component of the IFN-γ receptor, referred to as a transducer or accessory factor, is coded for by the gene IFNGR2 on chromosome 21. DS cells may also be more responsive in general to a variety of external stimuli acting through cell-surface receptors.
In continuous cell culture, the rate of cell population doubling of matched pairs of fibroblasts decreased linearly with time, with the DS cells always having a slightly lower rate (about 10 to 15 percent).286 Furthermore, the cumulative number of population cell doublings was reduced by 20 percent (from a mean of 51.5 to 40) in the cultured DS cells. In contrast to these results, which suggest some degree of impairment of cell proliferation in vitro, other workers also using matched fibroblasts found that the mean number of cumulative population doublings was not reduced and that doubling times were not significantly increased.287,288 However, each of these means had a substantial standard deviation. At present, therefore, the data favoring or denying a difference in proliferative rates and cumulative population doublings seem to be about equally persuasive.
Sensitivity to Radiation and Chemicals.
Because of the increased susceptibility of children with DS to the development of leukemia, considerable interest is focused on the sensitivity of trisomic cells to mutagenic and carcinogenic agents, including radiation, chemicals, and viruses. The objective of these studies is to determine whether there is an intrinsic defect in DS cells that might make them more susceptible to oncogenic transformation. All of these studies are summarized in detail in reference7 .
There are numerous reports describing an increased radiosensitivity of trisomic lymphocytes as measured by a variety of techniques and at different stages of the cell cycle. When data from several of these reports were summarized,7 the most striking conclusion was that an effect, when one is present, is relatively small—the increased production of aberrations by trisomic cells being on the order of 1.1 to 2.1 times. In some experiments, when the dose of irradiation or the stage of the cell cycle at which radiation occurred was changed, the effect was no longer detectable. Based on experiments demonstrating a decreased survival of irradiated DS lymphoblastoid lines, it has been proposed that there is defective repair rather than an increased amount of x-ray-induced damage.289 Experiments on irradiated peripheral blood lymphocytes have also been interpreted as indicating enhanced chromosomal radiosensitivity resulting from a developmentally regulated repair deficiency.290
Mutagenic and Carcinogenic Chemicals.
Data on the effects of mutagenic and carcinogenic chemicals, generally alkylating agents, on the induction of chromosome aberrations in trisomic cells are more limited than for radiation. For the present, the published data are insufficient to support a conclusion that trisomic cells are inherently more sensitive to mutagenic or carcinogenic chemicals.7
Another probe of the sensitivity of DS lymphocytes to chromosomal damage is viral infection, either spontaneous or induced by vaccination. Measles infection is reported to increase the number of chromosome breaks per cell 4.8 times in individuals with DS, whereas the increase in normal subjects was only 1.2 times.291 Similarly, the number of chromosome breaks per cell immediately after chickenpox infection increased 2.8 times in DS but only 1.8 times in normal individuals.292 These data are insufficient to know what significance to attach to them.
The situation with the SV40 transformation of DS fibroblasts is similar to that described earlier for cell proliferation and sensitivity to radiation. There seems to be something different between DS and diploid cells, albeit a difference that is generally small in magnitude. But, the results are not always consistent, their interpretation is unclear, and their significance is uncertain.7 Despite the great amount of effort devoted to them, the outcome of these investigations must be considered as disappointing.