Down syndrome is associated with either an extra chromosome 21 or an effective trisomy for chromosome 21 by its translocation to another chromosome, usually chromosome 14, or, less often, to another acrocentric chromosome, especially chromosome 21 or 22 (19).

A few terms require definition. In the general population about 1 couple in 500 carries a reciprocal translocation. A reciprocal translocation is a structural alteration of chromosomes that usually results from breakage of two chromosomes with the subsequent exchange of the resultant chromosomal segments. In general, this event occurs most frequently at prophase of the first meiotic cell division. The segments exchanged are nearly always from nonhomologous chromosomes and are usually not the same size. Such an rearrangement is said to be balanced when none of the chromosomal material appears to be duplicated or deleted on standard or high-resolution analysis.

Robertsonian translocation results from centromeric fusion of two acrocentric chromosomes. A larger chromosome is formed, with the resultant loss of the short-arm regions of the participating chromosomes, resulting in a complement of 45 chromosomes in the balanced carrier. In a survey that was based on prenatal genetic studies performed with banding the frequency of balanced chromosomal rearrangements was 1 in 250 or 0.4%. Reciprocal translocations were seen in 0.17%, inversions in 0.12%, and Robertsonian translocations in 0.11% (19a). On a clinical basis, it is impossible to distinguish between patients with Down syndrome caused by ordinary trisomy 21 and those caused by translocation. The frequency of trisomy 21 increases with maternal age and reaches an incidence of 1 in 54 births in mothers aged 45 years or older (20). In contrast to ordinary trisomy, the incidence of translocation Down syndrome is independent of maternal age. Most translocations producing Down syndrome arise de novo in the affected child and are not associated with familial Down syndrome. Data obtained between 1989 and 1993 on prenatal and postnatal diagnoses of 1,811 Down syndrome children born to mothers aged 29 years or younger show regular trisomy 21 in 90.8% (19). Of a group of 235 translocation Down syndrome individuals, 42% of cases involved a translocation between chromosome 21 and chromosome 14, whereas 38% showed a translocation involving two 21 chromosomes. In translocation patients for whom cytogenetic results were available from both parents, 21;21 translocations were almost invariably de novo, whereas 37% of 14;21 translocations were inherited from the mother and 4% derived from the father (19). Of 51 cases of 21;21 translocation investigated, 50 were de novo and one was of maternal origin (19).

Approximately 1% of couples experience the recurrence of Down syndrome as a result of regular trisomy 21. In most instances, this is caused by previously unrecognized mosaicism in one parent (21). In families in whom Down syndrome results from a translocation, the risk for subsequent affected children is significantly higher; it is 15% if the mother is the carrier, but less than 5% if the father is the translocation carrier (22).

By the use of polymorphic DNA markers, several studies have concluded that the extra chromosome is maternally derived and mainly is the consequence of errors in the first meiotic division in more than 90% of cases (23). The mean maternal age associated with errors in meiosis is approximately 33 years, significantly higher than the mean reproductive age in the United States. In 4.3%, there were errors in paternal meiosis. In these cases, and in the remainder, caused by errors in mitosis, maternal age is not increased (24). Several explanations have been put forth to account for the maternal age effect. With increasing age there are a decreasing number of chiasmata, that is, crossovers, sites where recombination occurs because of breakage and reunion between homologous chromosomes (25). The most likely hypothesis is that the decrease in chiasmata contributes to nondisjunction by disrupting the process of separation of the chromosomal homologues.

To understand the molecular pathogenesis of Down syndrome, two questions must be answered: (a) How does
the presence of a small acrocentric chromosome in triplicate and the increased expression of genes on this chromosome produce the anatomic and functional abnormalities of the Down syndrome phenotype, and (b) are we able to identify specific regions of chromosome 21 whose duplication is responsible for each of the phenotypic features of Down syndrome?

The sequencing of chromosome 21 has resulted in the identification of more than 300 genes, of which at least 165 have been confirmed experimentally (26). Of these at least 9 are believed to affect brain development and function (Table 4.1). Studies on individuals with partial trisomy 21 have suggested that overexpression and subsequent interactions of genes on chromosome 21q22 contribute significantly to the phenotype of Down syndrome (25,27). Two genes in this region have received particular attention. The gene for a Down syndrome cell adhesion molecule (DSCAM) is expressed in the developing nervous system, and, like other cell adhesion molecules, this molecule is critical for cellular migration, axon guidance, and the formation of neural connections (see Chapter 5) (25). Another gene localized to the 21q22 region is that for DYRK1A, a serine/threonine protein kinase, required for postembryonic proliferation of neuronal cell types. The overexpression of this gene is believed to interfere with postembryonic neurogenesis (27). However, the 21q22 region can hardly be considered “critical” for the production of the clinical syndrome, and duplication of genes in regions distinct from 21q22 are believed to be responsible for many of the typical Down syndrome features (28).

It also is not known how the presence of extra copies of genes and their regulatory sequences produces the Down syndrome phenotype. Although, on a theoretical basis, one would expect gene product levels 1.5 times normal, this is not always the case. For example, expression of the amyloid precursor protein (APP) is approximately four times normal in the brains of patients with Down syndrome (29). Its role in the development of early-onset Alzheimer disease in patients with Down syndrome is considered in the subsequent section.

Malformations affect principally the heart and the great vessels. Approximately 20% to 60% of Down syndrome individuals have congenital heart disease. Defects in the atrioventricular septum were the most common abnormalities encountered by Rowe and Uchida in 36% of their patients, most of whom were younger than 2 years of age (30). A ventricular septal defect was present in 33% and a patent ductus arteriosus was present in 10% of patients. Among the other malformations, gastrointestinal anomalies were the most common. These included duodenal stenosis or atresia, anal atresia, and megacolon. Hirschsprung disease was seen in approximately 6% of patients (31).
Malformations of the spine, particularly of the upper cervical region, can occasionally produce neurologic symptoms. These are considered at another point of this chapter.

Grossly, the brain is small and spherical, and the frontal lobes, brainstem, and cerebellum are smaller than normal. The number of secondary sulci is generally reduced, the tuber flocculi persist, and the superior temporal gyrus is poorly developed (Fig. 4.1). A number of microscopic abnormalities also have been described (32,33). In essence, these involve reduction of neuronal density in various areas of the cortex, a loss of cortical interneurons, an accumulation of undifferentiated fetal cells in the cerebellum, and a reduction in the number of spines along the apical dendrites of pyramidal neurons, believed to indicate a reduction in the number of synaptic contacts (34). Interestingly, the dendritic tree is greater than normal in early infancy, but the excessive early outgrowth is followed by atrophy (35). Becker and colleagues explained these observations as an abortive attempt by neurons to compensate for the decreased number of spines and synapses on their receptive surfaces (35).

Abnormalities of the basal nucleus have received particular attention because an early and significant loss of cholinergic neurons in this area is a feature of both Down syndrome and Alzheimer disease. In Down syndrome the cell count is one-third normal, even before the onset of dementia, and it decreases progressively with age (36).

The most intriguing neuropathologic observation is the premature development of changes within the brain compatible with a morphologic diagnosis of Alzheimer disease. The spatial pattern of involvement of the brain by senile plaques and tangles follows that seen in Alzheimer disease. Thus, the amygdala, hippocampus, and the association areas of the frontal, temporal, and parietal cortex are particularly vulnerable to these changes (37). They are found in 15% of patients with Down syndrome aged 11 to 20 years, in 36% of patients aged 21 to 30 years, and in all patients who died aged 31 years or older (38). Microscopic alterations include pigmentary degeneration of neurons, senile plaques, and calcium deposits within the hippocampus, basal ganglia, and cerebellar folia. The calcium deposits in the cerebellar folia can be extensive enough to be seen on neuroimaging studies. As in Alzheimer disease, the brains of individuals with Down syndrome have reduced choline acetyltransferase activity, not only in areas that contain plaques, but also in those that appear microscopically normal (39,40).

Underlying the evolution of Alzheimer disease in children with Down syndrome is an excessive buildup of amyloid β-protein (AβP). This buildup is believed to be the consequence of an overexpression of the gene for amyloid β precursor protein (AβPP), mapped to chromosome 21q21. AβPP is cleaved to form AβP through the sequential action of beta-secretase and gamma-secretase. The gene for beta-secretase is also located on chromosome 21q22, and levels of this enzyme are significantly higher in Down syndrome fetal tissue than in controls, an indication that this gene is also overexpressed in Down syndrome (41). Cleavage of AβP by beta-secretase produces Aβ40, a soluble intracellular form, and plasma and tissue levels of soluble Aβ40 are higher in individuals with Down syndrome than in controls (42,43). Longer, less soluble forms, Aβ42 and Aβ43, are produced by the action of gamma-secretase, and Aβ42 is present in the brain of fetuses affected with Down syndrome as early as 21 weeks’ gestation (44,45). These insoluble aggregates of AβP readily form fibrils and are responsible for the ultimate appearance of both senile plaques and amyloid deposits in cerebral blood vessels (46). Why the appearance of plaques and amyloid deposits is delayed for decades after the appearance of Aβ42 remains unclear. Also unclear is the role played by mitochondrial dysfunction in the abnormal processing of AβPP (47).

The clinical picture of Down syndrome is protean and consists of an unusual combination of anomalies rather than a combination of unusual anomalies (22). The condition is seen more frequently in male individuals, with one study showing a male-to-female ratio of 1.23 to 1, but in mosaic individuals the male-to-female ratio is 0.8 to 1 (19).

The birth weight of Down syndrome infants is less than normal, and 20% weigh 2.5 kg or less (48). Neonatal complications are more common than normal, a consequence of fetal hypotonia and a high incidence of breech presentations. Physical growth is consistently delayed, and the
adult Down syndrome individual has a significantly short statue (49). The mental age that is ultimately achieved varies considerably. It is related in part to environmental factors, including the age at institutionalization for non–home-reared individuals, the degree of intellectual stimulation, and the evolution of presenile dementia even before puberty. As a rule, the developmental quotient (DQ) is higher than the IQ and decreases with age (Table 4.2) (50). Most older patients with Down syndrome have IQs between 25 and 49, with the average approximately 43. The social adjustment tends to be approximately 3 years ahead of that expected for the mental age (50). Del Bo and coworkers found that the decline in full-scale IQ with age was faster in those individuals who carry the apolipoprotein E4 allele, an important risk factor for both sporadic and familial late-onset Alzheimer disease (51).

Mosaicism can be found in approximately 2% to 3% of patients with Down syndrome. In these instances, the patient exhibits a mixture of trisomic and normal cell lines. As a group, these individuals tend to achieve somewhat higher intellectual development than nonmosaic individuals, and, in particular, they possess better verbal and visual-perceptual skills (52).

Aside from mental retardation, specific neurologic signs are rare and are limited to generalized muscular hypotonia and hyperextensibility of the joints. This is particularly evident during infancy and occurs to a significant degree in 44% of patients younger than 9 years of age (53).

Whereas major motor seizures are seen no more frequently in Down syndrome infants than in the general population, the association between infantile spasms and Down syndrome is greater than chance (54). Attacks can occur spontaneously or, less often, follow insults such as perinatal hypoxia. The electroencephalogram (EEG) demonstrates hypsarrhythmia or modified hypsarrhythmia (55). In the experience of Nabbout and coworkers a 6-month course of vigabatrin monotherapy has been effective, and with prompt treatment the prognosis for seizure control and preservation of intelligence is relatively good (54,56). In the experience of Stafstrom and Konkol, only 3 of 16 patients with Down syndrome with infantile spasms had persistent seizures, and the degree of cognitive impairment did not exceed that expected for the general Down syndrome population (55). A progressive disorganization of the EEG accompanies the evolution of Alzheimer dementia (57). Neuroimaging characteristically reveals large opercula, an indication of the underdeveloped superior temporal gyrus, and, in older patients, evidence exists of premature aging (58). Symmetric calcifications in basal ganglia, notably in the globus pallidus, are common, particularly in adults (59,60).

Numerous case reports and series have associated atlantoaxial instability and dislocation with Down syndrome. The instability, seen in some 15% to 40% of patients, results from laxity of the transverse ligaments that hold the odontoid process close to the anterior arch of the atlas (61). The instability is usually asymptomatic, but neck pain, hyperreflexia, progressive impairment of gait, and urinary retention have been encountered (62). Other patients have experienced an acute traumatic dislocation. In view of this catastrophic complication, children with Down syndrome should undergo a complete neurologic examination, including neuroimaging with lateral views of the cervical spine in flexion and extension, if they plan to participate in competitive sports (e.g., Special Olympics) or in sports that could result in trauma to the head or neck. Children who have this abnormality should be excluded from these activities. Children with atlantoaxial instability who develop neurologic signs require surgical stabilization of the joint (62,63).

In addition to these neurologic abnormalities, patients with Down syndrome exhibit a number of dysmorphic features. None of these is present invariably, nor are any consistently absent in the healthy population, but their conjunction contributes to the characteristic appearance of the patient.

The eyes show numerous abnormalities, almost all of which have been encountered in other chromosomal anomalies (64). The palpebral fissures are oblique (upslanting) and narrow laterally. Patients have a persistence of a complete median epicanthal fold, a fetal characteristic rarely present in healthy children older than age 10 years but observed in 47% of trisomy 21 patients aged 5 to 10 years and in 30% of older patients (65). Brushfield spots are an accumulation of fibrous tissue in the superficial layer of the iris. They appear as slightly elevated light spots encircling the periphery of the iris (Fig. 4.2). According to Donaldson, Brushfield spots are present in 85% of Down syndrome individuals, as compared with 24% of controls (66). Blepharitis and conjunctivitis are common, as are lenticular opacifications and keratoconus, particularly in older patients. Many children with Down syndrome benefit from spectacles to correct refractive errors and astigmatism.

Anomalies of the external ear are also frequent. The ear is small, low set, and often C-shaped, with a simple helix
and hypoplastic tragus. The cartilage is often deficient. Additionally, the diameter of the external auditory meatus is abnormally narrow, which precludes good visualization of the tympanic membrane.

Structural anomalies of the middle and inner ear might contribute significantly to the language delay commonly encountered in children with Down syndrome. Congenital malformations of the bones of the middle ear, permanent fixation of the stapes, and shortening of the cochlear spiral are encountered frequently (67). Additionally, children, particularly infants, are prone to acute and chronic otitis, middle ear effusions, and endolymphatic hydrops with subsequent conductive and neurosensory hearing loss.

According to Balkany and colleagues (68), 64% of patients with Down syndrome have binaural hearing loss. In 83%, the hearing loss is conductive, and in the remainder, sensorineural. Brainstem auditory-evoked potentials can be used to determine the type and severity of hearing loss in young or uncooperative children (69). Because of the frequency of impaired hearing, a comprehensive hearing evaluation is indicated during the first 6 to 12 months of life.

The lips of the patient with Down syndrome have radial furrows, and, as a consequence of the generalized hypotonia, the tongue, often fissured, tends to protrude because the maxilla is too small and the palate is too narrow to accommodate it. A typical finding, particularly evident in infants, is a roll of fat and redundant skin in the nape of the neck, which, combined with the short neck and low hairline, gives the impression of webbing.

The extremities are short. The fifth digit is incurved, and the middle phalanx is hypoplastic (clinodactyly). As a consequence, its distal interphalangeal crease is usually proximal to the proximal interphalangeal crease of the ring finger. Additionally, the distal and proximal interphalangeal creases are closely spaced, and there might be a single flexion crease on the fifth digits. The simian line, a single transverse palmar crease, is present bilaterally in 45% of patients (Fig. 4.3). In the feet, a diastasis between the first and second toes (sandal gap) is the most characteristic anatomic abnormality.

A juvenile rheumatoid arthritis–like progressive polyarthritis has been seen with some frequency. A number of other autoimmune disorders, notably diabetes mellitus type 1, also have a greater-than-chance association with Down syndrome, as do a variety of endocrine abnormalities (70). Down syndrome is associated with several autoimmune conditions and with a variety of endocrine abnormalities (71). An elevation of antithyroid antibody is common, and nearly 50% of trisomy 21 patients, mostly male patients, have reduced thyroid function in later life (72). Congenital hypothyroidism and primary gonadal deficiency are fairly common, but hypothyroidism can appear at any age. Gonadal deficiency progresses from birth to adolescence and becomes manifest in adult life with resultant infertility in virtually all nonmosaic male patients (73).

The dermatoglyphic pattern of the patient with Down syndrome shows several abnormalities. Of these, a distally displaced triradius, the palmar meeting point of three differently aligned fine creases, is seen in 88% of patients but in only 10% of controls (50). Dermatoglyphic abnormalities of the fingerprint patterns are equally characteristic (see Fig. 4.3) (50,74).

Abnormalities of the skin are common. Xeroderma and localized chronic hyperkeratotic lichenification are seen in 90% and 75% of patients, respectively. Vitamin A levels are reduced in 15% to 20% of patients.

As of 1997, the median age at death of Down patients was 49 years (75). Several factors contribute to the reduced life expectancy. The most important of these is the high incidence of major cardiovascular malformations; these account for 80% of deaths. In one study, 92.2% of Down syndrome patients without congenital heart disease survived to age 24 years, as contrasted with 74.6% of patients with congenital heart disease (76). As expected, mortality
in those with congenital heart disease is the greatest during the first year of life (77). Of less significance in terms of influencing life expectancy is a 10- to 20-fold increase in lymphoblastic leukemia (78). As a rule, acute myeloid leukemia predominates in children with Down syndrome younger than age 4 years, whereas acute lymphoblastic leukemia predominates in older children (78). Also shortening the life expectancy of children with Down syndrome is an unexplained high susceptibility to infectious illnesses and the early appearance of Alzheimer disease, which results in a marked decrease in survival after 35 years of age (75,79). The clinical picture of Alzheimer disease in patients with Down syndrome corresponds to that in patients without Down syndrome. Deterioration of speech and gait are early findings. Epileptic seizures and myoclonus are common and were seen in 78% and 85% of patients, repsectively, in the Dutch series of Evenhuis (80). Loss of cognitive function, including memory loss, generally remains unrecognized until the later stages of the disease.

The diagnosis of Down syndrome is made by the presence of the characteristic physical anomalies and is confirmed by cytogenetic analysis. Karyotyping of all cases of Down syndrome is indicated to identify those that result from chromosomal translocation. When translocation is present, the karyotype of both parents must be ascertained to determine whether one of them carries a balanced translocation.

First-trimester screening is indicated for mothers ages 35 or older at term as well as in the young mother who has had a previous child with Down syndrome. Low maternal serum α-fetoprotein, reduction of unconjugated estriol, and elevated chorionic gonadotropins are independent predictors of Down syndrome, as is an ultrasonic measurement of the fetal nuchal translucency (81). Serum inhibin, a glycoprotein of placental origin, is elevated in maternal serum in women with Down syndrome fetuses and has been suggested as another useful screening marker (82), as is pregnancy-associated protein A (83). Biggio and coworkers discussed the cost-effectiveness, reliability, and complications of the various current screening strategies (84).

The diagnosis of a mosaic Down syndrome does not present any difficulty except when the frequency of the abnormal karyotype is low (85). However, accurate prediction of the phenotype in mosaic cases is problematic. Eventually, routine screening of all mothers for Down syndrome will be possible. One approach is the implementation of a polymerase chain reaction (PCR)–based technique that uses chromosome 21 markers to detect abnormal gene copy numbers in fetal cells (86,87).

Despite the number of vigorously and fervently advocated regimens, none has proved to be successful in improving the mental deficit of the child with Down syndrome. Medical intervention is directed toward treatment and prophylaxis of infections, treatment of hearing and visual
deficits, early recognition and treatment of hypothyroidism, and, if possible, correction of congenital heart disease or any other significant malformation. Although not proven statistically, early intervention appears to be of benefit in enhancing communication and self-help skills.

The early administration of 5-hydroxytryptophan, a serotonin precursor, appears to reverse the muscular hypotonia characteristically present in the infant with Down syndrome (88), and in some instances can accelerate motor milestones. Unfortunately, this has no effect on the ultimate level of intelligence (89).

The treatment of the Down syndrome child with mental retardation is similar to that of children with mental retardation from any cause and having the same potential of intellectual and social function. The topic, particularly the role of early intervention and total communication programs, is discussed in Chapter 18.

Trisomy 13 (Patau syndrome) occurs in fewer than 1 in 5,000 births (91). Approximately one-half of cases are diagnosed prenatally through a combination of routine ultrasound and serum screening (92). The clinical picture is characterized by feeding difficulties, apneic spells during early infancy, and striking developmental retardation (93,94,95). Patients have varying degrees of median facial anomalies, including cleft lip and/or palate, premaxillary agenesis, and micrognathia. The ears are low set and malformed, and many infants are deaf. Polydactyly, flexion deformities of the fingers, and a horizontal palmar crease are common. The dermatoglyphics are abnormal (Fig. 4.4). Cardiovascular anomalies are present in 80% of patients, most commonly in the form of a patent ductus arteriosus or a ventricular septal defect. Approximately 33% of patients have polycystic kidneys. An increased frequency of omphalocele and neural tube defects also exists. Microcephaly is present in 83% and microphthalmus in 74% of cases (94).

The major neuropathologic abnormality is holoprosencephaly (arrhinencephaly), a complex group of malformations that have in common absence of the olfactory bulbs
and tracts and other cerebral anomalies, notably only one ventricle and absence of the interhemispheric fissure (see Chapter 5). On autopsy, a number of microscopic malformations are observed, including heterotopic nerve cells in the cerebellum and in the subcortical white matter (96,97,98).

Absence of the olfactory apparatus is not specific for trisomy 13. In the series of Gullotta and coworkers (99), this malformation was encountered at autopsy in 40% of trisomy 13 patients. It also occurs with deletion of the short arm of chromosome 18 (18p), in the trisomy 18 syndrome, and with deletion of the long arm of chromosome 13 (13q). A condition termed pseudotrisomy 13 syndrome is fairly common. This entity is characterized by alobar holoprosencephaly, cardiac anomalies, and postaxial polydactyly, accompanied by apparently normal cytogenetics (100). Cardiac, pulmonary, genital, or other skeletal malformations also can be present (101). The condition is transmitted as an autosomal recessive trait (102).

The prognosis for children with chromosome 13 trisomy is poor. Approximately 50% die during the first month of life, and only 20% survive into the second year.

Trisomy 18 (Edwards syndrome) was first described in 1960 by Edwards (103). Its incidence appears to be on the increase; with the most recently recorded prevalence in Hawaii being 4.7 in 10,000 (91). The incidence in conceptuses is much higher, and only 2.5% of trisomy 18 conceptuses are live born. The anomaly is seen much more frequently in girls, the most recent male:female ratio being 0.65 (104). This suggests that a high proportion of affected male fetuses succumb during gestation. Like other autosomal trisomies, trisomy 18 results from an error in maternal meiosis, with the additional chromosome demonstrating maternal origin in 96% of cases (105).

The clinical picture is highlighted by a long, narrow skull with prominent occiput, characteristic facies, low-set, malformed ears, a mildly webbed neck, and marked physical and mental retardation (94,99). A typical picture of camptodactyly (flexion contractures of the fingers) and abnormal palmar flexion creases occurs. The second and fourth fingers characteristically overlie the third, and the fifth finger overlies the fourth. Distally implanted, retroflexible thumbs are encountered frequently. As in trisomy 13, omphalocele, polycystic kidneys, and congenital heart disease are common. A striking dermatoglyphic pattern, relatively less common in other autosomal anomalies, is the presence of simple arches on all fingers.

No consistent central nervous system malformation is associated with the trisomy 18 syndrome. The most common anomaly is agenesis of the corpus callosum, occasionally associated with nerve cell heterotopias of the cerebellum or white matter (97,99). In more than 50% of patients, the brain is small, but normal on gross and routine microscopic examination (99). The prognosis for children with trisomy 18 is poor, and 90% die by 1 year of age. The mean survival time is 10 months for girls and 23 months for boys (106). The natural history of trisomy 18 and trisomy 13 in long-term survivors has been well characterized (106,107).

Other trisomies are much less common (see Table 4.3) but have been found with relatively high frequency in spontaneous human abortions (9). Mosaic trisomy syndromes have been recognized for chromosomes 8, 9, 16, and 20. Mosaicisms for other autosomal trisomies have been reported very rarely (108). Their clinical appearance is reviewed by Schinzel (12) and Tolmie (109).