Chromosomal Anomalies

Autosomal Abnormalities TRISOMY 21 (DOWN'S SYNDROME)

Pathogenesis and Pathophysiology. Several cytogenetic variants can produce Down's syndrome, and trisomy 21 is the most frequent. In this variant, Down's syndrome is due to an extra chromosome 21 or parts of it.[1 Trisomy of subbands 21q22.1 to 22.3 of the distal part of the long arm of chromosome 21 is the smallest component sufficient to cause Down's syndrome. In patients with trisomy 21, the genes on the extra segment of the chromosome are not found in a double dose as is normal but are tripled. In approximately 1 to 2 percent of cases, Down's syndrome occurs in the setting of mosaicism, in which there are two or more cell populations. Each cell population has a different karyotype, and one has a trisomy 21. The fusion of chromosome 21 with another acrocentric chromosome, most commonly chromosome 14, 21, or 22, may also result in a clinical syndrome that does not differ from that produced by the triplication of the subband 21q22. Finally, a rare familial form of Down's syndrome has been reported that may result from familial mosaicism, maternal trisomy 21, or other cytogenetic causes. The exact method by which these chromosomal anomalies cause the clinical sequelae of Down's syndrome has yet to be determined.

Epidemiology and Risk Factors. Down's syndrome is the most common autosomal chromosomal abnormality in human live births that results in structural malformations associated with developmental retardation. This disorder occurs in about 1 of 1000 neonates, and the frequency of trisomy 21 increases with maternal age. While familial forms of Down's syndrome are rare, the risk of a mother having a second affected infant is approximately 0.5 percent. In a child with a translocation, chromosomal karyotyping should be performed in both parents, since if one parent has the translocation, the risk of having a similarly affected child is much higher.

Clinical Characteristics and Associated Disorders. The physical characteristics of patients with Down's syndrome are commonly recognized in the first month of life, if not in the newborn nursery. Common features include

brachycephaly with a round face, Brushfield's spots, a small mouth and a large protruding tongue, small ears, epicanthal folds with upslanting palpebral fissures, and a flattened or depressed nasal bridge. Although epicanthal folds and a transverse simian palmar crease are considered characteristic of Down's syndrome, they are found in only 50 percent of these patients. Brachydactyly and clinodactyly of the fifth finger are observed more commonly than the simian palmar crease. There is a widened space between the first and second toes.

In addition to the typical phenotypic features of the syndrome, associated congenital cardiac and gastrointestinal abnormalities may be present. A third to a half of patients with Down's syndrome have congenital cardiac defects, of which one third are endocardial cushion defects, and the remainder are ventricular septal defects. Tetralogy of Fallot and atrial septal defects also occur, and there is an increased incidence of moyamoya disease. More than half of patients have bilateral hearing loss, of which many cases are attributable to anomalies of the inner and middle ear. Malformations of the gastrointestinal tract, including intestinal atresia and imperforate anus, occur in about 5 to 7 percent of patients, and there is a reported increased incidence of Hirschsprung's disease. Although abnormalities of T-lymphocyte function have been reported, no specific relationship of these to the infection rate has been established. Other associated abnormalities include gastroesophageal reflux, pulmonary hypertension, upper airway obstruction, obstructive sleep apnea, and an increased incidence of thyroid dysfunction, diabetes mellitus, cataracts, and leukemia.

The major neurological features of Down's syndrome are developmental delay and severe, diffuse muscular hypotonia, which affects most patients. Convulsive disorders are also more commonly present in these patients. The pathogenesis of the convulsive activity in this population is probably multifactorial and may result from a combination of medical risk factors and inherent neurological abnormalities. As individuals with Down's syndrome age, however, other neurological signs may appear. About 20 percent of patients complain of neck pain or discomfort, and they may demonstrate torticollis, gait impairment, or corticospinal tract dysfunction. These features are believed to be related to atlantoaxial subluxation and instability and result in compression of the medulla and spinal cord.

By about the fourth decade of life, additional deterioration of cognitive function may become apparent. This deterioration has been attributed to dementia, which results from a degenerative process that has neuropathological similarities to Alzheimer's disease. y Olfactory abnormalities may also appear, and these can pre-date the onset of dementia by 10 to 15 years. y

Differential Diagnosis. It is impossible to distinguish the clinical features of Down's syndrome resulting from the "typical" trisomy 21 from those resulting from translocation. Other chromosomal abnormalities should be considered, but the phenotypic features and neurological signs generally make the diagnosis clear.

Evaluation. The diagnosis of Down's syndrome is made by the presence of the typical physical abnormalities and can be confirmed by chromosomal karyotype. Radiological studies such as plain skull films may demonstrate a brachycephalic skull in which the anterior fontanelle and metopic suture close late. Computed tomography (CT) may show calcifications in the basal ganglia and a large opercula, while magnetic resonance imaging (MRI) reveals evidence of delayed myelination in some cases.y Other MRI studies have demonstrated smaller hippocampal and neocortical structures in patients with Down's syndrome compared to controls. y Additionally, these investigations suggest that patients with Down's syndrome develop signs associated with brain aging at an earlier age than normal; these signs include increased rates of ventricular dilatation, peripheral atrophy, and deep white matter lesions. The electroencephalogram (EEG) may be abnormal and can become progressively disorganized with the evolution of Alzheimer's type dementia. Reports of postmortem evaluation have noted the presence of a small, spherical brain and a cerebellum that is reduced in size. Microscopic abnormalities include reduced neuronal density in cortical regions, a loss of cortical interneurons, a reduction in the number of spines along pyramidal cells, and an accumulation of undifferentiated fetal cells in the cerebellum. Abnormalities in the basal nuclei of the brain include a reduced cell count that shows a continued steady decline with age. In nearly all subjects who die after reaching the age of 35, changes consistent with Alzheimer's disease are found.

Management and Prognosis. There is no specific treatment for Down's syndrome. Compared to the general population, these patients have increased morbidity and mortality, primarily from cardiac causes.


Edwards' syndromey is the second most common autosomal chromosomal abnormality associated with an extra autosome. The incidence of trisomy 18 is 0.3 per 1000 live births, and females are affected more often than males (3:1). In the majority of patients the entire chromosome 18 is trisomic, whereas other affected patients may have a mosaic state of partial trisomy. This anomaly is more frequent in the offspring of older mothers. A history of decreased in utero activity is typical, and there is an even distribution of premature, normal term, and postmature neonates with this disorder. Affected infants have a feeble cry, decreased adipose and subcutaneous tissue, and a paucity of muscle bulk. The face is generally small with a high nasal bridge, short palpebral fissures, ptosis, small mouth, narrow palate, and micrognathia. The hands are clenched, with the second finger overriding the third and the fifth overriding the fourth. The nails are hypoplastic, especially those on the fifth fingers and toes. Other commonly associated findings include rocker-bottom feet, a short sternum, small pelvis, umbilical and inguinal hernias, and diastasis recti. The skin can be redundant, and hirsutism of the head and back is notable. Cardiac malformations include ventricular and atrial septal defects and patent ductus arteriosus.

No consistent central nervous system (CNS) abnormalities are found in this disorder, but agenesis of the corpus callosum is the most common anomaly and may be associated with cerebellar or cerebral white matter heterotopias.

In those individuals who survive early infancy, severe mental retardation may occur. No specific therapy is available for patients with this syndrome. About half of patients expire before the age of 6 months, and only 10 percent survive 1 year.


The incidence of this trisomic syndrome, which occurs primarily in the offspring of older mothers, is approximately 1 in 7000, and it affects mainly females. M It should be noted that translocation can also result in this syndrome, but mothers of these children are usually younger. The clinical characteristics of this syndrome include multiple congenital anomalies with varying degrees of mid-facial anomalies. Infants may have ophthalmic abnormalities including anophthalmia, cyclopia, microphthalmia, and colobomas. Facial defects, such as cleft palate and lip and micrognathia, can also occur. A variety of congenital cardiac abnormalities such as ventricular or atrial septal defects and patent ductus arteriosus may be present. Intestinal malrotation, Meckel's diverticulum, and a spectrum of urogenital structural abnormalities are commonly seen. Polydactyly, with the third and fifth fingers overlapping the fourth, occurs in most affected infants. Neurologically, patients have developmental retardation as well as an increased frequency of neural tube defects and microcephaly. Pathologically, the most common abnormality is arrhinencephaly, and this may be associated with the absence of the interhemispheric fissure and the olfactory bulbs and tracts as well as with a single ventricle. Sample case reports have also noted the presence of corpus callosum lipomas and frontal cranial defects. As in infants with trisomy 18, heterotopias in the cerebellum and cerebral white matter may be observed. As is true of other trisomic conditions, no specific therapy is available. The average length of survival is about 9 months, and about 90 percent of affected patients die before the age of 12 months.


The Prader-Willi syndrome is a sporadic disorder that occurs in about 1 in 20,000 live births and has a risk of recurrence in the same family of about 1 in 1000. The responsible abnormality on chromosome 15 can be documented by cytogenetic studies, and in about 50 percent of patients there is a deletion at 15q11-q13. The disorder that produces Angelman's syndrome has the same gene locus. The use of cytogenetic techniques and DNA polymorphisms has made it possible to discern the origin of the parental deletion. Patients with Prader-Willi syndrome inherit the chromosomal disorder from their father, whereas patients with the Angelman syndrome inherit the chromosomal abnormality from their mother.^

Mothers of infants with the Prader-Willi syndrome note decreased in utero fetal activity, and often these neonates are born in breech presentation. The affected individuals are of short stature and have small hands and feet and a narrowed cranial bifrontal diameter. y Their eyes are almond-shaped, and they often have strabismus. The face is long, and nearly 50 percent of patients have hypopigmentation of the skin. Other common features include a small phallus, cryptorchidism, and hypogonadism with a small flat scrotum. Affected infants have a feeble suck and severe hypotonia, which commonly requires the use of a feeding tube. Near the end of the first year of life, however, the hypotonia may become less severe. The degree of mental retardation may seem more prominent in early life and may be correlated with the severity of the hypotonia. At 1 to 3 years of age the patients gain considerable weight and become obese because of hyperphagia. As the hypotonia becomes less severe, they also seem to be more mentally alert, yet the intelligence level usually ranges from an IQ of 40 to 60. Although the primary explanation for the short stature, hyperphagia, and hypogonadism has not been specifically defined, there is evidence that suggests the presence of primary hypothalamic dysfunction. Recent improvements in MRI scanning techniques have demonstrated anomalous cortical growth on the banks of the Sylvian fissure in some children with Prader-Willi syndrome. y These "growths" are seen even more frequently in children with Angelman's syndrome and are thought to represent misrouting of long projection axons. Electrophysiological studies and muscle biopsies have failed to reveal any clues to the cause of the severe hypotonia seen in these patients. At the present time, no direct therapy is available for the neurological aspects of this disorder.

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