Trisomy 21

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117 Trisomy 21

Nilika B. Shah

Down syndrome, or trisomy 21, is the most common chromosomal abnormality among live-born infants and is the most frequent microscopically identifiable genetic cause of mental retardation. An extra copy of chromosome 21 results in an overexpression of the genes found on this chromosome to result in the phenotypic differences seen in patients with Down syndrome. This disorder is characterized by a variety of dysmorphic features, congenital malformations, and medical problems (Figures 117-1).

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Figure 117-1 Trisomy 21 (Down syndrome).

Etiology and Pathogenesis

Although trisomy 21 is responsible for 1 : 150 first-trimester spontaneous abortions, the live-born incidence is approximately 1 : 800-1 : 1000, and its incidence is highly correlated with advanced maternal age. The additional copy of chromosome 21 usually occurs from meiosis I nondisjunction, when the pair of homologous chromosomes 21 fail to separate. Errors that occur during meiosis are nearly always maternal in origin, and the incidence increases with advancing maternal age. This is likely attributable to the years from oocyte formation during maternal embryogenesis to the time of fertilization that the oocyte spends suspended in meiosis I.

Although trisomy of chromosome 21 (e.g., 47,XY, +21) in which a complete extra copy of chromosome 21 is present, causes approximately 94% of cases, other causes are also seen. Approximately 2% to 3% of cases of trisomy 21 can present with mosaicism (e.g., 47,XY, +21 [50%] or 46,XY[50%]) in which there is a mixture of trisomic cells and normal cells. This can lead to an attenuated phenotype, but it depends on the relative mosaicism of different tissues. Finally, approximately 3% to 4% of cases are caused by a Robertsonian translocation, in which the q arm of chromosome 21 is translocated onto another chromosome. This results in a fetus with 46 chromosomes but three copies of the long arm of chromosome 21, which carries all of the functional genes of this chromosome (e.g., 46,XY,der(15 : 21)(q10;q10), +21; Figure 117-1). Although most Robertsonian translocations are new mutations and occur regardless of maternal age, it is important to distinguish the cause and rule out a translocation carrier parent, which substantially increases the risk of recurrence.

The risk of recurrence for parents of children with Down syndrome varies according to maternal age at the time of birth of the affected infant. Mothers who were of advanced maternal age maintain their age-related risk, but mothers younger than 30 years old have a sixfold increased risk compared with their age-related peers. The reason for this increased risk is not entirely clear, although it may be related to a lower rate of spontaneous abortion of affected fetuses or an increased risk of nondisjunction that is unrelated to age. Furthermore, some evidence suggests a higher incidence of early pregnancy losses in mothers of children with Down syndrome, although, second- and third-degree relatives of individuals with trisomy 21 are not at an elevated risk of having children with Down syndrome. Parents of children with de novo translocations are not at increased risk of having another affected child; however, a man carrying balanced Robertsonian translocation has a 3% to 5% risk, but a woman has a 10% to 15% risk for recurrence. Of note, parents carrying a balanced 21;21 translocation have a 100% recurrence risk.

Clinical Presentation and Differential Diagnois

The diagnosis of trisomy 21 is often made by prenatal screening. When no prenatal diagnosis has been made, Down syndrome is usually recognized from the characteristic phenotype present in the newborn. The diagnosis is confirmed with a karyotype.

Phenotypic Features

The pathogenesis of the characteristic appearance of infants with trisomy 21 and associated malformations of Down syndrome are presumably related to dosage effects of genes on chromosome 21, specifically those in a 5Mb region on 21q22. Certain malformations occur more frequently than others, thus supporting the concept that certain genes rather than a specific embryologic event are involved. The diagnosis of Down syndrome is often straightforward and is based on the overall appearance and characteristics of individuals. Neonates with Down syndrome are typically hypotonic and have poor developmental reflexes. Neonates can also have redundant nuchal skin folds. The skull may be mildly microcephalic with a small occiput and large fontanelles. The eyes are almond shaped with epicanthal folds and upslanting palpebral fissures, and the irises may demonstrate Brushfield spots. The nose is usually short with a low nasal bridge. Usually, the mouth is downturned, and because the oral cavity is small, the tongue often protrudes. The ears may be low set with an overfolded superior helix. The hands are short and commonly have the characteristic single palmar crease.

Developmental Impairment

Nearly all individuals with Down syndrome have some degree of cognitive impairment, although the range is quite wide. Most affected are mildly to moderately mentally retarded, with IQ in the 50 to 70 or 35 to 50 ranges, respectively. Some may be severely impaired with IQ ranges from 20 to 35. Cognitive impairment is evident within the first year of life. Developmental milestones are met typically at twice the age compared with the average population with sitting at around 11 months, creeping at around 17 months, and walking around 26 months. The sequence of the development of language is the same, but the rate is much slower. First words are spoken on average at around 18 months. Affected children will still gain new skills, but the IQ tends to decline through childhood and plateaus in adolescence.

In more than 60% of children, the profile of cognitive impairment is one in which language comprehension is equal to mental age, and language production is more delayed. However, in about a third of children with Down syndrome, language comprehension, mental age, and language production are equal.

Comorbidities

Several important comorbidities are associated with Down syndrome. Among these, it is important to recognize heart disease, gastrointestinal abnormalities, growth problems, eye problems, hearing loss, hematologic disorders, immune deficiency, endocrine disorders, reproductive disorders, atlantoaxial instability (AAI), sleep apnea, skin disorders, and behavior disorders.

Heart Disease

Approximately 50% of children with Down syndrome have congenital heart disease that includes atrioventricular septal (ASDs), atrioventricular canal or endocardial cushion defects (45%), ventricular septal defects (35%), isolated secundum ASDs, (8%), isolated patent ductus arteriosus (7%), and tetralogy of Fallot (4%). Furthermore, asymptomatic children without congenital structural heart disease may develop valve abnormalities, including mitral valve prolapse, mitral regurgitation, and aortic regurgitation.

Gastrointestinal Disease

Gastrointestinal tract abnormalities occur in about 5% of children with trisomy 21 with the most common being duodenal atresia or stenosis (2.5%), sometimes occurring with an annular pancreas. The characteristic radiographic finding associated with duodenal atresia or stenosis is the “double-bubble” sign. Other anomalies, although less frequently seen, include imperforate anus and esophageal atresia with tracheoesophageal fistula. Conversely, nearly 30% of patients with duodenal atresia or stenosis and 20% with annular pancreas have Down syndrome. Hirschsprung disease is more common in trisomy 21 compared with the general population, although the risk is less than 1%. Trisomy 21 appears to be strongly associated with celiac disease with an incidence of between 5% and 16%, which is five- to 16-fold greater than the general population.

Growth and Stature

Head circumference, length, and weight are all lower in infants and children with trisomy 21 than unaffected children. Compared with their siblings, at birth, children with trisomy 21 weigh on average 0.2 to 0.4 kg less. The rate of growth of children with trisomy 21 is reduced, especially during infancy and adolescence, and is more severely reduced in children with congenital heart disease. In adolescence, the growth spurt of affected children occurs earlier, further blunting the ultimate height. In adults with Down’s syndrome, the average height in men and women is 61.7 and 57 inches (157 and 144 cm), respectively, and the average weight is 157 and 140 lb (71 and 64 kg), respectively.

The cause of trisomy 21–associated growth retardation remains unknown. In some patients, low serum levels of insulin-like growth factor 1 (IGF-1) and lower spontaneous and induced secretion of growth hormone (GH) have been reported. Hypothalamic dysfunction may lead to suboptimal endogenous GH production. Selective deficiency of IGF-1 has been seen in individuals with Down syndrome who are older than the age of 2 years.

Obesity

The prevalence of obesity (body mass index >27.8 kg/m2 in men and >27.3 kg/m2 in women) is higher in individuals with trisomy 21 than in the general population. When comparing people with Down syndrome with the general population, obesity rates are 45% versus 33% for males, and 56% versus 36% for females. It is thought that children and adults with trisomy 21 have a reduced resting metabolic rate that results in a majority of children becoming obese by 3 to 4 years of age.

Disturbances of Vision

Ophthalmologic disorders that require monitoring and intervention affect the majority of children with trisomy 21. These include refractive errors (myopia, hyperopia, astigmatism) in 35% to 75%, strabismus, in 25% to 55%, and nystagmus in 18% to 22%.

Cataracts can also occur in up to 5% of newborns. Starting in the second decade of life, many children develop corneal opacities and may also develop glaucoma. The frequency of ocular disorders increases with age, and eye abnormalities have been reported to increase from fewer than 40% of infants 2 to 12 months of age up to 80% of children age 5 to 12 years. The development of ocular anomalies continues to increase into adulthood and is thought to be prevalent in nearly all adults with Down syndrome.

Disturbances of Hearing

Hearing impairment affects 40% to 80% of individuals with trisomy 21. In 50 children with Down syndrome 2 months to 3.5 years of age, auditory brainstem response testing demonstrated unilateral loss in 28%, bilateral loss in 38%, and normal hearing in 34%. The hearing loss was conductive in 19 ears, sensorineural in 16, and mixed in 14 with the extent of loss being mild, moderate, and severe to profound in 33, 13, and three ears, respectively. About 50% to 70% of children with Down syndrome develop otitis media. Because of its high prevalence, monitoring for this condition is crucial to the maintenance of hearing.

Hematologic Disorders

Abnormalities affecting all hematopoietic lineages, red blood cells, white blood cells, and platelets are common in people with trisomy 21. Most notably, the risk of leukemia in Down syndrome is 1% to 1.5%.

Nearly 65% of newborns with trisomy 21 have polycythemia that has been suggested to be attributable to an elevated plasma erythropoietin concentration. This suggests that ongoing fetal hypoxemia may contribute to the increased incidence of polycythemia. Whether the chronic hypoxia is related to placental insufficiency or other factors remains unclear.

Children with trisomy 21 often have macrocytosis. The mean corpuscular volume (MCV) in children with trisomy 21 between ages 2 to 6 years has been reported to be greater than in control subjects (86.9 vs. 80.6 fL), with MCVs above the 95th percentile for age seen in 66% versus 11% of control subjects.

Oncologic Disorders

Transient Leukemia

Transient leukemia, also known as transient myeloproliferative disorder (TMD), is a form of leukemia that almost exclusively affects newborns with trisomy 21, with an incidence of about 20%. Usually, affected infants are asymptomatic, and the disorder resolves spontaneously by 2 to 3 months of age. Vesicopustular skin eruptions filled with blasts may be associated but also resolve by 3 months of age. In the rare cases that result in death, infants are often antenatally affected with fetal hydrops. The disorder is characterized by the presence of blast cells in the peripheral blood, typically with hemoglobin, platelet, and neutrophil counts being normal, although morphology may be different. Giant platelets and fragments of megakaryocytes may be seen. Bone marrow biopsy of transient leukemia demonstrates a lower percentage of blasts in bone marrow than in peripheral blood, and cytogenetic analysis reveals no clonal abnormalities in the marrow other than trisomy 21.

Life-threatening complications of transient leukemia occasionally occur. A Pediatric Oncology Group study of nearly 50 children with transient leukemia reported seven patients who developed hepatic fibrosis and two who developed cardiopulmonary failure. In retrospective analyses, the clinical features associated with early death of children with transient leukemia included preterm delivery, white blood cell count of 100,000 cells/µL or greater, direct bilirubin of 4.8 mg/dL (83 µmol/L) or greater, ascites, and bleeding disorders. Hepatic fibrosis presents as progressive obstructive jaundice and results in death in approximately 50% of cases. Cardiopulmonary disease presents most commonly as whole-body edema, with pulmonary edema, pericardial effusions, and ascites; the mechanism is unknown.

Acute Megakaryoblastic Leukemia

Up to 25% of infants with transient leukemia later develop acute megakaryoblastic leukemia (AMKL), also known as the FAB M7 subtype of acute myeloid leukemia (AML-M7). AML-M7 occurs in 0.5% to 2% of children with Down syndrome, and the incidence is nearly 500 times greater in children with trisomy 21. Usually, AML-M7 develops during the first 4 years of life, and 20% to 70% of affected patients present with myelodysplastic syndrome, consisting of progressive thrombocytopenia and anemia. Neutropenia is not commonly seen. Some children develop hepatomegaly and liver failure secondary to fibrosis. Treatment issues are complicated, and children with Down syndrome affected with either acute lymphoblastic leukemia (ALL)or AML are subject to increased rates of treatment-related mortality.

Acute Lymphoblastic Leukemia

The risk of developing ALL is approximately 10 to 20 times higher in those with trisomy 21. The clinical presentation is similar to that of children without trisomy 21, and at presentation, includes similar leukocyte count and leukemic cell mass, slightly older age of trisomy 21 patients (median age, 6 vs. 4.7 years), less frequent mediastinal mass (1.6% vs. 8.9%), and central nervous system leukemia (0% vs. 2.7%), both of which are favorable prognostic signs. Less favorable prognostic signs seen in patients with trisomy 21 include lower rates of T-cell leukemia, higher rates of translocation of (9;22) or t(4;11), and less hyperdiploidy.

Importantly, children with trisomy 21 with ALL often respond to chemotherapy as well as do children without trisomy 21.

Immune Deficiency

Down syndrome is associated with a variety of immunologic deficiencies that likely contribute to susceptibility to infection, autoimmune disorders, and malignancies. These immunologic impairments include chemotactic defects, decreased immunoglobulin G (IgG) levels, specifically IgG4, and abnormalities of T- and B-cell systems. It has yet to be established whether these represent intrinsic or secondary immune deficiencies.

Endocrinologic Disorders

The most common endocrine abnormalities in individuals with trisomy 21 include thyroid dysfunction and diabetes. The prevalence of thyroid disease varies depending on the population examined, and hypothyroidism has ranged from 3% to greater than 50%. Hyperthyroidism is also relatively common in adults with trisomy 21, occurring in 2.5%. Thyroid disease is also seen in children with Down syndrome, and even in patients younger than 25 years of age, 35% have been shown to have hypothyroidism, with 50% developing the disorder before age 8 years.

Recent data have suggested that the risk of type 1 diabetes in trisomy 21 is three times greater than in the general population. Furthermore, the prevalence of type 1 diabetes in affected children up to 9 years of age is thought to be eight times greater than in age-matched control subjects.

Reproductive Concerns

Women with trisomy 21 are fertile and may become pregnant. Offspring may or may not be affected by trisomy 21, depending on the type of mutation. As always, counseling should be provided for managing menstruation and contraception. Alternatively, nearly all men with trisomy 21 are infertile because of impairment of spermatogenesis, although fathers with trisomy 21 producing offspring have been reported.

Atlantoaxial Instability

AAI, which is excessive mobility of the joint between the atlas (C1) and the axis (C2), may lead to cervical spine subluxation. Although 13% of individuals with trisomy 21 are asymptomatic, spinal cord compression caused by AAI affects approximately 2%. Lateral neck radiographs of neutral position, flexion, and extension help to confirm the diagnosis. Spinal cord compression may present as neck pain, torticollis, gait abnormalities, loss of bowel or bladder control, and quadriparesis or quadriplegia. If such symptoms arise, immediate stabilization may be required. Asymptomatic individuals appear to remain so whether or not physical activity is restricted.

Sleep Apnea

About 30% to 75% of children with trisomy 21 have obstructive sleep apnea, independent of obesity. This is likely because of soft tissue and skeletal causes of upper airway obstruction. Chronic intermittent hypoxemia may contribute to pulmonary hypertension, which may further deteriorate mental capacities.

Skin Disorders

Most children with trisomy 21 have benign skin changes, which may include palmoplantar hyperkeratosis, seborrheic dermatitis, cutis marmorata, fissured or geographic tongue, and xerosis. Skin problems often worsen in adolescence, with half developing folliculitis.

Behavior Disturbances

Behavior and psychiatric disorders are more common in trisomy 21 than typical children but not as common than in those with other reasons for mental retardation. Psychiatric disorders have been reported to affect nearly 20% of individuals with trisomy 21 younger than 20 years of age. These include behavioral disorders such as attention-deficit hyperactivity disorder, conduct or oppositional disorder, and aggressive behavior as well as psychiatric disorders (most often major depressive illness or aggressive behavior); these disorders affect 25% of adults with trisomy 21. Autism occurs in as many as 7% of children with trisomy 21, and when compared with children without trisomy 21, the diagnosis is often delayed.

Recent Advances and Future Directions

Numerous recent advances in genomics have led to an increased understanding of trisomy 21. The number of genes currently known on chromosome 21 is around 400, and this number is expected to increase. One of the major focuses of research into the pathology of trisomy 21 is to identify which of the genes on chromosome 21 lead to the various Down syndrome–associated phenotypes. To facilitate this understanding, mouse models of trisomy 21 have been developed to further understand pathologic mechanisms and dosage-sensitive genes. Ongoing discoveries similar to those outlined below are helping us to understand the pathology of trisomy 21 on the brain, heart, and hematopoietic anomalies.

Learning and Memory

All people with trisomy 21 have some degree of learning disability. A number of genes located on chromosome 21 that are overexpressed, including DYRK1A, synaptojanin 1, and SIM2, have been shown to contribute to learning and memory deficits in mouse models. In addition, extra copies of neuronal channel proteins such as GIRK2 may also contribute to learning difficulties.

Alzheimer Disease

Individuals affected by trisomy 21 have a notably increased risk of early-onset Alzheimer disease compared with unaffected individuals. It has been shown that amyloid precursor protein is encoded on chromosome 21, and overexpression of this gene likely contributes to the 50% to 70% of people with trisomy 21 who develop dementia by age 60 years.

Cancer

As noted above, trisomy 21–affected people have a much higher risk of developing AMKL and ALL. Recent evidence has suggested that AML-M7 may result from a mutation in the GATA-1 transcription factor that is required for normal differentiation of megakaryocytes. It is thought that these mutations are acquired in utero and that finding such mutations at birth might serve as a biomarker for an increased risk of transient leukemia and subsequent AMKL. Furthermore, mutations in Janus Kinase 3 (JAK3) have been noted in some populations of patients with TMD/AMKL. Because JAK3 has been a target of pharmacologic development, JAK3 inhibitors may be a potential source of therapy for these disorders in patients with trisomy 21, although further work needs to be done to elucidate if JAK3 mutations are loss-of-function or gain-of-function in AKML before therapeutic evaluation.

Cognitive Ability

Most recent therapeutic work for people with trisomy 21 has centered on treatment to enhance cognitive ability. In a trisomy 21 mouse model, picrotoxin and pentylenetetrazole improved learning associated with the hippocampus, even after treatment stopped. These therapeutics decrease γ-aminobutyric acid–mediated inhibition in the hippocampus as their mechanism of improving cognitive ability. Furthermore, in the same mouse model, cognition is improved by treatment with N-methyl-D-aspartic acid receptor (NMDAR) antagonist memantine. The biggest contributor for identifying treatments for people with Down syndrome will be to determine which genes specifically contribute to specific cognitive phenotypes. To accomplish this, standardized multicenter protocols will be necessary to assess sufficient numbers of patients. Large-scale collaboration has been successful in other medical fields in developing treatment algorithms, and the same principles can be used to treat trisomy 21. Mouse studies currently being used to model trisomy 21 in humans will be a first step in the development of new therapeutics.

Despite the past, when Down syndrome was thought to be untreatable because of its genetic complexity, marked advances in the understanding of Down syndrome have occurred and will likely usher in new treatment approaches for improving the cognition, health, and well-being of these patients.

Suggested Readings

American Academy of Pediatrics. Health supervision for children with Down syndrome. Pediatrics. 2001;107:442.

Epstein CJ. Down syndrome (trisomy 21. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. ed 8. New York: McGraw-Hill; 2001:1223.

Kumin L. Speech and language skills in children with Down syndrome. MRDD Res Rev. 1996;2:109.

Massey GV, Zipursky A, Chang MN, et al. A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children’s Oncology Group (COG) study POG-9481. Blood. 2006;107:4606.

Myrelid A, Gustafsson J, Ollars B, et al. Growth charts for Down’s syndrome from birth to 18 years of age. Arch Dis Child. 2002;87:97.

Weijerman ME, van Furth AM, Vonk Noordegraaf A, et al. Prevalence, neonatal characteristics, and first-year mortality of Down syndrome: a national study. J Pediatr. 2008;152:15.

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