Trisomy 21

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117 Trisomy 21

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).

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.

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.

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.