There are two major genetic abnormalities associated with Down syndrome.

The most common abnormality occurs in children born to parents with normal karyotypes. It is caused by the nondisjunction of chromosome 21 during meiotic segregation, resulting in one extra chromosome 21 (trisomy 21), with 47 chromosomes on karyotyping.

Alternatively, Down syndrome can be caused by DNA rearrangement resulting in the fusion of chromosome 21 to another acrocentric chromosome via its centromere. This abnormal chromosome is called a robertsonian translocation chromosome. Unlike those with trisomy 21, these individuals have 46 chromosomes on karyotyping. This type of translocation can sometimes be inherited from a carrier parent.

Both these genetic abnormalities result in a 50% increase in gene dosage for nearly all genes on chromosome 21. In other words, the amount of protein produced by all or nearly all genes on chromosome 21 is approximately 150% of normal in Down syndrome. The genes that have been shown to contribute to the Down syndrome phenotype include the gene that encodes the amyloid protein found in the senile plaques of Alzheimer disease and the one that encodes the cytoplasmic form of superoxide dismutase, which plays an important role in free radical metabolism.

This additional genetic material alters the course of development and causes the characteristics associated with Down syndrome. A few of the common physical traits of Down syndrome are low muscle tone, small stature, an upward slant to the eyes, and a single deep crease across the center of the palm – although each person with Down syndrome is a unique individual and may possess these characteristics to different degrees, or not at all.

A chromosomal analysis called a karyotype is done to confirm the diagnosis. To obtain a karyotype, doctors draw a blood sample to examine the baby’s cells. They photograph the chromosomes and then group them by size, number, and shape. By examining the karyotype, doctors can diagnose Down syndrome. Another genetic test called FISH can apply similar principles and confirm a diagnosis in a shorter amount of time.

How might this woman’s age contribute to her risk of having a child with Down syndrome?

It is not known why advanced maternal age is associated with an increased risk of Down syndrome as a result of trisomy 21. One theory suggests that biochemical abnormalities affect the ability of paired chromosomes to disjoin and that these abnormalities accumulate over time. Because germ cell development is completed in females before birth, these biochemical abnormalities are able to accumulate within the egg cells as the mother ages, thereby increasing the risk of nondisjunction. Another hypothesis is that structural, hormonal, and immunologic changes occur in the uterus as the woman ages, producing an environment less able to reject a developmentally abnormal embryo. Therefore, an older uterus would be more likely to support a trisomy 21 conceptus to term. Alternatively, it is possible that a combination of these and other genetic factors may contribute to the relationship between advanced maternal age and an increased incidence of Down syndrome.

 


Why does the extra genetic material of chromosome 21 lead to Down syndrome?

C. Down syndrome illustrates the principle of gene dosage, which states that the amount of a gene product produced per cell is proportionate to the number of copies of that gene present. In other words, the amount of protein produced by all or nearly all genes that lie on chromosome 21 is 150% of normal in trisomy 21 cells. There may be a critical region of chromosome 21, which, when present in triplicate, is both necessary and sufficient to produce the phenotypic features of Down syndrome.

 

Down syndrome occurs approximately once in every 700 live births.


 

A 25-year-old woman recently gave birth to a baby diagnosed with Down syndrome. Neither she nor the baby’s father have a personal or family history of Down syndrome. Karyotyping of the parents shows that the mother has a balanced robertsonian translocation: 45,XX,+t(14q;21q).

What is the chance that this couple would have a subsequent child with Down syndrome?

For a female carrier of a balanced robertsonian translocation, 45,XX,+t(14q;21q), the chance of having a child with Down syndrome is 10%. Unlike with Down syndrome as a result of trisomy 21 (47,XX+21 or 47,XY+21), this risk not affected by maternal age.


 

 

 

A 15-year-old boy develops acute lymphoblastic leukemia. Shortly after birth, he was diagnosed with duodenal atresia, which was treated with surgical intervention. Which of the following factors most likely contributed to the development of his condition?

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The correct answer is C. You answered D.

The question is describing two well-known complications for patients with Down syndrome, acute lymphoblastic leukemia, and duodenal atresia. Of the choices, Down syndrome is associated with increased maternal age.

 

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