Chapter 21 Down Syndrome
PATHOPHYSIOLOGY
Down syndrome, the most common chromosomal condition that results in intellectual disabilities, is associated with an extra chromosome on chromosome 21. Current genetic studies have found that this chromosome consists of 329 genes. Understanding how these genes work will provide a real opportunity to understand how this condition occurs and how the characteristics of this condition result.
Down syndrome may occur by one of three mechanisms: a free trisomy or nondisjunction (about 95% of cases), translocation (about 3% to 5%), or mosaicism (about 1% to 2%). Free trisomy or nondisjunction occurs when three copies of chromosome 21 result in 100% of the cells. This situation arises from an unequal distribution of chromosomes in anaphase 1 or 2 during meiosis or in the anaphase of mitosis. The phenotype for nondisjunction and translocation is the same.
Nondisjunction occurs by maternal meiotic origin in approximately 90% of cases; it results in three copies of chromosome 21. Nondisjunction usually occurs spontaneously and is not familial. Approximately 8% of cases are caused by paternal factors, most often advanced paternal age, of 55 years or older. Factors that can influence the occurrence of nondisjunction Down syndrome are maternal age, earlier menopause, and gene polymorphisms that influence folate metabolism.
Translocation happens when all or part of a chromosome is exchanged with another chromosome. This can result in a balanced or unbalanced translocation, depending upon the amount of chromosomal material involved. In Down syndrome, translocations are unbalanced; the most common combination of chromosomes involved is 14 and 21 (14;21), followed by both copies of the chromosome 21 (21;21). In 75% of all cases of unbalanced translocations, the cause is not familial, but it is in 25% of the cases. The cause is considered to be multifactorial and independent of parental age.
Mosaicism is characterized by the absence of trisomy (three copies) of chromosome 21 in 100% of the cell lines. This form of Down syndrome is most frequently caused by maternal meiotic nondisjunction. Individuals with mosaic Down syndrome have fewer phenotypic features. Diagnosis of the genotype of Down syndrome is made through a chromosome analysis (American Academy of Pediatrics Committee on Genetics, 2001; Lashley, 2005).
There are many physical features of Down syndrome, also called the phenotype, that do not exist in every child who has the condition. Presence or absence of a physical feature usually does not indicate severity of the condition. The exception is the degree of mental retardation, which would affect developmental outcomes. For information on the complications and secondary problems associated with Down syndrome, refer to Complications in this chapter.
INCIDENCE
1. The incidence of Down syndrome is approximately 1 in 800 live births, and the prevalence is generally accepted to be 1 in 650 to 1000 live births.
2. The availability of prenatal diagnosis, especially in women of advanced maternal age, has influenced these figures.
3. The incidence of having a child with Down syndrome for a woman in her twenties is approximately 1 in 2000 live births. This figure increases to approximately 34 in every 1000 live births for the woman who is age 45.
4. Down syndrome may occur three ways: nondisjunction, translocation, or mosaicism.
5. Down syndrome is found in all ethnic groups and races. Incidences are higher in Hispanic and African American mothers who are age 35 years and older.
6. The risk of recurrence varies by the type of transmission.
CLINICAL MANIFESTATIONS
1. Down syndrome is diagnosed at birth because of distinctive phenotype, but confirmed by karyotype (see more under Laboratory and Diagnostic Tests in this chapter).
2. Visual diagnosis may be more difficult in newborns of color since the phenotypic characteristics may not be obvious and other signs such as Mongolian spots, common in African Americans, may not be identified as part of a syndrome.
3. There are more than 50 characteristic features of Down syndrome occurring on the skull, the eyes, the ears, the nose, the mouth, the neck, the chest, the abdomen, and the extremities, and affecting physical growth and development in all domains. No one feature is diagnostic, and not every characteristic feature is present in any one person with Down syndrome.
4. The most common features are generalized hypotonia, mental retardation, incurved fifth finger, simian crease, flattened occipital, small nose with flat nasal bridge, epicanthic folds, Brushfield’s spots, absent Moro reflex, wide spaces between the first and second toes, hearing impairment, ocular problems, thyroid problems, dental problems, and/or orthodontic problems.
COMPLICATIONS
1. Premature aging is present and affects development throughout life; early-onset Alzheimer’s disease may be a factor.
2. Congenital anomalies that occur with greater frequency in Down syndrome include congenital cardiac disease (endocardial cushion defects and septal defects most common), gastrointestinal malformations (duodenal or esophageal atresia and congenital megacolon most common), celiac disease, and leukemia (transient myeloproliferative disorder, in particular).
3. Mental health problems: behavioral problems, depression, and/or attention deficit hyperactivity disorder (ADHD) can also occur in children with Down syndrome (Crocker, 2006; Lashley, 2005; Nehring, 2004).
LABORATORY AND DIAGNOSTIC TESTS
1. The best practice to obtain an accurate diagnosis is to offer pregnancy screening by blood test for chromosomal anomalies and neural tube defects, followed by cytogenic diagnosis. This combination serum test, often called a quadruple screen, includes alpha fetoprotein, human chorionic gonadotropin, unconjugated estriol, and dimeric inhibin-A in maternal serum. This blood test is done during weeks 16 to 18 of pregnancy. Researchers are currently examining the use of the quadruple screen with a fetal ultrasound for nuchal translucency during gestational week 11 and adding the quadruple screen during the second trimester for confirmation, as a more efficacious screening protocol.
2. Invasive screening tests include chorionic villi sampling during gestational week 12 and amniocentesis during week 16.
3. Diagnosis of Down syndrome is made through chromosome analysis.
4. Ocular defects are common; the child with Down syndrome should see an ophthalmologist by 6 months of age and then, beginning around age 3 years, every 2 years. Vision should be checked yearly.
5. Auditory defects are also common. Auditory brainstem response testing should be completed by 3 months of age, followed by evaluation by a specialist every 6 months up through age 3 years and annually thereafter.
6. Otoscopy and tympanometry should be done at each visit by the specialist.
7. Periodontal disease is common, so the child with Down syndrome should see a dentist every 6 months beginning at age 18 months.
8. A full cardiac evaluation should be completed in infancy, with follow-up as needed according to occurrence of cardiac conditions.
9. Thyroid-stimulating hormone levels should be measured at 6 and 12 months and annually thereafter, since thyroid dysfunction is a common condition.
10. Children with Down syndrome should first be checked for atlantoaxial instability between 3 and 5 years and then as needed before athletic involvement.
11. The risk for hip dislocation is present, so the child should be checked for this condition during well-child visits through 10 years of age and if a gait abnormality is present.
12. Because of the risk of mitral value prolapse, this condition should be checked for, beginning in adolescence.
13. IgA-antiendomysium antibodies of immunoglobulin A class should be assessed when the child is between 2 and 3 years old because of the higher prevalence of celiac disease.
