OVERVIEW: What every practitioner needs to know Are you sure your patient has trisomy 21? What are the typical findings for this disease?

Trisomy 21, or Down syndrome, is the most common cause of intellectual disability. Resulting from an extra copy of chromosome 21 in every cell of the body, it is also the most common chromosomal abnormality.

Other physical features: hypotonia, short stature, short and broad hands, fifth-finger clinodactyly, single palmar crease, increased space between great toe and second toe.

Intellectual disability: mild to severe mental retardation wtih global delays

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Congenital heart defects (40%-50%): most commonly endocardial cushion defect (ECD), ventricular septal defect (VSD), secundum atrial septal defect (ASD), tetralogy of Fallot, and patent ductus arteriosus (PDA). Approximately 70% of infants with ECD are affected with trisomy 21.

Esophageal atresia and/or tracheoesophageal fistula, duodenal atresia, celiac disease, other gastrointestinal abnormalities (~15%)

Atlantoaxial or atlantooccipital instability (15%)

Hirschsprung disease (<1%)

Acute myeloid or lymphocytic leukemia (0.75%)

Thyroid abnormalities

Immune dysfunction

Significant causes of morbidity and mortality in trisomy 21 are congenital heart defects (CHDs), esophageal atresia with or without tracheoesophageal fistula, duodenal atresia, and/or Hirschsprung disease. Intellectual disability is universal, usually in the mild to moderate range of mental retardation, but it can be severe. Life expectancy depends on secondary defects, particularly CHDs, but is typically 85% to age 1 year and 50% to age 50 years.

What other disease/condition shares some of these symptoms?

Multiple chromosomal and/or single gene disorders can have dysmorphic facial features and other sequelae of trisomy 21, but can be differentiated by karyotype. Other common chromosome abnormalities to consider include trisomy 18 and sex chromosome abnormalities with multiple X chromosomes.

Zellweger syndrome, a peroxisomal disorder, has similar facial features, including upslanting palpebral fissures, epicanthal folds, flattened midface, protruding tongue, hypotonia, and heart defects such as VSD and PDA. Other features of Zellweger syndrome that are not consistent with Down syndrome include liver abnormalities and hepatomegaly, brain abnormalities such as gyral defects, and stippled epiphyses on radiography.

Feingold syndrome has several features similar to those of trisomy 21, including epicanthal folds, upslanting palpebral fissures, duodenal atresia, tracheoesophageal fistula, and intellectual disability. However, a typical feature of Feingold syndrome includes an absent middle phalanx of the second and fifth fingers and 2/3 toe syndactyly, and the overall facial gestalt of Feingold syndrome is different from trisomy 21.

Prader-Willi syndrome is associated with neonatal hypotonia and intellectual disability, but has different physical manifestations and is not typically associated with organ defects.

What caused this disease to develop at this time?

Trisomy 21 is caused by the presence of an extra chromosome 21 in every cell of the body in the majority of cases (94%). Around 3% of cases are due to mosaicism, and 3% are due to robertsonian translocations.

Most cases of trisomy 21 are due to maternal nondisjunction in meiosis I, and the risk for trisomy 21 increases with maternal age. Mosaicism typically occurs from the loss of chromosome 21 from a trisomic embryo, resulting in a cell line with trisomy 21 and a cell line with a normal chromosomal constitution.

Robertsonian translocation with a 21;21 chromosome occurs as a de novo event in 75% of cases and is inherited from a parent in 25%. Importantly, the affected parent of a child with a familial 21;21 robertsonian translocation has a 100% chance of each child being affected with trisomy 21.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A karyotype, or chromosome analysis, should be ordered if trisomy 21 is suspected. The presence of full trisomy 21 versus mosaic trisomy 21 or a robertsonian translocation can be determined. If mosaicism is being considered, a karyotype counting at least 20 cells should be requested.

Fluorescence in situ hybridization (FISH) can determine trisomy 21 with a rapid turnaround time. A chromosomal microarray can also diagnose trisomy 21 or other more subtle chromosomal abnormalities but is typically more expensive with a longer turnaround time.

Prenatal screening is performed to determine pregnancies at risk for trisomy 21, including maternal serum screening and first-trimester screening that examines the nuchal translucency size with maternal serum markers. Definitive prenatal diagnosis by chorionic villus sampling or amniocentesis is available to women with abnormal screening results or those of advanced maternal age .

Would imaging studies be helpful? If so, which ones?

Echocardiography can distinguish affected individuals with heart disease. Cervical radiograms with lateral and extension views should be conducted at 3 years of age to rule out atlantoaxial instability.

If you are able to confirm that the patient has trisomy 21, what treatment should be initiated?

Once a diagnosis is confirmed, the American Academy of Pediatrics Guidelines, “Health Supervision for Children with Down Syndrome” should be followed. It can be accessed at http://pediatrics.aappublications.org/content/128/2/393.full.pdf+html.

In the neonatal period, the following tests should be performed: an echocardiogram to check for the possibility of CHD associated with trisomy 21, thyroid function studies, a complete blood count (CBC), auditory brainstem response (ABR), and an ophthalmologic examination.

Referral to a pediatric gastroenterologist should be carried out if features of celiac disease or structural abnormality are present.

Genetic counseling should be offered, which would discuss the cause and natural history of trisomy 21 and the recurrence risk for future pregnancies based on the mode of inheritance in the patient.

Longer term treatment includes referral to local early intervention programs that can provide physical, occupational, and speech therapies. Developmental assessments can be done to determine strengths and weaknesses in cognitive areas.

Dental abnormalities can be common; therefore, prompt and regular dentist referrals should be made.

A sleep study is recommended if obstructive sleep apnea is suspected.

Counseling regarding appropriate diet and lifestyle modifications should be made to reduce the risk of obesity, which is common in trisomy 21.

Individuals with trisomy 21 may be more sensitive to chemotherapeutic agents such as methotrexate.

Premature aging occurs, with a greatly increased risk for Alzheimer’s disease in middle age.

What are the possible outcomes of trisomy 21?

Trisomy 21 is a relatively common condition; thus, there is a great deal of information regarding prognosis. With full trisomy 21, intellectual disability is universal, typically in the mild to moderate range. Some individuals with trisomy 21 are severely disabled intellectually. Typically, affected individuals learn to walk, talk, and read, and some learn to drive a car. Patients with trisomy 21 cannot usually live independently but can function in a group home setting.

Morbidity and mortality are associated with CHDs, gastrointestinal abnormalities, and leukemia. Currently, the typical life span with appropriate interventions for medical problems is up to 50 years of age, but may increase with medical advances over time. Affected individuals with mosaic trisomy 21 usually are more mildly affected, but this is variable depending on the number of cells with trisomy 21 in each organ system.

What causes this disease and how frequent is it?

Trisomy 21 is caused by the presence of an extra chromosome 21 in every cell of the body in 94% of cases. The majority are due to maternal nondisjunction in meiosis I, followed by maternal meiosis II errors. Rarely, paternal meiosis II errors are causative. The risk for trisomy 21 increases with maternal age; a 25-year-old woman has a risk of 1 in 1250 of having a live-born child with trisomy 21, whereas a 45-year-old woman’s risk is 1 in 24.

Around 3% of cases are due to mosaic trisomy 21, usually caused by a trisomic fetus losing the extra chromosome in a cell, resulting in 2 cell lines. Trisomy 21 caused by a robertsonian translocation occurs in around 3% of cases, and 75% of these occur de novo. If a parent is a carrier of a robertsonian translocation excluding the 21;21 isochromosome, recurrence risk is typically 15%-20% for each pregnancy. With a 21;21 robertsonian translocation carrier, recurrence risk is 100% for each pregnancy.

Trisomy 21 occurs in around 1 in 800 live births in the United States.There are no known environmental or infectious causes for trisomy 21. There is thought to be a “trisomy 21 critical region” on 21q22 that contains genes implicated in the phenotype of the syndrome.

How do these pathogens/genes/exposures cause the disease?

The features of trisomy 21 are caused by the presence of an extra copy of the genes on chromosome 21, due to a dosage effect.

How can trisomy 21 be prevented?

There is no way to prevent the occurrence of trisomy 21. Prenatal screening and diagnosis are available in the general population. First-trimester screening is performed between 11 and 14 weeks’ gestation and determines the thickness of the nuchal translucency in the fetus, as well as beta human chorionic gonadotropin (beta hCG) and pregnancy-associated plasma protein A (PAPP-A) levels in maternal serum. A risk of trisomy 21 is calculated based on these measurements comparing normal and affected fetuses. The detection rate is up to 85%.

Second-trimester quadruple maternal serum screening is performed at 14-18 weeks’ gestation and determines the values for alpha-fetoprotein (AFP), beta hCG, unconjugated estriol, and inhibin A levels, creating a calculated risk similar to a first-trimester screening. Sensitivity is around 75% for trisomy 21. Level II ultrasonography is around 50% sensitive for finding abnormalities associated with trisomy 21 (i.e., CHD, increased nuchal skin, short femurs, absent nasal bone).

Prenatal diagnosis by chorionic villus sampling (10-13 weeks’ gestation ) or amniocentesis (15-18 weeks’ gestation) is offered to women with abnormal screening test results, advanced maternal age (considered to be 35 years of age or greater at delivery in most institutions), or a family history of chromosome abnormalities. These tests look directly at the chromosomal makeup of the fetus and are thus considered 100% sensitive for trisomy 21, but they carry a risk of miscarriage of around 1 in 200-400.

What is the evidence?

“Health Supervision for Children with Down Syndrome”. Pediatrics. vol. 107. pp. 442-9. (Experts in the field convened and submitted guidelines for the care and management of children with trisomy 21, including age-specific reference tables.)