Down Syndrome (Trisomy 21)

In about 95% of cases, there is an extra separate chromosome 21 (trisomy 21), which is typically maternally derived. Such people have 47 chromosomes instead of the normal 46.

About 3% of people with Down syndrome have the normal count of 46 chromosomes but have an extra chromosome 21 translocated to another chromosome (the resulting abnormal chromosome is still counted only as 1).

The most common translocation is t(14;21), in which a piece of an additional chromosome 21 is attached to chromosome 14. In about half of people with the t(14;21) translocation, both parents have normal karyotypes, indicating a de novo translocation. In the other half, one parent (almost always the mother), although phenotypically normal, has only 45 chromosomes, one of which is t(14;21). Theoretically, the chance that a carrier mother will have a child with Down syndrome is 1:3, but the actual risk is lower (about 1:10). If the father is the carrier, the risk is only 1:20.

The next most common translocation is t(21;22). In these cases, carrier mothers have about a 1:10 risk of having a child with Down syndrome; the risk is smaller for carrier fathers.

A 21q21q translocation chromosome, which occurs when the extra chromosome 21 is attached to another chromosome 21, is much less common. It is particularly important to determine whether a parent is a carrier of, or mosaic for, translocation 21q21q (such mosaics have some normal cells and some 45 chromosome cells with the 21q21q translocation). In such cases, each offspring of a carrier of the translocation will either have Down syndrome or monosomy 21 (the latter is not typically compatible with life). If the parent is mosaic, the risk is similar, although these people may also have offspring with normal chromosomes.

Down syndrome mosaicism presumably results from nondisjunction (when chromosomes fail to pass to separate cells) during cell division in the embryo. People with mosaic Down syndrome have two cell lines, one with the normal 46 chromosomes and another with 47 chromosomes, including an extra chromosome 21. The prognosis for intelligence and risk of medical complications probably depends on the proportion of trisomy 21 cells in each different tissue, including the brain. However, in practice, risk cannot be predicted because it is not feasible to determine the karyotype in every single cell in the body. Some people with mosaic Down syndrome have very subtle clinical signs and may have normal intelligence; however, even people with no detectable mosaicism can have very variable findings. If a parent has germline mosaicism for trisomy 21, an increased risk, above the maternal age-based risk, exists for a second affected child.

As with most conditions that result from chromosome imbalance, Down syndrome affects multiple systems and causes both structural and functional defects ( ). Not all defects are present in each person.

Most affected people have some degree of cognitive impairment, ranging from severe (IQ 20 to 35) to mild (IQ 50 to 75). Gross motor and language delays also are evident early in life. Height is often reduced, and there is an increased risk of obesity.

About 50% of affected neonates have congenital heart disease; ventricular septal defect Ventricular Septal Defect (VSD) A ventricular septal defect (VSD) is an opening in the interventricular septum, causing a shunt between ventricles. Large defects result in a significant left-to-right shunt and cause dyspnea... read more and atrioventricular canal (endocardial cushion) defect are most common.

About 5% of affected people have gastrointestinal anomalies, particularly duodenal atresia, sometimes along with annular pancreas Annular pancreas The duodenum can be obstructed by atresia, stenosis, and pressure due to an extrinsic mass. (See also Overview of Congenital Gastrointestinal Anomalies.) This anomaly is the 2nd most common... read more . Hirschsprung disease Hirschsprung Disease Hirschsprung disease is a congenital anomaly of innervation of the lower intestine, usually limited to the colon, resulting in partial or total functional obstruction. Symptoms are obstipation... read more and celiac disease Celiac Disease Celiac disease is an immunologically mediated disease in genetically susceptible people caused by intolerance to gluten, resulting in mucosal inflammation and villous atrophy, which causes malabsorption... read more also are more common. Many people develop endocrinopathies, including thyroid disease (most often hypothyroidism Hypothyroidism in Infants and Children Hypothyroidism is thyroid hormone deficiency. Symptoms in infants include poor feeding and growth failure; symptoms in older children and adolescents are similar to those of adults but also... read more ) and diabetes Diabetes Mellitus (DM) Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more . Atlanto-occipital and atlantoaxial hypermobility, as well as bony anomalies of the cervical spine, can cause atlanto-occipital and cervical instability; weakness and paralysis may result. About 60% of people have eye problems, including congenital cataracts Congenital Cataract Congenital cataract is a lens opacity that is present at birth or shortly after birth. Diagnosis is clinical and sometimes with imaging. Treatment is surgical removal of the cataract. (See also... read more , glaucoma, strabismus Strabismus Strabismus is misalignment of the eyes, which causes deviation from the parallelism of normal gaze. Diagnosis is clinical, including observation of the corneal light reflex and use of a cover... read more , and refractive errors Overview of Refractive Error In the emmetropic (normally refracted) eye, entering light rays are focused on the retina by the cornea and the lens, creating a sharp image that is transmitted to the brain. The lens is elastic... read more . Most people have hearing loss, and ear infections are very common.

The aging process seems to be accelerated. In recent decades, the median life expectancy has increased to about 60 years, and some affected people live into their 80s. Comorbidities contributing to decreased life expectancy include heart disease, increased susceptibility to infections, and acute myelogenous leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more . There is an increased risk of Alzheimer disease Alzheimer Disease Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more at an early age, and at autopsy, brains of adults with Down syndrome show typical microscopic findings. The results of recent research indicate that Black people with Down syndrome have a substantially shorter life span than White people. This finding may be the result of poor access to medical, educational, and other support services.

Affected women have a 50% chance of having a fetus that also has Down syndrome; however, many pregnancies are spontaneously lost. Men with Down syndrome are infertile, except for those with mosaicism.

(See also Next-generation sequencing technologies Genetic Diagnostic Technologies Genetic diagnostic technology is rapidly improving. A small amount of DNA can be amplified using the polymerase chain reaction (PCR) process, which can produce millions of copies of a gene or... read more .)

Diagnosis of Down syndrome may be suspected prenatally based on physical anomalies detected by

Fetal ultrasonographic abnormalities include increased nuchal translucency, atrioventricular canal defect, and duodenal atresia. Maternal serum testing may show abnormal levels of plasma protein A in late 1st trimester and alpha-fetoprotein, beta-hCG (human chorionic gonadotropin), unconjugated estriol, and inhibin in early 2nd trimester (15 to 16 weeks gestation). More recently, noninvasive prenatal screening Screening Chromosomal anomalies cause various disorders. Anomalies that affect autosomes (the 22 paired chromosomes that are alike in males and females) are more common than those that affect sex chromosomes... read more (NIPS), in which fetal DNA obtained from the maternal circulation is tested, has become a screening option for trisomy 21 because it has good sensitivity and specificity.

If Down syndrome was suspected based on maternal serum screening tests or ultrasonography, fetal or postnatal confirmatory testing is recommended. Fetal confirmatory methods include chorionic villus sampling Chorionic Villus Sampling All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated... read more and/or amniocentesis Amniocentesis All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated... read more with testing by karyotype analysis. Karyotyping is the test of choice to rule out an associated translocation so that parents can receive appropriate genetic counseling regarding recurrence risk. The option of prenatal confirmatory testing is offered to all patients with an abnormal, indeterminate, or unclear NIPS result. Management decisions, including termination of pregnancy, should not be made based on NIPS alone.

Maternal serum screening and diagnostic testing for Down syndrome are options for all women who present for prenatal care before 20 weeks gestation regardless of maternal age.

The American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Obstetrics, Committee of Genetics, and the Society for Maternal–Fetal Medicine 2020 practice bulletin advises that cell-free fetal DNA testing be offered to all pregnant women regardless of age or additional risk factors.

If diagnosis is not made prenatally, then neonatal diagnosis is based on physical anomalies and confirmed by cytogenetic testing.

The underlying disorder cannot be cured. Management depends on specific manifestations, but surveillance is fairly uniform for all children. Some congenital cardiac anomalies are repaired surgically. Hypothyroidism is treated with thyroid hormone replacement.

Care should also include genetic counseling for the family, social support, and educational programming appropriate for the level of intellectual functioning ( see Intellectual Disability Intellectual Disability Intellectual disability is characterized by significantly subaverage intellectual functioning (often expressed as an intelligence quotient < 70 to 75) combined with limitations of adaptive... read more ).

The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.