Down Syndrome 

Down syndrome is by far the most common and best known chromosomal disorder in humans and the most common cause of intellectual disability.^{[1, 2, 3, 4, 5]} It is characterized by mental retardation, dysmorphic facial features, and other distinctive phenotypic traits. Down syndrome is primarily caused by trisomy of chromosome 21; this is the most common trisomy among live births. The term mongolism was once commonly used but is now considered obsolete.^{[6, 7, 8]}

Like most diseases associated with chromosomal abnormalities, trisomy 21 gives rise to multiple systemic complications as part of the clinical syndrome. This chromosomal anomaly leads to both structural and functional defects in patients with Down syndrome. However, not all defects occur in each patient; there is a wide range of phenotypic variation.

The extra chromosome 21 affects almost every organ system and results in a wide spectrum of phenotypic consequences. These include life-threatening complications, clinically significant alteration of life course (eg, mental retardation), and dysmorphic physical features. Down syndrome decreases prenatal viability and increases prenatal and postnatal morbidity. Affected children have delays in physical growth, maturation, bone development, and dental eruption.

Two different hypotheses have been proposed to explain the mechanism of gene action in Down syndrome: developmental instability (ie, loss of chromosomal balance) and the so-called gene-dosage effect.^[9] According to the gene-dosage effect hypothesis, the genes located on chromosome 21 have been overexpressed in cells and tissues of Down syndrome patients, and this contributes to the phenotypic abnormalities.^[10]

The extra copy of the proximal part of 21q22.3 appears to result in the typical physical phenotype, which includes the following:

• Mental retardation - Most patients with Down syndrome have some degree of cognitive impairment, ranging from mild (intelligence quotient [IQ] 50-75) to severe impairment (IQ 20-35); patients show both motor and language delays during childhood
• Characteristic facial features
• Hand anomalies
• Congenital heart defects - Almost half of affected patients have congenital heart disease, including ventricular septal defect and atrioventricular canal defect

Molecular analysis reveals that the 21q22.1-q22.3 region, also known as the Down syndrome critical region (DSCR), appears to contain the gene or genes responsible for the congenital heart disease observed in Down syndrome. A new gene, DSCR1, identified in region 21q22.1-q22.2, is highly expressed in the brain and the heart and is a candidate for involvement in the pathogenesis of Down syndrome, particularly with regard to mental retardation and cardiac defects.

Abnormal physiologic functioning affects thyroid metabolism and intestinal malabsorption. Patients with trisomy 21 have an increased risk of obesity. Frequent infections are presumably due to impaired immune responses, and the incidence of autoimmunity, including hypothyroidism and rare Hashimoto thyroiditis, is increased.

Patients with Down syndrome have decreased buffering of physiologic reactions, resulting in hypersensitivity to pilocarpine and abnormal responses on sensory-evoked electroencephalographic (EEG) tracings. Children with leukemic Down syndrome also have hyperreactivity to methotrexate.

Decreased buffering of metabolic processes results in a predisposition to hyperuricemia and increased insulin resistance. Diabetes mellitus develops in many affected patients. Premature senescence causes cataracts and Alzheimer disease. Leukemoid reactions of infancy and an increased risk of acute leukemia indicate bone-marrow dysfunction.

Children with Down syndrome are predisposed to developing leukemia, particularly transient myeloproliferative disorder and acute megakaryocytic leukemia. Nearly all children with Down syndrome who develop these types of leukemia have mutations in the hematopoietic transcription factor gene, GATA1. Leukemia in children with Down syndrome requires at least 3 cooperating events: trisomy 21, a GATA1 mutation, and a third undefined genetic alteration.

Musculoskeletal manifestations in patients with Down syndrome include reduced height, atlanto-occipital and atlantoaxial hypermobility, and vertebral malformations of the cervical spine. These findings may lead to atlanto-occipital and cervical instability, as well as complications such as weakness and paralysis.

About 5% of patients with Down syndrome have gastrointestinal (GI) manifestations, including duodenal atresia, Hirschsprung disease, and celiac disease. Many patients with trisomy 21 have otorhinolaryngologic manifestations, including hearing loss and recurrent ear infections. About 60% of patients have ophthalmic manifestations.

The American College of Obstetricians and Gynecologists (ACOG) has published pertinent guidelines on screening for fetal chromosomal abnormalities.^[11]

Down syndrome is caused by the following 3 cytogenic variants:

• Trisomy 21
• Chromosomal translocation
• Mosaicism

In 94% of patients with Down syndrome, full trisomy 21 is the cause; mosaicism (2.4%) and translocations (3.3%) account for the remaining cases. Approximately 75% of the unbalanced translocations are de novo, and approximately 25% result from familial translocation.

A free trisomy 21 results from nondisjunction during meiosis in one of the parents. This occurrence is correlated with advanced maternal and paternal age. The most common error is maternal nondisjunction in the first meiotic division, with meiosis I errors occurring 3 times as frequently as meiosis II errors. The remaining cases are paternal in origin, and meiosis II errors predominate.

Advanced maternal age remains the only well-documented risk factor for maternal meiotic nondisjunction. However, understanding of the basic mechanism behind the maternal age effect is lacking. Maternal age risk factors are as follows:

• With a maternal age of 35 years, the risk is 1 in 385
• With a maternal age of 40 years, the risk is 1 in 106
• With a maternal age of 45 years, the risk is 1 in 30

Translocation occurs when genetic material from chromosome 21 becomes attached to another chromosome, resulting in 46 chromosomes with 1 chromosome having extra material from chromosome 21 attached. It may occur de novo or be transmitted by one of the parents. Translocations are usually of the centric fusion type. They frequently involve chromosome 14 (14/21 translocation), chromosome 21 (21/21 translocation), or chromosome 22 (22/21 translocation).

Mosaicism is considered a postzygotic event (ie, one that occurs after fertilization). Most cases result from a trisomic zygote with mitotic loss of one chromosome. As a result, 2 cell lines are found: one with a free trisomy, and the other with a normal karyotype. This finding leads to great phenotypic variability, ranging from near normal to the classic trisomy 21 phenotype.

Cytogenetic and molecular studies suggest that dup21(q22.1-22.2) is sufficient to cause Down syndrome. The DSCR contains genes that code for enzymes, such as superoxide dismutase 1 (SOD1), cystathionine beta-synthase (CBS), glycinamide ribonucleotide synthase-aminoimidazole ribonucleotide synthase-glycinamide formyl transferase (GARS-AIRS-GART).

Down syndrome is the most common autosomal abnormality. The frequency is about 1 case in 800 live births. Each year, approximately 6000 children are born with Down syndrome.^[12] Down syndrome accounts for about one third of all moderate and severe mental handicaps in school-aged children.

Age-related demographics

Down syndrome can be diagnosed prenatally with amniocentesis, percutaneous umbilical blood sampling (PUBS), chorionic villus sampling (CVS), and extraction of fetal cells from the maternal circulation. It is often diagnosed shortly after birth by recognizing dysmorphic features and the distinctive phenotype. The characteristic morphologic features will be obvious in children older than 1 year. Some dermatologic features increase with advancing age.

Occurrence is strongly dependent on maternal age. The incidence of this syndrome at various maternal ages is as follows:

• 15-29 years - 1 case in 1500 live births
• 30-34 years - 1 case in 800 live births
• 35-39 years - 1 case in 270 live births
• 40-44 years - 1 case in 100 live births
• Older than 45 years - 1 case in 50 live births

On rare occasions, the disease can be observed in a few members of a family. The risk for recurrence of Down syndrome in a patient’s siblings also depends on maternal age.

Sex-related demographics

Overall, the 2 sexes are affected roughly equally. The male-to-female ratio is slightly higher (approximately 1.15:1) in newborns with Down syndrome, but this effect is restricted to neonates with free trisomy 21.

Female patients with trisomy 21 have a 50% chance of having a child who also has the syndrome. However, many affected fetuses abort spontaneously. On the other hand, men with Down syndrome may be infertile, except for those with mosaicism.

Race-related demographics

Down syndrome has been reported in people of all races; no racial predilection is known. African American patients with Down syndrome have substantially shorter life spans than white patients with trisomy 21.

The overall outlook for individuals with Down syndrome has dramatically improved. Many adult patients are healthier, are better integrated into society, and have increased longevity than before. However, their life expectancy is still reduced.

Approximately 75% of concepti with trisomy 21 die in embryonic or fetal life. Approximately 25-30% of patients with Down syndrome die during the first year of life. The most frequent causes of death are respiratory infections (bronchopneumonia) and congenital heart disease. The median age at death is 49 years. However, some patients many reach their sixth decade.

Congenital heart disease is the major cause of morbidity and early mortality in patients with Down syndrome. In addition, esophageal atresia with or without transesophageal (TE) fistula, Hirschsprung disease, duodenal atresia, and leukemia contribute to mortality. The high mortality later in life may be the result of premature aging.

In elderly persons with Down syndrome, relative preservation of cognitive and functional ability is associated with better survival.^[13] Clinically, the most important disorders related to mortality in this population are dementia, mobility restrictions, visual impairment, and epilepsy (but not cardiovascular disease). In addition, the level of intellectual disability and institutionalization are associated with mortality.

Individuals with Down syndrome have a greatly increased morbidity, primarily because of infections involving impaired immune response. Large tonsils and adenoids, lingual tonsils, choanal stenosis, or glossoptosis can obstruct the upper airway. Airway obstruction can cause serous otitis media, alveolar hypoventilation, arterial hypoxemia, cerebral hypoxia, and pulmonary arterial hypertension with resulting cor pulmonale and heart failure.

Leukemia, thyroid diseases, autoimmune disorders, epilepsy, intestinal obstruction, and increased susceptibility to infections (including recurrent respiratory infections) are commonly associated with Down syndrome.

The aging process seems to be accelerated in patients with Down syndrome. Many patients develop progressive Alzheimer-like dementia by age 40 years, and 75% of patients have signs and symptoms of Alzheimer disease.

A delay in recognizing atlantoaxial and atlanto-occipital instability may result in irreversible spinal-cord damage. Visual and hearing impairments in addition to mental retardation may further limit the child’s overall function and may prevent him or her from participating in important learning processes and developing appropriate language and interpersonal skills. Unrecognized thyroid dysfunction may further compromise central nervous system (CNS) function.

Career preparation should include acquisition of job skills, choice of job area, development of work-support behavior, and opportunities for job mobility. The goal of successful transition from school to the world of work is meaningful employment and optimal function in the least restrictive environment.

Opportunities to participate in community life should be made available. Individuals should be encouraged to pursue daily living tasks with minimal or no assistance. They should participate in cultural, leisure, and recreational activities during the growing years. Patients may qualify for supplemental security income (SSI) depending on their family’s income.

A parent’s guide to the genetics of Down syndrome is available.^[7] Additional resources can be obtained from the following organizations:

• National Down Syndrome Society, 666 Broadway, 8th floor, New York, NY 10012-2317; 212-460-9330; fax, 212-979-2873; info@ndss.org
• National Down Syndrome Congress, 1370 Center Drive, Suite 102, Atlanta, GA 30338; 770-604-9500; info@ndscenter.org
• National Association for Down Syndrome, PO Box 206, Wilmette, IL 60091; 630-325-9112
• International Resource Center for Down Syndrome, Cleveland, OH
• The Arc, 1010 Wayne Avenue, Suite 650, Silver Spring, MD 20910; 301-565-3842
• The Down Syndrome Web site

For patient education resources, see the Brain and Nervous System Center, as well as Down Syndrome.