Down Syndrome

Updated: Jan 17, 2017
  • Author: Gratias Tom Mundakel, MBBS, DCH; Chief Editor: Maria Descartes, MD  more...
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Overview

Practice Essentials

Down syndrome is by far the most common and best known chromosomal disorder in humans and the most common cause of intellectual disability. It is primarily caused by trisomy of chromosome 21 (see the image below), which gives rise to multiple systemic complications as part of the syndrome. However, not all defects occur in each patient; there is a wide range of phenotypic variation. [1]

G-banded karyotype showing trisomy 21 (47,XY,+21). G-banded karyotype showing trisomy 21 (47,XY,+21).

Signs and symptoms

When recording the history from the parents of a child with Down syndrome, the clinician should include the following:

  • Parental concern about hearing, vision, delay in growth and development, respiratory infections, and other problems
  • Feeding history to ensure adequate caloric intake
  • Prenatal diagnosis of Down syndrome
  • Vomiting secondary to gastrointestinal tract blockage by duodenal web or atresia
  • Absence of stools secondary to Hirschsprung disease
  • Delay in cognitive abilities, motor development, language development (specifically expressive skills), and social competence
  • Arrhythmia, fainting episodes, palpitations, or chest pain secondary to a heart lesion
  • Symptoms of sleep apnea, including snoring, restlessness during sleep, difficulty awaking, daytime somnolence, behavioral changes, and school problems

On physical examination, patients with trisomy 21 have characteristic craniofacial findings, such as the following:

  • Flat occiput and a flattened facial appearance
  • Small brachycephalic head
  • Epicanthal folds
  • Flat nasal bridge
  • Upward-slanting palpebral fissures
  • Brushfield spots
  • Small nose and small mouth
  • Protruding tongue
  • Low-set, small, and dysplastic ears
  • Short neck and generous nuchal skin

General physical features in patients with Down syndrome may include the following:

  • Shortened extremities
  • Short, broad hands, with short fifth finger with hypoplasia of the middle phalanx and clinodactyly, along with single transverse palmar creases (~60% of patients)
  • Joint hyperextensibility or hyperflexibility
  • Neuromuscular hypotonia
  • Diastasis recti
  • Dry skin
  • Premature aging
  • Congenital heart defects

Complications of Down syndrome can involve almost every organ system of the body.

See Presentation for more detail.

Diagnosis

Laboratory studies that may be helpful include the following:

  • Complete blood count with differential
  • Bone marrow examination to rule out leukemia
  • Thyroid-stimulating hormone (TSH) and thyroxine (T4) to rule out hypothyroidism
  • Papanicolaou smears every 1-3 years in sexually active women
  • Cytogenetic studies (karyotyping) for diagnosis of trisomy 21
  • Interphase fluorescence in situ hybridization (FISH) for rapid diagnosis of trisomy 21
  • Assessment of mosaicism for trisomy 21 (lymphocyte preparations, buccal mucosa cellular preparations, FISH, scoring frequency of trisomic cells)
  • Immunoglobulin G
  • Maternal serum biochemical markers

Current evidence does not support performing routine screening radiographs for the assessment of potential atlantoaxial instability in asymptomatic children. However, imaging studies that may be considered include the following:

  • Echocardiography in every newborn suspected of having trisomy 21 to identify congenital heart disease, since approximately 50% of those with Down syndrome will have congenital heart disease
  • Ultrasonography

Postnatal diagnostic tests that may be warranted include the following:

  • Auditory brainstem response (ABR), or brainstem auditory evoked response (BAER)
  • Pediatric ophthalmic examination

See Workup for more detail.

Management

There are no medical treatments for intellectual disability associated with Down syndrome, but improved medical care has greatly enhanced quality of life and increased life expectancy. The American Academy of Pediatrics has issued guidelines for the care of children with Down syndrome. [2]  Elements of medical care include the following:

  • Genetic counseling
  • Standard immunizations and well-child care
  • Management of specific manifestations of Down syndrome and associated conditions (eg, endocrine, infectious, cardiac, respiratory, neurologic, psychiatric, dermatologic, and dental disorders)
  • Early intervention programs (may improve the social quotient)

Special considerations in adolescents are as follows:

  • Ongoing monitoring measures, including annual audiologic evaluation and annual ophthalmologic evaluation
  • Ongoing management of manifestations of the syndrome and associated conditions
  • Discussion of issues related to the transition to adulthood
  • Vocational training

Appropriate surgical management of associated conditions should be provided, as follows:

  • Timely surgical treatment of cardiac anomalies is crucial for optimal survival
  • Prompt surgical repair is necessary for gastrointestinal (GI) anomalies, most commonly, duodenal atresia and Hirschsprung disease
  • Surgical intervention may be necessary to stabilize the upper segment of the cervical spine if neurologic deficits are clinically significant
  • Congenital cataracts must be extracted soon after birth and subsequent correction with glasses or contact lenses provided
  • Careful anesthetic airway management is needed because of the associated risk of cervical spine instability
  • Adenotonsillectomy may be performed to manage obstructive sleep apnea

See Treatment and Medication for more detail.

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Background

Down syndrome is by far the most common and best known chromosomal disorder in humans and the most common cause of intellectual disability. [3, 4, 5, 6, 7] It is characterized by intellectual disability, 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 for Down syndrome but is now considered obsolete. [8, 9, 10]

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. [1]

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Pathophysiology

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, intellectual disability), 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. [11] 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. [12]

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

  • Intellectual disability - 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 intellectual disability 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 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.

A study by Romano et al indicated that in persons with Down syndrome, brain cortical thickness is reduced with increasing age. The study involved 91 persons with Down syndrome, none of whom had dementia, with cortical thickness measured using magnetic resonance imaging (MRI). Frontal, temporal, parietal, and cingulate gyrus measurements showed bilateral cortical thinning in association with age, with thickness apparently declining more significantly and rapidly between the ages of 20 and 30 years. [13]

The American College of Obstetricians and Gynecologists (ACOG) has published pertinent guidelines on screening for fetal chromosomal abnormalities. [14]

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Etiology

Down syndrome is caused by the following 3 cytogenic variants:

  • Three full copies of chromosome 21
  • Chromosomal translocation that results in 3 copies of the critical region for Down syndrome
  • 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. About 95% of the time, the error is maternal nondisjunction, with meiosis I errors occurring three times as frequently as meiosis II errors. The remaining 5% 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.

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, two 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).

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Epidemiology

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. [15] Down syndrome accounts for about one third of all moderate and severe mental handicaps in school-aged children. The prevalence of Down syndrome worldwide has increased because of increases in life span in the last few decades.

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 two 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.

Perhaps 50% of female patients with trisomy 21 are fertile, and these females have up to a 50% chance of having a live child who also has trisomy 21. (However, many affected fetuses abort spontaneously.) On the other hand, men with Down syndrome are usually 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.

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Prognosis

The overall outlook for individuals with Down syndrome has dramatically improved. Many adult patients are healthier and better integrated into society, and life expectancy has improved from 25 years in 1983 to 60 years or higher today.

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 in the mid-50s.

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. [16] 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 intellectual disability 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.

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Patient Education

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. [9]  Parents might benefit from joining a local Down syndrome support group. Additional resources can be obtained from the following organizations:

Books for parents [2]

  • Skallerup SJ. Babies with Down Syndrome: A New Parents Guide.
  • Pueschel SM, ed. A Parent's Guide to Down Syndrome: Toward a Brighter Future.
  • Simmons J. The Down Syndrome Transition Handbook: Charting Your Child's Course to Adulthood
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