Down Syndrome (Trisomy 21)
Overview
Plain-Language Overview
Down Syndrome, also known as Trisomy 21, is a genetic condition caused by the presence of an extra copy of chromosome 21. This extra genetic material affects the development of the body and brain, leading to characteristic physical features and intellectual disabilities. People with Down Syndrome often have distinct facial features such as a flat face, upward slanting eyes, and a small nose. They may also experience delays in speech and motor skills, as well as an increased risk for certain health problems like heart defects and thyroid issues. Despite these challenges, individuals with Down Syndrome can lead fulfilling lives with appropriate support and care.
Clinical Definition
Down Syndrome is a genetic disorder caused by the presence of a full or partial extra copy of chromosome 21, resulting in a total of three copies instead of the usual two, hence the term Trisomy 21. This chromosomal abnormality leads to a constellation of phenotypic features including characteristic craniofacial dysmorphisms such as brachycephaly, epicanthal folds, and a flat nasal bridge. The syndrome is associated with varying degrees of intellectual disability, hypotonia, and developmental delays. Common systemic manifestations include congenital heart defects, particularly atrioventricular septal defects, gastrointestinal anomalies like duodenal atresia, and an increased risk of hematologic malignancies such as acute lymphoblastic leukemia. Endocrine disorders, including hypothyroidism, are also prevalent. Neurologically, individuals have an increased risk of early-onset Alzheimer disease. Diagnosis is confirmed by karyotype analysis demonstrating trisomy 21. The condition arises primarily from nondisjunction during meiosis, with advanced maternal age being a significant risk factor. Management is multidisciplinary, focusing on early intervention and monitoring for associated complications.
Inciting Event
- Nondisjunction during meiosis in gamete formation leads to trisomy 21.
- Robertsonian translocation involving chromosome 21 can cause familial Down Syndrome.
- Mosaicism arises from mitotic errors after fertilization.
Latency Period
- none
Diagnostic Delay
- none
Clinical Presentation
Signs & Symptoms
- Developmental delay and intellectual disability.
- Hypotonia with poor muscle tone.
- Characteristic facial features including upslanting palpebral fissures and flat nasal bridge.
- Short stature and growth retardation.
- Congenital heart defects causing cyanosis or heart failure symptoms.
- Feeding difficulties and gastrointestinal obstruction.
- Increased susceptibility to infections due to immune dysfunction.
History of Present Illness
- Newborns may present with hypotonia and feeding difficulties.
- Characteristic facial features such as flat nasal bridge and epicanthal folds are noted.
- Developmental delays and intellectual disability become apparent in infancy and early childhood.
Past Medical History
- History of congenital heart defects such as atrioventricular septal defect is common.
- Previous diagnosis of hypothyroidism or recurrent infections may be present.
- History of gastrointestinal anomalies like duodenal atresia can be relevant.
Family History
- Family history of Down Syndrome or chromosomal abnormalities increases risk.
- Parental balanced translocations involving chromosome 21 may be identified.
- No strong inheritance pattern in most cases due to sporadic nondisjunction.
Physical Exam Findings
- Presence of upslanting palpebral fissures.
- Single transverse palmar crease (Simian crease).
- Flattened facial profile with a small nose.
- Macroglossia with protruding tongue.
- Hypotonia with decreased muscle tone.
- Short neck with excess nuchal skin.
- Brachycephaly with a flat occiput.
- Brushfield spots on the iris.
Diagnostic Workup
Diagnostic Criteria
Diagnosis of Down Syndrome is established by identifying the presence of an extra copy of chromosome 21 through karyotype analysis. Clinical suspicion arises from characteristic physical features such as hypotonia, upslanting palpebral fissures, a single transverse palmar crease, and distinctive facial morphology. Prenatal screening includes maternal serum markers and ultrasound findings, but definitive diagnosis requires cytogenetic confirmation. The presence of trisomy 21 in all or a significant proportion of cells confirms the diagnosis. Mosaicism or translocation variants may require additional genetic testing.
Pathophysiology
Key Mechanisms
- Down Syndrome results from trisomy 21, where there is an extra copy of chromosome 21 leading to gene dosage effects.
- The presence of an extra chromosome 21 causes abnormal cellular development and impaired organogenesis.
- Overexpression of genes on chromosome 21 disrupts normal neurodevelopment and immune function.
| Involvement | Details |
|---|---|
| Organs | Heart frequently affected by congenital defects such as atrioventricular septal defects. |
| Brain exhibits intellectual disability and increased risk of early Alzheimer's disease. | |
| Thyroid gland commonly develops hypothyroidism requiring monitoring and treatment. | |
| Immune system is compromised, increasing susceptibility to infections. | |
| Tissues | Brain tissue shows reduced volume and altered neuronal connectivity. |
| Cardiac tissue often has structural defects like atrioventricular septal defects. | |
| Thyroid tissue may be hypoplastic or dysfunctional leading to hypothyroidism. | |
| Cells | Lymphocytes show altered function contributing to immune deficiency in Down syndrome. |
| Neurons exhibit abnormal development leading to intellectual disability. | |
| Cardiomyocytes may be structurally abnormal causing congenital heart defects. | |
| Chemical Mediators | Amyloid-beta peptides accumulate prematurely in the brain, contributing to early-onset Alzheimer's disease. |
| Thyroid hormones are often deficient due to hypothyroidism in Down syndrome. | |
| Cytokines such as TNF-alpha may be dysregulated, affecting immune responses. |
Treatment
Pharmacological Treatments
Thyroid hormone replacement
- Mechanism: replaces deficient thyroid hormones in hypothyroidism common in Down syndrome
- Side effects: palpitations, weight loss, insomnia
Antibiotics
- Mechanism: treat recurrent respiratory infections due to immune dysfunction
- Side effects: gastrointestinal upset, allergic reactions
Anticonvulsants
- Mechanism: control seizures which are more prevalent in Down syndrome
- Side effects: dizziness, sedation, rash
Non-pharmacological Treatments
- Early intervention programs improve cognitive and motor development.
- Physical therapy enhances muscle tone and motor skills.
- Speech therapy supports communication abilities.
- Occupational therapy aids in developing daily living skills.
- Regular cardiac monitoring and surgical correction for congenital heart defects when indicated.
Prevention
Pharmacological Prevention
- none
Non-pharmacological Prevention
- Prenatal screening with maternal serum markers and ultrasound to identify risk of trisomy 21.
- Genetic counseling for at-risk couples to discuss recurrence risk and reproductive options.
- Early intervention programs including physical, occupational, and speech therapy to improve developmental outcomes.
- Regular monitoring and management of comorbidities to prevent complications.
Outcome & Complications
Complications
- Congestive heart failure from untreated atrioventricular septal defects.
- Thyroid dysfunction leading to hypothyroidism complications.
- Respiratory infections due to immune deficiency and airway anomalies.
- Leukemia development, especially acute lymphoblastic leukemia and acute myeloid leukemia.
- Atlantoaxial instability causing spinal cord compression.
- Gastrointestinal obstruction from duodenal atresia or Hirschsprung disease.
| Short-term Sequelae | Long-term Sequelae |
|---|---|
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Differential Diagnoses
Down Syndrome (Trisomy 21) versus Edwards Syndrome (Trisomy 18)
| Down Syndrome (Trisomy 21) | Edwards Syndrome (Trisomy 18) |
|---|---|
| Upward slanting palpebral fissures and epicanthal folds | Clenched fists with overlapping fingers |
| Single palmar crease (simian crease) | Rocker-bottom feet deformity |
| Hypotonia and characteristic facial features including flat nasal bridge | Severe growth retardation and micrognathia |
Down Syndrome (Trisomy 21) versus Patau Syndrome (Trisomy 13)
| Down Syndrome (Trisomy 21) | Patau Syndrome (Trisomy 13) |
|---|---|
| Hypotonia with characteristic facial features such as flat facial profile | Holoprosencephaly and severe CNS malformations |
| Simian crease and epicanthal folds | Polydactyly and cleft lip/palate |
| Congenital heart defects like atrioventricular septal defects | Microphthalmia and scalp defects (cutis aplasia) |
Down Syndrome (Trisomy 21) versus Turner Syndrome (45,X)
| Down Syndrome (Trisomy 21) | Turner Syndrome (45,X) |
|---|---|
| Intellectual disability and characteristic facial features | Webbed neck and widely spaced nipples |
| Hypotonia and single palmar crease | Lymphedema of hands and feet at birth |
| Congenital heart defects such as atrioventricular septal defects | Short stature with lack of secondary sexual characteristics |