Down Syndrome
Down syndrome, also known as trisomy 21, is a genetic disorder resulting from the presence of all or part of a third copy of chromosome 21. The condition arises due to nondisjunction events during meiosis or, less commonly, mitotic errors, leading to an extra chromosome in some or all cells. This chromosomal imbalance disrupts normal development, giving rise to a characteristic phenotype that includes intellectual disability, distinctive facial features, hypotonia, and various congenital anomalies. The pathogenesis involves overexpression of genes located on chromosome 21, which affects multiple cellular pathways, contributing to the neurological, cardiac, gastrointestinal, and immunological manifestations observed in affected individuals. Health impacts are broad and may include congenital heart disease, increased risk of leukemia, early-onset Alzheimer’s disease, endocrine disorders, sensory impairments, and increased susceptibility to infections. Lifespan has improved significantly with advances in medical care, but individuals with Down syndrome continue to experience higher morbidity and mortality rates compared to the general population.
This is the most common form of Down syndrome, accounting for approximately 95% of cases. It results from a nondisjunction event during meiosis, typically in the maternal gamete, leading to an embryo with three copies of chromosome 21 in all cells. The extra chromosome disrupts normal genetic balance and is responsible for the classic phenotype associated with Down syndrome.
Translocation Down syndrome occurs when part or all of chromosome 21 becomes attached (translocated) to another chromosome, often chromosome 14 or 21. This type represents about 3-4% of cases. Although individuals have the usual two copies of chromosome 21, the presence of extra material due to the translocation leads to the clinical features of Down syndrome. Translocations can be inherited from a parent who is a balanced carrier.
Mosaicism accounts for about 1-2% of Down syndrome cases. It arises from a postzygotic mitotic error, resulting in two or more cell lines within the same individual: some with the normal chromosomal complement and others with trisomy 21. The clinical presentation may be milder, depending on the proportion and distribution of affected cells.
Down syndrome is the most common chromosomal disorder, with a global incidence estimated at 1 in 700 live births. The prevalence varies by region and is influenced by maternal age, with the risk increasing markedly in mothers over 35 years old. Advances in prenatal screening and elective termination have led to fluctuations in birth prevalence in some countries. There is no predilection for race or socioeconomic status. Improvements in medical care, particularly for congenital heart defects and infections, have increased median life expectancy from less than 10 years in the early 20th century to over 50 years in many developed countries today. Despite these gains, individuals with Down syndrome experience higher rates of morbidity and mortality from associated conditions such as congenital heart disease, leukemia, and early-onset dementia.
Diagnosis of Down syndrome involves a combination of clinical assessment and cytogenetic testing. Prenatal screening methods include maternal serum markers (such as free beta-hCG and PAPP-A), nuchal translucency measurement by ultrasound, and noninvasive prenatal testing (NIPT) using cell-free fetal DNA. Definitive prenatal diagnosis is achieved through invasive procedures like chorionic villus sampling or amniocentesis, followed by karyotype analysis to detect trisomy 21 or related chromosomal abnormalities. Postnatal diagnosis is typically based on characteristic physical features, such as hypotonia, upslanting palpebral fissures, epicanthic folds, flat facial profile, and single palmar crease, followed by chromosomal analysis to confirm the diagnosis and determine the specific type (nondisjunction, translocation, or mosaicism). Additional assessments may include echocardiography, hearing and vision screening, thyroid function tests, and neurodevelopmental evaluation to identify and manage associated comorbidities.
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