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Genetic and Congenital Disorders. Down Syndrome. Introduction Down syndrome (DS) is the most prevalent chromosomal abnormality. Down syndrome can occur in individuals of any race or socioeconomic background, but the likelihood increases with maternal age, primarily due to increased meiotic nondisjunction in older oocytes (Porth et al., 2019, p 90). A woman who is 35 years old has a 1 in 350 chance of having a baby with Down syndrome, and this risk gradually rises to 1 in 100 by age 40. By the age of 45, the probability reaches approximately 1 in 30 (de Graaf et al., 2017). While maternal age is the primary risk factor, advanced paternal age (>50 years) may slightly increase the risk due to increased mutations in sperm. However, the effect is much smaller compared to maternal age (Porth et al., 2019, p 90).
Common Phenotypic Features
This genetic condition leads to a wide range of physical and intellectual features, with each person exhibiting distinct traits. Typical phenotypic characteristics of DS include low muscle tone plus unique craniofacial features and features of the extremities. Craniofacial features include flat facial profile, shortened skull, skin folds covering the inner corner of the eyes, upward slanting eye openings, small, low-set ears, and large tongue or protruding tongue. Features of the extremities include short, broad hands with curved fifth fingers and increased space between the first and second toes. People with DS are usually short in stature, have low muscle tone, have mild to moderate intellectual disability and some developmental delays. Additionally, individuals with the condition face a higher risk of congenital heart defects,
respiratory complications, gastrointestinal abnormalities, thyroid disorders and an increased risk of leukemia and Alzheimer’s disease (Porth et al., 2019, p 90).
Genetic Abnormalities
Down syndrome can arise from several genetic mechanisms, including nondisjunction translocation and mosaicism involving chromosome 21. Nondisjunction occurs due to abnormal cell division during the formation of an egg or sperm, leading to a gamete with 24 chromosomes instead of the usual 23. Consequently, after fertilization, the resulting zygote contains 47 chromosomes rather than 46. Translocation involves an extra full or partial copy of chromosome 21 being attached to another chromosome. In cases of mosaicism, only a portion of the body's cells carries the additional chromosome 21. While some translocation-related DS cases are linked to genetic inheritance, nondisjunction and mosaicism typically occur spontaneously (Arumugam, 2016).
How Genetic Abnormalities Lead to Clinical Features
Two hypotheses have been proposed to explain how the extra copy of chromosome 21 contributes to the clinical characteristics of Down syndrome. The first, known as the "developmental instability hypothesis," suggests that the presence of an additional chromosome 21 disrupts genetic balance among its numerous genes, leading to altered gene expression in developmental pathways. The second, the "gene-dosage effect hypothesis," proposes that having three copies of chromosome 21 genes instead of the usual two results in an abnormal phenotype, where overexpression of genes can influence neurodevelopment, facial structure, cardiac development, and immune function (Arumugam, 2016).
de Graaf, G., Buckley, F., & Skotko, B. G. (2017). Estimation of the number of people with Down syndrome in the United States. Genetics in medicine: official journal of the American College of Medical Genetics , 19 (4), 439–447. https://doi.org/10.1038/gim.2016.
Porth, C.M., & Matfin, G. (2019). Pathophysiology: Concepts of altered health states (10th ed.). New York: Lippincott Williams & Wilkins. ISBN: 978-1-4963-7755-
