The term aneuploidy refers to any abnormal karyotype, or chromosomal endowment. With the exception of gametes and the XY sex chromosomes males, most human cells are diploid, meaning they contain two copies of the other 22 chromosomes (referred to as autosomes). Some cases of aneuploidy involve monosomies, or the deletion of a chromosome during or shortly after fertilization. Trisomies (and rarely tetrasomies) also occur. Abnormal gene expression and chromosomal transport during mitotic cell division is thought to account for the anomalies observed in these syndromes; gene mutations themselves play at most a minor role.
The loss of all or part of a chromosome results in distinct developmental abnormalities. In Turner Syndrome, the deletion of an X chromosome (karyotype 45 XO) results in a female with short stature and a rudimentary or non-existent reproductive tract. Without estrogen replacement therapy, females with Turner syndrome seldom develop secondary sexual characteristics. Turner syndrome occurs in an estimated 1 in 2500 female births.
No complete autosomal monosomy is compatible with life. A partial deletion of chromosome 5 results in a severe developmental disorder called Cri-du-chat (cry of the cat), named for the unusual sounding cries of infants with this syndrome.
Klinefelter syndrome, and trisomies XYY and XXX
A person with the karyotype XXY is said to have Klinefelter syndrome. Although the person is male, owing to the presence of one Y chromosome, the extra X chromosome imparts some secondary female characteristics such as wide hips and gynecomastia (breast enlargement). Most men with Klinefelter syndrome undergo puberty but produce few or no sperm. Many also exhibit mild mental retardation.
In contrast to the 47 XXY karyotype, men and women born with trisomies 47 XYY and Triple X syndrome respectively, are often normal in appearance and capable of bearing children. People with these trisomies often have subtle cognitive impairments, but these deficits are almost never as severe as those seen in other chromosomal aneuploidies.
The main trisomies compatible with life include Down syndrome (Trisomy 21); Patau syndrome (Trisomy 13); and Edwards syndrome (Trisomy 18). Down syndrome is the most common autosomal trisomy in humans, occurring in approximately 1 in 800 births. The Down syndrome phenotype is instantly recognizable; its features include short stature, a small head, close set eyes, a lolling tongue, and mild to severe mental retardation.
Around 50% of babies born with Down syndrome have cardiac defects. They are also at a higher risk developing leukemia as well as early onset dementia. The reasons underlying the higher incidence of leukemia remain obscure; abnormal mitoses in leukocyte precursors probably play a role. As far as dementia goes, chromosome 21 is the site of the APP (Amyloid Precursor Protein) gene. The consensus among geneticists is that an extra copy of the APP gene results in dementia similar to Alzheimer’s disease in most Down syndrome patients who live to age 40.
The other two autosomal trisomies produce far more severe abnormalities compared to Down syndrome. To put it in perspective, 50% or more of babies born with Down syndrome survive to young adulthood. In comparison, few infants with Patau or Edwards syndrome survive beyond the first year of life. Defective development of the heart, lungs, and kidneys are the major causes of mortality.
This extremely rare condition results from a partial tetrasomy of chromosome 12. For unclear reasons, the person’s tissues exhibit
mosaicism; some of the cells have a normal karyotype whereas others contain an extra, aberrant copy of chromosome 12 called an
isochromosome, in which the p arm of the chromosome is duplicated. This results in four copies of 12p genes in each affected cell. People born with PKS have craniofacial malformations, moderate to profound mental retardation, and in many cases, diaphragmatic hernias, which impair normal development of the heart and lungs. Approximately 100 cases of PKS have been documented in the medical literature.