GENETIC DISORDERS DUE TO AN ABNORMAL CHROMOSOME NUMBER

How do chromosomal anomalies happen?

All our cells have copies of our unique genetic identity in strands of DNA. These are all packaged into organized structures called chromosomes. Each normal cell has two copies of 23 chromosomes (thus called diploid cells), and these are duplicated as a cell undergoes cell division.

Let’s do a review of the special type of cell division that sex chromosomes go through - meiosis.

How meiosis occurs

Cells that are created for reproduction are called germ cells. They undergo meiosis, a type of cell division that is unique to germ cells only. All other cells of the body go through mitosis, which is a simpler version of meiosis.

In males, meiosis starts during adolescence, while in females, the process starts even before they are born.

Meiosis starts with a diploid cell that contains 46 chromosomes, like other body cells. In the first part of meiosis (meiosis I), all chromosomes align with their counterpart and exchange genetic information between each other. This is called genetic recombination. The cell splits into two, with each new cell taking one member of each pair. These daughter cells now contain only one copy of all 23 chromosomes (now called haploid cells).

In the second part of meiosis (meiosis II), genetic information in these haploid cells is duplicated. Afterwards, the cell divides again into two new daughter cells, each of which still contains 23 chromosomes.

During fertilization of the egg by a sperm, the 23 chromosomes of both cells combine to restore the number to 46 chromosomes. This cell now has two copies of each chromosome; one comes from the mother and the other from the father. This cell then divides into two, and these two cells divide as well into two each, and so on. This continuous cell division forms the embryo, which will eventually grow into a fetus.

Why Problems Occur

Cell division may occasionally lead to errors. The most common problem occurs when two chromosomes do not separate during division. This is called nondisjunction. One daughter cell ends up with two copies of the same chromosome, while the other daughter cell doesn’t have a copy of that particular chromosome.

Genetic Disorders Due to Chromosomal Anomalies in Number

An abnormal number of chromosomes leads to changes in the expression of genes, which in turn is seen as differences in the growth and development of affected people.

Aneuploidy is the most common classification of chromosomal abnormalities in humans. It refers to people whose cells do not have the typical number of chromosomes nor any multiple of that number (e.g., 46 (2n) or 69 (3n) chromosomes). Well-known types of aneuploidies are trisomies and monosomies.

Trisomies

In trisomy, the genetic makeup involves one chromosome having three copies instead of two (a total of 47 chromosomes). This is the most common type of aneuploidy.

1. Down syndrome (Trisomy 21)

Down syndrome is the most common form of trisomy. For every 733 babies that are born, one newborn is affected. In this disorder, there are three copies of chromosome 21 in affected persons. People with Down syndrome often have cognitive impairment, congenital anomalies, and certain dysmorphic features.

Most children develop mild to moderate intellectual disability. Dysmorphic features usually include a flat face, upward slanted palpebral fissures, small and unusually shaped ears, slightly small head, a small nose with a flat nasal bridge, a big and protruding tongue, and speckled irises called Brushfield spots.

Physical examination findings include decreased muscle tone, hyperflexible joints, short neck with loose skin, short fingers, a single straight palmar crease, wide gap between the first two toes, unusually shaped pelvis and a short breastbone.

Infants with Trisomy 21 may also have congenital anomalies, such as septal defects in the heart, a patent ductus arteriosus, pulmonary hypertension, underdeveloped duodenum (duodenal atresia), unusually shaped pancreas (annular pancreas), an abnormal connection between the trachea and the esophagus (tracheoesophageal fistula), closed-off anal opening, and Hirschsprung disease.

Children born with Down syndrome can perform most daily activities and are able to live up to 50-55 years of age. Some studies show that affected individuals are prone to endocrine problems, premature aging, Alzheimer disease and leukemia.

2. Edward syndrome (Trisomy 18)

People with Edward syndrome have three copies of chromosome 18 in their cells. This condition is not as common as Down syndrome, although it is the second most common form of trisomy. For every 4,000 to 5,000 babies that are born, one newborn is affected.

Infants with this disorder often have serious congenital heart disease and severe intellectual disability. Other characteristic features include a prominent skull, a small mouth and jaw, low-set and malformed ears, short palpebral fissures, short breastbone, overlapping fingers, rocker-bottom feet, and clubfeet.

In Edward syndrome, only about 40% live beyond the first month of life, and 2 to 8% reach one year of age. A few studies observed that some spontaneous miscarriages are fetuses with trisomy 18.

3. Patau syndrome (Trisomy 13)

Patau syndrome is the third most common type of trisomy. For every 12,000 newborns, one baby is affected.

The growth of infants with this genetic disorder are already affected before birth — they commonly exhibit growth restriction from inside the womb and are born with small skulls. A physical examination of these newborns may reveal cyclopia (a single or partially divided eye), a sloping forehead, small and unusually shaped ears, cleft lip, cleft palate, clubfeet or rocker-bottom feet.

Problems with the nervous system are common; they may present with alobar holoprosencephaly. Some genital problems may also be exhibited, such as underdeveloped labia minora in females, and cryptorchidism or hypospadia in males.

Most infants born with Patau syndrome live for a few months. Only 5 to 10% live beyond the first year of life; however, these patients tend to develop severe neurologic issues.

Monosomies

Babies with monosomies rarely develop beyond the womb, with the exception of Turner syndrome, where the X chromosome is affected. For every 2,500 female newborns, one is affected with this disorder.

In Turner syndrome, most of the cells have only 45 chromosomes, with the sex chromosome (X) missing a partner. Patients with this disorder exhibit some form of mosaicism, having 2 or more cell lines (sets of chromosomes). This may be because the error in cell division occurs after fertilization, so some cells have the original cell line, while other cells in the body have the second cell line attributed to Turner syndrome.

Infants commonly have congenital heart defects and abnormal structures in the kidney. The gonads are underdeveloped, leading to a delay or lack of development of secondary sexual characteristics. There is also a 6% chance of having some form of intellectual disability.

Other features include a low hairline, blue sclerae, small chin, webbed neck, widely spaced nipples, short fourth fingers, swelling (lymphedema) of the hands and feet, scoliosis and decreased growth.

Most affected newborns reach adulthood but require thorough monitoring as they are prone to develop other conditions as they grow older. These include problems with the aorta (aortic dilation, dissection or rupture), heart valve problems, elevated blood pressure, urinary tract infections, problems with vision or hearing, abnormal development of the teeth, autoimmune problems and short stature.

Summary

Errors in cell division may lead to chromosomal anomalies. These affect the expression of genes, leading to abnormal growth and development of a child’s anatomy and physiology. Some of the common genetic disorders are due to an abnormal number of chromosomes; these include trisomies and monosomies. While some disorders may reach into adulthood, others are lethal even before birth and rarely progress beyond the first few years of life.

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Sources:

• Kliegman, R.M. (2020). Cytogenetics. Nelson Textbook of Pediatrics 21st edition. Elsevier.
• Merritt, T.A. et al. (2012). Trisomy 18 and Trisomy 13. NeoReviews. Taken from: https://neoreviews.aappublications.org/content/13/1/e40
• Levy, P.A. & Marion, R. (2018). Trisomies. Pediatrics in Review. Taken from: https://pedsinreview.aappublications.org/content/pedsinreview/39/2/104.full.pdf
• Trent, R.J. (2005). Chromosomal Mosaicism. Molecular Medicine, 3rd edition. Elsevier. Taken from: https://www.sciencedirect.com/topics/medicine-and-dentistry/chromosome-mosaicism
• Loscalzo, M.L. (2008). Turner Syndrome. Pediatrics in Review. Taken from: https://pedsinreview.aappublications.org/content/29/7/219

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