Autosomal Abnormalities

The majority of human chromosomal abnormalities occur in the autosomes.  Most of these abnormalities are monosomies or trisomies.  All fetuses with autosomal monosomies spontaneously abort early in pregnancy.  Likewise, almost all fetuses with autosomal trisomies die before birth.  Those that survive usually have multiple physical malformations, mental retardation, and relatively short lives.

The most well known and most common autosomal abnormality is Down syndrome .  This is a mild to severe form of mental retardation accompanied by distinctive physical traits.  People with Down syndrome have an irregularity with autosome pair 21.  In most cases, there is an extra chromosome (i.e., trisomy 21).  More rarely (3-5%), there is a structural modification in this chromosome.  Specifically, there is a translocation of all or part of chromosome 21 to chromosome 14 or 15.  The actual genes on chromosome 21 that are responsible for Down syndrome are now being identified.  It is thought that there are at least 350 genes involved.  About 2-4% of the people with Down syndrome are genetically mosaic.  That is, some of their cells have chromosome 21 trisomy while others do not, resulting in generally milder symptoms.  The translocational type of Down syndrome also usually has less severe symptoms.

8-year-old boy with Down syndrome

People with Down syndrome typically have short, stocky bodies with thick hands and feet.  Their hands also commonly have a "simian crease", which is a crease in the palm that runs completely from one side of the hand to the other.  In addition, they typically have broad, short heads with small low-set ears, small concave saddle-shaped or flattened noses, relatively large ridged tongues that roll over a protruding lower lip, loose joints, and low muscle tone that contributes to poor motor skills.  Frequently, their eyes have an East Asian-like appearance due to an epicanthic fold .  This is a fold of skin over the inner corner of each eyelid, which makes the eyes appear to slant upward.  Because of this eye characteristic, Down syndrome was referred to as Mongoloidism  when it was first described in 1866 by the English physician John Langdon Down.  However, this term was misleading because Down syndrome can occur in any human group, not just Asians.  As a result, Mongoloidism has been rejected as a synonym for Down syndrome.  It wasn't until 1959 that it was discovered that Down syndrome individuals have an irregular number of chromosomes.

People with Down syndrome frequently have other medical problems.  These include epilepsy , hypothyroidism , crossed eyes, near-sightedness or far-sightedness, cataracts , hearing impairment that makes it difficult to process auditory information, heart defects, intestinal malformations, hernias , and a marked susceptibility to respiratory infections, such as pneumonia.  Childhood leukemia  is as much as 20 times more common than average for them.  However, there is considerable variability within the Down syndrome population in regards to susceptibility to these medical problems.  This is likely due to variable penetrance.  That is, the alleles for the Down syndrome genes may cause an effect in the phenotype of some individuals but not others.  It is likely that the abnormal traits characteristic of Down syndrome are at least in part a result of the over expression of the involved genes.  This over expression is a consequence of the presence of an extra chromosome 21.  One advantage of over expression is the increased protein production coded by the DSCR1 gene.  This results in significantly lower rates of colon, breast, and other solid tumor cancers among people with Down syndrome.

Down syndrome individuals appear to age at an accelerated rate.  By age 35, at least 25% of those who have non-mosaic Down syndrome have begun to develop Alzheimer syndrome .  This was not a problem a century ago because most people with Down syndrome died in childhood.  The life expectancy for a child with Down syndrome in the United States in 1929 was only 9 years.  In 1980, it was still only 25.  Today, however, people with this syndrome can expect to live into their 50's and possibly even their early 60's in the United States and most other developed nations.  Unfortunately, this is not the case in poor countries with inadequate medical care.  About 55% of South American babies who have Down syndrome die in their first year of life.

The most prominent and debilitating trait of people with Down syndrome is mental retardation.  They usually only reach a mental age level of a 3-7 year old normal child.  They are slow learners and their abstract reasoning is particularly limited.  However, some high achieving individuals with Down syndrome have mental levels of 12 year olds, which is sufficient to function in society with little assistance.  People with Down syndrome usually have gentle, trusting personalities and are very warm and loving.  Family members and friends often refer to them as having joyous, uninhibited, friendly personalities.

The majority of Down syndrome fetuses are not sufficiently viable to survive to birth--approximately 85% of them spontaneously abort.  It is likely that as many as 1/4 of all miscarriages are due to the trisomy form of Down syndrome.  However, about 400,000 people with Down syndrome in the U.S. have survived birth and are alive today.  While this is a large number, it is important to realize that not all mentally retarded people have Down syndrome.

The overall incidence of Down syndrome is only about 1 in 800 live births.  However, the rate varies markedly with the age of the mother when conception occurs.  This is the case for the common trisomy form of Down syndrome but not the rare translocational form.  Women who are 20 years old apparently have the lowest chance (1 in 2000) of having a Down syndrome child.  Women do not reach the average risk rate of 1 in 800 until they are about 30.  Older mothers have a far higher frequency as indicated in the table below.  As a result, amniocentesis is regularly recommended for women 35 and over.  It is not routinely recommended for younger women because the diagnostic benefits do not outweigh the risk of miscarriage.

Age of Mother	Frequency of Down Syndrome	Frequency of Any Chromosomal Disorder
20 25 30 35 36 37 38 39 40 41 42 43 44 45	1 in 1667        1 in 1250        1 in 952        1 in 378 1 in 289 1 in 224 1 in 173 1 in 136 1 in 106 1 in 82        1 in 63        1 in 49        1 in 38        1 in 30	1 in 526 1 in 476             1 in 385             1 in 192             1 in 156             1 in 127             1 in 102             1 in 83             1 in 66             1 in 53             1 in 42             1 in 33             1 in 26             1 in 21

Source:The American Congress of Obstetricians and Gynocologists
(based on data published in the Journal of the American Medical
Association 1981;58:282-285 and 1983;249:2034-2038).  Other
published sources have somewhat different risk ratios, but the trend
of increasing risk with the mother's age is the same.

From these data, it would seem likely that most Down syndrome children are born to older mothers.  However, this is not the case because older women are much less likely to have children.  In the U.S., 75-80% of Down syndrome children are born to women under 35.  The majority of mothers giving birth to Down syndrome children are still in their 20's.  Only .03% of all births in the U.S. are to mothers 45 and older.

There is some increase in the risk of Down syndrome children being conceived when the father is older.  However, little data are available to support this.  One study estimates that only about 5% of all Down syndrome children are the result of defective sperm.  It has been suggested that defective sperm are less likely than ova to carry a Down syndrome related mutation because the entire male meiosis process resulting in the production of a sperm cell takes only 74 hours.  In contrast, the female meiosis process resulting in ova actually begins before birth and is completed usually one or a few cells at a time later in life before each ovulation.  An oöcyte can be stored in an ovary for 40-50 years or more before becoming an ovum.  During that time, environmental contamination theoretically can render it defective.  The very short life of sperm cells reduces the chance of such contamination.  In addition, defective sperm are less likely to reach an ovum because they are more easily eliminated from competition in the process of traveling through a woman's reproductive tract.

Women who have already had a Down syndrome child are at a slightly higher risk of subsequent children also inheriting this problem.  Women with Down syndrome are at a much higher risk of having children with this condition.  Half of their offspring would be expected to inherit it.  However, many affected fetuses are lost in miscarriages.  Apparently, Down syndrome men can father a child though it is very rare--there has been only one documented instance of it.