Derrick Garwood, Freelance Medical Writer and Editor

Apart from ova and spermatozoa, normal human cells have 23 pairs of chromosomes. Each one is composed of a long double filament of DNA coiled into a helix, and contains its own unique sequence of genes. There are 22 pairs of autosomes plus two sex chromosomes; females have two X chromosomes while males have one X chromosome and a very much smaller Y chromosome. To revise the structure and relevant terminology, scroll down to the last section of this lecture from University College, London.

About 20% of conceptions have some sort of chromosomal disorder, but because of the lethal nature of these conditions only about 0.6% come to term. A later lecture in the University College series gives a clear account of some of the mutations which can occur, such as the addition or loss of complete sets of chromosomes, known as euploidy. By contrast, aneuploidy does not involve a whole set and generally results from a single chromosome – most frequently a sex chromosome – failing to complete division. Other structural abnormalities are inversions (a section of chromosome breaks free and is re-inserted the wrong way round), translocations (two chromosomes break and rejoin in the wrong combination) and deletions (a section of chromosome is missing). Some of the more frequent syndromes resulting from these mutations are described on the Merck site.

By far the best-known is Down's Syndrome, caused by an additional chromosome 21 (trisomy 21), which affects almost every organ in the body. Moderate to severe intellectual disability is accompanied by small stature, characteristic facial appearance, premature ageing, immunodeficiency and often congenital heart defects. The emedicine.com site has a wealth of detail on the clinical features and different therapies that may be required.

A proportion of these patients exhibit Down's Syndrome Mosaicism: i.e. some cells have an extra chromosome 21, but others are normal. In some individuals both types of cell occur throughout all tissues, while in others one type predominates in different organs, and the specific distribution influences the impact of the condition.

The greatest risk factor for conceiving a Down's Syndrome child is advanced maternal age, the incidence rising to 1 in 30 by the age of 45. Blood samples from expectant mothers can be screened at about 16 weeks gestation using the triple test (alpha foetoprotein, human chorionic gonadotrophin and unconjugated oestriol) and a risk value calculated (http://www.womens-health.co.uk/downs.htm). Where this is greater than around 1 in 250 the patient is generally offered an amniocentesis to establish whether the foetus does have trisomy 21. Very recently, ultrasound scans have shown that the nasal bone is absent in almost two thirds of 15 - 22 week old foetuses with Down's Syndrome, but only in 1% of normal foetuses (http://www.nature.com/nsu/021216/021216-14.html). In combination with other tests this will increase the accuracy of prediction and reduce the need for amniocentesis, which carries about a 1% risk of miscarriage.

A less common trisomy is that causing Edward's Syndrome, when either all or a critical region of chromosome 18 appears three times in the karyotype. Again, mosaicism can occur and the effects can be extremely variable, but typical features include a small chest, micrognathia, distinctive malformations of the head, clubfoot, overlapping flexed fingers, congenital heart problems and respiratory difficulties. Most foetuses with the syndrome are miscarried, and the multitude of anomalies means it is unusual for babies born alive to survive for long (http://medgen.genetics.utah.edu/photographs/pages/trisomy_18.htm).

Patau's Syndrome (trisomy 13) was first identified in 1960 and occurs in approximately 1 in 10,000 live births. Most cases result from either partial or total trisomy, but up to 25% arise from an inherited translocation involving chromosome 13 and another chromosome. The severity of the condition depends upon the type of anomaly, but median survival is only 2.5 days and survival to adulthood is rare. Often there is incomplete development of the forebrain and the structures of the mid-face, microcephaly, respiratory difficulties and serious cardiac anomalies (http://author.emedicine.com/ped/topic1745.htm). Survivors have severe intellectual impairment and are at increased risk of malignancy.

In triploidy, three complete sets of chromosomes (i.e. 69 rather than 46) result from either defective sperm or egg formation, or two sperms fertilising a single egg (dispermy). A table of the most common karyotypes can be found on the Texas Department of Health site, along with much useful information about prenatal diagnosis and clinical features of the condition, which is lethal. Interestingly, in women who have a triploidy pregnancy it is usually preceded or followed by a molar pregnancy, which results in a tumour of the placenta.

Physical anomalies can result when a section of chromosome is missing. In Wolf-Hirshhorn Syndrome, deletion of the distal short arm of chromosome 4 causes severe growth retardation and intellectual impairment, as well as contracture of hands, wrists and feet. A review of a large number of cases can be found on this US site.

When a similar loss of material affects chromosome 5, the result is Cri-du-Chat Syndrome. Affected infants have low birth weight, poor muscle tone and a characteristic high-pitched cry, which gives the syndrome its name. Other distinguishing features are delayed psychomotor development and varying degrees of intellectual disability.

Contiguous gene syndromes are multi-system developmental disorders caused by a series of neighbouring genes being deleted from a single chromosome. Two examples are the WAGR Continuous Gene Syndrome, and the Smith-Magenis Syndrome, which may often pass undiagnosed because its clinical features can be quite subtle.

The most common genetically-inherited form of intellectual disability is Fragile X Syndrome. Although believed to be an X-linked recessive trait with variable expression and incomplete penetrance, 30% of female carriers are affected. The cause is duplication of a region of the FMR-1 gene that increases its length. If the number of repeats is less than 200 the individual often shows no sign of the disorder. For a fascinating account of the (complicated!) mechanism of inheritance click here .

As many as 1 in 700 males have an additional X chromosome, making them XXY – Klinefelter's Syndrome. The condition is often not recognised until puberty, when the testes remain small and some boys exhibit gynaecomastia. A tall, lanky build is characteristic, and intelligence is generally within the normal range, although there may be some reduction in verbal IQ scores (http://www.bsped.org.uk/NN/KLINEFLT.htm). As a rule, men with Klinefelter's Syndrome are infertile, but in those with mosaicism the condition is less marked.

Conversely, in some females all or part of one X chromosome is absent. The condition is known as Turner's Syndrome and the main clinical features are short stature and non-functioning ovaries, although many other signs and symptoms may be present. Like men with Klinefelter's Syndrome, women with Turner's Syndrome are capable of becoming happy, productive members of society (http://arbl.cvmbs.colostate.edu/hbooks/genetics/medgen/chromo_eg/turners.html).

To end on a positive note, although many chromosomal abnormalities have a devastating effect from conception onwards, the overwhelming majority can be picked up by pre-natal testing. For a concise review of this topic, click here – just ignore the marketing blurb on the last two pages.

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