CS Handbook

THE COCKAYNE'S SYNDROME HANDBOOK, version of 9 March 98 by David Busch

This is a handbook on Cockayne's syndrome (CS), modeled after "The Xeroderma Pigmentosum
Handbook" by Mary Ellen Fitzgerald and Richard Ng; and "Understanding Xeroderma
Pigmentosum" by Ken Kraemer. 

WHAT IS COCKAYNE'S SYNDROME?

WHAT OTHER PROBLEMS MAY BE SEEN IN CS?

HOW IS A CASE OF CS DISCOVERED?

ARE THERE TESTS FOR CS?

WHAT IS THE VALUE OF LAB TESTS FOR CS?

WHERE ARE LAB TESTS DONE?

WHAT CAN BE DONE TO HELP CS PATIENTS?

HOW CAN UV SENSITIVE CS PATIENTS BE PROTECTED?

PSYCHOSOCIAL ASPECTS OF CS

WHAT IS THE LIFESPAN OF A CS PATIENT?

HOW CAN I LEARN MORE ABOUT CS?

WHAT IS COCKAYNE'S SYNDROME?

Cockayne's syndrome (Cockayne syndrome; CS) is a rare and devastating genetic disease. It is
present in about 1/100,000 live births. Its inheritance is autosomal recessive. In other words, it
occurs if both the father and the mother pass on a damaged gene to the affected child, with the
parents themselves having no health problems related to CS, and with 1/4 of the siblings expected to also have CS. CS may be diagnosed if both of the following major criteria and three of the five minor criteria are met:

Major criteria:
1. Height below fifth percentile for age and sex.
2. Developmental delay (absence or delayed occurrence of normal nervous system developmental milestones, such as ability to speak or walk).

Minor criteria:
1. Abnormal sensitivity to sunburning by UV-C from sunlight and other sources.
2. Sensorineural (nerve) deafness.
3. Cataracts or pigmentary retinopathy (retinitis pigmentosum), either of which may cause blindness.
4. Unusually severe dental problems, including tooth decay.
5. Characteristic facies (facial apperance). This may include unusually large ears for head size ("Mickey Mouse ears"); small chin with prominent, pointed nose ("birdlike"); deficiency in adipose tissue ("fat") under skin, giving sunken eyes and skeletal appearance. Face overall may appear aged or wizened, and head size is likely to be unusually small for age and sex of patient (microcephaly).

WHAT OTHER PROBLEMS MAY BE SEEN IN CS?

Some of the many other problems that may occur include premature aging, low weight for height, poor feeding, decreased tolerance for infections, and seizures.

HOW IS A CASE OF CS DISCOVERED?

Circumstances vary. A child at birth may meet both major and enough minor criteria for diagnosis, with prompt recognition of the abnormality and rapid subsequent identification of the syndrome.

Often, however, the problems seen in CS develop insidiously over a period of years, so that for example height may be normal at birth, low but still normal at two, and clearly abnormal at six. Emergence of a characteristic abnormality of CS, such as development of blindness, deafness, difficulty walking, or poor weight gain or observation of extreme sun sensitivity, may result in an encounter with a medical specialist who will start the process of reviewing possible explanations.

Due to the rarity of CS, there may be considerable delay between when a problem first is noticed, and when CS is diagnosed.

ARE THERE TESTS FOR CS?

Yes. 

Radiography (MRI or CT scans) may show characteristic brain structural abnormalities, including calcium deposits in the basal ganglia and ventricular enlargement without obstruction. 

Laboratory procedures requiring establishing a culture of skin cells (fibroblasts), obtained by collecting a small skin biopsy (fragment) using local anesthesia. Laboratory procedures include:

1. UV survival curve

Measures how easily UV light kills cells. CS cells are killed abnormally easily by UV; typically only about 1/2 to1/4 as much UV is required to kill a particular fraction of CS cells, compared to normal cells. If this test is abnormal, further testing may include:

2. RNA synthesis inhibition assay

CS cells differ from normal cells in lacking the ability to rapidly repair genes that have been damaged by UV (a process called transcription coupled repair). The genes normally are used to make RNA, which is used by the cells to provide instructions on how to make the cell's proteins. UV damage to genes blocks RNA synthesis (and protein production). 

Thus, after UV exposure, CS cells and normal cells both produce less RNA. But after a while, thanks to their rapid repair ability, normal cells begin to regenerate their genes and thus start making more RNA; while CS cells, lacking this rapid repair, are slower to recover their ability to make RNA. In this test, then, cells are treated with UV, and several hours later their RNA content is measured and is compared with the RNA content of the same cells which have not received UV irradiation. 

CS cells will show a lower ratio of RNA in irradiated cells: RNA in unirradiated cells than normal cells in about 90% of cases of CS.

3. Complementation testing

This identifies what gene is affected in the CS patient. This includes the CS-A gene, ERCC8 , in about 25% of cases; and the CS-B gene, ERCC6, in about 75% of cases. There are extremely rare cases of CS due to mutation in one of three genes affected in patients with a similar disease, xeroderma pigmentosum (XP). 

These include the XP-B (ERCC3), XP-D (ERCC2), and XP-G (ERCC5) genes. CS patients affected in XP genes may also develop skin problems characteristic of XP in sun exposed areas such as the face, including freckling, actinic keratoses, and skin cancer.

4. Mutation analysis

This determines in what way the genes in the CS patient have been damaged. It is likely that CS patients who are relatives will have a gene damaged in the same way, while unrelated patients are likely to have the gene damaged in different ways, or even will be damaged in different genes entirely.

WHAT IS THE VALUE OF LAB TESTS FOR CS?

By measuring the degree of the cells' UV sensitivity, the UV survival curve test is helpful in showing whether there is unusual sun sensitivity that may indicate a need for improved sun protection, and also may be helpful in showing the parents to not be responsible for any old sunburn injuries resulting from normal sun exposure. The test may be helpful in diagnosing CS, especially if the sun sensitivity was previously unrecognized and is needed to make the diagnosis.

The RNA synthesis inhibition assay is expected to be abnormal only in CS, XP, and concurrent CS and XP; so it may be helpful in making a diagnosis of CS. It also provides another measure of how far the cells vary from normal cells. It also shows that complementation testing may be performed.

Complementation testing currently is more of research interest than of immediate value to patients, although this may change in several years assuming breakthroughs in biotechnology therapy. Knowing the affected gene allows performance of mutational analysis for research or carrier identification, by indicating which gene is to be studied for damage. In time, using advanced biotechnology that still has not been designed and may require several breakthroughs in research, it may be possible to use complementation testing to plan protein therapy or gene therapy, in which the patient would be supplied with the protein normally made by cells with the help of the CS gene that is defective in the patient; or with the gene itself in a normal form. Such developments are not expected for some time, and are not to be depended on by current CS patients.

Mutational analysis is of research interest in that it allows a determination of how different forms of damage to CS genes have different effects on health and on how CS patients' cells behave. It could be used to identify healthy carriers who, like CS patients' parents, have one normal and one damaged copy of a CS gene. This could be helpful in rare isolated and small communities in which CS is relatively common, but is of little value for most relatives of CS patients.

WHERE ARE LAB TESTS DONE?

UV survival curve, RNA synthesis inhibition assay, and complementation testing is being done in only one US laboratory. 

Prenatal diagnosis of CS is not available in the US, but is done at two European laboratories. For information, try: 

WHAT CAN BE DONE TO HELP CS PATIENTS?

CS children have the same needs that other children have, including love and attention, although they do require an unusual amount of attention. Their specific health problems may be evaluated and treated by appropriate specialists, such as clinical geneticists, pediatricians, dermatologists, ophthalmologists, otolaryngologists, audiologists, and rehabilitation therapists. 

They also may benefit from special education (including sign language training), and from devices such as ankle and foot orthotics (to assist walking), and hearing aids. If feeding is very unsatisfactory, a feeding tube may be provided to allow direct insertion of a liquid diet into the stomach whenever it is needed.

HOW CAN UV SENSITIVE CS PATIENTS BE PROTECTED?

Fortunately, few CS patients will develop the skin cancers seen in XP, so the consequences of inadequate protection are less serious than in XP. However, the sunburning may be quite serious, so protection appropriate for the individual child's level of UV sensitivity is needed. Some approaches:

1. Block window UV at home and elsewhere

At home, this may be done cheaply by covering the window with black plastic garbage bags; or more expensively but more acceptably by covering windows with plastic film that blocks UV but not visible light. Regular curtains may well provide adequate UV protection as well. 

Possible information sources about UV blocking window plastics include:

These window films may be used at home, in cars (in some cases needing a permit from motor vehicles department requiring a doctor's letter), and in areas of the school where the child is taught.

Another approach is to replace window glass with plastic, UV absorbing windows; or to put UV absorbing sheets of plastic against windows. One material used for this is LEXAN, available from: 

General Electric Plastics
General Electric Company
One Plastics Ave.
Pittsfield, Ma. 01201
800-451-3147

2. Changing lighting

may be useful, since unlike incandescent lights, which give off little UV, much UV may be emitted by fluorescent, halogen, and mercury vapor lamps. For information about covers to block UV from fluorescent light, try:

R and R Plastics, Inc.
P.O. Box 1961
Clifton, N.J. 07015
201-365-8083

3. The effectiveness of measures 

to block the UV may be observed crudely by seeing if sunburning has stopped; or more reliably using UV meters to determine the intensity of UV light in a rom (or car). Sources for such devices include:

4. Special clothing

 can block UV. Two sources of such clothing are:

Some regular clothing also can block UV. Best results may be with layering of clothing, and with selcetion of clothing that can block visible sunlight when held up to the sun. Minimizing of skin exposure may be important, including using gloves and wide brimmed hats. In addition, UV proof sunglasses protect the eyes. Additional skin protection may be provided by SPF15 or higher sunscreen.

5. The child also may be restricted from playing outside during the day, and special arrangements may be made to minimize brief occurrences of transient sun exposure from such sources as entering and exiting cars, and opening of front doors. However, because CS patients lack a risk of skin cancer, they in general will need such strict protection much less than do XP children.

PSYCHOSOCIAL ASPECTS OF CS

Despite their many problems, CS children tend to be affectionate and cheerful with sunny dispositions. 

However, their families are under enormous stress due to such considerations as need to provide the extra attention, burden of unusual medical bills of which many may not be covered by insurance, burden of child's attendant care needs, medical emergencies due to complications of CS (which may occur very frequently), concerns about CS in future family members, loss of friends who have trouble dealing with a disabled child, and loss of free time.

Social workers, family counselors, mental health workers, government health and public assistance programs, relatives, and other resources may be very useful in dealing with some of these problems.

WHAT IS THE LIFESPAN OF A CS PATIENT?

The oldest CS patient known to Share and Care Cockayne Syndrome Network is in the late 30s. For children born with cataracts, the life expectancy is 12 years, and many CS patients die in infancy. Both the severity of the genetic damage in the individual patient, and the quality of care including ensuring adequate food intake, are important determinants of the lifespan.

HOW CAN I LEARN MORE ABOUT CS?

Share and Care Cockayne Syndrome Network Inc., 

POC Jackie Clark 
P.O. Box 282, Waterford, VA 20197 

Office 703-265-3719, Cell 703-727-0404, Home 540-882-3380 

email: JackieClark@aol.com

is an educational, advocacy and support organization for helping CS patients and their families. Shirley Rodriguez is Coordinator.

Visit Dr. Busch's webpage at: http://members.aol.com/DBBusch/shareandcarehome.html