Genetic Testing in Coffin-Lowry Syndrome: Your questions answered

   You’re probably familiar with DNA, or deoxyribonucleic acid, from watching gory TV crime shows like CSI and Law and Order or reading books and newspaper articles about genetics discoveries. If you paid close attention or really liked science, you may even recall a few things from your high school biology class. If this is the case, you already have the framework to learn about DNA-based genetic tests that doctors use to make a diagnosis. This article will answer questions about the DNA tests that are specially designed for Coffin-Lowry syndrome (CLS).

What do the genetic tests look for?

   Genetic tests for CLS involve reading the genetic code from cells in the patient’s blood or other type of sample. The genetic code is made up of four chemical structures, which are represented by the letters A, T, C and G. Each gene is made up of a unique sequence using these four letters of the DNA alphabet. Just as the words on this page have meaning because of the order of the letters, so do the letters in a gene. Each gene serves a purpose, which is to provide instructions for a unique protein to be made by the body. It’s as if the DNA in genes is a biological recipe. Once the DNA recipe makes a protein, the protein has a specific function. Proteins must work properly and be in the right amount to prevent genetic disease.
   A specific gene, known as RSK2, was identified by a group of researchers studying patients with CLS in France, Philadelphia and England (Trivier, et al. 1996). When they compared the DNA from patients who have CLS to people who do not have CLS, they found differences in the DNA code. These differences are called genetic mutations. The researchers wanted to see if the mutations they found in the RSK2 gene cause CLS, so they studied how the mutations affect the way the RSK2 protein, called a kinase, works. What they found was that patients with CLS did not have any normally functioning RSK2 kinase. This led them to conclude that mutations in the RSK2 gene cause the RSK2 kinase to be made improperly, and the creation of an abnormal kinase leads to all of the symptoms associated with CLS. When a DNA laboratory does the test for CLS on a patient, they are looking for mutations in the RSK2 gene. Amazingly, the RSK2 gene is made up of thousands of DNA letters and yet it is not uncommon for just one letter to be changed in a patient with CLS. The genetic test requires reading the DNA code from a patient’s sample, letter-by-letter, to find these small changes.

My doctor isn’t sure that my child has CLS. Will doing genetic testing on him help to make the diagnosis?

   Genetic testing may indeed be helpful, especially for younger children. Many young children do not have all of the symptoms of CLS and it is more difficult for the doctors to make the diagnosis in them. There may be other genetic conditions that the doctors are considering, many of which have some of the same symptoms. If the RSK2 gene test shows a mutation, then the result is “positive,” and the diagnosis of CLS can definitively be made. If it is negative, or no mutation is found, there may be other things to consider, but it doesn’t necessarily mean that the diagnosis is not CLS.
   There are some symptoms that become apparent later on in CLS patients, and these can be anticipated if the diagnosis is known early. In particular, scoliosis (curvature of the spine) is common in adolescents, particularly boys, with CLS. Because it may not be present when the child is first evaluated, the doctors will know that a child with a positive DNA test for CLS has a higher chance than other children to develop scoliosis. The fact that they can anticipate this potential medical complication allows them to treat it earlier. The learning problems associated with CLS can also be approached with early intervention if the diagnosis is known. Lastly, there may be a social and emotional benefit to having the diagnosis early, because it allows newly diagnosed children and their families to connect with other parents. Other parents and families can be invaluable and it is often helpful to talk to others who understand about the problems, and the joys, unique to CLS.

I’ve been told by my doctor that my child definitely has CLS. What will a genetic test tell us that we don’t already know?

   In addition to confirming the diagnosis and determining the inheritance pattern (discussed later), genetic testing can also provide important information to family members. For example, the mother, sisters, aunts or cousins of a boy or man with CLS may want to have children now or some day in the future. When a child with any genetic condition is born into a family, other family members may want to know if they need to consider the possibility that they may have a child with that condition as well. The most helpful approach to determining the chances of having a baby with CLS is to test the person who has CLS first. If that person shows an RSK2 gene mutation, then other family members can also be tested. This may be difficult to bring up with family members, but it is important to discuss and is something your relatives might be wondering about. Sometimes getting it out in the open is a relief to everyone. If they can find out their chances of bearing a child with CLS, it helps them to prepare for the possibility and consider all of their options for having a family. Anyone with a family history of CLS who wants more information about risks, testing and their reproductive options can meet with a genetic counselor. Genetic counselors can be found by going to http://www.nsgc.org or by requesting a referral from a gynecologist or family doctor.

I understand that CLS is a genetic condition. How is it inherited? Is it always inherited?

   We’ve already established that CLS is caused by a mutation in the RSK2 gene. Genes, and the DNA that makes them up, are packaged into structures called chromosomes. Each of us has 23 pairs of chromosomes, and the important chromosome in CLS is the X chromosome. Females have two X chromosomes and two copies of the RSK2 gene. Males have only one X chromosome and only one RSK2 gene. If a boy has a mutation in his RSK2 gene, he will not make a functional RSK2 kinase. However, if a female has a mutation in one of her two RSK2 genes, she will make normal RSK2 kinase from the other copy of the gene. The normal copy of the RSK2 gene may compensate, totally or in part, for the deficiency caused by the mutation. There are many females with some mild features of CLS, however, and these girls and women don’t have enough normal RSK2 kinase being produced to completely prevent the CLS symptoms. One thing to note is that it is rare for a female with an RSK2 mutation to have all of the same features as a male with the condition.
   The inheritance of CLS is X-linked, because it is on the X chromosome. Females with an RSK2 mutation are called “carriers” and have a 50% chance, with each pregnancy, of passing on the mutation. If the mutation is inherited by a female, she will be a carrier. If the mutation is inherited by a male, he will have CLS. Overall, before a pregnancy is conceived, there is a 25% chance to have a son with CLS and a 25% chance to have a carrier daughter. As mentioned, female carriers may have some of the symptoms associated with CLS although they are usually more mildly affected.
   CLS is not always inherited, however. Based on a relatively small number of cases in which there was no family history of CLS, the medical literature suggests that over half of the mothers of most boys with RSK2 mutations are not carriers (Jacquot, et al. 1998). If the mother of a child with CLS has no symptoms and no family members with CLS, genetic testing may be the only way to determine if she is a carrier or not. Mothers who are not carriers still have a small chance of having a daughter who is a carrier or more than one affected son; however, this risk is likely to be low (on the order of 1%). If a woman who has a child with CLS is not a CLS carrier, her mother, sisters, cousins and nieces would also not be carriers and they do not have an increased chance of having a child with CLS. The family members of an unaffected father of a child with CLS also need not be concerned about an increased chance for having a baby with CLS, because of the X-linked inheritance pattern.

My child had the RSK2 gene testing done and it was negative. What could this mean?

   Genetic testing for CLS currently only looks at the DNA sequence of the RSK2 gene. If a mutation is present, the diagnosis of CLS is confirmed. If no mutation is found, there are a few possible explanations. For one, there is some evidence in mice that another gene exists which causes the same symptoms as CLS (Yang, et al. 2004). A negative result of RSK2 testing may be due to the fact that there is a DNA mutation, but it lies in another gene. At this point, the role of another gene or genes in CLS has not been confirmed in patients with CLS.
   A second possibility is that a mutation is present in the RSK2 gene, but was not picked up by the methods used in the lab. This is a limitation of the technology that is available to us at this time. Because CLS is a rare condition, it is difficult to know how many mutations are not being detected, but the estimate is that it is likely to be low. Certain types of rarely-occurring mutations cannot be detected in females, and testing an affected boy in the family (if one is available) may be recommended.
   Lastly, some doctors order RSK2 testing for patients that don’t completely fit the CLS phenotype, meaning that they may have only some of the symptoms associated with CLS and may even have other symptoms that are not typically seen in CLS patients. This is not uncommon, and many tests may be ordered to get to the bottom of the diagnosis. Sometimes one of the tests comes back positive, and then the diagnosis is known. Other times, we are limited by our current understanding of genetics and the available technology, and the tests are all negative. Because of our rapidly advancing knowledge in genetics, checking in with your geneticist or genetic counselor on an annual basis is a good idea, as they can discuss new discoveries with you as they are made.

How do I get the testing done?

   The testing is currently being offered at two laboratories in the US: GeneDx, Inc. (http://www.genedx.com) and Greenwood Genetic Center (http://www.ggc.org). RSK2 gene testing must be ordered by a physician or genetic counselor, who will discuss the results with the patient and family. The testing is slightly different between these two labs, and your doctor or genetic counselor can help you decide which lab is best for you. Testing can be done on a blood sample that can be shipped to the lab, so there is no need to travel if you want the testing done. The Greenwood Genetic Center (GGC) requires a special tube that the blood must be shipped in, which they will send to your doctor’s office free of charge. The special kit is only necessary for the first person tested in the family. After that, blood samples for carrier testing can be sent in the tubes available at any drawing station. If you’d prefer not to have blood drawn at all, GeneDx can send a brush kit to your doctor or your home to collect cheek cells for DNA testing. The accuracy, turnaround time and cost are the same for blood and cheek brush samples. Unfortunately, unlike the quick results the investigators seem to get on TV programs, the results of DNA testing for CLS usually take several weeks, and many steps go into the analysis. The time is well-spent, however, and the laboratory works hard to insure that the results they report to your doctor are accurate.
   Because of the methods they use, GGC prefers doing the initial testing on males with CLS while GeneDx has experience testing both affected males and females. Both labs require testing the person with CLS first, and can then offer carrier testing to other family members. Testing a sample from a pregnancy is also available when a mutation is known in a family. It is important to be aware of the billing policy of the lab before sending a sample, as the testing is expensive ($1,300 - $2,600, for the first person in the family; $250 - $1,050 for carrier testing and testing on a pregnancy). Insurance frequently covers RSK2 testing, but you will probably want to check with your insurance company to see if you will be responsible for all or part of the cost of testing.
   This article covers some commonly-asked questions about genetics and DNA testing. The next time you’re watching a crime show on TV or reading an article that describes DNA, you’ll have a better understanding of genetics and the methods used to examine genetic material. Of course, it’s especially nice to know that not only is this technology helpful in solving crimes, but it can also be used to help families like yours.
   If there are any questions about this article or genetic testing for CLS, please feel free to contact the author at cheryl@genedx.com.

Cheryl Scacheri, MS, CGC

Director of Genetic Counseling Services

GeneDx, Inc.

Gaithersburg, MD

http://www.genedx.com/services/dis_cls.php 

References:
Trivier, et al (1996) Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature. 384:567-570.
Jacquot, et al (1998) Germline mosaicism in Coffin-Lowry syndrome. European Journal of Human Genetics. 6:578-582.
Yang, et al (2004) ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology: Implication for Coffin-Lowry syndrome. Cell. 117:387-398.

Curt Cheney, Age 32
Tammy Cheney, Age 36

   Although I am new to the Internet scene for CLS, I have received your wonderful newsletters for years and have benefited greatly from reading the postings of others. I have not been very good about supplying information about our own situation and am just now finding that I am needing the support of others. In some ways I feel like a pioneer in the CLS field. Tammy and Curt were born in 1969 and 1973 and the syndrome was named in 1972, I believe. They were diagnosed in the 1980’s. We have been lucky with our Tammy and her health issues have been few, and she is a lovely young woman who has met her potential well I feel.
   Our Curt has been less fortunate with his health, but he is the brightest spot in our lives. When I see the pictures in the newsletter of all the young boys with CLS, I am just amazed at the resemblance that most of them have to our Curt as a young person. He is now 32 years old and although he continues to have spinal cord issues he has amazing resilience and humor. Our children although affected with CLS have been a true gift from God, and have truly shown us what quality of life is all about.
We are still in the process of figuring out Curt’s neck situation. He has spinal cord impingement at C4-5 and C5-6. It is recommended that he have a anterior dissection with fixation at that level. Basically coming in from the front of the neck and taking out the disks in the spaces above and using cadaver bone to fuse and then put a plate on the front of the spinal column to hold the discs together.
   We are also awaiting decision from cervical spine specialist in Minneapolis. We saw him 5/10/05. However in a mix up all of his records did not get sent to him so we are waiting for the cervical MRI to be sent to him for review. We should hear tomorrow and if his recommendation is different than the first one listed above then have to weigh the differences and decide who and where the surgery will be done.
   In the meantime, Curt is stable. He has regained part of the use of his leg. However, still drags it some and the potential of him falling and further injuring the spine is very significant. Will keep you informed.

Sandy Cheney
Barnum, MN

Alexander Banchero, Age 12

   It's been a long time since I've sent in an update.  Alex is doing wonderful, we've had a great response to vesting for Scoliosis,

 he's now up to 20º (from 51º) - and his general health has been great.  We have since had another son (2 years old), and am expecting another boy - both healthy so far, and all testing comes back clear.  

   Alex has been a great brother, exceeding my expectations by miles.  His patience and kind disposition is so dramatic that I find I have to defend him quite a bit, but I'd rather it be that way then the opposite of course.  Though he does get back in his own little way...  I will see him get that sly little smile and I'll know that trouble is brewing. 

    Having Alex was the best thing that EVER happened to me.  I know that sounds soppy - but he seriously changed my life’s course.  I owe so much to him that words fail me in describing...  It's true that God won't give you more than you can handle.  Sometimes I wondered just how well He really knew me, to entrust such a huge responsibility to such an irresponsible person - but it turns out that He knew exactly what I needed.  I'm all straightened out now! 

   All the best to everyone.  It has been a trying 12 years for me, but Alex being such a loving child has gotten me through the worst of it.  We are doing so well together, that time seems to be slipping past more quickly now then ever!  Or... maybe that's just me slowly losing my mind!!  Probably both...  Either way... we're happy and healthy here in Iowa.

Carolyn Meyer (nee Banchero)

Charles City, IA

Ryan Stevens, Age 24

   Ryan is doing very well these days.  He has a 30 hour a week job at Citibank, where he makes $6.50/hr.  He thinks he's rich!  But he likes his job and seems to enjoy going there every day.  He rides a paratransit bus to and from since he is in a wheelchair pretty much full time.  You remember all that he went through with the botched up back surgery, e-coli and the fall in the hospital.

   We are hoping he will go to a group home to live with 3 other males soon.  I feel it is the natural progression for him and he will adapt well.  We'll see.

   Hope all is well with both you and Davis.  Thank you for all you do.

Fondly,

Sherry Medek

Robert Lewis, Age 15

Dear Mary,

   Do you know of any connection with liver disease and CLS? Robert has CLS and always had problems with food. Up until two years ago symptoms had always presented as hyperactivity and bowel problems. Then referred to Royal Free Hospital in London, liver function tests revealed high ALT level(indication of damage to liver cells).  It seems he has a problem breaking down certain
foods.

   As far as I understand it he is unable to break down fully chemicals in food gluten caisen amines phenolic compounds etc these partially broken particles leak into bloodstream cross blood brain barrier causing hyperactive behaviour (leaky gut) they have to go through the liver which cannot get rid of them the liver sees them as toxins as in drugs hence the damage to liver cells.

   I’ve tried the enzymes and he reacted very badly to them, especially papain. One consultant tried Nalcrom anti-histamine and his sister was taken into care temporarily for her own protection that’s how bad he gets. There are a few natural remedies that have been recommended to me but the problem now he goes to a residential school Mon - Fri is that they refuse to administer anything not prescribed not even pro biotics. He also has very high B12 level due apparently to an excess of bad gut bacteria. No its because he reacts so badly to everything that is supposed to help him that I am beginning to think like I said that the problem is the liver first causing the problem with food.

   Everyone I have spoken to except doctors (eg biochemists, nutritionists) say this is the case they say doctors only look at the disease and can’t get to grips with the cause. School refuse to remove these foods from the diet so I am left worrying about permanent damage to the liver. It has only recently occurred to me that I could have the problem the wrong way around. It seems obvious to me that food is the connection but that a problem with liver (this is where I wondered whether there was a connection with CLS) could be the reason why he has this inability to break down foods.      

   Robert has been tested for all the viral hepatitis negative hence the monitoring of ALT off the problem foods ALT returned to normal over a period of 18 months reintroduction of foods caused level to start rising again off foods again for three weeks level has dropped slightly. Consultant has now acknowledged that there is a problem with liver but refuses to believe this may be connected with the food.

   At the end of the day the only answer may be to keep him off school and off these foods. I may always be wondering why but I live in hope that someone will be able to find out and dare I hope find a solution to the problem.

   I am still waiting for feedback from consultant seen a month ago. I have now decided I am going to have to be very firm and insist on seeing a liver specialist. Do we ever stop fighting?

Thanks for your help.

Sue Lewis

Littlehampton W Sussex

Great Britain

I wish I could offer more assistance, but I have not heard of this problem. If anyone else has information related to liver problems, please contact Sue.—MCH

Daniel McGrath, 12 Months

   Daniel is now 12 months old and he still isn’t crawling. He is rolling around like mad. I am starting to think that he may never crawl. He has got me a bit worried. Also I was shocked to find out that in most cases a male with CLS doesn’t live past the age of 30, is that true? The only reason I am asking this as Daniel's uncle who has CLS almost died of pneumonia - he was in hospital for four weeks. It was very touch and go there for a while. He was only released last Monday. The doctors have told us that because Ivan can’t move like normal people (sorry), he is prone to every infection and the next time he gets pneumonia there is nothing they can do for him. Doctors have told us to be prepared but how can you be prepared for something like that?

Sharyn McGrath
Australia

   Not crawling by 12 months is not unusual for CLS kids. Some never crawl, they go right into walking. Just so you know what to expect, they usually start walking around age 2, and start using recognizable words around age 4.
Life expectancy is very hard to predict. It depends a lot on what individual problems each person has. Those with more complications, like scoliosis, heart problems, etc., are of course going to have more medical issues than those that do not have those complications. Most have poor muscle tone and have difficult coughing effectively which means it is harder for them to clear mucous out of their lungs, therefore they tend to be more prone to pneumonia. You have to be alert to any change in their condition and get them adequate medical attention early on. They often cannot tell you when they are sick or in pain.   - MCH

“B.J.” Myers (Stewart), Age 16

Dear Mary  
   First the good news. B.J. was accepted for a wish from Make a Wish Foundation. We are so happy for him. His wish was to meet Tony Stewart the Nascar driver and go to a race.
   Second I want to thank you for the newsletter you do. It helps us so much.  
   B. J. has been having a hard time with his bowels. He can not go on his own. This has just started recently and the doctors do not seem to take it seriously. My husband and I have done everything, giving him mineral oil daily, stool softeners, apple juice, etc. We are having to have to give him enema's every three day to get him to go and then he still does not go very much. Is this an ongoing problem with kids that have CLS?
   B. J. is also having circulation problems in his feet and hands. They are always purple. I have to elevate his feet to get them to normal color. Is this a typical?   B.J. is not getting very big. He had his second surgery for his scoliosis last year. He can not walk hardly at all anymore. He cannot straighten his knees to walk and his left foot goes out. He crawls around the house and can do it well. We try to encourage him to walk and he wants to, but can't. B.J. is also having trouble holding his head up if he get over stimulated. He tires easily. He is on three medications for his seizures, Lamitcal, Depecote, Keppra. He has break through every now and then.  
   Other then all that B.J. continues to bless us and make us smile - his personality is amazing. Dr Kahn from Morgantown University is doing her thesis on B.J. and he will be in the Physician Magazine soon.
B.J. loves noise toys and loves his drums. He loves books and puzzles. He can count to 15 now and knows his colors and shapes. He can read several words now. We are so proud of him. He is talking in 9-word sentences. He loves to fish with his Dad and loves to watch Nascar.   B.J. is a blessing in our life and we can't imagine life without him.   Thank you again for everything.  

David and Kathy Myers
Nemacolin, PA  

   In many ways, B.J. is mirroring the same issues that Davis has. He also crawls to get around, can only walk assisted for short distances, drags his left foot and doesn't straighten his knees.   Davis is prone to constipation but nowhere near as severe. His is helped by substituting soy milk for cow's milk. Before that, he was on Enulose every day and that also worked. Since he's on soy, he no longer needs the Enulose, but he does not pass stool every day - more like one big one every 3 days which seems to be normal for him. Children's Hospital here in Seattle recommends an enema of 50/50 milk and molasses. Nasty, but it works. It has the added benefit of not presenting a risk of electrolyte shock if the contents are not passed right away. Beyond this, you'd need to talk to your doctors.
   I haven't heard of anyone mentioning the purple hands and feet. I have noticed that Davis's hands get purple on occasion, and he also tires easily. Davis does have a mitral valve insufficiency. If you haven’t already had B. J. checked for cardiac problems, that might be advisable.  -MCH

Ever tried.  Ever failed.  No matter.  Try again.  Fail again.  Fail better. 

 ~Samuel Beckett

Thanks for Caring!

The following families or individuals have recently made generous donations to the Coffin-Lowry Syndrome Foundation:

Sherry Medek

In memory of Milton Scowcroft:

Jack and Mary Kerns

Martha G. Anthony

Peter K. Scowcroft and Nancy LaFargue

Anthony and Margaret Patterson

J. H. and Dorothea C. Hartman, Pennington, NJ

Jill Trask or Timothy Hartman, Pennington, NJ

Edward & Miriam Landesman

George, Antoinette and Jeannette Truman

Jane and Frank Geary

Dorothy Comery and Cynthia Ferguson

Sakis Onisiphorou

Send your donations to:  

Coffin-Lowry Syndrome Foundation

c/o Mary Hoffman

3045 255th Ave SE

Sammamish, WA 98075 

(U.S. Funds, please)