Chiari Malformation

Chiari malformation (spoken as kee-AHR-ee) is a disorder of the skull where the cranium that holds the brain is small at its base.  The brain is cradled and protected in a casing of bone called the cranium.  The cranium is made up of 6 fused bones- the frontal bone, sphenoid bone, ethmoid bone, parietal bone, temporal bone and occipital bone.   The occipital bone is the most inferior or lowest bone in the cranium and it protects the back of the brain.

The occipital bone in humans is curved at the base which allows it to cradle the round brain tissue inside.  This curved portion of the occipital bone is called the posterior fossa and it sits just under the ridge in the back of the head that you can feel (called the occipital protrubance). 

The posterior fossa cradles the most posterior (back) and inferior (lowest) portion of the brain called the cerebellum.  The cerebellum is a smaller domain of the brain that coordinates motor function- such as balance and coordination.  It has many nerve tracts that communicate with the cerebrum where your brain "decides" on how to move and react to its environment.  Also in the cerebellum are tiny channels and chambers that act as canals to move nutrient-rich fluid (called cerebral spinal fluid or CSF) around the brain feeding it and cleansing it of waste.   CSF acts much like the blood supply but unlike blood, it does not carry cells other than those of your immune system; essentially protecting it from viral and bacterial infection.  The CSF travels through the cerebellum in a canal, called the cerebral aquaduct, that moves from the cerebral area down into the brainstem.  The CSF accumulates in a chamber that sits just under the cerebellum, called the 4th ventricle.  From here it drains down another canal into the spinal cord through the central canal.  At the base of the occipital bone is a large opening called the foramen magnum where the brain stem exits the cranium and leads to the spinal cord. 

In WS, mis-shapen cranial bones are prevalent making Chiari an unfortunate complication of the disorder for some.  When the cranium is formed during fetal development, some people's posterior fossa is mis-shapen.  This can happen in two ways.  First the base of the skull that fuses with the facial bones, called the clivus, can be shorter than normal consequently crowding the cerebellum.  The second malformation that can occur is in the tentorium cerebelli.  This is a fiberous covering that separates the cerebrum from the cerebellum.  This membrane when situated in a steep fashion pushes down on the cerebellum and crowds the space.

Due to the crowding, a portion of the cerebellum called the cerebellar tonsils can be compressed into the base of the skull and/or extend down into the foramen magnum (the hole where the brainstem exits the skull and becomes the spinal cord).  If the cerebellum is crowded in this space, the tonsils extend down into the hole and essentially block the passage way of the CSF flowing out of the 4th ventricle into the central canal of the spinal cord. 

The arrows in the picture on the left show the normal flow of CSF through the brain.  The picture on the right shows that when the cerebellum sits too low in the posterior fossa it cuts off the flow of the CSF around the cerebellum.

The severity of crowding can cause pressure to be exerted on the cerebellum creating neurological or motor issues.  It can also close off the channels where CSF moves causing it to build up pressure and stop its flow which essentially will cut of supply of CSF to parts of the brain stem and spinal cord. 

picture from www.chiariinstitute.com

Types of Chiari
Chiari Malformation can occur in various degrees of severity.  It is considered a congenital disorder (where it is formed at birth) but symptoms are often not witnessed until adolescence or early adulthood because the pressure can cause neurological damage over time.  In Williams Syndrome (WS), type 1 Chiari Malformation occurs in 10% of cases.  Type 1 is less severe and often is not accompanied by any symptoms.  It's found more commonly than the other types and is often diagnosed in conjunction with other neurological disorders rather than on its own.  Type I is often considered an adult form because it is often not usually discovered until later in life. 

A brain scan showing Chiari type 1.

There are also two other types of Chiari Malformation.  Type II, also called Arnold-Chiari Malformation is typically found in conjunction with a disorder of the spinal cord called spina bifida where the spine doesn't close properly during growth in-utero and the spinal cord protrudes from the back.  This type is usually discovered during pregnancy in an ultrasound because it is accompanied with other spinal abnormalities that are more obvious.  The third type, which is rare and most severe is Type III which leads to long term debilitating neurological issues and requires surgery and long term treatment. 

There is not much known if Chiari is a hereditary disorder.  There are a few documented instances where it seems to run in a few families but not much is known about genetic links to this disorder.

Symptoms

Most people with Chiari will experience headaches typically at the base of the head or neck and are often treated for pain.  Many end up with severe headaches after coughing and sneezing.   Other symptoms include changes in the voice and difficulty swallowing often with gagging or choking.  Because the cerebellum controls coordination, body movements can become difficult.  This can include spatial difficulties, dizziness, blurred vision, poor fine motor control (such as holding a pencil and writing), numbness and tingling in the hands and slurred speech.  Other symptoms that are considered more rare are sleep apnea, ringing in the ears, poor bladder control, scoliosis and chest pain.

Unfortunately for those with WS, the symptoms of Chiari malformation are common issues in WS such as coordination issues, gagging and swallowing issues and fine motor delays so it may be difficult to spot them if your child cannot communicate that they have a headache.

If Chari malformation is suspected a neurologist will often complete an MRI to assess the bone formation.  They will conduct a special test called a cine-MRI which tests the flow of the CSF through the brain to see if there is blockage. 

In some people with Chiari, syringomyelia may develop due to nerve tract damage.  In this complication, a canal or cyst will develop in the spinal cord and fills with fluid.  This can cause additional pressure in the canals that carry CSF and can cause further nerve damage.

Arrows indicate regions of syringomyelia

Treatment
Surgery is the only treatment that can stop neurological damage to the central nervous system and depending on the severity several surgeries may be needed to effectively repair the cranial crowding.  If there is any doubt about need for surgery it will usually be delayed.  There are three reasons a neurologist would suggest surgery for this disorder: 1. There is obvious neurological damage especially if it worsens over time; 2. If other spinal cord issues are present as well (such as tethered cord, scoliosis, spina bifida, etc); and 3. If the symptoms of Chiari greatly affect the person's ability to cope day to day (such as if the headaches are too great to manage). 

The surgery itself is called decompression surgery.  The goal of the surgery is to relieve pressure exerted on the channels that carry CSF so that proper flow is restored and to relieve any pressure exerted on the cerebellum by the skull.  This is accomplished by performing an occipital craniectomy which means they remove some of the skull bone at the base of the skull to increase the space in the occipital posterior fossa.  This may  not require going into the brain itself; it focuses on changing the shape of the bone.  The surgery can also include a C1 laminectomy which is surgical change to the first bone in the vertebrae (cervical vertebrae #1).  In this procedure, they remove an archway that surrounds the spinal cord and possibly the ridge that forms the portion of the spine that you feel when you touch the back.  The goal of this is to relieve pressure where the cranium and vertebrae meet (where the headaches often exist).  In these sections where the bone is removed, the tough brain coverings that sit underneath the bone remain intact. 

At this point of the surgery some surgeons (5-10%) stop; about 45% also remove dura mater (called a duraplasty) which is the most common type of surgery for this disorder.  Dura mater (meaning "tough mother") is the very tough covering that surrounds the brain and spinal cord.  It has the consistency of thin plastic, like that of a water bottle.

 The dura mater would be cut and then a synthetic patch of it would be sewn in to increase the area and free up more space.  This procedure, called a graft, can use tissue from the patient itself, bovine pericardium (a sack lining that surrounds the heart of the cow) or synthetic material.  The material used is really the preference of the surgeon.  There is no research that shows one is better than another. 

From here another 45% of doctors will also remove the second layer surrounding the brain called the arachnoid space.  This layer is part of the channel system that skirts CSF around the brain and it often has lesions in it that when broken, can free up room for the cerebellum.  In some cases, the surgeon may also shrink the cerebellar tonsils themselves by either cauderizing them (which makes them shrink) or resecting them (cutting a portion out) to relieve the crowding and open up the channels for CSF flow.  This manipulation of the cerebellum itself is more risky because by interrupting the arachnoid layer, the patient can be exposed to risks of bacterial or viral infections in the brain such as meningitis. 

During surgery, ultrasounds are often use to constantly assess the flow of the CSF and the position of the cerebellar tonsils as room is freed up.  The success of the surgery really depends on the patient's severity and how the brain is compressed.  Some patients only need one surgery but approximately 30%, typically those with spinal or cranial deformities and other spinal complications, will need follow-up surgeries because the condition will relapse later in life.

What to do if you suspect Chiari
If you suspect Chiari malformation in your child with WS, it is important to see a neurologist.  The Mayo Clinic has a great web page with information you should bring to your first meeting and a list of questions to ask so you are well informed about the condition.



Sources used in this blog post:
National Institute of Neurological Disorders and Stroke
Chari and Syringomyelia Foundation
The Mayo Clinic

Upright Health: Posterior fossa and Chiari Malformation

Curved fingers and toes- Clinodactyly

Although it is a harmless condition and usually requires no treatment or even sought after advice from a specialist, many parents with children who have Williams syndrome remark about their curly fingers and toes.  Most often present in the 5^th finger (pinkie) or the 3, 4^th or 5^th toes, the digit is often seen curving inwards or overlapping with a neighboring finger or toe and the finger itself may look “stubby” or have a triangular or trapezoidal shape to its tip. 

Curly Toes (see a great picture of curly toes here )

Curly and overlapping toes are considered highly common in general population and don’t suggest any DNA issues.  They are usually found passed down through family lines.  The most common place to have a curly toe is when the 4^th and 5^th toes overlap.  Although there hasn’t been a great deal of research as to why this happens, there are some accepted theories as to why this occurs.  Many believe it is either due to the baby’s position in the womb or there is a slight deformity in the joint of the toe.   When the misaligned joint is coupled with either hypotonic or hypertonic muscles of the foot (see the muscles section of this blog), tension is placed on the tendon of the small toes pulling them out of alignment. 

A tendon is a strong cord of connective tissue that attaches muscles to bone.  Tendons often act like an ace bandage, creating tension around a joint to stabilize it and allow the muscle to move the bone to create motion in the body.  If the muscle is too weak or too tight it can cause the tension of the tendon to either be too low or too high.  This unbalanced tension then will cause the bone to become misaligned.   This can cause a more extreme overlapping of the toe than what you’d see in your family members. 

Usually clinodactyly doesn’t require any medical attention unless it progressively becomes worse turning into a joint contracture or if it interferes with walking.

A hooked finger

While curly toes are not used as a clinical diagnosis of any genetic anomalies, hooked fingers are.  A curved finger is considered typical in 10% of the general population but more likely than not, it indicates a DNA anomaly.  Found most common in individuals with Down Syndrome, a hooked pinkie is a structural abnormality that is present in approximately 60 different syndromes.   A hooked or curled pinkie finger indicates some sort of bone deformity usually attributed to delayed in utero growth (growth in the womb).  It often shows up on ultrasound and can be used to suggest further prenatal testing or guidance of a perinatalist although it is rarely a means of diagnosing any syndrome since it is so common in many genetic issues.  Basically, it can be used as a red flag.

The cause of clinodactyly in the pinky finger is due to a structural issue in the growth plate on the bone, called the epiphyseal plate.  The growth plate is a layer of cartilage at the end of a long bone (like those in the fingers and limbs).  As the child’s body grows, the cartilage is continually replaced with a bone matrix causing the bone to grow in length.  In clinodactyly, the bone’s growth plate is misaligned.  This causes the toe to grow in a curved fashion rather than straight.  In addition to growth in an abnormal direction, the tip of the finger will often end up looking triangular or trapezoid in shape. 

Again, unless there is extreme overlap on the finger to the point that it inhibits the child from gripping properly or having proper hand function, no treatment or worry is warranted.

Sources:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1255945/

http://www.podiatrynetwork.com/document_disorders.cfm?id=194

http://childrenshospital.org/az/Site1160/mainpageS1160P0.html

Updated muscles section

Greetings followers!  I have added more to the muscle page.  If you scroll past part 1 I've added a section on high tone in the muscles and joint contractures.  I spent most of the time talking about toe walking, which is the most common type.  I hope you find it useful!

If you have any topics that you'd like to learn more about, leave a comment.  I'd be happy to make a post for you.

Take care and happy fall!
Sarah

Absorbing calcium

Although the cause of hypercalcemia is a mystery 1in Williams syndrome, we do know a little about how the calcium is absorbed in the gut. Many people think that the stomach is the main area of digestion in your body. Although it does digest proteins, the majority of the food is broken down and absorbed by the small intestine. The lining inside of your small intestine is a network of finger-like bumps that are filled with blood vessels and covered by a very thin layer of skin that sits between the vessels and the food/enzyme mixture in your gut.




Most calcium in your small intestine is absorbed in the lower regions called the ileum and jejunum. These are the main portions of your intestine that absorb nutrients and minerals. Calcium here will move passively into the blood stream. This means that it can easily slip through little spaces in the skin layer (called the epithelium) and into the blood. If your diet provides your body with enough calcium, this is the main type of transport you'll use.




If calcium levels are low, your body has to work a little harder to get the amount it needs. This is where vitamin D comes in. Vitamin D operates channels that collect calcium in the upper third of the small intestine, called the duodenum. These channels are activated when vitamin D binds to proteins in the epithelium (skin) layer. These proteins work with active transport, where the body uses energy to pump the calcium into the blood stream, increasing its levels in the blood. This is why, if you increase the vitamin D in your diet, you end up increasing the calcium in your blood stream.




This vitamin D metabolism is one of three theories I could find that try to explain infantile hypercalcemia in WS. Researchers have found that when children with hypercalcemia are managing their calcium levels and only slightly rise the vitamin D in their diet, their calcium levels increase dramatically. They found that by only making small increases in vitamin D, children with WS absorb 2-3 times more calcium than what would be expected in a typical child.




Another factor that influences calcium absorption is the type of food you eat. If you are a milk drinker, you're going to have more passive calcium absorption- the easy kind in the lower intestine. Milk contains sugars called lactose and an enzyme called lactase both of which help the body collect the calcium and absorb it into the blood stream. Other foods also contain calcium, such as spinach. Foods that are high in fiber and contain calcium tend to be harder for your body to digest. The fiber, called oxalate, binds to the calcium and holds on to it as it passes through the gut. Therefore, if your primary calcium sources are in high fiber foods, you will essentially absorb less of them and excrete more due to the food's chemical nature.







Oxalate has other affects on your body, too. If the level of calcium is low, your body will start to absorb more oxalate instead of excreting it. Essentially, if you are in a pinch for calcium, you'll take what you can get even if it's in a form that you don't really prefer. The increase in oxalate signals the kidneys to work harder to get rid of it. Calcium oxalate then builds up in the kidneys and can cause stones, or nephrocalcinosis (see the growth and diet page on this blog). This is why some doctors will place a child with hypercalcemia on a low oxalate diet- to prevent the uptake of calcium and reduce dangers of developing kidney stones.



It's important to note that although many WS infants with hypercalcemia have higher than normal levels of vitamin D, there are exceptions to the rule. There is a significant population of individuals who have high levels of calcium and LOW levels of vitamin D. Since most foods contain both, this can create quite the dilemma to try and maintain proper levels of each. Stay tuned for future blog posts discussing this topic and other theories of why our little ones have hypercalcemia!

WS- a major player in what we "know" about vitamin D

Over the past couple of days I've had a couple of parents send me questions about calcium and vitamin D and how they affect WS. Those questions will be answered in future blog posts but until then, I found some interesting information about how WS has changed the way many researchers have viewed vitamin D. I've enjoyed getting questions from other parents because I've learned so much in the quest to answer them! Keep them coming :)



Although this is a science-based blog, here is your history lesson for the day:

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  In the 1960's it was thought that supravalvular aortic stenosis (the characteristic heart defect of WS) was caused by the mother ingesting too much vitamin D during pregnancy. At the time, researchers didn't know about Williams syndrome and its genetic component. A study performed in the late 1950's drew a connection between SVAS and hypercalcemia (or high calcium in the blood). WS is the only identified disorder that has unexplained hypercalcemia before the age of 1. So, the researchers put two and two together and concluded that high levels of vitamin D lead to heart defects and all the symptoms of what we today know as Williams syndrome- SVAS, low IQ, and hypercalcemia. The study started a Vitamin D scare that changed the Food and Nutrition Board recommended values for Vitamin D to lower levels in Britain and the US. Until the 1980's when genetics identified that SVAS is due to a genetic defect did the vitamin D theory change.

Recently, a new vitamin D theory has surfaced and again, it's basic idea is based on what else, Williams syndrome:

• A group of researchers began in 2007, studying a link between vitamin D deficiencies with the increase of autistic children. The researchers studying this connection are using Williams syndrome as the basis of their hypothesis. Their reasoning is that the highly sociable personalities of WS are opposite those of autistic children. They think that social behavior is directly related to vitamin D levels- WS, having high levels of calcium and vitamin D in the first year of life leads to high social nature versus autism that could potentially have low levels of vitamin D and exhibiting anti-social behaviors. Their hypothesis is that vitamin D levels in the body determine the social nature of each disorder.

They don't comment on the fact that some kids with WS are also autistic, making me skeptical, but still an interesting study! It just goes to show you, what you "know" today may not be considered right in the future. And that my friends, is what makes science so interesting to me. There is always more to learn.

updated eye section

A fellow WS mom pointed out that elastin may not cause the star burst pattern in the eye, so I dug a little deeper on the subject. Although I couldn't find information on genetically why our little ones have the star burst pattern in their eyes, I did find great information about how the iris is structured differently to cause the pattern... if you've already read the eyes section, check it out one more time.

I also fixed the links to blogs and websites on the right. It seems I had some broken links... enjoy!

Interpreting microarray results

So, if you are one of the chosen few to get a microarray genetics test to diagnose Williams syndrome, you will receive a result that will look something like this:

"A 1.55 Mb deletion was observed at 7q11.23 from linear location 72,337,897 - 73,837,643"

Size of the deletion

So what does this mean? Let's start with the 1.55 Mb. Mb stands for million basepairs. DNA is made up of a string of base pairs (adenine or A, thymine or T, guanine or G and cytosine or C). A stretch of base pairs or gene is basically the blueprint for one functional protein. So, if you get results that there is a 1.55 Mb deletion then your child is missing 1, 550,000 total base pairs from their DNA. The classic or average deletion in a person with WS is 1.5-1.8 Mb.

Chromosome maps

Chromosome labels give specific information about the location of the gene so that scientists can communicate information easily. The WS deletion is at 7q11.23. The first number on the location marker represents the chromosome the gene is found on. There are 23 total chromosomes in the human genome and Williams syndrome is a deletion on the 7th chromosome.

The next letter tells the scientists which half of the chromosome to find the gene. Chromosomes look like two threads tied together near the center by something called the centromere. Think of the centromere like a belt. The belt usually fits off-center so one side of the chromosome will have longer sections (called arms) than the opposite side of the centromere. This is where the q comes in. The q (short for queue) means that the deletion sits on the long arm of the chromosome. If the deletion was on the short arm it would say p (short for petite).

When scientists study a chromosome, they stain it and take a photograph called a karyotype. The stain will create a banding pattern on the chromosome. This band is how genes are grouped and labeled. The numbers at the end of the chromosome map indicate how far that band sits from the centromere. The 11 indicates that the WS region is the 11th band away from the centromere and sits at a sub-band 23.

So what genes are missing?

The final section of the microarray results will tell you what gene locations are missing. The base pairs are numbered throughout the chromosome. So, this hypothetical person is missing base pairs #72,337,897-73,837,643. At the end of this blog post, I've listed the genes in the WS region with their base pair ranges. You can see what region of the chromosome your child is missing and then look up the functions of the genes, some of which I've described on the genetics page of this blog. You'll find that there are some numbers missing from the list. These areas are considered "genetic junk" Most genes have long strands of base pairs that do not code for any useful protein and are largely ignored by the body.

Mitral valve prolapse

Valve prolapse is not as common among individuals with WS but it does occur in some. In the world of congenital heart defects (CHD) which are heart defects present at birth, it actually affects about 2-3% of the CHD population.

What is a valve?

In order to understand how prolapse occurs, you should first be familiar with the function and anatomy of a valve. Valves are used throughout the cardiovascular system to direct blood flow. They act like one-way doorways that swing open, allowing blood to move through, and close behind, preventing it from flowing backwards. This essentially seals off each chamber in the heart so that when the muscles squeeze and push blood into a vessel, blood isn't pushed backwards. This is important for many reasons. Without valves, blood pressure would be more difficult to achieve. You wouldn't have the pressure of the blood pushing on the vessels if it had another outlet to flow into. Second, if there were multiple outlets, some blood could get caught in limbo between the two chambers, just swishing back and forth and not really moving anywhere. This is dangerous because it could cause it to clot. Clots can lead to several issues including heart attack. So, you can see, valves are important structures to keep everything flowing properly.

Valves are structured much like a balloon or parachute, attached to cords called chordae tendonae and anchored to the muscle wall of the ventricle (lower heart chamber). The valve itself is made up of cusps or flaps that fit together tightly to create a seal. On the left side of the heart you find the mitral valve between the two chambers (left atrium and left ventricle). The mitral valve also has two other names- the bicuspid valve, because it has 2 cusps or flaps, and the left a-v valve, because it separates the left atrium (a) from the ventricle (v). There is an analogous valve on the right side of the heart called the tricuspid or right a-v valve that functions in the same way and can also undergo prolapse for all the same reasons.

What does it mean to have valve prolapse?

When a person is born with valve prolapse, the layers of tissue that form the flaps or cusps of the valve are thicker than normal. The valve cusps are made up of three layers of tissue. One of those layers is connective tissue. When prolapse is present, the connective tissue builds up into a thicker layer than normal. This causes the cusp to fit improperly with the others and makes a leaky seal.

Most people with mitral valve prolapse show no signs of heart distress. If the seal does not allow too much blood to flow backwards, the overall function of the heart is maintained. Doctors will hear a murmur or click when they listen to the person's heart. A murmur is a swishing sound created when the blood squeezes through that opening. The smaller the opening, the louder the murmur will actually be.

Some people have a larger opening in the valve or it can progressively become worse over time. If the opening becomes large and a significant amount of blood flows backwards you can have issues with clotting and blood pressure. When blood flows backwards into the atrium it is called mitral regurgitation. If this occurs, a cardiologist will most likely prescribe medication called beta blockers or blood thinners to prevent clotting.

As the opening becomes larger, a lot of pulling can take place on the cords that anchor the valve. They can become stretched out, causing the opening to become larger still and eventually can rupture or break. You can imagine what would happen to a parachute if you cut one of the cords that attaches it. The parachute would become loose and wouldn't catch the air properly. The same thing can happen to the valve. If this happens, the heart simply wouldn't function properly and a valve repair or replacement surgery may be necessary.

If my child has valve prolapse, what can I do to prevent this from progressing?

Although the progressive nature of this condition can be scary, most people go their entire life without any issues. Whenever a child has a CHD, it's important to maintain optimal cardiovascular health by monitoring their diet, getting proper cardiovascular exercise and seeing a cardiologist regularly to monitor the defect. Diet, especially watching sodium intake and avoiding caffeine and energy drinks, will keep their heart functioning properly.

Sources:
Mitral valve diseases in Williams syndrome by Collins

Mitral valve prolapse by Medline

New genetics page

Check out the genetics page, which is now complete!

Welcome!

Welcome to my new blog! I'm only beginning to set up all the pages, so I'll update this as I go and let you know when each section is ready. The conditions that I'm including on each page are considered likely issues in WS according to guidelines given to pediatricians and family practitioners. I'm willing to add others, by request, so if you wonder about a condition or how something works, just let me know and I'll try to include it.

For now, the cardiovascular page is finished. I hope you find it useful!