What are the types of bone problems?

Over half of the children over 5 years of age will develop a number of orthopaedic problems including scoliosis, kyphosis, tight heel-cords and tight hips.
Physical therapy is important initially to strengthen weak muscles but as tone increases with age and muscles strengthen, physical therapy can help to maintain range of motion in hips and knees. Fewer than about 10% of children will require surgery for the scoliosis but it is important to realise that the progression can be extremely rapid from a slight curvature to severe scoliosis in just one year, so it should be followed closely.

All orthopaedic problems will need lifetime monitoring as we have seen the evolution of loss of physical abilities even into young adulthood.

What are the common neurological problems?

The most common neurological issue in Costello syndrome is hypotonia, or low muscle tone.This means that the person with CS shows little resistance when the limbs are moved. Tone is different from strength, and CS children do not have necessarily have reduced muscle strength. Hypotonia can be noted on a physical exam, for example by a paediatrician, geneticist or neurologist.It does not require treatment, but sometimes hypotonia contributes to developmental delay.
Other neurological issues are related to the brain structure itself.Hydrocephalus (too much fluid within the brain) is slightly more common in individuals with CS.In very young infants this can be checked by doing a brain ultrasound. In older children, either a CT or an MRI study is needed.If an individual has hydrocephalus, surgery may be needed, which usually requires placement of a ?shunt? to drain the extra fluid.

In individuals with CS, the brain grows very fast in early infancy, and it may become too large for the space of the skull.That leads to the lowest part of the brain being squeezed into the upper spinal canal. If this problem is mild, it is called ?cerebellar tonsillar herniation?. If it is more severe, it is called a Chiari 1 abnormality.

One consequence of a Chiari 1 abnormality can be the accumulation of fluid in the spinal cord canal called “syrinx” (or syringomyelia). This can in turn cause other neurological problems, such as loss of strength in the limbs and a curve in the back (scoliosis).

All these abnormalities are best seen on MRI studies.They usually require an evaluation by either a neurologist and/or neurosurgeon, often followed by surgery.

Some individuals with CS have an abnormal lower end of the spinal cord which is attached to the spinal column. This is called a tethered cord. This is best seen on an MRI (best if it?s a video MRI, or ?cine MRI?) and is usually treated surgically.

Lastly, a few CS individuals have seizures. If suspected, a neurologist will order an EEG (a brain wave study) to further evaluate this. An individual with a seizure disorder may need medication for this problem.

If a child with CS is not suspected of having seizures, an EEG is not needed as a screening test.

Should a CS person automatically get an imaging test of the brain?

Because there can be number of different brain issues, and it is helpful to compare early imaging studies to later studies, it may be a good idea to have a brain and upper spinal cord MRI done, especially in a young child whose brain is still growing. Any new neurological problems may also be evaluated with a brain MRI, which can then be compared with the first examination.

Should there be a baseline test?

If an EEG was done, sometimes a second study several months or years after the first study is needed.

We are still learning about Costello syndrome, and about how it affects the brain and spinal cord structure. The recommendations could change if we learn more. For this reason it is very important that the physician who takes care of an individual reviews the current medical literature on CS, and share any unusual findings with doctors who know about Costello syndrome, such as the members of the Costello Syndrome Professional Advisory Board.

Is it true that young children with CS can get cancer?

Although we do not know exactly why children and young people with CS have a increased risk of cancer, we do know that the HRAS gene is important in cancers in everybody.

How common is it?

The risk of cancer in CS seems to be around 15% or 1 chance in 7 children with CS. Most of that risk is up until age 6.

What are the types of Cancer?

Most of that risk is up until age 6, for a muscle cancer called rhabdomyosarcoma. This often occurs inside the abdomen (or tummy), but it can be on the face or arms or legs. Rarer tumours are neuroblastoma in infancy and early childhood as well, and bladder cancer in young adults.

How do doctors treat the cancers which occur in Costello syndrome?

The treatment for cancers in CS is the same as for the same type of cancer in other children.

Is the treatment different in CS then for the non CS population?

No, the treatment is exactly the same in both populations of children.

Do doctors monitor for cancers?

Some doctors think an ultrasound of the tummy (abdomen) should be done every 3 to 6 month until at least age 6. There is no evidence at present that this is effective. In teenage years, a check of the urine once a year seems sensible. The main thing, however, is to report to your child?s doctor any unusual symptoms that don?t go away after a week or so.

What is the lifespan of a person with CS?

Two factors make this difficult to answer:

first, CS was first described in the 1970s, so there is very little information available on older individuals.

Secondly, CS is so rare that it?s difficult to get good data on lifespan.

What we do know is that there are a number of individuals with CS in their twenties and thirties. The oldest person we are aware of is a man who was born in 1960. In general, the life-threatening complications of CS are cancer and severe heart issues.

What kind of medical issues might we prepare ourselves for as our children move into adulthood?

Generally speaking, the health issues in adults with CS are similar to those in childhood. Adults with CS often need multiple sub-specialists to deal with their medical issues.

There is a long list of problems that may occur, but remember that each person with CS is unique.

Short stature and learning disabilities are ongoing, but individuals with CS continue to learn new skills and there is no evidence of losing skills.

Heart problems may continue from childhood. The adult with CS should continue to be monitored for heart muscle problems.

High blood pressure may develop.

Some individuals experience gastro-esophageal reflux in adult life.

It appears that adults with CS are prone to low bone density and osteoporosis. They should be assessed, and may need treatment for this. Other skeletal issues such as worsening of scoliosis can occur in adult life.

The main tumor risk in adults is bladder carcinoma. This can develop as early as the 20?s, though the youngest person with CS reported to have developed it was aged 12. The outcome for those who develop this type of cancer is good ? we know of no person with CS who has died from this type of cancer.

Benign breast disease such as breast papilloma have also occurred in women with CS. Most individuals will have some skin papilloma, which recur through adulthood.

Chiari malformation of the brain may rarely become a problem in adult life, causing difficulty with walking, feeding and other symptoms.

Some adults with CS have managed to live alone with some assistance, while others have required more supervision.

Can you tell me something about puberty and Costello syndrome?

Around half of individuals with CS have had delayed or ?late onset? puberty (puberty starts late).

Some women don?t have periods at all, or it starts and then stops. Adolescents with CS who are late entering puberty should seek an assessment with an endocrinologist, as they may require hormone treatment to get puberty started. The hormones associated with pubertal development are important not just for puberty, they are important for bone density and cardiovascular health.

A small number of children developed precocious puberty (puberty starts early). Precocious puberty may be treated with medication, to slow down the development of puberty.

Can you tell me about hearing loss in general?

Hearing loss can be divided into conductive deafness (a problem of the external or middle ear, for example related to fluid) and sensorineural deafness (problem of the inner ear).

In the general population hearing loss is the most common birth defect. One of every 500 newborns has bilateral (both ears) permanent sensorineural hearing loss.

Hearing loss can affect language development.

Does it occur in Costello syndrome?

Significant hearing loss is uncommon in Costello syndrome, although there are some children who have either conductive or sensorineural hearing loss.

Should parents check for it?

It is possible that your child has already had his or her hearing tested, either as part of a newborn screening program (in some areas) or as part of their ongoing medical workup.

If a parent is concerned about their child’s hearing, an evaluation is reasonable.

Your doctor may also arrange ongoing hearing assessments if there are additional risk factors for hearing loss, or a history of fluid in the ears, just to be certain that unsuspected hearing loss isn’t worsening the delayed speech that is part of CS.

My child was thought to have a storage disease before they diagnosed CS. I never understood what that meant. I mean, why should one syndrome look like another. Aren’t they different?

The word, ‘syndrome’ refers to a collection of medical findings. At any one time, especially when children are young, they may not yet have developed all the clues that point toward a particular syndrome. For example, a child with Costello syndrome may first develop certain facial features that overlap with the facial features of a child with a “storage disorder “. Children with a storage disorder are unable to break down certain types of large molecules in the body and/or brain, depending which storage disorder it is. Children with Costello syndrome look like they might have a storage disorder, but their test results for the known storage disorders are negative.

Other children with Costello syndrome may first develop a cardiac problem and be diagnosed with a different condition because of it. Usually, as children become older and develop more of the typical Costello facial features or short stature, it becomes easier for geneticists to think of the diagnosis. This situation is quite common for many different syndromes, especially if they’re rare.

What other syndromes can CS resemble? Can you list some?

Other syndromes that may be considered in children before a correct diagnosis of Costello syndrome include:

Mucopolysaccharidosis (storage disorders)
Beckwith-Wiedemann syndrome (large at birth and a high risk of developing tumors)
Simpson-Golabi-Behmel syndrome (large at birth, cardiac defects, a high risk of developing tumors)
CFC syndrome
Noonan syndrome

Can you tell me more about the syndromes that CS resembles most – Noonan and CFC syndromes?

Noonan syndrome (NS) and CFC syndrome have a number of similarities with CS. As children grow older and when they’re adults, it’s usually easier to tell them apart. Because the genes causing these syndromes belong to the same biochemical pathway, the ‘gene products’ cause similar body changes.

Facial features in people with NS and CFC can show some similarities to those of people with CS, but they are usually less coarse. The lips may not be so thick, or the mouth not as large.

Structural heart problems that individuals with NS and CFC have are similar to those seen in individuals with CS, but arrhythmias are less common in those with CFC than in CS.

Significant feeding problems are common in infancy in children with all three conditions, though they are usually less severe in NS than in CS and CFC. Tube feeding by way of nasogastric (ng-) or gastrostomy (g-) tube may be needed in CFC and NS, like in CS.

Learning problems are present in nearly all people with CFC, and may be severe (often more severe than those in people with CS). People with NS can have some learning problems, but they’re usually mild, if they are present at all.

Epilepsy (seizures with unknown causes) is more common in people with CFC syndrome.

Skin problems occur in people with CFC syndrome, including very dry skin (which they share in common with people with Costello syndrome) and sparse eyebrows (something people with Costello syndrome do not develop). Hair texture is often similar between individuals with CFC and CS, and eczema may develop on a person with either condition. People with NS are less likely to have problems with their skin and hair, though these may occur.

For all three syndromes, low muscle tone may occur, as well as skeletal differences such as short stature, scoliosis (curvature of the spine) and joint contractures (limitations of joint movement).

The risk of developing cancer in CFC and NS is not as great as in CS appears to be very low. CS has a 15% risk of malignant tumour development.

How do doctors tell the difference between CS and CFC and NS? Do they just look at the patients, or do blood tests?

Although physical features can suggest the diagnosis of Costello syndrome, CFC or Noonan syndrome, the clinical diagnosis requires molecular confirmation. Costello syndrome is defined by HRAS mutations, and HRAS mutations are associated only with Costello syndrome. In contrast, several gene mutations cause CFC syndrome, and the same is true with Noonan syndrome.

We suggest that readers visit Genetests.org for detailed summaries of all of these syndromes. Click on the GeneReviews button on the top row and type in the syndrome name. Once you arrive at the next page, select Reviews for a description of how to manage the syndrome, and Tests to find clinical labs to test for the syndrome.

Who authored the FAQ?

The Medical information was authored by:
International Costello Syndrome Professional Advisory Committee

It was reviewed by
Dr. Angela Lin, Dr. Bronwyn Kerr and Lisa Schoyer,

Last review date March 2010.

Can my child go to school?

Yes, your child can and should attend school. By law schools in the US must address the educational needs of children with disabilities from birth (usually through early intervention programs) to age 21 (some states go beyond age 21). The Individuals with Disabilities Education Act (IDEA) is a US federal law.

One of the parts to this law gives students the right to a Free, Appropriate Public Education (FAPE) that prepares them for further education, employment and independent living.

What is therapy?

Therapy usually refers to specific interventions for the particular delay being treated by a professional trained to address the specific delay.

Therapists will work with your child to build on what your child can already can do and challenge your child by helping to meet milestones with assistance.Therapies also involve parents practising with their child at home. Some of these therapies will be done within the school setting.They can be included in the child’s IEP (Individual Education Plan).

What are the developmental disabilities in Costello syndrome?

Developmental disability usually refers to difficulty with age appropriate activities of daily living.In children, these are often called delays rather than disabilities.
In infants, developmental delay/disability usually means not meeting developmental milestones at age appropriate times, and/or difficulties with feeding and/or motor development.As children grow older, developmental disability includes intellectual disability.

What does it mean when I hear that Costello syndrome children have developmental delay?

In the US school setting, intellectual disabilities are still referred to as mental retardation, though the federal government is working to change that with a law. It is one of 13 categories of disability under which children may be identified for special education services under IDEA (Individuals with Disabilities Education Act).

In the UK, the NHS designation is learning disability, which means something quite different in the US., or special educational needs.

How common is it?

All children with Costello syndrome have at least some type of delay.

How do you test for this?

When a child does not meet a developmental milestone within age expectations, the appropriate medical specialist can assess whether a delay or disability exists. ?Tests? usually involved standardised assessments of milestones.

For early motor milestones, this assessment could be done by a Physical or Occupational Therapist.

Feeding delays are usually assessed by both Physical or Occupational Therapists and Speech Pathologists.

Cognitive/intellectual/social/learning delays are assessed by a Psychologist.

Can you tell me about hearing loss in general?

Hearing loss can be divided into conductive deafness (a problem of the external or middle ear, for example related to fluid) and sensorineural deafness (problem of the inner ear).

In the general population hearing loss is the most common birth defect. One of every 500 newborns has bilateral (both ears) permanent sensorineural hearing loss.

Hearing loss can affect language development.

Does it occur in Costello syndrome?

Significant hearing loss is uncommon in Costello syndrome, although there are some children who have either conductive or sensorineural hearing loss.

Should parents check for it?

It is possible that your child has already had his or her hearing tested, either as part of a newborn screening program (in some areas) or as part of their ongoing medical workup.

If a parent is concerned about their child’s hearing, an evaluation is reasonable.

Your doctor may also arrange ongoing hearing assessments if there are additional risk factors for hearing loss, or a history of fluid in the ears, just to be certain that unsuspected hearing loss isn’t worsening the delayed speech that is part of CS.

Will my child become deaf?

It would be unusual for a child -or adult- with Costello syndrome to become deaf. Your child?s doctor should consider other genetic or environmental causes of deafness.

Can you tell me about the eye problems in Costello syndrome?

Almost all children with Costello syndrome have eye issues. They include common problems such as refractive errors, strabismus, amblyopia, and rarer disorders such as nystagmus and optic nerve anomalies. An abnormal head posture may be because of an underlying eye problem and should be checked with an eye exam. The head tilt may be making up for when the eyes are not looking directly at the target of interest. The chin might be held up or down, the head might tilt to the right or left, and face might turn to the right or left, depending on what it is the child needs to do, to the see the object best.

What kind of eye problems have been seen in Costello Syndrome?

Refractive errors happen if light rays are not focused on the retina (light sensitive tissue at the back of the eye) that converts light to nerve impulses enabling our brains to see clearly.

The types of refractive errors are myopia (nearsightedness), hyperopia (farsightedness) and astigmatism (blurred vision from an irregular curvature of the cornea). Myopia is the most common refractive error in Costello syndrome, where objects in the distance appear blurry but can be seen more clearly close up. Hyperopia causes near and distant objects to appear blurry – although if mild, objects in the distance can be clear. Astigmatism causes blurring of both near and distant vision. Refractive errors are easily correctable by glasses.

Strabismus (crossed eyes, wandering eyes) is a condition when there is misalignment of one or both eyes – the eyes are not straight when looking at an object. One or both eyes may turn in, out, up or down. “Constant strabismus” is when the eye turn occurs all of the time and “intermittent strabismus” is when the eye turn occurs only some of the time. If the eyes turn inward it is called esotropia and if they turn outward it is called exotropia. Depending on the type of strabismus, correction can be done with glasses or surgery or both.

Amblyopia (lazy eye) is a decrease in the child?s vision that can happen when one or both eyes send a blurry image to the brain, which could be from an uncorrected refractive error or strabismus, for example. The brain “turns off” the eye with the blurry image, causing amblyopia. If untreated, amblyopia can cause permanent decrease in vision. Treatment is involves correcting the underlying cause, and by patching or drops.

Nystagmus describes an involuntary shaking, ?to and fro? movement of the eyes. It can be idiopathic (cause unknown) or an underlying disorder of the eye such as optic nerve hypoplasia.

The optic nerve functions like a cable, transmitting visual signals from the eye to the brain. Optic nerve hypoplasia (ONH) is a condition in which the optic nerve is underdeveloped (described as small, grey or anomalous). ONH can vary from mild to severe and may affect one or both eyes. Vision impairment varies from mild to severe. It is usually stable and non-progressive, vision does not deteriorate with time. In some instances of delayed visual maturation (the processing of the images in the brain develops later than usually expected), vision improves with time.

Optic nerve swelling or optic atrophy (degeneration) can sometimes develop as a complication of central nervous system problems such as hydrocephalus (also called ?water on the brain?) if left untreated. An MRI is recommended if any optic nerve problem is seen.

Will my child need glasses?

Your child may need glasses if there is a refractive error or for correction of strabismus.

Will my child be blind?

Blindness is very rare in Costello syndrome. Very severe optic nerve hypoplasia can end up with very poor vision, but it?s rare.

When should I take my child for an eye exam?

Paediatricians should assess children for eye problems in regularly scheduled health exams, starting in the newborn period. The first eye exam with a paediatric ophthalmologist is recommended between 3 to 6 months years old or earlier, if any abnormalities are seen. If there are no abnormalities seen at that time, an eye exam should be done yearly.

How common are feeding problems in Costello syndrome?

From birth, children with CS have feeding difficulties, including a severe aversion to taking solids or fluids orally, and reflux (vomiting after feeding). Some babies require tube or gastronomy feeding (where food is placed in the baby’s stomach so they do not have to swallow it).

Feeding difficulties are considered the most common and challenging clinical problem in Costello children. The feeding situation might be very stressful and exhausting for the whole family, which already has to deal with the situation of having a child with a genetic syndrome, and additionally has feelings of stress and guilt regarding the baby?s nutrition.

When do they appear, do they change over time?

This begins with milk, breast or bottle, and also with solid food. Most children have a gastronomy for feeding. Over time, the feeding difficulty does improve, starting at about 3-5 years old. Thereafter, many children with CS seem to have the desire to eat, but have persistent problems with texture and thickness.

Tell me about treatment – medical and devices

Most children have a gastronomy for feeding, however most children outgrow the need for the gastronomy tube, but a few continue, because their caloric need is greater than their ability to take in food by mouth.

Can you give me tips about specific foods?

Many families on the Costellokids listserv have reported that their child loves to eat tomato paste, or slightly spicy foods. Dipping fingers into salad dressing is a common favourite too. Other foods they enjoy are instant mashed potatoes, but made with cream or full fat milk instead of water. Parents looking for cooking tips will find them on the list serve from helpful parents.

One family’s experience: “I would make pasta dishes, blend them with a little extra sauce, then freeze them to send to school for lunch. Usually, spaghetti, fettuccine, lasagne, and ravioli. My son likes Italian things. Also, anything you can puree with extra gravy. Gravy adds good calorie content. We also found a chocolate shake can really increase the calories. Gerber has a line of toddler foods you might try if you don?t want to have to cook separate meals from the family.?

What is Costello syndrome?

Costello syndrome is a genetic disorder that affects many parts of the body. It includes developmental (neurocognitive) delays and impaired learning, unique facial features that make people with the condition look like they’re related to each other, loose folds of extra skin (especially on the hands and feet), and unusually flexible joints. Problems with the heart are common. Although infants with Costello syndrome may be large at birth, they have difficulty feeding and grow more slowly than other infants. Their final height will be shorter than average.

Beginning in early childhood, people with Costello syndrome are at an increased risk of developing certain tumors. These include noncancerous papillomas (small growths that usually develop around the nose and mouth or near the anus), as well as malignant tumors.

How common is Costello syndrome?

This condition is very rare. Based on the numbers in the UK, the risk of having a child with Costello syndrome is 1:500,000.

When was Costello syndrome first described?

First description: In 1975 and 1977, Dr. Jack Costello, a New Zealand pediatrician, published the descriptionof two children with similar physical characteristics and mild intellectual handicap.

First molecular gene finding: in 2005, Aoki et al in Japan.

What is the history of its description over the years?

First description: In 1975 and1977, Dr. Jack Costello, a New Zealand pediatrician, published the descriptionof two children with similar physical characteristics and mild intellectualhandicap.

Early Reports: In 1991, Dr. Vazken Der Kaloustian from Montreal reported a similar child and suggested that this particular pattern of physical and developmental characteristics be called Costello syndrome. Additional articles followed, and by 1996, when Dr. Costello published an update on his original cases, he included a review of 16 literature cases

Geneticists and other clinicians around the world continued to describe Costello syndrome in single patient reports, case series, and a few large reviews. In addition to general descriptions, specialists focused on specific organs or issues. A search of the genetic cause was always at the top of the research list of priorities. Also important was establishing diagnostic criteria (how to identify a child with the syndrome), because, as the cause was unknown, the diagnosis was based on presence or absence of certain clinical features.

The large number of publications over the last decade demonstrates the power of combined family and professional networking. These publications increased knowledge of the impact of Costello syndrome on the health and lives of children, adults, and their families.

Clinical genetic research: Until 2005, the cause of Costello syndrome remained unknown. Family studies had demonstrated that a new genetic change in the affected person was the likely cause (a ?spontaneous? or ?de novo? mutation). Since the cause was unknown, the diagnosis was based on the presence or absence of clinical features linked to Costello syndrome.

Molecular genetic research: In 2005, a group of Japanese researchers led by Drs. Aoki and Matsubara discovered that mutations (a gene change affecting a gene’s function) in a gene called HRAS causes Costello syndrome. It had been known for many years that Costello syndrome was similar to two other conditions, Noonan syndrome (NS) and Cardio-facio-cutaneous syndrome (CFC). All three syndromes are now known to be part of the Ras/MAPK pathway.

Since that first publication, other genes in the pathway have been found to be important causes of both Noonan syndrome (NS) and Cardio=facio-cutaneous syndrome (CFC), two disorders that may resemble CS. Many researchers have now molecularly tested groups of patients with a possible clinical diagnosis of CS, NS, or CFC.

HRAS is a gene that had been known about for a long time, because mutations in it are common in cancers seen in the general population. These mutations are said to arise somatically, this means they arose in a tissue in a person, ( eg bowel or lung) as an error in normal cell division. This is different to a gene mistake being present in an egg or sperm, and therefore in all cells in the body. These types of mistakes, in egg or sperm, are called germ-line, and this is the type of HRAS mutation seen in CS. It was a surprise that a cancer associated gene like HRAS could cause a developmental syndrome.

How does CS affect the skin?

Costello syndrome has many features that involve the skin. Some of the most notable are thickening of the palms of thehands and bottoms of the feet and areas of pressure. Another skin issue that can develop are small wart-like growths called “papillomas” around the nose and other areas close to a body opening (mouth, ears, anus). Other common skin issues in Costello syndrome are dry itchy skin, increased body odor in early childhood and slow growing, thin scalp hair.

Can the skin problems be treated?

The treatment depends on each skin condition and should be designed by your child’s general physician or dermatologist. In some cases, simple skin care strategies can work. In other cases a topical or oral medication may be needed.

What is a gene?

In almost every cell in the body, each of us has 23 pairs of chromosomes (46 chromosomes total). The first 22 pairs are the ordinary chromosomes, numbered from 1-22 by convention. The 23rd pair is made-up of the sex chromosomes: either XX and in a woman or XY in a man. Female chromosomes are described as “46, XX” and male chromosomes are described as “46, XY”.

It’s important to understand that you have two copies of each chromosome, except for X and Y chromosomes in a man. One set of 23 chromosomes is inherited from the mother in the egg, and the other set of 23 chromosomes is inherited from the father in the sperm.

Chromosomes are made up of DNA. DNA is like a necklace of different letters strung together to spell different words and make different sentences that act as instructions. These are the body’s cell’s instructions to build proteins that will help the body develop and function. A gene is a particular section of DNA that gives a specific instruction to make a protein.

Where did the Costello syndrome gene come from?

Sometimes genes can acquire a change in one of the letters that makes up a word in that part of that particular gene’s instruction. Sometimes the change is inherited from a parent. Sometimes the change happens new in the sperm or the egg before that baby is formed. Research has shown that in CS, the change usually happens in sperm. There are some genetic conditions that only occur if both copies of the gene have a spelling mistake (“autosomal recessive”). There are some genetic conditions that occur even if only one copy of the gene is not working properly (“autosomal dominant”).

In genetics, the word “dominant” generally refers to a type of inheritance in which an affected person has a 50% chance of passing on the condition that they have to each of their children. There are two causes of dominant genetic conditions:

Haplo-insufficiency: “half is not enough” – the cell needs the amount of protein that would be made by both copies of the gene, and only having one functional copy is not enough to meet the cell’s needs.

Negative interference: the abnormal protein (made from the copy of the gene with the mutation) interferes with the function of the normal protein (made from the normal copy of the gene) and prevents it from effectively doing its job.

Costello syndrome is an autosomal dominant (AD) genetic condition, where mutations in the HRAS gene lead to a dominant negative effector interference, because the abnormal protein stays active all the time, rather than turning off when it should.

Most of the Costello syndrome mutations are errors that happen during sperm formation in the parent. We know of two children who inherited the syndrome from a parent who has mosaic Costello syndrome (only some of the cells have the mutation). In these cases, the mutation probably occurred in one of the child’s grandparents.

What is the Costello syndrome gene?

Costello syndrome is an autosomal dominant (AD) genetic condition, where mutations in the HRAS gene lead to a dominant negative effect or interference, because the abnormal protein stays active all the time, rather than turning off when it should.

Will my next child also have it?

In families who have one child with CS, the best advice is to let both your Geneticist and your Ob-Gyn doctors know if you are thinking about getting pregnant so that they can talk to you about the chance of having another child with CS, and the specific tests that they would recommend during your pregnancy.

If you did not have this discussion with your doctor and just found out that you are pregnant, it’s important to let your Geneticist and Ob-Gyn doctors know as soon as you have a positive pregnancy test so they can talk with you about the chance of having another baby with Costello syndrome (very low*), and the specific monitoring that they would recommend that you have during the pregnancy.

The most common test that your doctors may recommend is an ultrasound test, which uses sound waves to create a picture of your uterus, the amniotic fluid, and your developing fetus. Ultrasound is very frequently used by Ob-Gyn doctors to evaluate the growth of a fetus, the amount of amniotic fluid surrounding the fetus, and to closely look at certain structures of your growing fetus such as their head, heart, arms, legs, hands, stomach, and intestines.

A typical amniocentesis test is not able to identify Costello syndrome, but DNA from the amniocentesis can be tested for an HRAS mutation.
* There are very few reports from families that have more than one child with Costello syndrome. Of those who have, none have had confirming molecular HRAS testing.

Can Costello syndrome be diagnosed by physical examination alone?

A clinical diagnosis of Costello syndrome is based on a thorough evaluation of the past medical history, current health, and examination by a geneticist and other medical specialists. Sometimes the clinical diagnosis is clear, while other times it can be difficult to tell Costello syndrome from some of the closely related Ras/MAPK pathway syndromes,especially CFC syndrome, and, less often, Noonan syndrome.

A molecular diagnosis of Costello syndrome is made when a disease-causing mutation in the HRAS gene is identified. HRASis the only gene associated with Costello syndrome. A molecular diagnosis confirms a clinical suspicion of Costello syndrome. In other words, if an individual is thought to have a clinical diagnosis of Costello syndrome,molecular (genetic) testing is important because it helps either confirm that Costello is the correct diagnosis, or tells the doctors that they should consider the possibility of another closely related disorder that shares Costello syndrome’s features.

Genetic testing is an important part of a complete evaluation. Here?s an example: A person with a broken leg has tenderness,swelling, and inability to bear weight, but the x-ray confirms the break.

Every individual with Costello syndrome has a mutation in HRAS. If a person with a clinical diagnosis of “Costello syndrome” has a normal HRAS genetic test, their doctor should consider other closely related syndromes. Because of the striking similarities in physical appearance and types of medical problems to CFC and NS, a number of individuals with a clinical diagnosis of CS have later had their diagnosis changed based on the result of their molecular genetic test results.

The genetic test for Costello syndrome looks at the entire length of DNA within the HRAS gene to try to identify a change (“mutation”). This is like trying to find a spelling error of a word on the page of a book.

In Costello syndrome, most of the mutations so far have been found in one area within the HRAS gene called codon12. The most common mutation is called G12S. “G” is the code for an amino acid called glycine, and “S” is the code for the amino acid serine. The “12” refers to the location of the mutation (codon 12). So, at codon 12, there is a “spelling error” change from glycine to serine. This change causes the formation of an abnormal HRAS protein.

Is a blood test necessary for the gene test?

Not absolutely. Some labs can do the test with a DNA sample from a cheek swab, others will prefer blood.

What is growth hormone?

Growth hormone (GH) is a hormone that increases final height by lengthening the shaft of the bones. It has been used for many years in children with GH deficiency and is safe with respect to side effects.For children with GH deficiency, it also helps to maintain normal blood sugar and muscle mass.

Who needs growth hormone, even if you don’t have Costello syndrome?

GH is currently recommended when a GH stimulation test has been done and shows a deficiency. The definition of deficiency varies from country to country, and even from region to region within a country (e.g. the United States). Some genetic syndromes where use is approved, in the US and UK, include Turner and Noonan syndrome. In the US, recently, there has also been approval for use for idiopathic short stature (ISS) (short stature of unknown cause).

Is testing required?

The standard test used by most paediatric endocrinologists to determine if someone is GH-deficient is a GH stimulation test with 2 agents, usually given by injection. After the injection, blood is drawn several times over a period of time to see the effect of the two agents.

Many people with Costello syndrome have undergone testing and have proven to have GH deficiency. Several have been treated and continue to be treated without complications, which can be directly attributed to their GH treatment. Some doctors are concerned that children with Costello syndrome may have had problems due to Costello syndrome which could worsen while on GH, such as an increase in scoliosis, cardiomyopathy and tumours. Additional research is needed to determine if GH itself causes change in problems like these.

What about growth hormone for children with Costello syndrome?

Short stature is one of the features of Costello Syndrome. Most children will be seen by a paediatric growth specialist (endocrinologist) because of this. Growth hormone testing and treatment will then be discussed with your child’s endocrinologist.

How common are heart problems?

Heart problems occur in most (three-fourths) people with Costello syndrome.

What type of problems are they?

There are 3 main types:

A congenital heart ?defect? (CHD) which involves the heart valves or septum (wall between left and right sides of the heart);

Hypertrophic cardiomyopathy (HCM) in which the heart muscle is thick;

Arrhythmia in which the heart rhythm is abnormal, usually a fast heart beat (tachycardia).

How do you test for them?

Every person with Costello syndrome needs a full evaluation by a paediatric cardiologist. This should include an echocardiogram and ECG (electrocardiogram).In children who are experiencing tachycardia or other arrhythmia, the cardiologist will probably order a 24 hour Holter monitor too. The Holter monitor involves connecting ECG wires from the body to a small transistor radio-sized box to track the child?s heart activity for a full day.

I have so many questions about the heart. I don’t know where to begin?

It helps to learn about the structure of the heart. Here is a link to the educational website of the Children?s Hospital of Boston :

http://www.childrenshospital.org/az/Site480/mainpageS480P0.html

And oneto the Royal Children?s Hospital in Melbourne:

http://www.childrenshospital.org/az/Site480/mainpageS480P0.html

You can also click the link below which is from the 2007 Costello syndrome Family Network Meeting and listen to the talk given by Dr. Angela Lin. She is one of the three Co-Directors of the Professional Advisory Board. Dr. Lin discusses all of this information in detail.

The heart and Costello syndrome

Can you tell me something about puberty and Costello syndrome?

Around half of individuals with CS have had delayed or ?late onset? puberty (puberty starts late).

Some women don?t have periods at all, or it starts and then stops. Adolescents with CS who are late entering puberty should seek an assessment with an endocrinologist, as they may require hormone treatment to get puberty started. The hormones associated with pubertal development are important not just for puberty, they are important for bone density and cardiovascular health.

A small number of children developed precocious puberty (puberty starts early). Precocious puberty may be treated with medication, to slow down the development of puberty.

Can you give me some resources for myself, family and friends?

You have found an excellent first resource here at the Costello syndrome website. As you navigate through the site you will find links to an information booklet for parents, a discussion forum, photographs, conference information and much more.

Once you have become familiar with the “core” information in these FAQs, you may want to consider attending the Costello syndrome conferences which have been hosted in different cities in North America every 2 years since 1999. The 2007 (Portland, Oregon) and 2009 (Berkeley, California) conferences have been expanded to include a research symposium, allowing families not only the opportunity to interact with one another but to meet physicians and researchers interested in Costello syndrome, and learn about the progress made in this field.

A medical geneticist or a genetic counsellor in your area can be an excellent resource. If you have not met with one lately, you may benefit from setting up an appointment, which can include an assessment of your child or family member, and an update on new information about Costello syndrome. Your geneticist can also serve as a helpful resource person if your family member with Costello syndrome is in the transition from care in a paediatric/Children’s hospital to the ‘adult world’.

How about additional reading material for my doctors?

Costello syndrome is rare, and our understanding of this condition has increased dramatically over the last few years. So there might not be much information on Costello syndrome in many standard paediatric textbooks.

Even in Clinical Genetics textbooks the information may be brief, or not fully updated.Instead, your physician may find the internet to be a more helpful up-to-date resource on Costello syndrome. One such site with detailed, updated information on medical and genetic aspects of Costello syndrome is the entry in GeneTests.org, run by the University of Washington and funded by the NIH:

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=costello

The entry on Costello syndrome has been authored by Dr. Karen Gripp and Dr. Angela Lin.

A resource textbook your physician may find helpful is the textbook, Management of Genetic Syndromes published by Wiley (edited by Dr. S. Cassidy and Dr. J. Allanson), currently in its 2nd edition with a 3rd edition available in 2010.

This text provides system-by-system detailed information of the management and screening recommendations for important genetic syndromes, including Costello syndrome. Finally, your child’s doctors should also be encouraged to get updates from the genetics clinic in your area. It is likely that doctors there will have access to information on the current best practice clinical care and research having to do with Costello syndrome.

Does the Costello syndrome website have a library of web links and articles?

For family members, we provide:

Hot links to additional websites.

PDFs of selected medical articles, usually from the American Journal of Medical Genetics, with approval from the Editor-in-Chief, Dr. John Carey, member of the Professional Advisory Board. Access to these documents are password protected.

The documents are stored in our forum http://forum.costellokids.com which is only available to members of the support group, and is not indexed or otherwise publicly available.

How does CS affect the skin?

Costello syndrome has many features that involve the skin. Some of the most notable are thickening of the palms of the hands and bottoms of the feet in areas of pressure, and small wart-like growths called papillomas around the nose and other areas close to a body opening (mouth, ears, anus). Other common skin issues in Costello syndrome are dry itchy skin, increased body odour in early childhood and slow growing, thin scalp hair.

Can these be treated?

The treatment depends on each skin condition and should be designed by your child?s general physician or dermatologist. In some cases, simple skin care strategies can work.In other cases a topical or oral medication may be needed.

Will they get worse?

The skin problems usually begin to appear in later childhood and can get worse through adolescence and early adulthood.

What is the role of support groups to help Costello syndrome families?

Starting with the Costello Syndrome website http://costellokids.com and the International Costello Syndrome Support Group (ICSSG) in the mid- 1990s, a network of families and professionals has developed into a dynamic partnership.
This has facilitated education and promoted awareness of medical, social and research issues. Biannual conferences have been held in North America since 1999 for families and professionals. This parent/professional relationship has been vital in increasing knowledge about CS.

Are there CS support groups outside of the US? How large are they? Where do they meet?

TheFrench association : Association Française dusyndrome de Costello, http://costello.free.fr/

This association expanded to include families with CFC syndrome in 2005. Most of the members are French, but there are also families from other European and non European countries. Around 50 families (30 families with Costello syndrome, and 20 with CFC syndrome)maintain contact with the association using e-mail. This is done in different languages (English,Spanish, etc.). Biannual meetings are organised so that people with Costello and CFC syndromes can benefit from specialised clinics. Sessions also focus on non-medical topics (for example,the role of the grandparents, the siblings).Currently, these meetings have been organised in France. A translator is proposed for the non-French-speaking families to expand their role to become a “Euro-Costello” group.

The Italian association does not have a website.
The address for the Swiss site is http://www.costellokids.ch

Do you have a support group in the USA?

Yes we do, its called the Costello Syndrome Family Network. You can find their website at http://www.costellosyndromeusa.org/

What is the lifespan of a person with CS?

Two factors make this difficult to answer:

first, CS was first described in the 1970s, so there is very little information available on older individuals.

Secondly, CS is so rare that it?s difficult to get good data on lifespan.

What we do know is that there are a number of individuals with CS in their twenties and thirties. The oldest person we are aware of is a man who was born in 1960. In general, the life-threatening complications of CS are cancer and severe heart issues.

What kind of medical issues might we prepare ourselves for as our children move into adulthood?

Generally speaking, the health issues in adults with CS are similar to those in childhood. Adults with CS often need multiple sub-specialists to deal with their medical issues.

There is a long list of problems that may occur, but remember that each person with CS is unique.

Short stature and learning disabilities are ongoing, but individuals with CS continue to learn new skills and there is no evidence of losing skills.

Heart problems may continue from childhood. The adult with CS should continue to be monitored for heart muscle problems.

High blood pressure may develop.

Some individuals experience gastro-esophageal reflux in adult life.

It appears that adults with CS are prone to low bone density and osteoporosis. They should be assessed, and may need treatment for this. Other skeletal issues such as worsening of scoliosis can occur in adult life.

The main tumor risk in adults is bladder carcinoma. This can develop as early as the 20?s, though the youngest person with CS reported to have developed it was aged 12. The outcome for those who develop this type of cancer is good ? we know of no person with CS who has died from this type of cancer.

Benign breast disease such as breast papilloma have also occurred in women with CS. Most individuals will have some skin papilloma, which recur through adulthood.

Chiari malformation of the brain may rarely become a problem in adult life, causing difficulty with walking, feeding and other symptoms.

Some adults with CS have managed to live alone with some assistance, while others have required more supervision.

Can we cure CS now?

Costello syndrome is the result of a change in a gene carried in every cell of the body, so there is no ‘cure’ for Costello syndrome. However, ongoing research allows us to hope for therapies in the near future that may help as a ‘treatment’ for the problems that the gene mutation causes.

If there is no cure, then how do we treat our children?

The management plan for a person with Costello syndrome is individualised, and focuses on the specific symptoms that each person develops. Sometimes surgery can help repair certain heart or bone abnormalities. Feeding problems can be addressed by feeding specialists.

A feeding tube may be needed to be sure that enough calories can be provided for the child?s body to absorb through the GI tract. Enrolment in infant and child programs (?early (childhood) intervention? programs) to address the developmental delays can help each child achieve his/her full potential.

Pro-active screening for tumours is also recommended. Families can benefit working with a Clinical Geneticist, Paediatrician, or other health care provider to help coordinate care of the multiple sub specialists typically involved.

More information about treatment of Costello syndrome can be found in the Management section of
Gene Review for Costello syndrome can be found at at the NIH via this link

Is there drug therapy in the future?

At present, individuals with Costello syndrome are treated for potential or actual medical issues as they develop. If a clinical trial for a drug therapy is designed for Costello syndrome, it would be listed at:

http://www.clinicaltrials.gov You can search this site by typing in key word(s). It tells you whether the trial is still enrolling, what the conditions for inclusion are, and what the goals of the study are.

The CostelloKids website website and listserv will also provide updates and links.

Thinking more broadly, the ultimate drug therapy for Costello syndrome would be a drug that could target the problem at the cellular level. Since we know that the abnormal HRAS protein is stuck in the ?on? position, a drug that specifically ?dials down? the abnormal HRAS amino acid function protein while leaving the normal HRAS protein intact would be ideal.

Further research into how HRAS functions in different tissues will be important in understanding the potential effects of different types of drug treatments.

What else might develop, what about other trials in the future, besides drugs?

A number of people wonder about the possibility of gene therapy as a possible ‘cure’ for Costello syndrome. Since the completion of the Human Genome Project in 2003, many people wonder why researchers aren’t any closer to gene therapy. The reality is that the Human Genome Project was just the beginning. The real work comes in understanding not only where gene mutations are and what they do, but also how genes are regulated, by control elements both near and far from the gene itself. Much is left to be done.