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IntroductionA syndrome is a collection of findings or symptoms that has been seen recurring over and over again in patients. They are often referred to as congenital defects. Congenital means that you were born with it.
Dr. Angelo DiGeorge is accredited with being the first to diagnose the collection of findings associated with DiGeorge Syndrome in the 1960's. He is a retired endocrinology doctor at St. Christopher's Hospital for Children in Philadelphia, USA. The findings were complex heart problems and a lack of thymus gland which were noted during post mortem.
Velo-cardio-facial syndrome refers to the collection of findings made by Dr Robert Shprintzen, a speech pathologist from Syracuse, New Jersey in patients who had problems with their soft palate (velum), heart (cardiac), along with characteristic facial features.
The underlying cause of DiGeorge syndrome/VCFS is generally a missing piece of genetic information. Specifically this is referred to as a "chromosome 22q11.2 deletion". It is now known that there are over 180 anomalies associated with the deletion none of which are noted with 100% frequency.
What is a 22q11.2 deletion?Genes are the recipe book of life. Even identical twins are subtly different individuals and that's because everyone's cooking is different! Genes are sections of DNA and long strands of DNA form chromosomes.
Most people have 23 pairs of chromosomes (46 in total), with one of each pair coming from the mother and the other from the father. Chromosomes are numbered 1 (the largest pair) to 22 (the smallest pair); the 23rd pair are called sex chromosomes (X and Y) because they determine whether a person is male or female and the others are called autosomes. Each of the 46 chromosomes has a 'p' arm, which is short, ('p' for petite) and a 'q' arm, which is long, ('q' follows 'p' in the alphabet - and you thought this was complicated!). Located along these arms are clusters of genes.
A person with DiGeorge syndrome/VCFS has the 2nd portion of the 1st sub-division of the 1st cluster of information on the 'q' arm of one of their 22nd chromosomes missing. This is very small!
Thus 22q11.2 is the genetic address of the missing genes.
Why did this happen to us?This is generally not known as the majority of patients who have a 22q11.2 deletion, which caused their DiGeorge syndrome/VCFS, do not have an affected parent, therefore, the change in their chromosome 22 is a "new mutation" (de novo) in them. Only in about 10% of cases is a parent also affected.
There is nothing that either parent could have done before or during the pregnancy to have prevented the deletion from happening or could have done to have caused the deletion to occur. This is a defect of the human race not of one particular person.
It is vital to understand that this is no-ones' "fault".
The chromosome deletion was present in either the egg or sperm from which the baby was conceived. In other words the baby was destined to be born with the deletion from the instant of conception.
Could this happen again?
Genetic counselling is usually offered to parents with a child that is diagnosed with DiGeorge syndrome/VCFS and blood samples are tested to find out if one of them has the deletion. The test is called FISH which stands for 'Fluorescence In-Situ Hybridisation'. In basic terms, a piece of replicated DNA is propelled towards the 22nd chromosomes. If it sticks to a matching piece of DNA it lights up. If it doesn't light up then there is no matching piece on the chromosome and so there is a deletion.
If the parents' chromosomes are normal, then the chance of having a further baby with the deletion is quite low (less than 1%).
If one parent has the deletion then that person has a 50% chance of passing it on to each of their children, (it is termed "autosomal dominant"), the chance of having more than one child affected is random.
It is important to point out that it is not possible to predict the degree to which an individual is affected by the deletion. There may be multiple problems or no problems. Also the degree of severity of those problems is very variable. For example from a very mild heart problem to a very severe heart problem, or no heart problem at all.
Is a 22q11.2 deletion a rare genetic disorder?It is the most frequently occurring chromosome deletion and the second most common cause of congenital heart defects. It is currently estimated that as many as 1 in 1,800 of the population may be affected by the 22q11.2 deletion. However it not particularly well known as often the symptoms are mild or sometimes there are no obvious symptoms at all and the FISH test has only been commonly available in the last few years.
The 22q11.2 micro-deletion spectrum of disorders includes: DiGeorge syndrome, VCFS (velo-cardio-facial syndrome/ Shprintzen syndrome), Opitz G/BBB syndrome, conotruncal anomaly face syndrome (CTAF) and Velo-Pharyngeal Insufficiency (VPI).
The diagnostic name which is given to a patient is generally determined by the specialist to whom the patient presents. For example, patients diagnosed with CTAF often present to cardiology because of their heart defect. The same is true for many patients with DiGeorge syndrome (who often have problems with calcium and their immunity in addition to their heart problems). Patients diagnosed with VCFS are usually older, presenting to the cleft palate clinic for follow-up due to a cleft/soft palate problem (VPI), and patients with Opitz G/BBB syndrome often present to the ear, nose and throat doctors due to their noisy breathing (this can also be due to a problem with the 10th chromosome).
What are the most frequently noted anomalies?
The HeartCardiac defects, or congenital heart disease, are found in many patients with 22q11.2 deletion. In previous years this was the main feature of those cases diagnosed as genetic testing and detailed investigations were only triggered by a condition such as this.
The most common cardiac defects affect the main outflows of the heart such as the aorta and the pulmonary arteries, with tetrology of Fallot and interrupted aortic arch being the most common.
Not all heart defects require surgery, and if your child has not been diagnosed with a heart defect as a baby then it is unlikely that one will be found in later life. However, you may feel that as this is a common anomaly associated with the deletion that you wish your child to be referred for heart investigations.
The investigations usually take the form of an echocardiogram, (which is a detailed ultra sound scan of the heart using a machine very similar to those used during pregnancy), or an electrocardiogram (which monitors the heart beat). These are not invasive procedures and are completely harmless and painless.
The Immune SystemIn babies and young children the immune system is controlled by the thymus gland in the chest and sometimes this can be partially or completely absent or just not work well. Again the symptoms can be mild or severe. Often children are just more susceptible to colds and viral infections and fungal infections such as thrush.
We have taken the advice of many doctors and specialists in this area. The general advice is that caution should be taken with immunisations (particularly LIVE vaccines) until it has been proven that gross 'T' cell counts are over 0.5 x 109 per litre and 'B' cell (antibody) counts are within the average/normal range.
Oral polio and BGC are live vaccines. The meningitis C vaccine is an inactivated type. The MMR jab is a live vaccine but is thought not to offer any higher risk than to children in the general population.
We would advise that parents be particularly aware of the risks of chicken pox, which can be severe, please contact your doctor if you feel your child has been exposed. Only a small number of children are particularly vulnerable but we would advise caution. A blood test can reveal whether your child has the cells required to defend against this virus.
Specific advice should be sought from your immunologist. Further information is available.
Facial FeaturesThe facial characteristics noted are often very subtle and only apparent when a group of children are together. For example small, low set ears are noted, but if your family has large ears then your child's ears may just be small for your family.
Other features include: dark/ red rings under the eyes, long slender fingers, a slightly open mouthed expression, abundant scalp hair, a broad bridge of the nose, short stature, a small jaw and small or missing adenoids.
Development and LearningMany children with a 22q11.2 deletion will have some sort of learning difficulty and/or developmental delays. These are not the same thing.
Your child may have delays in learning to crawl, walk and often talk, in comparison to other children. This could be due to your child being very sick and spending time in hospital or be due to problems associated with the deletion such as poor motor skills, muscle tone and lack of co-ordination. Some children will only have mild delays others will have more significant problems.
Often children will have communication problems. This may be due to palate or ear problems, or due to problems with language comprehension.
The areas of learning where children are most commonly noted to struggle are English comprehension, language skills, complex maths and higher cognitive processes such as abstract reasoning and problem solving. They often have difficulty with time concepts, shape, colour and size. They can also have disorganised thinking and become obsessed with one topic or idea.
It is frequently noted that the children have poor performance IQ compared to assessed IQ. This is often termed a "Non-Verbal Learning Disability" and is unusual in people without a 22q11.2 deletion.
Most children will attend mainstream school but may need some classroom assistance or special needs lessons. It is vital that your child is monitored and that any signs of difficulty are identified early on and the appropriate intervention given. Whatever your child's difficulties there are ways of encouraging and supporting learning.
BehaviourThere are also common behavioural traits noted. These often include poor social skills in a peer group, immature or inappropriate behaviour patterns, hyperactivity, impulsiveness, be overly gullible and suffer from mood swings.
Children are often noted as having low self-esteem, lack confidence and perform better when one to one with an adult whom they are familiar and confident with rather than their peer group and they often 'give up' at the slightest set back.
It should be noted that occasionally children may suffer from 'attention deficit disorder' or ADD and that medication such as Ritalin should not be given as it can cause an adverse reaction.
CalciumCalcium is important to the body in the firing nerve endings and muscles. Some children will suffer with hypocalcaemia, or an inability to metabolise calcium. This can cause tetany or muscle spasms and in severe cases, seizures.
It is important for your baby to have their calcium levels monitored. However it is unlikely that your child will develop hypocalcaemia in later childhood if they do not suffer from it as a small baby, though small numbers have reported on-set at puberty.
This problem is caused by anomalies of the parathyroid gland which produces a hormone called parathyroid hormone or PTH (this also runs with high serum phosphorous levels). Medication is given to keep calcium levels higher and it appears that most children will outgrow this problem after their first birthday.
Growth may also be affected by differences in hormone levels and you can ask to be referred to an endocrinologist if you feel your child is affected in these ways.
The PalateThis is one of the most common areas where an anomaly is noted. The types of problems are very variable and can often be a combination of anomalies. You should ask for your child to be seen by a cleft palate team, a plastic surgeon or a speech therapist if you feel your child may be affected in this area.
The hard and soft palate can be affected. Babies often have reflux or vomiting through the nose, and older children have difficulty with chewing/ swallowing lumpier foods, and problems with speech. The need for speech therapy and/or surgery is quite common.
Hearing/EarsSome children suffer repeated ear infections and glue ear is not uncommon, which can lead to temporary hearing loss. This is important to investigate as hearing loss can impede speech development. If your child suffers with ear infections then a review by an ENT specialist is recommended.
Very occasionally patients will suffer from mental health problems such as bi-polar/manic depression. Specialist advice must be sought if a problem is suspected, further information is available from Max Appeal!