Chromosome 22q11.2 duplication syndrome

An individual with 22q11.2 duplication syndrome has a 1 in 2 (50%) chance with each pregnancy of either passing on their chromosome 22 with the duplication and having a child with 22q11.2 duplication or passing on their chromosome 22 without the duplication, and having a child without 22q11.2 duplication.

Genetic counseling is available for individuals and families interested in more information about their chances of recurrence of 22q11.2 duplication syndrome. The National Society of Genetic Counselors "Find a Genetic Counselor" search feature can be used to locate a genetic counselor in the United States or Canada.

When an individual is diagnosed as having 22q11.2 duplication syndrome, genetic testing should be considered for that individual’s parents (to determine if the 22q11.2 duplication was inherited from a parent who also has 22q11.2 duplication, or appears to have occurred de novo (new in the affected individual)). The parents of an individual with 22q11.2 duplication syndrome do not have to have known symptoms of 22q11.2 duplication syndrome in order to have 22q11.2 duplication.

If the person with 22q11.2 duplication has children, each child has a 1 in 2 (50%) chance of either inheriting or not inheriting the 22q11.2 duplication from their affected parent, and so genetic testing in the children of an individual with 22q11.2 duplication syndrome should be considered.

During a consultation with a medical geneticist or genetic counselor, it is typical for a family’s genetic family history (pedigree) to be reviewed, and as part of that process the geneticist or genetic counselor will review which of an individual’s relatives should be offered testing for 22q11.2 duplication syndrome. If you are interested in locating a genetic counselor in the United States or Canada, there is a searchable directory on the National Society of Genetic Counselors website called "Find a Genetic Counselor".

Facial Features
Some individuals with 22q11.2 duplication syndrome may have distinctive (known as dysmorphic) facial features. One researcher found that when individuals with 22q11.2 duplication syndrome had distinctive facial features, the most common features were widely spaced eyes (known as hypertelorism), a broad flat nose, small lower jaw and chin (known as micrognathia), unusually formed ears, skinfolds across the inner corners of the eyes (known as epicanthal folds) and downslanting eyes. A less common feature may be tiny holes or skin tags in front of the ears.

Changes affecting the mouth
Cleft palate: Some individuals with 22q11.2 duplication syndrome are born with a condition known as cleft palate. Cleft palate is a birth defect in which the roof of the mouth (palate) doesn’t form correctly and needs to be surgically closed after birth.

Velopharyngeal insufficiency: Around 70% of people with 22q11.2 duplication syndrome have been reported with velopharyngeal insufficiency (VPI), which is a disorder that results from the soft palate at the back of the mouth not forming correctly and allowing air to escape through the nose instead of the mouth. People with VPI have difficulty pronouncing most consonants correctly, including p, b, g, t and d, and their speech may also sound nasal, as if they have a chronically stuffy nose.

Hearing Loss
While most individuals with 22q11.2 duplication syndrome have normal hearing, a significant number have some hearing loss. Overall, around one child or adult in three (32/112) known to have 22q11.2 duplication has some degree of hearing loss. It is very common for children with 22q11.2 duplication syndrome to have a type of treatable hearing loss that is caused by a build-up of fluid inside the ear spaces (sometimes called glue ear, or chronic otitis media). Sensorineural hearing loss is much less common, but can also occur. This type of hearing loss is permanent and is due to damage to the inner ear (cochlea) or problems with the nerve pathways from the inner ear to the brain.

Eyesight
Individuals with 22q11.2 duplication syndrome may have droopy eyelids (ptosis), which may cause a problem with vision if the pupil of the eye is covered. Other individuals have been described to have strabismus, which is a problem in which the eyes are not aligned properly, so that one eye may be looking straight ahead while the other eye turns in a different direction. A few children (3 reported by Unique) have been reported with nystagmus, which is a jerky movement of the eyes that can be caused by a structural problem within the eye or a change in the visual pathway from the eye to the brain.

Teeth
Children with a chromosome disorder, including 22q11.2 duplication syndrome, may have a higher rate of teeth problems compared to typically-developing children. This may be due to a number of problems, such as unusual development of the teeth and/or jaw, which can lead to overcrowding or widely spaced teeth. Other issues such as problems with feeding and delayed eating and chewing activity, tooth grinding (which wears down the enamel) and widely spaced teeth may also cause tooth problems. Teeth may emerge late, and milk teeth (also known as baby teeth) may be late to fall out. Extra teeth may be found and either milk or adult teeth may be missing.

These and other symptoms that have been reported in individuals with 22q11.2 duplication syndrome may also be found in individuals with other types of chromosome changes, or as isolated issues in individuals with no known underlying chromosome or other genetic problem. If you have questions about whether health or developmental symptoms present in yourself or a family member may be related to a chromosome change such as 22q11.2 duplication syndrome, you may consult your primary care physician or a medical geneticist, who may decide whether genetic testing for chromosome changes such as 22q11.2 duplication syndrome or other possible genetic conditions is warranted.

Finding a primary care provider willing to familiarize himself/herself with the medical literature available on 22q11.2 duplication syndrome should benefit patients with 22q11.2 duplication syndrome, and consultation with a medical geneticist and/or genetic counselor is recommended. The National Society of Genetic Counselors website includes a "Find a Genetic Counselor" searchable directory to locate genetic counselors throughout the United States and Canada.

Most primary care providers, medical geneticists and other specialists (ophthalmologists, cardiologists, neurologists, etc.) who may be involved in the care of individuals with 22q11.2 duplication syndrome may not have experience treating others with 22q11.2 duplication syndrome. However, the medical and developmental issues that may be associated with 22q11.2 duplication syndrome are not unique or specific to 22q11.2 duplication syndrome. Individuals with many different underlying conditions may be affected by issues similar to those that may be experienced by individuals with 22q11.2 duplication syndrome. Since treatment for 22q11.2 duplication syndrome is based on the symptoms that a given individual is experiencing, working with your primary care provider to find a specialist in the specific condition(s) relevant to each patient will lead to the best care. Many children with 22q11.2 duplication may benefit from occupational, physical and/or speech therapy. Depending on an individual’s specific symptoms, specialists such as ophthalmologists, audiologists, cardiologists, neurologists or others may be beneficial (to address vision, hearing, cardiac (heart) and neurological problems such as seizures, respectively). Regular and high quality dental care is recommended.

The most common findings in 22q11.2 duplication syndrome (ie, intellectual disability, learning disability, delayed psychomotor development, growth retardation and weak muscle tone (hypotonia)) are common and mostly nonspecific indications for genetic testing. The extent to which duplication 22q11.2 is a cause for any of these findings in an individual with 22q11.2 duplication syndrome is currently unknown.

It may be appropriate to consider further testing of a child with severe developmental problems and/or multiple congenital anomalies who has been diagnosed with 22q11.2 duplication syndrome to determine whether additional genetic diagnoses are contributing to these symptoms.

One potential area of confusion regarding changes on chromosome 22 is that in addition to 22q11.2 duplication syndrome, there is also a 22q11.2 deletion syndrome, which involves a deletion of this same region of chromosome 22. 22q11.2 deletion syndrome is well described in the medical literature and goes by many different names, and so when a change involving chromosome number 22 is being considered, it should be clearly stated whether the change being discussed is a duplication or deletion.

Overall, children and adults with a 22q11.2 duplication are generally healthy. The difficulties some children with 22q11.2 duplication have with fine motor skills mean that affected children may be late to learn how to undress, dress, and wash themselves. Toilet training may also be delayed.

Unique (a rare chromosomal support group) reports a small number of young children with 22q11.2 duplication syndrome with frequent respiratory infections (that can become serious chest infections) and an even smaller number (three children and one adult) have significant allergies. A further small number, around six per cent, have been reported with frequent headaches or migraines.

Overall, a small number of children with 22q11.2 duplication seek medical care at a hospital more often than typically developing children. The most common reason for seeking medical care at a hospital is temporary hearing loss that is caused by a build-up of fluid inside the ear spaces, with respiratory infections being another common reason.

The medical and developmental symptoms found in individuals with 22q11.2 duplication syndrome vary significantly from one affected individual to another, even within the same family. Some individuals with 22q11.2 duplication do not experience any known symptoms at all. Therefore, the impact of having 22q11.2 duplication syndrome on an individual’s overall well being also varies greatly.

22q11.2 duplication syndrome results when an individual has a duplicated region (extra genetic material) on part of one of their chromosome number 22s. The q11.2 refers to the specific location of the duplication on chromosome 22 (like the house number on a street). The features that this condition causes in an individual can be very different from person to person, even when there are multiple affected individuals in the same family. The most common findings in people with 22q11.2 duplication syndrome include developmental delay, intellectual disability, slow growth leading to short stature, and weak muscle tone (hypotonia). However, many individuals with the duplication have no known physical, intellectual or developmental problems. Medical geneticists and genetic counselors are often involved in the diagnosis and care of individuals with 22q11.2 duplication syndrome. For more information about genetic services in your area, you may ask your primary care physician for a referral. The National Society of Genetic Counselors website includes a searchable "Find a Genetic Counselor" directory, which may help you locate a genetic counselor in the United States and Canada.

Doctors most commonly refer to this condition as "22q11.2 duplication syndrome".

Growth
Most babies with 22q11.2 duplication syndrome grow at a typical rate before birth and are born around the expected weight and length. After birth, the growth rate of some babies and children with 22q11.2 duplication may slow down. Some babies and children with 22q11.2 duplication are diagnosed with "failure to thrive" which means that they are not gaining weight at the expected rate, regardless of how much food they eat.

Development
Having a 22q11.2 duplication may increase the likelihood of developmental delay, but does not necessarily cause it. Developmental delay in children with the 22q11.2 duplication is typically mild-to moderate. Overall, two people in three reported in the medical literature with 22q11.2 duplication syndrome has experienced some delay, which may be most obvious in the areas of behaviour, responding to others, learning to move, concentrating, and/or learning to talk. However, it is possible that there are more people with a 22q11.2 duplication who have experienced no delay and never come to the attention of doctors. When an individual is diagnosed with 22q11.2 duplication syndrome, it is not possible to predict whether that individual will experience developmental problems or how severe those problems may be, including amongst affected individuals in the same family.

Gross Motor Skills
Some children with 22q11.2 duplication syndrome may experience developmental delay in gross motor skills. Specifically, a delay in being able to roll over, sit, become mobile and walk is common in individuals with 22q11.2 duplication syndrome. Low muscle tone leading to floppiness (hypotonia) is a common finding in individuals with 22q11.2 duplication syndrome, as are loose, mobile joints, which means that children may have to work harder to become mobile.

Fine Motor Skills
The possible combination of developmental delay, low muscle tone and loose joints means that children with 22q11.2 duplication syndrome are typically slow to use their hands purposefully and to coordinate hand-eye movement. As a result, babies with 22q11.2 duplication syndrome may be late to play with toys and to hold, drop and pick up objects. Affected children may also experience delays in learning how to feed themselves.

Learning
A baby born with a 22q11.2 duplication may be more likely to need learning support than a baby without the duplication. However, the range of learning difficulty is very broad and many adults and children have the duplication without experiencing any learning difficulty or disability. Even members of the same family, all with the 22q11.2 duplication, may have very different learning profiles.

Speech and Behavior
Speech and language can be the most delayed area of development for individuals with 22q11.2 duplication syndrome. It is not yet known whether any particular behavior is associated with having a 22q11.2 duplication. When behavioral problems occur, they usually involve activity levels (overactive, hyperactive), temper control, aggression and concentration. A small number of children with 22q11.2 duplication syndrome have been diagnosed with autism and more are believed to have autistic traits, such as tight adherence to routine. Other behavioral problems reported with 22q11.2 duplication syndrome include immaturity, anxiety, and poor impulse control.

Epilepsy
Twelve children within the Unique population (a rare chromosomal disorder support group) have been diagnosed with epilepsy, which is a condition where abnormal electrical activity in the brain can cause unpredictable seizures and other health problems.

Medical management of an individual diagnosed with 22q11.2 duplication syndrome may be overseen by a primary care physician or a medical geneticist. It should involve screening an affected individual for possible physical health problems reported in some individuals with 22q11.2 duplication syndrome and following up with the appropriate specialists if concerns are noted, as well as monitoring development and considering appropriate interventional therapies (i.e., physical, speech, and occupational therapy) and learning supports as needed.

Chromosomes are made up mostly of DNA, and are the structures in the body’s cells that carry genetic information (known as genes), which direct the body how to grow and develop. Humans have 46 chromosomes in most cells of their body, which are arranged in 23 pairs. The first 22 pairs of chromosomes are called autosomes and are numbered 1-22. The 23rd pair is known as the sex chromosomes (XX for female and XY for male). Each chromosome has a short (p) arm and a long (q) arm, and sections known as bands are numbered on the p and q arm (like the house number on a street).

Individuals with 22q11.2 duplication syndrome have an extra copy of a small piece of chromosome 22 on the long arm (q) of this chromosome, labeled, q11.2. The typical duplication (extra genetic material) at 22q11.2 results in a person having an additional 3 megabases (3 Mb) of DNA or an extra 30-40 genes.

Not everyone with 22q11.2 duplication has the exact same area of chromosome 22q duplicated. Some people have larger duplications (from 4-6 Mb), where a small number of affected individuals have a shorter duplication in the same region. The size of the duplication will also change the number of genes involved, with larger duplications meaning that more genes are involved and smaller duplications meaning that fewer genes are involved in the duplication. Variation in the size of the specific duplication (and therefore which genes are involved) may contribute to some of the differences seen between individuals who have 22q11.2 duplication syndrome.

The function of all of the genes involved in 22q11.2 duplication syndrome are not well understood. It is not currently known why duplication in these genes causes the health and developmental problems in some individuals with 22q11.2 duplication syndrome, and why others with 22q11.2 duplication syndrome do not have any obvious physical, medical or developmental differences as a result of having this duplication. It is possible that having extra copies of these genes leads to some of the symptoms seen in 22q11.2 duplication syndrome. Since so little is known about the function of many of the genes in this region, researchers are working to determine which duplicated genes may contribute to the developmental delay and other problems that can affect people with 22q11.2 duplication syndrome.

The medical specialty commonly involved in diagnosing and providing care for individuals with chromosome changes, including 22q11.2 duplication syndrome, is medical genetics. If you are interested in finding out more about medical genetics services in your area, you may be able to ask you primary care physician for a referral. The National Society of Genetic Counselors website includes a searchable "Find a Genetic Counselor" directory, which may help you locate a genetic counselor in the United States or Canada.

As of June 4, 2016, there are no clinical research studies available on clinicaltrials.gov for 22q11.2 duplication syndrome.

Unique, a rare chromosome disorder support group, reports that 18 out of their 112 known individuals with 22q11.2 duplication syndrome (around 18%) have been identified to have differences in how their heart is formed (structural birth defects), or how it functions. These reported heart problems vary in severity, ranging from clinically insignificant, mild problems, to complex, life threatening problems. The following heart problems have all been described in individuals with 22q11.2 duplication syndrome:

Coarctation of the aorta: The aorta is the main blood vessel through which the blood flows out of the heart and into the rest of the body. In this condition, the aorta is narrowed. This forces the heart to pump harder to push blood through the narrowed vessel. The problems associated with coarctation of the aorta can range from mild to severe.

Septal Defects: A septal defect is a hole in one of the muscular walls of the heart, either between the two upper chambers of the heart (atria), known as atrial septal defect (ASD), or between the two lower chambers of the heart (ventricles), known as ventricular septal defect (VSD). ASDs and VSDs are structural heart defects that are present from birth. Some septal defects may close on their own or not cause any clinical problems, where other septal defects require surgical closure to prevent damage to the heart and/or lungs.

Pulmonary stenosis: The pulmonary artery carries deoxygenated blood from the heart to the lungs. In pulmonary stenosis, the opening to this artery is unusually narrow, which means the heart has to work harder to pump blood through the narrowed valve. Depending on the amount of narrowing an individual with pulmonary stenosis has, he or she may experience no symptoms, or develop problems such as fatigue or fainting.

Mitral Valve Prolapse: The mitral valve separates the upper left heart chamber and the lower left chamber. In individuals with mitral valve prolapse this valve does not close properly and therefore a small amount of blood is leaked backwards through the valve. Sometimes individuals with mitral valve prolapse have an audible heart murmur on examination.

Persistent Ductus Arteriosus: The ductus arteriosus is a channel between the aorta and the pulmonary artery that should be open during fetal development to take blood from the aorta to the lungs. It usually closes shortly after birth. In persistent ductus arteriosus, this valve stays open, and so the lungs receive a greater volume of blood than they should, causing the heart to work harder than normal to pump the increased blood volume back out from the lungs. Persistent ductus arteriosus may be surgically corrected.

Patent Foramen Ovale: This is when a normal opening found between the two upper chambers of the heart does not close in the first year of life, as expected. When it remains open, extra blood passes from the left to the right side of the heart. Most individuals with a patent foramen ovale do not experience symptoms as a result and never require treatment.

Tetralogy of Fallot: Tetralogy of Fallot is a complex heart defect caused by the combination of four different structural problems within the heart. It results in deoxygenated blood being unable to easily get to the lungs to pick up oxygen. Some of this deoxygenated blood returns to the body without having been to the lungs to pick up oxygen. Some individuals with Tetralogy of Fallot require surgical intervention in infancy, while others are not diagnosed until later in life.

Transposition of the Great Arteries: In this condition, the two main blood vessels taking blood away from the heart are reversed (transposed), which, if left uncorrected, changes the way that blood flows throughout the body and causes a shortage of oxygen. Most babies born with transposition of the great arteries require surgery shortly after birth.

Hypoplastic Left Heart: This is a condition in which the left side of the heart is significantly underdeveloped at birth and cannot function properly. Medication and surgery, potentially including heart transplant, is necessary for babies born with hypoplastic left heart.

These heart conditions, while all reported in individuals with 22q11.2 duplication, also occur in individuals with other chromosome changes and genetic conditions, as well as occur as isolated findings in individuals with no other known health or developmental problems or underlying diagnoses. These conditions would be most commonly diagnosed and managed by a cardiologist (pediatric or adult).

There is a lot of variability in the specific symptoms seen in individuals with 22q11.2 duplication syndrome, even within the same family. Not every individual with a 22q11.2 duplication has any known medical or developmental problems resulting from having the duplication. When a child is diagnosed with 22q11.2 duplication syndrome, it is common to offer genetic testing to that child’s parents, and the 22q11.2 duplication may be found in a parent who has never had any known medical or developmental problems as a result of having the 22q11.2 duplication.

When an individual with 22q11.2 duplication has symptoms, the most common ones include developmental delay, intellectual disability, slow growth leading to short stature and weak muscle tone (hypotonia). Other symptoms include differences in heart structure or function, hearing loss and velopharyngeal insufficiency (which involves the improper closing of the roof of the mouth which can affect speech).

Because of the variability in symptoms between individuals with 22q11.2 duplication, and the possibility that a person with 22q11.2 duplication may not have any known health or developmental problems, it is not possible at the time of diagnosis, especially of a young child, to predict what symptoms, if any, that individual may have of 22q11.2 duplication syndrome, including the degree of developmental delay or intellectual disability he or she may develop, or whether he or she will be affected with any obvious issues from the 22q11.2 duplication syndrome at all.

If you have questions about whether symptoms present in yourself or a family member may be the result of a chromosome change such as 22q11.2 duplication syndrome, you may ask your primary care physician, or consult with a medical geneticist. For more information about the availability of genetic services in your area, you may ask your primary care physician or check the "Find A Genetic Counselor" directory on the National Society of Genetic Counselor website to locate genetic counselors in the United States and Canada.

Digestion
Some individuals with 22q11.2 duplication syndrome experience digestion problems, such as gastroesophageal reflux (known as GERD). GERD may also be described as heartburn or acid indigestion. In reflux, stomach contents back up out of the stomach and into the esophagus and may cause a burning chest pain, a bitter ("acid") taste in the mouth, coughing and/or vomiting. The stomach contents may also be inhaled into the lungs, raising the risk of an infection known as aspiration pneumonia. GERD may be treated by diet and lifestyle changes, over the counter and prescription medications, and in some cases, a surgery known as fundoplication.

Anomalies in the Genital Area
Babies with a chromosome condition, such as 22q11.2 duplication, are more likely to have a genital anomaly than babies in the general population. These changes may be more obvious in boys. Unique (a rare chromosome support group) reports that around 11 out of 52 boys known to them with 22q11.2 duplication syndrome (approximately 20%) have a difference in their genitals. The specific changes present in these boys vary, and include a hidden penis (in which the penis is partially or completely "hidden" below the surface of the skin), hypospadias (in which the external opening normally found at the end of the penis is on the underside instead), undescended testicles (in which one or both testicles have not moved from the abdomen down into their proper position in the scrotum, which is the bag of skin hanging below the penis), blockage in the urethra (the tube leading out from the bladder through the penis) and an inguinal hernia (failure of the opening that allows the testes to descend into the scrotum during fetal life to close properly).

Breathing
Most people with 22q11.2 duplication syndrome breathe normally, however Unique (a rare chromosome support group) has reported that around five percent of individuals with 22q11.2 duplication, mostly children, have sleep apnea (in which they experience shallow breaths, or their breathing repeatedly stops and restarts, during sleep).

When these symptoms are present in an individual, it does not necessarily mean that he or she has 22q11.2 duplication syndrome, as these conditions are both found very commonly with other chromosome changes and genetic syndromes, as well as occur as isolated problems in individuals without any known chromosome changes or other health concerns. If you have questions about whether health or developmental symptoms present in yourself or a family member may be related to a chromosome change such as 22q11.2 duplication syndrome, you may consult your primary care physician or a medical geneticist, who may decide whether genetic testing for chromosome changes such as 22q11.2 duplication syndrome or other possible genetic conditions is warranted.

While it would be technically possible to diagnose 22q11.2 duplication syndrome on tissue obtained from a biopsy, it is not necessary. Biopsies are more invasive than obtaining a saliva or blood sample, and so it is not recommended for testing. Many commercial laboratories offer the genetic testing that would detect 22q11.2 duplication syndrome on both blood and saliva samples, making biopsy unnecessary and unjustified.

There is currently no treatment or cure to correct the underlying genetic change in 22q11.2 duplication syndrome. However, individuals with 22q11.2 duplication syndrome can seek treatment for their specific symptoms of 22q11.2 duplication syndrome. Depending on the individual, this may include: speech therapy, occupational therapy, physical therapy, ophthalmologist (eye specialist), cardiologist (heart specialist) and neurologist (involved with the study and treatment of disorders of the nervous system). Routine pediatric care, routine developmental assessments and monitoring of specific identified medical issues is also recommended. Individuals with learning or developmental problems may receive special services and educational support in school. Some individuals with 22q11.2 duplication syndrome have no known symptoms related to the duplication and do not require any specific medical intervention.

No, 22q11.2 duplication syndrome is not a condition that is tested for in routine newborn screening. The genetic testing which would detect 22q11.2 duplication syndrome is a test that is only routinely done in individuals when there is reason to suspect the possibility of a chromosome change, either because of the individual’s health or development or family history.

If there is reason to suspect that a baby has 22q11.2 duplication syndrome or another chromosome change, genetic testing would be an option at any age.

The specific conditions included in the general population newborn screening are determined by individual states. More information about newborn screening, including which disorders are included in the newborn screening panel in a particular state, is available at http://www.babysfirsttest.org.

Prenatal diagnosis during pregnancy and preimplantation genetic diagnosis (PGD) as a step in assisted reproductive technology for 22q11.2 duplication syndrome is technically possible. Targeted testing specifically for 22q11.2 duplication syndrome could be performed for parents who have a known risk for 22q11.2 duplication syndrome in their children. Additionally, the genetic technology which can diagnose 22q11.2 duplication syndrome along with many other chromosome changes is becoming more commonly used for genetic screening in prenatal and preimplantation genetic diagnosis situations.

Genetic counselors are available to discuss reproductive related issues including the risk of chromosome changes such as 22q11.2 duplication syndrome in a pregnancy as well as review an individual’s pregnancy screening and testing options. For more information, you can locate a genetic counselor in your area on the National Society of Genetic Counselors "Find a Genetic Counselor" searchable directory.

The common symptoms reported in 22q11.2 duplication syndrome (developmental delay, intellectual disability, slow growth leading to short stature and weak muscle tone (hypotonia)) are not sufficiently distinct enough to 22q11.2 duplication syndrome for this syndrome to be specifically suspected on these symptoms alone. However, it is reasonable to consider evaluation by a medical geneticist when an individual has these symptoms, and the testing needing to diagnose 22q11.2 duplication syndrome is routinely ordered by a medical geneticist when the possibility of a chromosome change like 22q11.2 duplication is suspected.

There is a growing appreciation that some individuals have more than one genetic diagnosis as the cause of their developmental problems. If an individual with severe developmental problems and/or multiple congenital anomalies is diagnosed with a 22q11 duplication, it may be appropriate to consider further testing to determine whether additional genetic diagnoses are contributing to these physical symptoms.

It is possible for an individual with 22q11.2 duplication syndrome to have other chromosome changes in addition to the 22q11.2 duplication. One in seven individuals identified by Unique (a rare chromosomal support group) who have 22q11.2 duplication syndrome also have another chromosome change in addition to 22q11.2 duplication. It is possible that in some individuals with 22q11.2 duplication syndrome, some or all of the medical and developmental issues that person has, if present, may be the result of a different condition, and not the 22q11.2 duplication.

No, individuals with 22q11.2 duplication do not always have any identifiable health or developmental differences or symptoms known to be related to having the 22q11.2 duplication. There is a significant amount of variability in symptoms between individuals who are known to have 22q11.2 duplication syndrome, even within the same family. Since 22q11.2 duplication syndrome has been identified in individuals with no known clinical problems (health or development), it is not possible to predict at the time of diagnosis what, if any, symptoms a person with 22q11.2 duplication may develop. When a child with health or developmental problems is identified as having 22q11.2 duplication syndrome, it is common to also find the 22q11.2 duplication in a healthy parent with no known complications from the chromosome duplication.

Management for 22q11.2 duplication syndrome should be multi-disciplinary with the medical geneticist and primary care physician playing essential roles in appropriate screening, surveillance and care. At the time of diagnosis of 22q11.2 duplication syndrome, an individual should undergo baseline cardiac evaluation including echocardiogram (to detect structural birth defects in the heart), vision, hearing, and developmental assessments. Assessments by other medical specialists should be considered based on any physical or developmental symptoms an individual with 22q11.2 duplication is experiencing. Individuals with 22q11.2 duplication syndrome should receive routine primary care. Growth and feeding should be monitored in childhood.

Some pregnancies of babies affected with 22q11.2 duplication have been reported as normal with no identified complications. When pregnancy complications have been reported in pregnancies with babies affected by 22q11.2 duplication syndrome, no specific pattern of recurrent abnormality was obvious. One pregnancy with a baby affected with 22q11.2 duplication syndrome included intermittent bleeding throughout the pregnancy and the baby was born at 36 weeks. Six mothers from the Unique population (a rare chromosomal support group) had pre-eclampsia (a condition in pregnancy characterized by high blood pressure). At the time of this publication, Unique has reported 34 members with a 22q11.2 duplication.

Some of the physical health issues which may affect babies with 22q11.2 duplication syndrome may be screened for prenatally (eg, a fetal echocardiogram to look for structural heart defects). If a baby is diagnosed prenatally with 22q11.2 duplication syndrome, the pregnant mother could consult a Maternal Fetal Medicine specialist (high risk pregnancy expert) for pregnancy management recommendations. The woman’s obstetrician could provide referral to the Maternal Fetal Medicine specialists in a given area.

It is difficult to know for certain how common 22q11.2 duplication syndrome is in the general population, because many people with 22q11.2 duplication syndrome are likely undiagnosed. Most people diagnosed with 22q11.2 duplication syndrome have come to medical attention because of a medical or developmental concern, such as developmental delay or hypotonia (low muscle tone), in themselves or a family member. However, many people with 22q11.2 duplication syndrome have no known medical or developmental problems and so they would have no reason to be tested and diagnosed.

In one study (Van Campernhout et. al., 2012) more than 15,000 individuals with developmental problems were tested and approximately 1 in 320 had 22q11.2 duplication syndrome.

As of March 1st, 2016, over 100 people with 22q11.2 duplication syndrome have been reported in medical journals. In addition, other support groups such as Unique (a rare chromosome disorder group) and Chromosome 22 Central (supporting people with chromosome 22 disorders such as 22q11.2 duplication syndrome) know of over 100 families with this condition. There are probably many more people with 22q11.2 duplication that have not been diagnosed or reported in the medical literature.

22q11.2 duplication syndrome is inherited in families in what is known as an autosomal dominant manner. In human cells, chromosomes are arranged in 23 pairs of 2. The first 22 pairs of chromosomes are called autosomes and are numbered 1-22, while the 23rd pair is known as the sex chromosomes and determines gender (XX for female and XY for male). Individuals with 22q11.2 duplication typically have this duplication on one chromosome 22. A change on only one of the two chromosomes in a pair is sufficient to cause symptoms of 22q11.2 duplication in affected individuals (referred to as dominant inheritance).

If an individual has the 22q11.2 duplication on one chromosome 22, then with each pregnancy there is a 1 in 2 (50%) chance of passing on the duplicated chromosome 22, therefore, children of an individual with 22q11.2 duplication syndrome have a 50% chance of either inheriting or not inheriting the duplication from their affected parent, regardless of the gender of either the affected parent or the child.

About 70 percent of individuals with 22q11.2 duplication syndrome inherit the duplication from a parent who also has a duplication 22q11.2. In the remaining approximately 30% of individuals with 22q11.2 duplication syndrome, neither of the parents have a duplication on their 22nd chromosomes. This is referred to as a de novo (new) change, which occurred as a spontaneous event in either the egg or sperm at conception.

When a 22q11.2 duplication has occurred de novo (for the first time in an affected individual), the chance of the unaffected parents having a subsequent affected child in future pregnancies is estimated to be less than 1%. There is a small possibility that a parent havimay have a 22q11.2 duplication in only their egg or sperm cell, but not the cells in the rest of their body (this is known as gonadal mosaicism), and if present, would raise the chance of recurrence of 22q11.2 duplication in a subsequent pregnancy, even if the parent’s chromosomes were normal when tested in the blood. Parents may also carry a different type of chromosome change other than the 22q11.2 duplication which raises the chances of 22q11.2 duplication or another chromosome change occurring in a pregnancy. Genetic testing on parents who have a child with 22q11.2 duplication is recommended.

When a 22q11.2 duplication occurs de novo in a pregnancy, there is nothing a parent can do to cause or reduce the chances of the 22q11.2 duplication in the child. No environmental, dietary, or lifestyle factors are known to cause this type of change in a chromosome.

When an individual has been diagnosed with 22q11.2 duplication syndrome, genetic testing and genetic counseling is an option for his or her parents and other family members who are concerned about the risk of recurrence of 22q11.2 duplication syndrome in other members of the family. The National Society of Genetic Counselors "Find a Genetic Counselor" search feature can locate a genetic counselor in the United States or Canada if a family is interested in genetic counseling regarding 22q11.2 duplication syndrome.

Genetic testing for 22q11.2 duplication syndrome can be ordered by your primary care physician, medical geneticist, or other specialist physician. There are many commercial laboratories that offer genetic testing for 22q11.2 duplication syndrome. Chromosome 22q11.2 duplication syndrome is most commonly diagnosed by technology known as array comparative genomic hybridization (aCGH), or chromosome microarray analysis, though there are other types of genetic testing technology that could detect 22q11.2 duplication syndrome. This testing is most commonly performed on blood, though, depending on the laboratory used, 22q11.2 duplication syndrome could also be diagnosed by specialized testing of saliva, skin or other tissue samples. Depending upon the specific testing done and the laboratory used, a typical turn around time for results is approximately 4-6 weeks.

If you or a family member have been diagnosed with 22q11.2 duplication syndrome, a medical geneticist or genetic counselor can help interpret your results, including explaining the specific size and exact location ("address") on chromosome 22 of the duplication. This information should be available on the laboratory report and is important information if you are going to read medical articles describing patients with a 22q11.2 duplication, because individuals with 22q11.2 duplication do not all have the exact same size and chromosome location of their duplication, which affects which genes are involved in their specific duplication. This variation in the specifics of the duplication from individual to individual may explain some, but not all, of the variability in symptoms from one individual with 22q11.2 duplication syndrome to another.

Individuals interested in clinical research for 22q11.2 duplication syndrome can check the following sources:

1. https://clinicaltrials.gov/ These are studies receiving US government funding. Some studies are supported by private industries.

2. One can contact the recruitment office at (800) 411-1222, (866) 411-1010, or [email protected] for clinical trials at the National Institute of Health Clinical Center in Bethesda, MD.

3. To learn about clinical trials sponsored by private sources, you can contact http://www.centerwatch.com/

4. Make sure to check NCBI for any new research studies

22q11.2 duplication syndrome is also called chromosome 22q11.2 duplication syndrome or microduplication 22q11.2.

Babies and children with a known chromosome disorder or developmental delay including 22q11.2 duplication syndrome should have a careful eye examination to ensure that any problem with vision is addressed early. For individuals who have a squint (strabismus), treatment may include patching the stronger eye, eye movement exercises, glasses to correct vision problems and surgery to realign the muscles that hold the eye in place. Children and adults with a 22q11.2 duplication may need special dental care, depending on whether or not they have any concerns with their teeth. Hearing should be monitored, and if hearing loss is present, should be identified and treated as quickly as possible.

Babies with 22q11.2 duplication may be born with a cleft palate, which is the result of a failure of normal closure of the palate (roof) of the mouth. Babies with a cleft palate may need adaptive equipment to enable proper feeding until their cleft palate is surgically repaired. In addition, individuals with 22q11.2 duplication syndrome may have velopharyngeal insufficiency (VPI), a disorder that results in the soft palate of the back of the mouth closing incorrectly, allowing air to escape through the nose instead of the mouth. Some individuals with VPI benefit from speech therapy, and some require surgical treatment.

Individuals with 22q11.2 duplication syndrome may have a variety of structural and functional heart problems. Depending on the specific heart issue, treatment may include monitoring, medication, and/or surgical intervention.

When individuals with 22q11.2 duplication have developmental issues, they typically fall in the mild-to moderate range and respond well to early intervention and therapy. Children with 22q11.2 duplication may benefit from occupational therapy as well as play therapy. If behavior management programs are not sufficient for individuals with 22q11.2 duplication who have behavior issues with immaturity, anxiety and poor impulse control, medication has often been tried, generally with success.

At the date of this publication, twelve children within the Unique population (a rare chromosomal support group) have been diagnosed with epilepsy. Medication is sometimes, but not always, successful in controlling seizures in children with epilepsy.

While there are many specialists who may be involved in evaluating and treating specific symptoms of 22q11.2 duplication syndrome (ophthalmologists, cardiologists, neurologists, etc), an individual with 22q11.2 duplication syndrome should still receive regular care from a primary care physician. A medical geneticist may be involved in ensuring that an individual with 22q11.2 duplication syndrome receives appropriate medical services (screening, diagnosis and management).

There are no unique, odd, unusual or specific findings to 22q11.2 duplication syndrome that would enable a doctor to identify this condition in an affected individual without doing the appropriate genetic testing. The clinical spectrum of the 22q11.2 duplication syndrome is variable and no single clinical feature is required to establish the diagnosis. The most common findings in 22q11.2 duplication syndrome (intellectual disability, learning disability, delayed psychomotor development, growth retardation and weak muscle tone (hypotonia)) are nonspecific and are common findings in many other genetic conditions as well as commonly occur as isolated findings in individuals with no known underlying diagnosis.

While some babies and children with 22q11.2 duplication syndrome experience no feeding issues, other affected individuals may experience feeding difficulties. Feeding problems, when present, frequently start in the newborn period when babies may lack the energy, coordination or ability to suck strongly enough to have enough intake to meet their own nutritional needs. Babies with cleft palate (incomplete closure of the palate (roof) in the mouth) may need adaptive feeding equipment until their palate is surgically repaired.

In some individuals with 22q11.2 duplication syndrome, early feeding difficulties later led to difficulties handling solids at weaning, and later a generally poor appetite. Some children with 22q11.2 duplication syndrome have delays in fine motor skills, which may lead to delay in learning to feed themselves. These children may benefit from adapted cutlery. Some individuals with 22q11.2 duplication syndrome experience gastroesophageal reflux (GERD), which may require medical intervention.

Individuals with 22q11.2 duplication syndrome may be able to be managed by their primary care physician, or may benefit from speech therapy, feeding therapy, and/or consultation with a gastroenterologist.

There are good umbrella support organizations and/or registries that could benefit individuals with 22q11.2 duplication and their families.

UNIQUE: Rare Chromosome Disorder Support Group:
The Rare Chromosome Disorder Support Group’s mission is to inform, support and alleviate the isolation of anyone affected by a rare chromosome disorder and to raise public awareness.

Contact:
P.O.Box 2189, Caterham Surrey CR3 5GN England
Telephone: 44 (0)1883 330766
URL: http://www.rarechromo.org/

Chromosome Disorder Outreach (CDO):
CDO’s mission is to provide support and information to anyone diagnosed with a rare chromosome syndrome. They promote research and a positive community understanding of all chromosome disorders. CDO offers an extensive library of available up-to-date articles to members and also maintains a detailed database registry. They also publish periodic newsletters, provide access to research opportunities and interaction with our medical advisory board. CDO offer members connections with others who are coping with the same or similar chromosomal diagnosis through our personalized networking programs.

Contact:
Address: P.O. Box 724, Boca Raton, FL 33429-0724
Phone: 888.236.6880 (toll free)
Web site: http://www.chromodisorder.org/

NORD:
National Organization of Rare Disorders is a patient advocacy organization dedicated to individuals with rare diseases. NORD is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and patient services.

Contact:
Address: National Organization for Rare Disorders National Headquarters 55 Kenosia Avenue Danbury, CT 06810
Phone: 203-744-0100
Website: http://rarediseases.org/

Global Genes:
Global Genes is a rare disease patient advocacy organization. This non-profit organization promotes the needs of the rare disease community. Global Genes consists of over 500 global organizations.

Contact:
Address: Global Genes World Headquarters 28 Argonaut, Suite 150 Aliso Viejo, CA 92656
Phone: 949-248-RARE (7273)
Website: https://globalgenes.org/contact/

Chromosome 22 Central:
Chromosome 22 Central is a parent run support organization which supports over 2000 families worldwide who are affected by many different chromosome 22 disorders. This group offers basic information on 22q11.2 duplication syndrome.

Contact:
Address: Chromosome 22 Central c/o Murney Rinholm
7108 Partinwood Drive, Fuquay-Varina, North Carolina, 27526 USA
Phone: (919) 567-8167
Website: http://www.c22c.org/
There are also specific support groups dedicated to individuals and their families who have chromosome 22 duplications.

22q11 microduplication Facebook Group:
This is a parent run support group to meet, share experiences, ideas, and suggestions.

Contact:
Website: search "The Unknown:Chromosome 22:DUPLICATION" on Facebook to join.

22q11 Microduplication Parent Discussion Group:
This group is for parents of children diagnosed with 22q11.2 duplication syndrome. This group was started for parents to compare notes, bounce ideas off each other and, most importantly, be a support for each other. Parents, researchers and medical professionals are all welcome to contribute.

Contact:
Website: https://groups.yahoo.com/neo/groups/22qduplication/info?yguid=284564197

Feel free to ask your genetic counselor, medical geneticist, or primary doctor if they have other contacts with information about 22q11.2 duplication syndrome, or familiarity with chromosome disorders in general that can serve as a source of information and/or a peer mentor for support.