DiGeorge syndrome

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DiGeorge syndrome

What is DiGeorge syndrome

DiGeorge syndrome also called 22q11.2 deletion syndrome, is a rare congenital (i.e. present at birth) disease whose symptoms vary greatly between individuals but commonly include a history of recurrent infection, heart defects, and characteristic facial features. DiGeorge syndrome is caused by a large deletion from chromosome 22 (a small band of chromosome 22 at the q11.2 area are missing) 1). The deletion of genes from chromosome 22 usually occurs as a random event in the father’s sperm or in the mother’s egg, or it may occur early during fetal development. Rarely, the deletion is an inherited condition passed to a child from a parent who also has deletions in chromosome 22 but may or may not have symptoms. The 22q11.2 deletion means that several genes (an estimated 30 to 40 genes) from this region are not present in DiGeorge syndrome patients. Many of these genes haven’t been clearly identified and aren’t well-understood. It appears that the variation in the symptoms of the disease is related to the amount of genetic material lost in the chromosomal deletion.

Other names for DiGeorge syndrome velo-cardio-facial syndrome (VCFS), conotruncal anomaly face syndrome (CTAF), Opitz G/BBB syndrome, and Cayler cardiofacial syndrome 2).

DiGeorge syndrome is associated with a range of problems including: congenital heart disease, palate abnormalities, immune system dysfunction including autoimmune disease, low calcium (hypocalcemia) and other endocrine abnormalities such as thyroid problems and growth hormone deficiency, gastrointestinal problems, feeding difficulties, kidney abnormalities, hearing loss, seizures, skeletal abnormalities, minor facial differences, and learning and behavioral differences 3). The symptoms of DiGeorge syndrome are extremely variable, even among members of the same family. No two people are ever exactly alike, even when they have the same syndrome, and not every person with the 22q11.2 deletion is affected in the same way.

The severity of DiGeorge syndrome also varies. Some children can be severely ill and very occasionally may die from it, but many others may grow up without realizing they have it.

Though not always present, the key characteristics of DiGeorge syndrome include combinations and varying degrees of:

  • heart defects
  • palate differences
  • feeding and gastrointestinal difficulties
  • immune system deficiencies
  • growth delay
  • kidney problems
  • hearing loss
  • low calcium and other endocrine issues
  • cognitive, developmental and speech delays
  • behavioral, emotional and psychiatric differences (ADHD, autism, anxiety and more)

The prevalence of DiGeorge syndrome has been estimated to be approximately 1/3000 to 1/6,000 live births. These numbers may well be higher due to the variability of the condition, difficulty in properly diagnosing, and lack of newborn screening. DiGeorge syndrome (22q11.2 deletion syndrome) is present in 1 out of every 1,000 live pregnancies, in 1 in 68 children with congenital heart disease, and in 5 to 8 percent of children born with cleft palate 4).

DiGeorge syndrome is often diagnosed soon after birth with a blood test to check for the genetic fault.

Although researchers now know that the DGS gene is required for the normal development of the thymus and related glands, counteracting the loss of DGS is difficult. Some effects, for example the cardiac problems and some of the speech impairments, can be treated either surgically or therapeutically, but the loss of immune system T-cells (produced by the thymus) is more challenging and requires further research on recombination and immune function.

There’s currently no cure for DiGeorge syndrome. Children and adults with the condition will be closely monitored to check for problems and these can be treated as they occur if needed.

For example, someone with DiGeorge syndrome may have:

  • regular hearing tests, blood tests, heart scans and measurements of their height and weight
  • an assessment of their development and learning abilities before starting school – if your child has a learning disability, they may need extra support at a mainstream school or they may benefit from attending a special school (read more about education for children with learning disabilities)
  • speech therapy to help with speech problems and dietary changes (or sometimes a temporary feeding tube) to help with feeding difficulties
  • physiotherapy for problems with strength and movement, and devices such as shoe inserts (orthoses) for leg pains
  • surgery for more severe problems – for example, surgery to repair heat defects or an operation to repair a cleft palate

You may find it useful to speak to a social worker, psychologist or counselor, who you can contact directly or through your doctor.

Genetic counseling may help you understand the risks of passing DiGeorge syndrome on to any children you have.

DiGeorge syndrome prognosis

Everyone with DiGeorge syndrome is affected differently and it’s difficult to predict how severe the condition will be. Most children survive into adulthood.

As someone with DiGeorge syndrome gets older, some symptoms such as heart and speech problems tend to become less of an issue, but behavioral, learning and mental health problems can continue to affect daily life.

Many of those who reach adulthood will have a relatively normal life span, but ongoing health problems can sometimes mean life expectancy is a bit lower than normal. It’s important to attend regular check-ups so that any problems can be spotted and treated early on.

Adults with DiGeorge syndrome are often able to live independently.

DiGeorge syndrome complications

The portions of chromosome 22 deleted in DiGeorge syndrome (22q11.2 deletion syndrome) play a role in the development of a number of body systems. As a result, the disorder can cause several errors during fetal development. Common problems that occur with 22q11.2 deletion syndrome include:

  • Heart defects. 22q11.2 deletion syndrome often causes heart defects that could result in an insufficient supply of oxygen-rich blood. For example, defects may include a hole between the lower chambers of the heart (ventricular septal defect); only one large vessel, rather than two vessels, leading out of the heart (truncus arteriosus); or a combination of four abnormal heart structures (tetralogy of Fallot).
  • Hypoparathyroidism. The four parathyroid glands in the neck regulate the levels of calcium and phosphorus in the body. 22q11.2 deletion syndrome can cause smaller than normal parathyroid glands that secrete too little parathyroid hormone (PTH), leading to hypoparathyroidism. This condition results in low levels of calcium and high levels of phosphorus in the blood.
  • Thymus gland dysfunction. The thymus gland, located beneath the breastbone, is where T cells — a type of white blood cell — mature. Mature T cells are needed to help fight infections. In children with 22q11.2 deletion syndrome, the thymus gland may be small or missing, resulting in poor immune function and frequent, severe infections.
  • Cleft palate. A common condition of 22q11.2 deletion syndrome is a cleft palate — an opening (cleft) in the roof of the mouth (palate) — with or without a cleft lip. Other, less visible abnormalities of the palate that may also be present can make it difficult to swallow or produce certain sounds in speech.
  • Distinct facial features. A number of particular facial features may be present in some people with 22q11.2 deletion syndrome. These may include small, low-set ears, short width of eye openings (palpebral fissures), hooded eyes, a relatively long face, an enlarged nose tip (bulbous), or a short or flattened groove in the upper lip.
  • Learning, behavioral and mental health problems. 22q11.2 deletion may cause problems with development and function of the brain, resulting in learning, social, developmental or behavioral problems. Delays in toddler speech development and learning difficulties are common. Some children develop attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder. Later in life, the risk of depression, anxiety disorders and other mental health disorders increases.
  • Autoimmune disorders. People who had poor immune function as children, due to a small or missing thymus, may also have an increased risk of autoimmune disorders, such as rheumatoid arthritis or Graves’ disease.
  • Other problems. A large number of medical conditions may be associated with 22q11.2 deletion syndrome, such as hearing impairment, poor vision, breathing problems, poor kidney function and relatively short stature for one’s family.

DiGeorge syndrome symptoms

DiGeorge syndrome can cause a range of problems, but most people won’t have all of these.

Some of the common features associated with DiGeorge syndrome include cleft palate, abnormalities of the heart, developmental delays and learning disabilities, psychiatric disorders, and distinct physical features.

Individuals with DiGeorge syndrome typically have a mild form of cleft palate. The lobe in the middle of the back of the soft palate (uvula) is split and there is a thin union of the two halves of the palate in the middle with a mucous covering on the rear portion of the mouth. The muscles under the soft palate do not fuse together and a notch can be felt where the hard and soft palates meet. This notch replaces the back spine of the palate.

Some of the most common issues are:

  • Learning and behaviour problems – including delays in learning to walk or talk, learning disabilities and problems such as attention deficit hyperactivity disorder (ADHD) or autism
  • Speech and hearing problems – including temporary hearing loss due to frequent ear infections, being slow to start talking and having a “nasal-sounding” voice
  • Mouth and feeding problems – including a gap in the top of the mouth or lip (cleft lip or palate), difficulty feeding and sometimes bringing food back up through the nose
  • Heart problems – some children and adults have heart defects from birth (congenital heart disease)
  • Hormone problems – an underactive parathyroid gland (hypoparathyroidism) is common and can lead to problems such as shaking (tremors) and seizures (fits)

Other possible problems include:

  • a higher risk of picking up infections – such as ear infections, oral thrush and chest infections – because the immune system (the body’s natural defence against illness) is weaker than normal
  • bone, muscle and joint problems – including leg pains that keep coming back, an unusually curved spine (scoliosis) and rheumatoid arthritis
  • short stature – children and adults may be shorter than average
  • mental health problems – adults are more likely to have problems such as schizophrenia and anxiety disorders

Other symptoms of DiGeorge syndrome:

  • Constipation
  • Leg pain
  • Differences in the blood vessels in the neck that lead to the brain (carotid arteries)
  • Bone differences, such as extra fingers, extra ribs, a missing forearm bone and spine problems including abnormal neck bones and abnormalities that
  • sometimes lead to spine curvature (scoliosis)
  • Spina Bifida
  • Juvenile rheumatoid arthritis or other autoimmune disorders
  • Eye and vision problems
  • Craniosynostosis (premature closure of the fontanels or “soft spots” of the skull)
  • Intestinal malrotation
  • Diaphragmatic hernia
  • Hirschsprung’s disease
  • Tracheoesophageal fistula
  • Laryngeal web
  • Imperforate anus
  • Absent uterus

If a child has these symptoms in any of these areas, he or she should be referred to a specialist.

Heart abnormalities

Abnormalities of the heart associated with DiGeorge syndrome often include conotruncal heart defects, or malformations of the cardiac outflow tract. These may include the following:

  • Tetralogy of Fallot, a congenital abnormality in which there is obstruction in the outflow from the right ventricle of the heart to the lungs, with an enlarged right ventricle and a displaced aorta that receives blood from both the right and left ventricles.
  • Truncus arteriosus, in which there is only a single outflow vessel instead of the typical two outflow vessels (pulmonary artery and aorta)
  • Interrupted aortic arch type B, a heart defect in which the aorta does not completely develop, thus resulting in an incomplete, or “interrupted” aortic arch
  • Ventricular septal defect, when the wall that separates the right and left chambers of the heart which receive blood and then force it back into the arteries does not form properly

Additional heart abnormalities may include differences in the structure of the aortic arch (right aortic arch, vascular ring).

Developmental delays

Developmental delays are common among children with DiGeorge syndrome. While difficulties with gross and fine motor skills are not unusual, the majority of children will demonstrate a significant delay in the development of language (70% will have minimal words by 24 months of age). Mild intellectual delay or learning disability is present in the majority of individuals with DiGeorge syndrome, with the average IQ around 70. The majority of individuals with DiGeorge syndrome will have an IQ in the range of 55-85 (general population average is 100). Problems with abstraction and comprehension in reading and math are usually apparent at school age. Severe intellectual disability is less frequent but may also be present with this syndrome.

Psychiatric disorders

Psychiatric disorders in individuals with DiGeorge syndrome include a higher prevalence of anxiety, attention-deficit disorder, and autism spectrum disorders. About one quarter of patients with DiGeorge syndrome are diagnosed with schizophrenia, which typically presents in late-adolescence. Clinical studies have shown that individuals with DiGeorge syndrome are about 25 times more likely than the general population to develop schizophrenic symptoms. However, the manifestation of schizophrenia in individuals with DiGeorge syndrome does not differ from that of the general population in regard to signs, symptoms, and treatment.

Distinct physical features

Distinct physical features sometimes associated with the syndrome include loss of muscle tone (hypotonia), small slender stature, tapered hands and fingers, small head circumference (microcephaly), recessed jaw (retrognathia), tubular nose, flat cheeks, long upper jaw, long vertical groove in the middle of the upper lip (philtrum), blue coloring under the eyes, small outer ears, thick outer rims of the ear, two different sized ears and nasal sounding speech secondary to cleft palate.

Some (but not all) of the following additional symptoms may be present in patients with DiGeorge syndrome:

  • An absent or underdeveloped thymus causing an insufficient production of antibodies
  • Deficiency of calcium in the blood (hypocalcemia)
  • Problems with thyroid function and growth hormone deficiency
  • Gastrointestinal difficulties including gastroesophageal reflux, chronic constipation, feeding difficulties, and dysmotility
  • Curvature of the spine (scoliosis)
  • Seizures and differences in the structure of the brain
  • Hearing loss
  • Eye abnormalities such as clouding of the lens of the eye or its surrounding membrane obstructing the passage of light (cataract), abnormal smallness of one or both eyeballs (microphthalmia), and twisted vessels in the optic disc
  • Rupture or protrusion in the groin or central abdominal region (inguinal or umbilical hernia)
  • Failure of the testes to descend into the scrotum in males (cryptorchidism)
  • Differences in the structure of the kidneys
  • Absent or small adenoids and absent or small tonsils.

In addition, newborn children may have obstructed breathing due to the recessed jaw and loss of muscle tone in the throat area.

DiGeorge syndrome causes

DiGeorge syndrome is caused by a problem called 22q11 deletion. This is where a small piece of genetic material is missing from a person’s DNA. Individuals with DiGeorge syndrome are missing a small part of chromosome 22. The deletion occurs at a specific location on the long arm (q arm) of chromosome 22 (region 22q11) and often includes a deletion of genes in the DiGeorge chromosomal region (DGCR) 5). The majority of individuals (85%) have a common, standard-size deletion of approximately 3 megabases (Mb). However, 15% of individuals with DiGeorge syndrome have a deletion of a smaller size, often referred to as “nested” or “distal” deletions 6). These individuals present with nearly the same spectrum of findings as those individuals with the standard deletion.

The 22q11.2 deletion is most often a “de novo” event, meaning that it is not inherited from either parent and does not usually run in a family. Only about 10% of children with the 22q11.2 deletion have a parent who is also affected. In the majority of individuals, the deletion happens sporadically without a previous family history of the condition. There is nothing the parents did or failed to do that caused the deletion to occur. For parents who do not have the deletion, the chance that a future child might be affected is very low. For individuals with the 22q11.2 deletion, there is a 50% chance of passing on the deletion to a child with each pregnancy. Individuals within the same family who have the deletion may or may not be similarly affected. For example, a mother could have very mild manifestations of the 22q11.2 deletion, while her child may have a severe heart defect needing surgery immediately after birth.

  • In about 9 in 10 (90%) cases, the bit of DNA was missing from the egg or sperm that led to the pregnancy. This can happen by chance when sperm and eggs are made. It isn’t a result of anything you did before or during the pregnancy. In these cases, there’s usually no family history of DiGeorge syndrome and the risk of it happening again to other children is very small.
  • In around 1 in 10 (10%) cases, the 22q11 deletion is passed on to a child by a parent who has DiGeorge syndrome, although they may not realize they have it if it’s mild.

What are the chances of my next child having DiGeorge syndrome?

If neither parent has DiGeorge syndrome, the risk of having another child with it is thought to be less than 1 in 100 (1%) 7).

If one parent has the condition, they have a 1 in 2 (50%) chance of passing it on to their child. This applies to each pregnancy.

Speak to your doctor if you’re planning a pregnancy and you have a family history of DiGeorge syndrome or you have a child with it.

They may refer you for genetic counseling to talk about your level of risk and discuss your options. These may include:

  • having a blood test to check if you or your partner carry the genetic problem that causes DiGeorge syndrome
  • having tests during pregnancy (chorionic villus sampling or amniocentesis) to check if your baby has the genetic problem that causes the condition – although this can’t show how severely your child will be affected
  • pre-implantation genetic diagnosis – a type of IVF where eggs are fertilized in a laboratory and embryos are tested for genetic problems before they’re implanted in the womb.

Genetic counseling may help you understand the risks of passing DiGeorge syndrome on to any children you have.

DiGeorge syndrome diagnosis

Diagnosing DiGeorge syndrome can be difficult because the condition affects each child differently, can display different symptoms that often vary in severity, and can be associated with many other disorders. In fact, most parents consult a number of physicians before their child’s problem is finally pinpointed.

If your child’s physician or specialist suspects your child has a DiGeorge syndrome, they will be referred for testing to confirm the diagnosis.

The diagnosis is confirmed by a blood test that can detect a microscopic chromosomal deletion on chromosome 22. There are many new tests to detect this deletion including whole genome array, SNP array, comparative genomic hybridization, and MLPA. FISH (fluorescence in situ hybridization) test — a highly accurate diagnostic blood test — to detect the 22q11.2 deletion, have also been useful in finding the deletion in most patients. Furthermore, routine chromosome (cytogenetic) testing is also performed because a small number of affected individuals have a chromosome rearrangement involving chromosome 22q which may change the recurrence risk counseling for the parents.

DiGeorge syndrome treatment

Although there is no cure for DiGeorge syndrome (22q11.2 deletion syndrome), many therapies and medical interventions are available to help address its associated symptoms. The earlier these symptoms are detected, the more doctors can do to help. That’s why, when diagnosed with DiGeorge syndrome, evaluation is recommended in the following areas:

  • Audiology
  • Cardiology
  • Child development and psychology
  • Cleft palate
  • Ear, nose and throat
  • Endocrinology
  • Feeding/nutrition
  • Genetics
  • Immunology
  • Neurology
  • Orthopedics
  • Urology

A team approach is often useful and generally recommended when making decisions about the treatment of symptoms in patients with DiGeorge syndrome. A geneticist, pediatrician, cardiologist, immunologist, endocrinologist, gastroenterologist, otolaryngologist, plastic surgeon, speech pathologist, audiologist, orthodontist, dentist, urologist/nephrologist, orthopedist, child development specialist, neurologist and psychologist may all be called in to consult with the parents, depending on the clinical presentation of the child.

Specialists on your care team may include these professionals and others, as needed:

  • Children’s health specialist (pediatrician)
  • Expert in inherited disorders (geneticist)
  • Heart specialist (cardiologist)
  • Immune system specialist (immunologist)
  • Ear, nose and throat (ENT) specialist
  • Infectious disease specialist
  • Hormone disorder specialist (endocrinologist)
  • Surgeon who specializes in correcting such conditions as a cleft palate (oral and maxillofacial surgeon)
  • Surgeon who specializes in correcting heart defects (cardiovascular surgeon)
  • Occupational therapist to help develop practical, everyday skills
  • Speech therapist to help improve verbal skills and articulation
  • Developmental therapist to help develop age-appropriate behaviors, social skills and interpersonal skills
  • Mental health professional, such as a pediatric psychiatrist or psychologist

Genetic counseling is recommended for families with an affected child.

Genetic counseling may help you understand the risks of passing DiGeorge syndrome on to any children you have.

Cardiology

Heart defects. Most heart defects associated with 22q11.2 deletion syndrome require surgery soon after birth to repair the heart and improve the supply of oxygen-rich blood.

Even if a child doesn’t have a known heart defect, a cardiologist’s evaluation is important, although the likelihood of finding a previously unrecognized problem is low. An evaluation usually includes a chest X-ray, an electrocardiogram (ECG), and an echocardiogram (sometimes called “echo’).

Child Development and Psychology

Your child will likely benefit from a range of therapies, including speech therapy, occupational therapy and developmental therapy. In the United States, early intervention programs providing these types of therapy are usually available through a state or county health department.

Children with a DiGeorge syndrome may have learning style differences requiring some extra help in school. In addition, young children may have delays in their developmental milestones and might benefit from early intervention, such as physical, occupational, and speech therapy. That’s why it’s important to have developmental testing on a regular basis. If your child is noted to be behind in any areas, appropriate interventions will be recommended.

Cleft Palate

Children with the deletion should see a plastic surgeon who specializes in cleft palate and velopharyngeal incompetence. In addition, they should see a speech and language pathologist who can also evaluate speech, language and — if they’re young — feeding. Some centers have specialized computer methods of objectively measuring speech to decide if intervention is necessary. Some teams also have growth specialists and dentists who monitor face, jaw, and tooth growth.

Ear, nose and throat (ENT) Audiology

This evaluation may be done as part of the cleft palate team work-up. Children with a cleft palate often have trouble with ear infections and can benefit from seeing an ear, nose and throat (ENT) doctor — also called an otolaryngologist. In addition, an ENT can help children who have problems with “noisy” breathing as a result of their disorder. Since some children with a DiGeorge syndrome may also have hearing loss, your child would benefit from a hearing test (audiogram), as well.

Endocrinology

Hypoparathyroidism can usually be managed with calcium supplements and vitamin D supplements.

Some children with DiGeorge syndrome have problems with low calcium when they’re newborns and may need a calcium supplement. During this time, the cardiologist or pediatrician will handle low calcium problems. If the problem continues, your child may need to see an endocrinologist (hormone doctor). In addition, some older children have problems with growth (called short stature) and may require growth hormone therapy. An endocrinologist can help.

Feeding / Nutrition

Children with a DiGeorge syndrome often have feeding difficulties, especially when they’re newborns. A pediatrician who specializes in feeding can help. Your child’s healthcare provider will only recommend an evaluation if a problem already exists.

Genetics

The geneticist is the person who’s most likely to have an overview of your child’s diagnosis. The geneticist stays up-to-date with the latest research about the DiGeorge syndrome. It’s important for a child with the deletion to have a yearly evaluation, so the geneticist can answer questions about his or her general care, as well as the chances that the disorder will recur in future generations of a family.

Immunology

Limited thymus gland function. If your child has some thymic function, infections may be frequent, but not necessarily severe. These infections — usually colds and ear infections — are generally treated as they would be in any child. Most children with limited thymic function follow the normal schedule of vaccines. For most children with moderate thymus impairment, immune system function improves with age.

Severe thymus dysfunction. If the impairment of the thymus is severe or there’s no thymus, your child is at risk of a number of severe infections. Treatment requires a transplant of thymus tissue, specialized cells from bone marrow or specialized disease-fighting blood cells.

Many newborns with a DiGeorge syndrome have problems with their immune systems, so they may have trouble with infections or certain vaccines. Most children outgrow this problem by their first birthdays, but some of them continue to have trouble into later childhood and adulthood. In addition, some children develop autoimmune diseases related to their immune deficiency, such as juvenile rheumatoid arthritis, idiopathic thrombocytopenia, vitiligo, and Graves disease. A child with the deletion should be evaluated by an immunologist at least once.

Neurology

Some children with a DiGeorge syndrome have a seizure disorder (unrelated to low calcium) or balance problems which require a neurologist’s services. A child’s healthcare team should determine if an initial evaluation with a neurologist may be helpful.

Psychiatry

Treatment may be recommended if your child is later diagnosed with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, depression, anxiety or other psychiatric illnesses or behavioral disorders. These may begin in childhood, but more often during teen or adult years. It is important to remember that psychiatric illnesses are treatable conditions. Changes in thinking, emotions, sleep patterns, and behavior may be early signs. Changes in functioning, e.g., socially with friends and family, and at school, home or at work may indicate the need for medical attention. Early diagnosis and effective management are best for everyone.

Urology

Some children have kidney problems — even a missing kidney — which a renal (kidney) ultrasound can detect. In addition, some children have urinary tract infections, urinary reflux, bedwetting or urinary frequency. Children having these types of problems should see a urologist familiar with DiGeorge syndrome.

Management of other conditions

These may include addressing feeding and growth issues, hearing or vision problems, and other medical conditions.

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