The Dalglish Family 22q Clinic

Recommended testing method

Chromosomal microarray analysis (CMA; also known as genomic SNP microarray or array comparative genomic hybridization (aCGH)) is the preferred initial clinical genetic test for suspected 22q11.2 deletion syndrome in a family.

This lab technique can show:

1. the size of the 22q deletion;
2. whether there are any other clinically relevant copy number changes (deletions or duplications) elsewhere in the genome; and
3. other chromosome disorders that have similar phenotypes (health issues) as 22q11.2DS

Older methods, such as fluorescence in situ hybridization (FISH), are not able to provide these important pieces of information. FISH may still be used for follow-up testing in other family members of individuals with a confirmed 22q11.2 deletion.

It is recommended that patients and families receive genetic counselling both before and after undergoing any genetic tests.

See also: How is Genetic Testing for 22q11.2 Deletions Done?

Inheritance

Any person (male or female) with 22q11.2DS has a 50% chance of passing the deletion onto his/her children. It is important for the person with 22q and their partner to receive genetic counselling and discuss the options available before planning any pregnancies. See Prenatal screening and diagnostic considerations for 22q11.2 microdeletions for more information.

Many adults with 22q11.2DS have learning difficulties or mild intellectual disabilities, but not everyone is affected to the same degree. There may be special challenges with:

• Problem solving
• Arithmetic / Math
• Flexibility
• Complex (e.g. abstract) concepts
• Working memory
• Concentration
• Impulse control
• Making “good” (safe and appropriate) decisions in social situations

Social cognition is also commonly affected, with difficulties recognizing emotions or sarcasm and interpreting others intentions and behaviour – so some find it difficult making or maintaining friendships. Inability to make good judgments and decisions increases the risks of being bullied and/or taken advantage of. This includes financially, sexually, and in interactions over the internet. However, some affected adults may not understand, or are unwilling to accept, that they need help.

There is a wide range levels of adaptive functioning (how affected individuals cope with the demands of their environment). Thinking is often literal or concrete, and most need some help with completing forms, managing money, and making complex decisions. It is recommended that teenagers (e.g., aged 16 – 17) with 22q11.2DS be assessed in regard to their cognitive and adaptive abilities, so that suitable supports can be set up for daily functioning, school/college, and potential employment, to maximize success.

Psychiatric illnesses (mental health problems) are treatable using standard effective therapies. Medical providers should take into account other health conditions and intellectual disabilities.

Family members should pay attention to onset or worsening of emotional or temper outbursts and irritability, which may be signs of untreated or undertreated anxiety or psychotic illness. Early detection and treatment are important for achieving the best outcomes.

• Common in adults with 22q11.2DS:
  • Anxiety disorders – Excessive fears/worrying that affect the person’s functioning at home, with people, and at school or work
  • Psychotic disorders – Include symptoms of being out of touch with reality (e.g. paranoid, hearing or seeing things) with major changes in functioning
• Less common in adults with 22q11.2DS:
  • Childhood conditions, e.g. attention deficit disorder, autism spectrum disorder
  • Substance-use disorder – Excessive use of alcohol and/or drugs like cannabis
  • Catatonia – Extreme physical slowness, not talking, odd postures

Schizophrenia is a serious but treatable illness. About 1 in every 4 to 5 adults with 22q11.2DS will develop schizophrenia. Some of the features include:

• Delusions – A false belief that cannot be changed with reasoning. e.g. Person believes that they are being followed.
• Hallucinations – A mistaken perception, e.g., the person hears voices that no one else can hear.
• Significant decline in ability to function (self care, school/work, social).
• Additional symptoms include (but are not limited to): disorganized thinking, disorganized behaviour.

Standard management for schizophrenia includes antipsychotic medications and support. Co-existing conditions (e.g. hypocalcemia, hypothyroidism, asthma) need to be taken into account.

For more information, see the Mental Health Series in Health Conditions Explained from the International 22q11.2 Foundation.

• Common in adults with 22q11.2DS:
  • Seizures – Sudden bursts of electrical activity in the brain that can be seen on an electroencephalogram (EEG). These may lead to uncontrolled movements. Seizures can be of various types. Sometimes seizures are associated with low calcium levels, low magnesium levels, fevers, certain medications, etc. The treatment of seizures usually depends on the seizure type.
• Less common in adults with 22q11.2D:
  • Epilepsy – Having two or more seizures with no known trigger. Adults with 22q11.2DS have a 4-fold increased risk of epilepsy.
  • Early-onset Parkinson’s disease – Brain cells that make dopamine (which controls movement) slowly stop working, leading to slowed movement, muscle stiffness, tremors, and trouble with balance and coordination. Specialist assessments can help with diagnosis and effective treatment.
• Rarer, but clinically relevant other movement disorders:
  • Dystonia – Muscles contract without warning
  • Myoclonus – Muscles jerk or twitch briefly, sometimes leading to dropping things
• Common, but not requiring clinical attention:
  • Asymmetric facies / hemifacial paresis – Muscles on one side of the face move more easily than on the other side, usually present from birth
  • White matter hyperintensity signals on MRI – Areas of brightness on magnetic resonance imaging (MRI) of the brain

Treatments that are helpful for seizures and movement disorders in the general population are also helpful for adults with 22q11.2DS.

Issues related to hormones that help the body function (and can usually be found with standard bloodwork) in adults with 22q11.2DS:

• Common:
  • Hypocalcemia – Having too little calcium in the blood.
    • This affects over half of the people with 22q11.2DS.
    • Usually associated with the parathyroid glands producing too little parathyroid hormone (PTH), a condition called hypoparathyroidism.
    • Hypothyroidism (low thyroid, see below) and hypomagnesemia (low magnesium, see below) can contribute to low calcium levels.
    • Can be worsened by alcohol and soft drinks, especially colas.
    • Often no symptoms (i.e., needs a blood test to detect) but can cause tiredness, irritability, muscle movements, and heart arrhythmia (irregular heart rate)
    • Seizures and osteoporosis (having bones that break very easily) are more likely when calcium levels are low.
  • Thyroid disease – Thyroid gland producing too little (or too much) thyroid hormone.
    • Almost 1 in every 4 adults with 22q11.2DS needs treatment for hypothyroidism (simple replacement of thyroid hormone in a little pill)
    • If untreated, weight gain, slowed thinking, and strain on the heart and other serious conditions are possible
  • Obesity – Obesity can increase the risk of diabetes, heart disease, high blood pressure and certain cancers. High triglyceride levels are common in 22q11.2DS at young ages. Both of these conditions can be prevented or managed through dietary changes and exercise/activities.
• Less common but clinically relevant:
  • Type 2 diabetes – The body cannot use glucose as a fuel properly, leaving too much glucose in the blood. In the long term, type 2 diabetes can lead to other major health problems.
  • Hypomagnesemia – Having too little magnesium in the blood.
    • Possible symptoms include shaking, tiredness, muscle spasms, and increased risk of low calcium and seizure.

All adults with 22q11.2DS need vitamin D supplements (and sometimes calcium). All adults with 22q11.2DS need regular checks for blood calcium levels and related measures. Checks for calcium levels should also be done before and after surgery, in acute illnesses, and during pregnancy. Please refer to the text of the guidelines for details of managing the endocrine aspects of 22q11.2DS.

Heart and lung issues in adults with 22q11.2DS:

• Common:
  • Congenital heart disease requiring follow up – Congenital heart disease (CHD) involves heart defects (differences in how the heart develops) that have been present since birth [See Heart Series in Health Conditions Explained from the International 22q11.2 Foundation].
    • Significant CHD is present in about 1 in every 4 individuals with 22q11.2DS
    • Although many heart conditions are repaired during childhood, the heart needs to be checked by specialists throughout life. In some cases, valves or conduits may need to be replaced or medications or pacemakers given, to help the heart to work.
  • Asthma – Inflammation or narrowing of airways; can start in childhood or adulthood. Puffers are often helpful.
• Less common:
  • Hypertension – High blood pressure
  • Arrhythmia – Irregular heart rate, which can be life-threatening.
  • Heart failure – Heart does not pump blood as well as it should.
  • Aortic root dilatation – Widening of part of the aorta, found on echocardiogram, can sometimes prevent the aortic valve from fully closing. [See 22q Glossary in Health Conditions Explained from the International 22q11.2 Foundation]
• Rare, but clinically relevant:
  • Lymphedema – Swelling (usually in arms and/or legs) due to build-up of lymph fluid, which is the fluid that brings cells to fight infections.

Some individuals with 22q11.2DS are at a higher risk of infective endocarditis, a severe heart problem caused by bacteria. This requires the person with 22q to need a dose of antibiotics before each dental appointment. The cardiologist (heart specialist) will let you know if you need this preventive treatment.

Issues related to sleep in adults with 22q11.2DS:

• Relatively common:
  • Sleep pattern disruptions (e.g. restless legs)
  • Obstructive sleep apnea (OSA) – Muscles in the throat become too relaxed during sleep and prevent proper breathing. Low oxygen levels can put a strain on the heart and cause memory loss or other problems with thinking.

Poor sleep can contribute to fatigue and negative mood and can also affect the person’s ability to function. Causes of poor sleep can include many factors, such as untreated or undertreated mental health problems, stress, and caffeine. Managing the underlying factors and proper sleep hygiene can help improve sleep as well as overall health.

To diagnose OSA, a sleep study is needed. Continuous positive airway pressure (CPAP) is an effective therapy that may be recommended, and adults with 22q11.2DS can use this successfully.

Diet, supplements, medications, and other health conditions such as anxiety, thyroid disease, and Parkinson’s disease may contribute to digestion issues such as:

• Common in 22q11.2DS:
  • Constipation – Stools become hard, dry, and difficult to pass. Ensuring a proper diet is the first line of management, but often stool softeners and/or other treatments are needed.
  • Gastro-esophageal reflux disease (GERD) – Stomach acid flows backwards, up into the esophagus (“heartburn”).
  • Dysphagia – Difficulty swallowing. If swallowing pills becomes difficult, check with a pharmacist and doctor to find other ways to take medications.
• Not very common:
  • Gallstones – Can be detected by abdominal ultrasound. May need surgery in some cases.
  • Fatty liver – Can be detected by abdominal ultrasound. Standard management as for obesity can prevent liver injury.

In addition to congenital anomalies (e.g. missing one kidney, blockage of ureters) that sometimes need surgery as a baby or child, other possible problems include:

• Dysmenorrhea – (in females) severe cramps during menstrual periods.
• Renal cysts – Pouches of fluid in the kidney that can be detected on ultrasound. Usually do not cause symptoms.
• Impaired kidney functioning – Several possible causes, including dehydration (too little water intake), too much calcium, diabetes.
• Pregnancy loss appears to be more common when the fetus has a 22q11.2 deletion.

Standard management is recommended for dysmenorrhea, renal cyst, impaired kidney functioning, and pregnancy loss.

Issues related to sexual intimacy (e.g. understanding what is meant by consent, sexually-transmitted infections), pregnancy, and childbirth:

• Pregnancy and delivery complications may be more likely if the fetus has a 22q11.2 deletion, regardless of whether the parent (mother or father) is affected.
• Standard methods of contraception and infection/disease prevention, and pregnancy and delivery management at a specialty clinic, are recommended.

See also: Prenatal screening and diagnostic considerations for 22q11.2 microdeletions

Issues in adults with 22q11.2DS that may need surgery:

• Hernias – A weakness in the connective tissue that holds organs in place
• Pilonidal sinus or cyst – Near the tailbone, a pocket of hair and skin that can get infected and cause pain.
• Varicose veins – Enlarged and twisted veins near the skin, usually in the leg, that sometimes needs special stockings or other treatments.

Recommendations:

• Attention to other health conditions.
• Check blood count and calcium levels before and after surgery.
• Watch out for possible differences in anatomy, e.g. may need smaller intubation equipment
• Calm fears

Some increase in routine risks of surgery that can be prevented or otherwise managed, for example:

• Bleeding
• Infections
• Seizures
• Collapsed lung

Issues related to bones and joints in adults with 22q11.2DS:

• Common:
  • Scoliosis – The spine (backbone) curves sideways (the extent of the curve varies from person to person). Severe cases may require bracing or surgery.
  • Patellar dislocation – The kneecap slips out of place and can cause a fall. Severe cases may require bracing or surgery.
  • Flat feet – When under pressure, the tendons under the feet cannot support the arches, so that the entire soles touch the floor. Flat feet that are severe enough to cause pain may need treatment and support (e.g., orthotic devices).
• Less common, but clinically relevant:
  • Clubfoot – One or both feet turn downward and inward (instead of being straight), because the tendons connecting muscles to bone are too short.
  • Arthritis – Inflammation or swelling of one or more joints, often with stiffness and pain.

Standard management will usually be effective.

Issues related to the body’s defense against infections and allergic reactions:

• Autoimmune diseases – The immune system attacks parts of the healthy body. These are common in adults with 22q11.2DS, and can include, e.g., thyroid diseases, psoriasis, and many other conditions.
Atopy – Having a tendency to develop allergies.
• Recurrent infections – May be associated with a type of immune deficiency.

All individuals with 22q11.2DS benefit from standard vaccinations, including those against COVID-19 and influenza (even if some may have a reduced vaccine responses).

Issues related to blood and cancers in adults with 22q11.2DS:

• Impaired hemostasis – Decreased ability for blood to clot normally. Examples include nosebleeds, heavy menstrual bleeding, and bleeding after surgeries.
• Anemia of chronic disease – Not having enough red blood cells because of a long-term illness that causes inflammation.
• Rare, but clinically relevant:
  • Immune thrombocytopenia (ITP) – The body’s immune system mistakenly destroys platelets (key blood cells that help with clotting). Immune suppressive strategies may be needed to treat this condition.
  • Hemolytic anemia – Red blood cells are destroyed faster than they can be made.
  • Possible increased risk of cancer – Healthcare provider should ensure that routine preventive cancer screening is done, e.g., for cervical cancer (Pap smear), for bowel cancer (fecal blood samples or colonoscopy), for breast cancer (mammograms).
• Common, but not requiring clinical attention:
  • Mild-moderate thrombocytopenia – Having relatively fewer platelets (which are normally involved in blood clots), but with no problems with excess bleeding.
  • Mild cytopenias – Having relatively fewer blood cells, e.g., white blood cells

Skin problems, e.g. seborrheic dermatitis and acne, are common in adults with 22q11.2DS. Some, e.g. psoriasis, are related to autoimmune diseases. Rashes are common. Standard treatments apply.

Issues related to the senses of hearing, vision, and smell in adults with 22q11.2DS:

• Common:
  • Hearing loss (especially high-frequency loss):
    • Conductive hearing loss involves the outer or middle ear. Sound waves do not fully travel to the inner ear.
    • Sensorineural hearing involves a problem with the hearing nerve.
    • Ear wax removal by a clinician is needed for many adults with 22q11.2DS.
    • Hearing aids may be helpful.
  • Vision problems – Glasses are sometimes needed for the individual to see clearly. Common in 22q11.2DS are:
    • Farsightedness – Closer objects are blurry.
    • Astigmatism – Objects up close and at a distance are blurry.
• Rare, but clinically relevant:
  • Olfactory deficits – Having some trouble smelling is common in 22q11.2DS. When severe, this decreases the individual’s ability to detect some dangers (e.g. smelling smoke or spoiled food), and affects the enjoyment of food.
  • Keratoconus, cataracts, other treatable eye problems

Regular vision and hearing checks are recommended.

Issues related to teeth in adults with 22q11.2DS:

• Common:
  • Dental caries (also called tooth decay or cavities) – Holes that form when acid from bacteria erodes the surface of the teeth
  • Enamel hypoplasia – The enamel (hard surface of the teeth) is not formed well
  • Low saliva secretion – There is not enough saliva to help clean the teeth and bring important minerals to keep the teeth healthy. This contributes to the weakening of the surface of the teeth, allowing acid to erode it more easily.
• Rare, but clinically relevant:
  • Malocclusion – Teeth not aligned properly.

Regular dental care is very important in 22q11.2DS. Standard management is recommended.

For more information about the three common dental issues mentioned above as well as tips on improving dental health, see the Dental Series in Health Conditions Explained from the International 22q11.2 Foundation.

Adults with 22q11.2DS are at risk of having certain conditions (obesity, type 2 diabetes, Parkinson disease (PD), and hearing loss) at a younger age than the general population.

Issues related to getting older in adults with 22q11.2DS:

• Common:
  • Multimorbidity – Having 2 or more long term health issues that need treatment.
• Rare, but clinically relevant:
  • Elevated premature mortality risk – Having a higher risk of dying earlier compared to the general population.

This is another reason for specialty clinics for adults with 22q11.2DS, and why a holistic, proactive, and multi-system approach to lifelong care is important.