Course:MEDG550/Student Activities/CHARGE Syndrome

CHARGE Syndrome

CHARGE syndrome is a genetic condition that got its name because of its recognizable features. CHARGE is an acronym for Coloboma, Heart defect Atresia of the choanae, Restricted growth and development, Genital hypoplasia, and Ear anomalies. Some combination of these features is always present in babies born with CHARGE syndrome, and they can be life threatening. CHARGE syndrome does not look the same in everybody, which means each individual will face unique challenges. This means that babies born with CHARGE syndrome will need a team of many different health care providers to follow them over time so that they can live fulfilling lives.

Clinical Features

CHARGE syndrome, while named after its core features, is actually associated with many minor features as well. The acronym describes these key features:

C - Coloboma

Coloboma is a defect of the eye where some of the normal tissue is missing. This defect can occur in many different parts of the eye, and can cause things like reduced vision, sensitivity to light, and blindness. An ophthalmologist (eye doctor) is needed to diagnose and treat this symptom.

H - Heart Defect

Heart defects that affect the structure and function of the heart are very common in babies with CHARGE syndrome. In some cases, these defects can be very serious and need surgery to correct. A cardiologist (heart doctor) is needed in order to assess the heart and determine the best course of treatment.

A - Atresia of the Choanae

Choanae are openings in the back of the nasal cavity that allow people to breathe through their nose. Atresia of the choanae means that the passage is blocked or underdeveloped, which makes it difficult or impossible to breathe through the nose. This can make it very difficult for babies to feed, leading to secondary issues like slow growth. Surgery is often needed to fix this problem.

R - Restricted Growth & Development

Babies with CHARGE syndrome are usually born a normal size and weight, but experience slow growth and development because of feeding issues. More than 90% of people with CHARGE syndrome have a hard time swallowing whole foods, and many experience reflux. This is because of other symptoms such as choanal atresia (described above), cranial nerve abnormalities making it hard to move the face muscles, or cleft palate. Soft or pureed foods are often eaten to help with growth. In order to help with diet and feeding problems, a care team may include a dietician, speech-language pathologist, occupational therapist, and/or physical therapist.

G - Genital Hypoplasia

Genital hypoplasia is underdevelopment of the external reproductive organs. In males, this might mean a small penis or undescended testicles (micropenis, cryptorchidism). In females, this may mean small labia or a missing uterus. In both sexes, there may be a delay in puberty requiring hormonal intervention.

E - Ear Anomalies

CHARGE ears.

People with CHARGE syndrome have very distinct looking ears (Figure 1). Along with the external features, the inner ear may also be underdeveloped causing hearing problems and clumsiness due to lack of balance.

Minor Features

- Cleft lip/pallete

- Cranial nerve dysfunction

- Tracheoesophageal fistula

- Developmental delay

- Growth deficiency

- Kidney problems

- Spine/neck/shoulder/hand anomalies

- Behavioural problems

- Etc.

Diagnosis

Clinical diagnosis of CHARGE syndrome is based on a list of criteria that divide the features into major and minor catagories. Major features are very commonly seen in people with the condition. These include coloboma, cranial nerve abnormalities, choanal atresia, and CHARGE ear. Minor features are not seen as frequently, or are less specific to CHARGE syndrome. These include (but are not limited to) heart defects, cleft lip/palette, genital abnormalities, kidney abnormalities, poor growth, limb abnormalities and characteristic facial features. In order to be clinically diagnosed with CHARGE syndrome, a person must have four major and three minor features.

If a clinical diagnosis is not certain, identifying a variant in the CDH7 gene through genetic testing will confirm the diagnosis. However, some people that are clinically diagnosed with CHARGE syndrome do not have a genetic variant that is detectable by our current technology and understanding. Having a negative genetic testing result does not change the diagnosis, and affected people should continue to be treated according to their clinical features.

In some cases, a CDH7 variant may be found prenatally. This depends on features seen on prenatal imaging screens that may indicate the need for genetic testing to find the cause of the abnormalities. Because the features of CHARGE syndrome are so variable and non-specific, a geneticist may decide that the best thing to offer is a whole exome sequencing (WES) test. In order to do this genetic test, a sample of DNA is needed from the baby. This can be collected through a CVS procedure, or an amniocentesis. Once the sample is collected, the lab can read the DNA sequence for all of the genes that act as instructions for the body. By doing a WES, they will find any potential spelling mistakes that could explain the ultrasound findings. In this way, they may find a CDH7 variant, and diagnose the fetus with CHARGE syndrome. Prenatal diagnosis can improve health outcomes as the healthcare team will be prepared upon the baby's arrival.

Genetics

Autosomal Dominant Inheritance

CHARGE syndrome is a genetic condition, which means that it is caused by a variant, or a change, in a persons genetic material (DNA). DNA is made up of many genes that are like instructions for the body - they tell the cells of the body how to properly function. When there is a genetic variant, it is like there is a spelling mistake in the instructions, which can sometimes have harmful effects on the body. People with CHARGE syndrome have a spontaneous (randomly occurring) change in the gene called CDH7. This gene provides instructions for the chromodomain helicase DNA-binding protein 7 (CDH7). The CDH7 protein plays a very important role in the creation of a certain type of cell that gives rise to many different structures of the body. When there is a variant in the CDH7 gene, the cells can no longer produce the CDH7 protein. Because the CDH7 protein is so important for many body structures, babies born without this protein have various features of CHARGE syndrome.

Inheritance

Most people with CHARGE syndrome have it because of a spontaneous (randomly occurring) change in the gene called CDH7. This happens in about 1/10 000 births. In very rare cases it is not spontaneous, but instead it is passed down from parent to child.

Typically, people have 46 chromosomes divided into 23 pairs. Each pair of chromosomes contains one copy that you inherit from your mother, and one copy that you inherit from your father. This means that everybody has two copies of every gene. People with CHARGE syndrome have one normal copy of the CDH7 gene, and one copy of the CDH7 gene that has a spelling mistake. These individuals then have a 50% chance of passing down the CDH7 gene that contains the spelling mistake to each new pregnancy. This is called autosomal dominant inheritance.

It is important to remember that CHARGE syndrome looks different in everybody. This means that a mildly affected parent may have a severely affected child, even though they both have the same spelling mistake in one of their CDH7 genes.

Genetic Counselling

A genetic diagnosis of CHARGE syndrome can be difficult for the affected person as well as their family members. There are many emotional side effects to raising a child with medical complications, and concerns around what that might mean when thinking about having more kids in the future. Having a genetic counsellor on your team can be useful to help talk you through those hard decisions, while sharing their knowledge about CHARGE syndrome and any related risks. Genetic counsellors can assist in every step of the process, from facilitating the genetic testing in order to reach a diagnosis, to helping a person with CHARGE syndrome work through the implications of their condition.

Diagnosis

Clinical diagnosis of CHARGE syndrome is based on a list of criteria that divide the features into major and minor catagories. Major features are very commonly seen in people with the condition. These include coloboma, cranial nerve abnormalities, choanal atresia, and CHARGE ear. Minor features are not seen as frequently, or are less specific to CHARGE syndrome. These include (but are not limited to) heart defects, cleft lip/palette, genital abnormalities, kidney abnormalities, poor growth, limb abnormalities and characteristic facial features. In order to be clinically diagnosed with CHARGE syndrome, a person must have four major and three minor features.

If a clinical diagnosis is not certain, identifying a variant in the CDH7 gene through genetic testing will confirm the diagnosis. However, some people that are clinically diagnosed with CHARGE syndrome do not have a genetic variant that is detectable by our current technology and understanding. Having a negative genetic testing result does not change the diagnosis, and affected people should continue to be treated according to their clinical features.

In some cases, a CDH7 variant may be found prenatally. This depends on features seen on prenatal imaging screens that may indicate the need for genetic testing to find the cause of the abnormalities. Because the features of CHARGE syndrome are so variable and non-specific, a geneticist may decide that the best thing to offer is a whole exome sequencing (WES) test. In order to do this genetic test, a sample of DNA is needed from the baby. This can be collected through a CVS procedure, or an amniocentesis. Once the sample is collected, the lab can read the DNA sequence for all of the genes that act as instructions for the body. By doing a WES, they will find any potential spelling mistakes that could explain the ultrasound findings. In this way, they may find a CDH7 variant, and diagnose the fetus with CHARGE syndrome. Prenatal diagnosis can improve health outcomes as the healthcare team will be prepared upon the baby's arrival.

Treatment & Management

Every person with CHARGE syndrome has different features with varying severity, so treatment and management is unique to each person. Because features of CHARGE are present at birth, babies that are affected by the condition may require immediate assessment by a team of medical specialists in order to determine a care plan. This team may include a geneticist, cardiologist, anesthesiologist, otolaryngologist, ophthalmologist, dietician, and others. Management strategies over the course of development may also include education, behaviour, and mental health specialists, as well as community supports.

Resources

Community and guidance can be so helpful for people with CHARGE syndrome and their family members. Below are a few resources to help with that.

The CHARGE Syndrome Foundation

https://www.chargesyndrome.org/

NORD: National Organization for Rare Disorders

https://rarediseases.org/rare-diseases/charge-syndrome/