Charge Syndrome

Overview

CHARGE syndrome is a recognizable genetic syndrome with known pattern of features. It is an extremely complex syndrome, involving extensive medical and physical difficulties that differ from child to child. CHARGE syndrome is correlated with genetic mutation to CHD7 and the prevalence of CHARGE syndrome is 1:10,000-1:15,000 live births.

Babies with CHARGE syndrome are often born with life-threatening birth defects. They spend many months in the hospital and undergo many surgeries and other treatments. Swallowing and breathing problems make life difficult even when they come home. Most have hearing two little girls sitting on a carpet, one girl has a trach and is biting her finger.loss, vision loss, and balance problems that delay their development and communication. Despite these seemingly insurmountable obstacles, children with CHARGE syndrome often far surpass their medical, physical, educational, and social expectations. One of the hidden features of CHARGE syndrome is the determination and strong character these children display.

While extensive research has been conducted, there is still a lot to learn. Continued research is needed to help us understand the medical and developmental challenges facing individuals with CHARGE. This understanding leads the way to medical and educational interventions and therapies which help people with CHARGE syndrome overcome many of the obstacles in their lives.

Diagnosis

(also see Medical Professionals)

Who might have CHARGE? CHARGE syndrome should be considered in anyone with multiple anomalies who also has at least one of the major features (see Signs & Symptoms).

• Coloboma
• Choanal Atresia
• Typical CHARGE external ears: CHARGE Ears
• CHARGE vestibular phenotype (small or absent semicircular canals)

Diagnosis of CHARGE can be challenging because:

Features overlap with many other syndromes (also see For Professionals>Medical Professionals>Diagnosis and Testing), especially 22q11.2 deletion syndrome, Kabuki syndrome and VACTERL association.

• Every feature of CHARGE can vary from severe to absent – no one feature is seen in every child with CHARGE
• Each affected individual has a unique set of features – no two children are alike
• CHD7 gene testing is not perfect
• 10-20% of individuals with CHARGE do not have an identifiable pathogenic CHD7 variant
• Not every CHD7 variant causes CHARGE

Signs and symptoms

Physical signs

There are some physical signs that are very common in children with CHARGE syndrome and relatively rare in other conditions. These include:

a slit or groove in one of the structures of the eye (coloboma of the eye), like the iris or retina, which causes vision loss

• blocked nasal passages (choanal atresia), which causes breathing problems
• no sense of smell (anosmia)
• difficulty swallowing, which causes feeding problems
• weakness or paralysis of the facial muscles (facial palsy)
• middle and inner ear malformations, which can cause hearing loss and balance problems
• outer ear malformations like floppy ears or small or absent earlobes
• short stature.

Other possible physical signs include:

• low muscle tone
• skeletal abnormalities
• cleft lip or cleft palate
• heart defects
• genital and/or urinary abnormalities.

Cognitive signs

Children with CHARGE syndrome have widely varying thinking and learning abilities. The development of these abilities can be delayed because of children’s complex medical issues.

Most children with CHARGE syndrome have problems with their hearing, vision and balance. This affects the development of gross motor skills, fine motor skills and communication.

Behaviour signs

Children with CHARGE syndrome often have behaviour challenges because they find it difficult to communicate effectively and self-regulate.

Possible behaviour signs can include:

• repetitive behaviour – for example, biting, pacing or talking
• sensation-seeking – for example, seeking bright colours or strongly flavoured food
• difficulty with self-regulation, especially when children are stressed or overwhelmed
• difficulty shifting attention and moving on to new things
• difficulty with focus and concentration.

Clinical Diagnosis

CHARGE is primarily a clinical diagnosis, based on having at least two major and several minor features (see Signs & Symptoms). CHD7 testing is recommended and extremely helpful, but the diagnosis is often certain even with negative DNA testing. The features that make up the name CHARGE are not used for diagnosis. For a summary of the clinical criteria most often used, see CHARGE Factsheet 3 Clinical Diagnosis and features. Clinical evaluation and testing by a medical geneticist (see www.abmgg.org) is recommended for all individuals with possible CHARGE syndrome.

esting

In order to determine which signs and symptoms of CHARGE are present, many tests are helpful. Your geneticist is likely to order imaging (echocardiogram, kidney ultrasound, inner ear MRI) and lab testing (chromosomal microarray, CHD7 gene sequencing with deletion duplication testing, and perhaps whole exome sequencing, WES). The medical geneticist will take all of the information and make a determination about the likelihood of CHARGE syndrome as the best diagnosis for your child.

CHD7 testing is recommended in all individuals with CHARGE or possible CHARGE. Why?

• If the clinical diagnosis is not certain, identifying a CHD7 variant can confirm the diagnosis
• Knowing the CHD7 variant provides information for the affected child and the family
• Provides reproductive information and options
• Allows for testing other family members
• Parents, siblings and other family members can have targeted mutation analysis – testing only for the CHD7 variant identified in the person with CHARGE.
• If CHD7 testing is negative, that does not rule out CHARGE. Additional testing options should then be discussed with your geneticist.

Medical Management

POSSIBLE BREATHING AND ANESTHESIA ISSUES IN CHARGE

• Poor coordination of suck and swallow is common: there is a big risk of aspiration when anything is given by mouth
• Weak tracheal cartilage is common: trachea may collapse easily
•  Many individuals have complications with anesthesia, especially difficulty with breathing when coming out of anesthesia

Swallowing difficulty is due to cranial nerve abnormalities. Swallowing often improves spontaneously within the first three years. It is important for a feeding team to understand the likely underlying neurologic basis even if cleft palate or choanal atresia is present. Until they are able to swallow their own saliva, the children are described as being very “goopy.” After swallowing improves, children and even some adults avoid certain foods or textures.

Gastroesophageal reflux occurs frequently and may continue for years. Surgery (Nissen fundoplication) and/or medications sometimes help.

Airway can be compromised due to choanal atresia, TE fistula, aspiration pneumonias, and/or floppy tracheal cartilage (an issue for anesthesia).

When Chronic Recurrent Otitis Media (fluid in the ears, ear infections) is presumed to be the cause of conductive hearing loss, ossicular malformations (middle ear bone abnormalities) are often overlooked. MRI of the middle and inner ears is recommended.

Sinusitis can be a major problem in childhood and a cause of increased school absence. A few children have had resolution of this problem when food allergies have been identified and an appropriate diet instituted.

Hearing aids frequently do not stay on because of floppy ear cartilage or because the tape used to attach the aid to the scalp gets wet from saliva. Cochlear implants have been successful even in the presence of cochlear abnormalities. Also, depending on the type of loss, bone anchored hearing aids (BAHA) may be a successful alternative.  BAHAs can be worn via a headband prior to surgical implantation.

Detached retinas as a complication of coloboma can result in total blindness. Any change in vision status should be treated as a medical emergency.

Short stature may result from illness, heart disease, and decreased caloric intake but growth hormone deficiency should be ruled out. Endocrine evaluation is appropriate for this (by age three) as well as for hormone replacement at puberty.

Scoliosis is frequent and appears to be neuromuscular in origin. Hippotherapy (horseback riding) is often helpful.

Sleep cycles are frequently disturbed, even in those without significant visual impairments. The cause is unknown.

Chronic constipation is becoming recognized as a frequent problem that often does not respond to simple measures such as increased fluid. The cause is unknown.

Development & Outlook

Sensory deficits in CHARGE

• Hearing loss
• Vision loss
• Balance disturbances
• Decreased or absent sense of smell and taste
• Tactile defensiveness

Interoception

Communication Bubble: Vision, hearing, and smell are the distance senses. If all are impaired, the child does not know what is happening unless the person or object is within the “communication bubble.” The bubble is how far out and how well and how the child sees, hears and smells.

• Multiple Delays, Multiple Causes
• Gross motor milestones (head control, sitting, walking, etc) will be delayed due to:
• Multiple hospitalizations and illness
• Vestibular dysfunction (balance)
• Upper body hypotonia (weakness)
• Vision loss
• Language acquisition is delayed due to hearing impairment.
• Reading and understanding the environment may be delayed due to visual impairment.

Social development is delayed due to being unable to “oversee” and “overhear” information, as well as being unable to smell body odors if anosmia (lack of sense of smell) is present.

Range of Developmental/Functional Outcomes:

Early childhood: Although nearly all children with CHARGE will be delayed, we do not know the true incidence of cognitive impairments because the appropriate educational programs are often not available early in the lives of children who are deafblind. “Approximately 50% of individuals with CHARGE have average cognitive functioning, while 25% experience moderate delays, and 25% have very poor cognitive outcomes.” (Salem-Hartshorne, 2011, CHARGE Syndrome: First Edition)

Assessment: Those with no vision impairment or no hearing impairment often have normal intelligence even as measured by standardized testing. No standardized test exists for evaluating individuals with combined visual and hearing losses. State Deafblind projects can help arrange appropriate testing for children with CHARGE. Early testing should not be used as a predictor of intelligence or ultimate outcome. People with deafblindness take longer to incorporate information from the world. Children who appear far behind their typical peers may eventually catch up. The best evaluations of individuals with CHARGE are done by those few psychologists who understand deafblindness or those who are willing to work with teachers of the deaf/hard of hearing and teachers of the blind/visually impaired. It is imperative to make sure the student understands the instructions and the psychologist knows which test elements may be outside the student’s possible experience.

Other: Some children with CHARGE do have specific learning disabilities. OCD-like (obsessive compulsive disorder) behaviors may be a common feature of CHARGE. Autism is at least as common in children with CHARGE as in the general populations.

Adults: Many adults with CHARGE live with family or in group homes where they have significant support. Many adults with CHARGE are college graduates and working in a variety of professional fields. A number of adults have accurately diagnosed themselves with CHARGE. There are adults with CHARGE who are married, some with families.