Charge Syndrome

Updated February 14, 2020

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A list of references is also included at the bottom of this article.

What is CHARGE Syndrome?

CHARGE syndrome is a genetic disorder characterized by several types of malformations throughout the body. These vary from person to person but can create multiple life-threatening medical problems.


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Disclaimer: Before You Read

It is important to know that your genes are not your destiny. There are various environmental and genetic factors working together to shape you. No matter your genetic makeup, maintain ideal blood pressure and glucose levels, avoid harmful alcohol intake, exercise regularly, get regular sleep. And for goodness sake, don't smoke.

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CHARGE syndrome is an abbreviation for several of the common features of this disorder:

Coloboma of the eye

Heart defects

Atresia of the choanae (choanal atresia)

Retardation of growth

Genital abnormalities (genital hypoplasia)

Ear abnormalities and deafness

It is also known as CHARGE association or Hall-Hittner syndrome.

Clinical Features / Signs and Symptoms of CHARGE Syndrome 

The clinical features, signs, and symptoms of CHARGE syndrome include:

Behavioral issues. Several have been noted, including repetitive, obsessive-compulsive, aggressive and self-abusive behaviors, and attention-deficit hyperactivity disorder (ADHD)

Brain abnormalities. Central nervous system issues can include arrhinencephaly, corpus callosum agenesis, posterior fossa anomalies and olfactory deficiencies. 

Choanal atresia. This congenital birth disorder occurs when abnormal bony or soft tissues block the back of the nasal passage. Depending on the severity, immediate resuscitation may be required.

Colobomata. Most people with CHARGE syndrome have eye problems that can include asymmetry in the eyes, light sensitivity, impaired vision, retinal detachment, and other related issues. 

Dental anomalies. Specific conditions can include a protruding jaw, overbite, and poor mineralization of the enamel.

Esophageal atresia or tracheoesophageal fistula. Approximately 1 in 5 infants with CHARGE syndrome may suffer from blockages that create feeding difficulties and respiratory distress.

Facial palsy. About half of all CHARGE syndrome patients can have unilateral or bilateral facial palsy resulting in a lack of facial expression.

Genitourinary abnormalities. More than half of all males have genital hypoplasia that results in a micro-penis and cryptorchidism.

Growth retardation. Due to low growth hormone secretion, children born with normal birth weight and length show a marked decline from in development later in infancy.

Hearing loss. This issue can range from minor to profound and may be caused by a malformed cochlea, hypoplasia of the auditory nerve, facial paralysis, or other similar conditions.

Heart defects. A vast majority of individuals often suffer from complex heart defects, including conotruncal anomalies, AV canal defects, and aortic arch anomalies, among others.

Immunodeficiency. Those with CHARGE syndrome can suffer from mild to severe T-cell deficiency.

Limb and bone abnormalities. A wide variety of limb abnormalities occur in 1 of 3 people diagnosed with CHARGE syndrome. That can include hypoplastic nails, polydactyly, brachydactyly, missing digits, missing ribs, abnormal vertebrae, clubfoot, tibial anomalies, joint hyper flexibility, and other related conditions.

Renal anomalies. This can include a solitary kidney, hydronephrosis, and renal hypoplasia.

Scoliosis. Defined as a curvature of the spine.

Sinusitis. This results in severe pain and sudden behavioral changes. 

Speech, language, and developmental delays.

Swallowing problems. Nerve abnormalities, choanal atresia, or cleft palate can create coughing, choking, nasal regurgitation, or gastroesophageal reflux often means infants require nasogastric or gastric tube feeding, sometimes for many years. Structural defects can lead to repeated bouts of pneumonia and long-term lung damage.

Vestibular abnormalities. This affects virtually all people with CHARGE syndrome and is characterized by abnormalities of the semicircular canals, leading to poor balance and delayed motor development.

Signs and symptoms are broken into either Major or Minor diagnostic characteristics, depending on the frequency that they occur.

Prevalence and Risk Factors of CHARGE Syndrome 

It is estimated that CHARGE syndrome occurs in approximately 1 in 8,500 to 10,000 newborns 1. It is considered a rare disorder that affects males and females equally and has been diagnosed in all races throughout the world.

Some experts believe that CHARGE syndrome occurs more frequently because it is either misdiagnosed or undiagnosed, especially in children with milder and fewer symptoms.

Many newborns often have several life-threatening medical conditions when multiple symptoms are present. The most significant risk factor appears to be recurrent feeding problems and is a leading cause of death in all age groups.

Causes of CHARGE Syndrome 

In most cases, CHARGE syndrome is caused by mutations in the CHD7 gene. This gene provides instructions for making a protein called chromodomain helicase DNA binding protein 7. 

The protein is found throughout the body, including eyes, inner ears, and the brain. The CHD7 gene is active in many parts of the brain, including the olfactory bulb, which is vital to the perception of odors.

Mutations of the CHD7 gene can produce an abnormal CHD7 protein that breaks down prematurely. When this happens, the resulting shortage disrupts gene expression. When changes in gene expression take place during embryonic development, researchers believe this leads to signs and symptoms of CHARGE syndrome.

It's estimated that more than 90% of CHARGE patients have mutations in the CHD7 gene 2. But in some cases, people with CHARGE syndrome do not have an identified CHD7 mutation. That may be because a genetic mutation affecting the CHD7 gene has not been found, or that there is a mutation in a different gene that could cause CHARGE syndrome.

Researchers have not found any exposures during pregnancy that are associated with CHARGE syndrome. Retinoic acid, which is a medicine taken for severe acne, can cause similar symptoms if taken during the first trimester of pregnancy. 

Does Charge Syndrome Run in Families?

CHARGE syndrome caused by CHD7 gene mutations follows an autosomal dominant pattern of inheritance. That means one copy of an altered gene in each cell can cause CHARGE syndrome.

In most cases, CHARGE syndrome is the result of new mutations to the gene. That means the condition will occur in people who have no history of CHARGE syndrome in their family and is described as de novo. A person rarely inherits the CHD7 gene mutation from a parent.

A few parents have gonadal mosaicism (other sperm or eggs that carry the CHD7 variant), which can place additional children at a 50-50 risk. Based on data collected thus far, it’s believed that the recurrence risk is about 1-2% 3.

Even if the CHD7 mutated gene is passed on, it is not possible to predict how an affected child will be impacted. When more than one sibling has CHARGE syndrome, the symptoms are often very different. Also, parents who are only mildly affected by CHARGE syndrome face the possibility that a child could be affected to a much higher degree.

Diagnosis of CHARGE Syndrome 

A clinical diagnosis of CHARGE syndrome is based on a combination of the presence of several major and minor diagnostic characteristics.

Diagnosis is categorized as Definite CHARGE syndrome when a person is diagnosed with all four major characteristics and three minor characteristics. It is diagnosed as Probable or Possible CHARGE syndrome when one or two major characteristics and several minor characteristics are noted 4.

Source: National Center for Biotechnology Information

If a diagnosis of CHARGE syndrome is possible but not certain, genetic testing will be recommended to determine if the CHD7 gene has mutated. Other family members may also be tested to determine if they also have a mutated gene.

It should be noted that even if CHD7 gene testing is negative, that does not entirely rule out the presence of CHARGE syndrome. Other testing may be required and should be discussed with a genetic counselor.

Additional testing may also result in a differential diagnosis. There are disorders similar to CHARGE syndrome that may be the actual medical condition at hand.

For example, DiGeorge sequence is a combination of complex heart defects, abnormalities of the thyroid and parathyroid glands, and immunodeficiencies. Sometimes, this disorder appears in CHARGE syndrome, and at other times, it does not.

Deletion 22q11.2 syndrome (also known as Velocardiofacial syndrome, VCF, or Shprintzen syndrome) is much more common than CHARGE syndrome. The two syndromes share many common features, including swallowing problems, cleft palate, heart defects, and facial malformations. A missing piece of chromosome 22 characterizes VCF. 

Kabuki syndrome overlaps with CHARGE syndrome in many ways, but they are considered different disorders. There is significant phenotypic overlap, but Kabuki syndrome is caused by a mutation of the lysine (K) methyltransferase 2D (KMT2D) as opposed to the CHD7 gene 5.

Some of the clinical symptoms of CHARGE syndrome can be detected through a prenatal level II ultrasound examination in a mother’s second trimester.

Potential Complications, Treatment and Care Options for CHARGE Syndrome 

Because there are so many possible serious medical conditions that can be associated with CHARGE syndrome, treatment often requires a simultaneous multidisciplinary approach.

Infants can be born with or develop several possible respiratory issues (i.e., choanal atresia, TE fistula, aspiration cases of pneumonia, tracheomalacia, or an aberrant subclavian vessel). As many as half of all patients may require a tracheostomy at some point 6. Airway intubation is usually needed early in life, and multiple surgeries are often necessary to keep the nasal airway open. 

Due to motor and sensory challenges, babies may have problems with feeding or swallowing. Extensive therapeutic approaches are often necessary and can include speech pathology, occupational therapy, and nutrition. 

Renal evaluations are often recommended to be on guard for urinary tract infections or to help explain fever or irritability in young children.

Visual issues due to photophobia or optic nerve defects may mean a child will need to wear tinted glasses and learn alternate forms of visual stimuli and sign language. Glasses may correct refraction issues. Since retinal detachment can occur, resulting in total blindness, vision changes should be treated as a medical emergency. 

Endocrine system monitoring may be required, especially when growth appears to be stunted. A growth hormone deficiency may require replacement therapy.

Because hearing loss is so common with CHARGE syndrome, it should be assumed a patient has a loss until proven otherwise. As soon as a loss is documented, hearing aids, auditory and speech training, and sign language should be implemented. Cochlear implants may also be recommended to improve sound awareness and speech recognition.

Children diagnosed with vision and hearing loss can be considered “deafblind” and eligible for educational resources in several states. Total hearing or vision loss is not a pre-condition for assistance. Referral to services as soon as possible after the diagnosis of a dual sensory loss is critical for developing an effective treatment plan. 

Sleep is often disrupted, sometimes due to obstructive sleep apnea. Melatonin and other medications may be required to promote and regulate sleep.

Psychological evaluations and treatment are often necessary to deal with communication and behavioral issues that occur in most CHARGE patients. That can include treating obsessive-compulsive disorder and ADHD. 

Heart, dental, and gastrointestinal treatment may be necessary to remedy a wide array of congenital challenges. 

There may also be challenges when performing procedures due to facial palsy and risks in using anesthesia due to problematic tissues.

The Prognosis of CHARGE Syndrome 

The prognosis of a person diagnosed with CHARGE syndrome depends greatly on the severity and number of major and minor characteristics that are present. There is a poor life expectancy and a high mortality rate in infants with heart and brain defects.

Feeding difficulties are also a major contributing factor to morbidity in all ages.

In other instances where symptoms are mild, with proactive and ongoing multifaceted treatment and monitoring, patients can live well into adulthood.

What to do Next: Living with CHARGE Syndrome 

Because CHARGE syndrome can present itself in many ways, a course of treatment must be responsive to the individual symptoms on a case by case basis.

Ongoing evaluations, especially for visual and airway related issues, are critical since changes can produce significant complications. Critical cardiac assessments may also be required if heart issues have been detected. CT scans and evaluation of cranial nerve functions are vital as well.

The best course of action is to work closely with a primary care physician and take proactive steps when indicated.

Depending on your particular situation, consultation with a genetic counselor may also be another wise course of action. 





For More Information

CHARGE Syndrome Foundation

141 Middle Neck Road

Sands Point NY 11050

Phone: 800-442-7604 (toll-free); 516-684-4720

Fax: 516-883-9060

Email: [email protected]

www.chargesyndrome.org

Referenced Sources

  1. CHARGE syndrome.
    Genetics Home Reference. February 2020.
  2. CHARGE syndrome due to deletion of region upstream of CHD7 gene START codon.
    Elisa Pisaneschi,corresponding author Pietro Sirleto, Francesca Romana Lepri, Silvia Genovese, Maria Lisa Dentici, Stefano Petrocchi, Adriano Angioni, Maria Cristina Digilio, and Bruno Dallapiccola. 2015.
  3. CHARGE Syndrome.
    Seema R Lalani, MD, Margaret A Hefner, MS, John W Belmont, MD, PhD, and Sandra LH Davenport, MD, CM. October 2, 2006; Last Update: February 2, 2012.
  4. CHARGE Syndrome.
    Seema R Lalani, MD, Margaret A Hefner, MS, John W Belmont, MD, PhD, and Sandra LH Davenport, MD, CM. October 2, 2006; Last Update: February 2, 2012.
  5. CHARGE Syndrome.
    National Organization for Rare Disorders (NORD). Retrieved online, Jan 2019.
  6. CHARGE Syndrome.
    Seema R Lalani, MD, Margaret A Hefner, MS, John W Belmont, MD, PhD, and Sandra LH Davenport, MD, CM. October 2, 2006; Last Update: February 2, 2012.