Years published: 1988, 1988, 1990, 1996, 1997, 1998, 2000, 2002, 2007, 2008, 2012, 2015, 2018, 2023
NORD gratefully acknowledges John M. Graham, Jr., MD, ScD, Pediatric Consultant in Clinical Genetics and Dysmorphology, Department of Pediatrics, Cedars-Sinai Medical Center and Harbor-UCLA Medical Center, for assistance in the preparation of this report.
CHARGE syndrome is a rare disorder that arises during early fetal development and affects multiple organ systems. The CHARGE acronym comes from the first letter of some of the more common features seen in these children: (C) = coloboma (usually retinochoroidal) and cranial nerve defects (80-90%); (H) = heart defects in 75-85%, especially tetralogy of Fallot; (A) = atresia of the choanae (blocked nasal breathing passages) (50-60%); (R) = retardation of growth (70-80%) and development; (G) = genital underdevelopment due to hypogonadotropic hypogonadism; (E) = ear abnormalities and sensorineural hearing loss (>90%). In addition to the CHARGE features above, many children with CHARGE syndrome have other features, including characteristic facial features: asymmetric facial nerve palsy, cleft lip or palate, esophageal atresia (blind-ending food pipe) or tracheoesophageal fistula (connection between the windpipe and the food pipe). The symptoms of CHARGE syndrome vary greatly from one child to another.
The cause of CHARGE syndrome is usually a new variant (change) in the CHD7 gene, or rarely, changes in the region of chromosome 8q12.2 where the CHD7 gene is located.
CHARGE syndrome affects multiple organ systems, resulting in multiple problems apparent at birth. Other characteristics of CHARGE syndrome may not become apparent until later in life. The diagnosis of CHARGE syndrome should be made by a medical geneticist based on the presence of at least one major criterion and several minor and/or occasional criteria of CHARGE syndrome (see below).
Major Diagnostic Criteria (The 4 C’s)
Features seen commonly in CHARGE syndrome that are rarely seen in other conditions include coloboma, cranial nerve abnormalities, choanal atresia and typical CHARGE ear.
A coloboma is a cleft or failure of the eyeball to close during fetal development. This can result in a keyhole-shaped pupil (iris coloboma) and/or abnormalities in the retina, macula or optic nerve. Very small eyes (microphthalmia) or missing eyes (anophthalmia) can be severe forms of coloboma. Colobomas of the retina or optic nerve may result in significant vision loss, including blind spots, problems with depth perception or legal blindness. Colobomas occur most frequently in the retina and are present in at least 70-90% of patients with CHARGE syndrome. Examination of 38 eyes in 19 patients with CHARGE syndrome and confirmed CHD7 variants revealed colobomata affected the posterior segment of 35 eyes in 18 patients. Both retinochoroidal and optic disk colobomata were observed in both eyes (bilaterally) in 15 patients and unilaterally in 3 patients. The coloboma involved the macula totally or partially in 21 eyes of 13 patients. Bilateral large retinochoroidal colobomata are the typical eye feature of CHARGE syndrome in patients with confirmed CHD7 variants; however, even eyes with large colobomata can form maculas. Many children with colobomas (even just an iris coloboma) may be sensitive to bright light (photophobia).
Cranial nerve abnormalities
Sensorineural (nerve) hearing loss in CHARGE syndrome is due to abnormalities in cranial nerve VIII. Cranial CT scans often reveal hypoplastic cochlea (81%) with absent semicircular canals in most patients. Hearing loss and difficulty with balance are the most common features associated with cochlear hypoplasia and absent semicircular canals. CHARGE syndrome is associated with characteristic external ears that tend to protrude and lack lobes. Hearing loss can range from a mild hearing loss to profound deafness. Hearing loss can be very difficult to measure in young children. Most affected children also have balance problems (vestibular abnormalities) associated with absent semicircular canals, which is a key finding in making the diagnosis of CHARGE syndrome.
Most children with CHARGE syndrome have swallowing problems (cranial nerves IX/X). These swallowing problems include the inability to coordinate suck and swallow, leading to gagging and aspiration of food into the lungs, which can cause pneumonia. Many children require feeding via a gastrostomy tube (tube directly into the stomach through the abdominal wall) until they can swallow safely.
Many children with CHARGE syndrome have asymmetric facial palsy resulting in paralysis of one side of the face (cranial nerve VII). This results in a lack of facial expression, which is important when a child is working with teachers or therapists.
Most children with CHARGE syndrome have an absent or reduced sense of smell (cranial nerve I) which makes it harder to learn to eat. Most patients with CHARGE syndrome have absent or abnormal olfactory bulbs on MRI, leading to a diminished sense of smell. Smell-testing can predict the presence of a problem in the production of male hormones called hypogonadotropic hypogonadism. The combination of a diminished or absent sense of smell with hypogonadotropic hypogonadism (termed Kallman syndrome) results in small external genitalia. This is very common in CHARGE syndrome and warrants consultation with an endocrinologist.
Choanae are the passages from the back of the nose to the throat that make it possible to breathe through the nose. In about half of all children with CHARGE syndrome, these passages may be blocked (atresia) or narrowed (stenosis). Among 12 patients with bilateral choanal atresia, 10 had related malformations, 3 of which had CHARGE syndrome. Surgery can often correct these defects. Unilateral atresia can usually be corrected with one surgical procedure at a later age (median 6 years, range 6 months to 18 years), while patients with the bilateral form need a median of 2.85 interventions at an early age (median 25 days, range 6 days-6 years). If both sides are affected, immediate measures must be taken to allow the newborn to breathe properly and prevent respiratory failure.
Most children with CHARGE syndrome have unusual external ears. The “typical CHARGE ear” is short and wide with little or no earlobe. The helix (outer fold) may end abruptly in mid-ear. The center of the ear (concha) is often triangular in shape. The ears are often floppy and may stick out due to weak cartilage. The two ears often look different from each other. There are also typical findings in the middle ear in CHARGE syndrome, including malformed bones of the middle ear (93%) and incomplete cochlea (Mondini defect), which is diagnosed with an MRI scan. In many patients, the external ear can be unique enough to suspect the diagnosis of CHARGE syndrome before examining other features, and a temporal bone CT scan to look for absent semicircular canals and evaluate the choanae for atresia or stenosis should prompt genetic testing for CHD7 variants to confirm the diagnosis.
Minor Diagnostic Criteria
Features less specific to CHARGE syndrome and/or not consistent enough to be considered major: heart defects, genital abnormalities, kidney abnormalities, cleft lip or palate, TE fistula or esophageal atresia, poor growth, hypotonia, typical CHARGE face and typical CHARGE hand.
About 75-80% of children with CHARGE syndrome have congenital heart defects. Although all types of heart defects have been seen in children with CHARGE syndrome, the most common are tetralogy of Fallot (33%), VSD (ventricular septal defect), AV (atrioventricular) canal defect and aortic arch anomalies. The heart defects can range from an innocent murmur to life-threatening heart defects involving the outflow tracts of the heart. Most require medication and/or surgery. Severe heart defects are a major cause of death in children with CHARGE. The heart defects in CHARGE are similar to those seen in a chromosome abnormality called 22q11.2 deletion syndrome.
Most males with CHARGE syndrome have a small penis, often with undescended testes (cryptorchidism). The urethral opening may not be at the end of the penis (hypospadias). Females may have small labia. Among 46 males with hypogonadotropic hypogonadism, 14 (30.4%) had Kallmann syndrome, 4 (8.7%) had CHARGE syndrome and 28 (60.9%) had hypogonadotropic hypogonadism without an abnormal sense of smell. Most children with CHARGE syndrome require hormone therapy to achieve puberty due to hypogonadotropic hypogonadism, and a pediatric endocrinologist should evaluate pituitary gonadal axis.
About 40% of children with CHARGE syndrome have kidney abnormalities. These can include hydronephrosis (extra fluid in the kidneys) or reflux (backflow into the kidneys); horseshoe kidney; small or absent kidney; or multicystic dysplastic kidneys. All children with CHARGE syndrome should have a kidney ultrasound.
Cleft lip and/or cleft palate
About 25% of children with CHARGE syndrome have a cleft lip or cleft palate. The cleft lip can be one-sided or two-sided and may or not include the palate. Some have cleft palate without cleft lip. The submucous cleft palate (just the muscle, not the bone in the posterior roof of the mouth) may be hard to diagnose. A family history of an individual with an apparently isolated unilateral major CHARGE syndrome anomaly, or someone with a few of the minor features, should be offered genetic testing for the affected child and both parents for CHD7 variants.
Tracheoesophageal fistula/esophageal atresia
About 15-20% of children with CHARGE syndrome are born with an esophageal atresia (EA), where the food pipe is not connected to the stomach or with tracheoesophageal fistula (TEF), where there is a connection between the windpipe (trachea) and the food pipe (esophagus). Both conditions require surgery. In addition, the trachea may be weak or floppy due to weak cartilage. This can complicate surgery to treat these conditions.
Although birth weight is usually normal, many children with CHARGE syndrome are small after birth. Sometimes this is due to nutritional problems, heart problems or multiple illnesses. Some children with CHARGE syndrome have growth hormone insufficiency, which can be evaluated with a growth hormone stimulation test.
Hypotonia of the trunk
Most children with CHARGE syndrome have upper body weakness (hypotonia). They are weak, especially in the trunk, and may have sloping shoulders. This weakness, especially combined with balance problems and/or vision problems, will delay walking. The average age of walking is about 3 or 4 years in children with CHARGE syndrome, and this results from the combination of hypotonia and diminished balance due to their underdeveloped semicircular canals.
Typical CHARGE face
Children with CHARGE syndrome often look like one another. The typical child has a square face, with broad prominent forehead, arched eyebrows, large eyes, occasional droopy eyelids, a prominent nasal bridge with square root, small nostrils, prominent nasal columella, flat midface, small mouth, occasional small chin, which improves with age. The face is often very asymmetric.
Typical CHARGE hand
Many children with CHARGE syndrome have a small thumb, broad palm with “hockey-stick” palmar crease and short fingers.
These features may be important for management, but not very helpful in making the diagnosis. Brain abnormalities, including small head (microcephaly), enlarged cerebral ventricles or other abnormalities identified by brain imaging such as MRI or CT scan are occasionally seen. Apnea and seizures are rarely seen in children with CHARGE syndrome. Weak cartilage (as seen in the ears) can also affect the trachea (windpipe) making it weak. Sometimes the baby has a very weak cry due to laryngomalacia (weak vocal cords). A few children with CHARGE syndrome have missing or extra nipples. Some have a relatively wide neck, with occasional cervical vertebral abnormalities. Rarely, children with CHARGE syndrome have an umbilical hernia, omphalocele or limb abnormalities, such as abnormal thumbs or extra fingers.
A few children with CHARGE syndrome have DiGeorge sequence, consisting of a complex heart defect, immune deficiency and abnormalities of the thyroid and parathyroid glands. Because these features are also seen in chromosome 22q11.2 deletion syndrome, children with possible CHARGE syndrome and no variants in CHD7 should have chromosomal microarray testing done. Some children with CHARGE syndrome appear to have a poor immune response, and in the presence of hypocalcemia should prompt an immunologic evaluation. Most children with CHARGE syndrome and immunodeficiency have T-cell deficiency.
Many children with CHARGE syndrome develop scoliosis, even as relatively young children. This may be due in part to their weak upper body, but a skeletal survey should be done to exclude skeletal anomalies, particularly those of the cervical spine.
Developmental features as signs of CHARGE syndrome
Most young children with CHARGE syndrome are developmentally delayed. Often, this is primarily due to sensory deficits (vision and/or hearing loss) and frequent illnesses and hospitalizations as infants and young children. Although developmentally delayed, many children with CHARGE syndrome will show significant catch up in later childhood, with normal intellectual abilities, and becoming independent adults. It is not possible to predict eventual development for any one child, and early intervention with a deaf-blind specialist is essential to treat their sensory deficits and prevent behavioral problems. Regardless of the extent of inner ear anomalies and intellectual faculties, cochlear implantation with careful treatment planning can be a highly effective option for hearing rehabilitation in children with sensorineural hearing loss and CHARGE syndrome.
As children with CHARGE syndrome grow older, challenging behaviors can emerge. Some children display autistic-like behaviors such as hand waving or head banging. Often, these are attempts at communication by a child who has not yet developed language or other communication skills due to hearing and vision problems. These behaviors occur less often when a communication system (speech, signs or a combination of both) is established. Older individuals with CHARGE syndrome may show signs of obsessive-compulsive disorder. Many children with CHARGE syndrome begin communication using sign language or some form of gestures and communication boards. Those with cochlear implants or hearing aids that bring hearing into the normal range will usually switch over to oral speech at some point. Learning signs first does not keep children from speaking later.
The cause of CHARGE syndrome is usually a new variant (change) in the CHD7 gene, or rarely, genomic alterations in the region of chromosome 8 (8q12.2) where the CHD7 gene is located. CHD7 function is required for the development of the retina and cranial motor neurons. Over 70-90 % of typical CHARGE syndrome patients have variants in the CHD7 gene.
Most cases of CHARGE syndrome occur sporadically, often in association with older paternal age. In rare cases, CHARGE syndrome has run in families, either two affected children or a parent and child affected. This could be due to a parent with some cells with a CHD7 variant (mosaicism) who is mildly affected or not affected at all.
There are no known teratogens (exposures during pregnancy) that have been associated with CHARGE syndrome. Retinoic acid or isotretonin (a medicine taken for severe acne) can cause similar malformations when taken during the first trimester of pregnancy.
CHARGE syndrome is a rare disorder, affecting 1:10,000-15,000 live births. It affects males and females in equal numbers and has been seen in all races and on every continent. There are far more cases of CHARGE syndrome than those described in the medical literature. Many cases are misdiagnosed or undiagnosed, especially in children with fewer problems. Although many features of CHARGE syndrome are apparent at birth, some features will not become apparent for weeks, months or perhaps years later. The recurrence risk of CHARGE syndrome for parents with one affected child is low, around 2-3 percent. The recurrence risk for an adult with CHARGE syndrome to have an affected child may be as high as 50 percent.
A medical geneticist or other specialist familiar with CHARGE syndrome should do a complete physical exam and order tests to look for the major and minor features of CHARGE syndrome listed above.
Molecular genetic testing is available to look for variants in the CHD7 gene associated with the condition, and if no disease-causing variants are found, a SNP chromosomal microarray should be done, because in a few patients, there has been a submicroscopic change in the chromosome 8q12.2 region. If both these tests are normal, whole genome or exome sequencing should be done, since other genetic disorders share some clinical features with CHARGE syndrome, and new variants in ZEB2, KMT2D and EFTUD2 have been found in children previously diagnosed as having CHARGE syndrome.
Children with CHARGE syndrome have many problems, but they can survive and become healthy, happy citizens. Many of the structural abnormalities (choanal atresia, heart defects, cleft lip, etc.) can be surgically corrected. Others, such as feeding problems and speech and language deficits may require years of therapy and other interventions. Infants diagnosed with CHARGE syndrome will need to be followed by several medical and developmental specialists, depending on their individual needs. Some of the medical specialists who often follow children with CHARGE syndrome include genetics, cardiology, audiology and ENT, ophthalmology, urology and endocrinology. A team approach is essential for these complex children.
Surgery cannot correct ocular colobomas. Near-sightedness or far-sightedness can be helped with glasses. Sunglasses and a hat with a protective bill can help photophobia. Part-time patching with refractive correction via glasses is an effective treatment for lazy eye (amblyopia).
More than 50% of children with CHARGE syndrome experience sleep disturbances, and obstructive sleep apnea appears to be common in children with CHARGE syndrome. The usual treatments for obstructive sleep apnea reduce symptoms. Botulinum toxin A (Botox) has been used to reduce excess salivary secretions in a ventilator-dependent infant with CHARGE syndrome who would have required a tracheotomy. Venous anomalies of the temporal bone were present in 10 of 18 (56%) patients with CHARGE syndrome. Recognition of these abnormal venous structures is critical to avoiding potentially catastrophic bleeding.
Because of the implications of cochlear nerve deficiency in decision-making about cochlear implantation, MRI evaluation of the eighth nerve should be considered in CHARGE syndrome patients with profound sensorineural hearing loss. In patients with markedly abnormal middle ear anatomy, CT image guided surgery is helpful. These children can be offered both sign language and verbal language early in life, to ensure best language outcomes. Children with CHARGE syndrome and progressive profound hearing loss have done well with cochlear implants and continued to use verbal language. Larger diameter of the cochleovestibular nerve on imaging and absence of severe intellectual disability were factors related to better outcomes after cochlear implantation, rather than the type of CHD7 variant. Auditory brainstem implantation may be a viable option in patients with CHARGE syndrome who have not benefited from cochlear implantation.
Other medical professionals involved in the treatment of children with CHARGE include deaf/blind specialists, occupational therapists, physical therapists and speech therapists. Appropriate therapies and educational interventions must take into account any hearing and vision loss that the child has. The intelligence of children with CHARGE syndrome is often underestimated due to the combined hearing and vision problems. A deaf/blind specialist (not just a vision specialist and a hearing specialist) is critical for any child with both vision loss and some hearing loss.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., visual handicaps, heart disease, short stature, etc.)
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