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NORD is very grateful to John M. Graham, Jr., MD, ScD, Director of Clinical Genetics and Dysmorphology, Cedars-Sinai 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 term CHARGE 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%)
Diagnosis is based on a specific set of features (see below). In addition to the CHARGE features above, most 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 wind pipe and the food pipe). The symptoms of CHARGE syndrome vary greatly from one child to another. The cause of CHARGE is usually a new mutation (change) in the CHD7gene, or rarely, genomic alterations in the region of chromosome 8 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, rarely in other conditions: Coloboma, Cranial nerve abnormalities, Choanal atresia, typical CHARGE Ear.
A coloboma is a cleft or failure to close of the eyeball 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 80-90% of patients with CHARGE syndrome. Many children with colobomas (even just an iris coloboma) may be sensitive to bright light (photophobia). 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 the photophobia.
Cranial nerve abnormalities
The sensorineural (nerve) hearing loss in CHARGE is due to abnormalities in cranial nerve VIII. Cranial CT scan often reveals a hypoplastic cochlea (81%) with absent semicircular canals in most cases. 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. The hearing loss can range from a mild hearing loss to profound deafness. Hearing loss can be very difficult to measure in young children. Many children with CHARGE receive cochlear implants to aid their sensorineural hearing loss. Most 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 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 are able to swallow safely.
Many children with CHARGE 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 have an absent or reduced sense of smell (cranial nerve I), which complicates learning to eat normally. Most patients with CHARGE syndrome have absent or abnormal olfactory bulbs in MRI, leading to a diminished sense of smell. Smell-testing can predict the presence of hypogonadotropic hypogonadism. The combination of defective olfaction (anosmia or hyposmia) with hypogonadotropic hypogonadism (termed Kallman syndrome) results in small external genitalia. This is very common in CHARGE syndrome and warrants consultation with an endocrinologist.
The 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, these passages may be blocked (atresia) or narrowed (stenosis). Surgery can often correct these defects. Many children with CHARGE require repeated surgeries to keep the passages open. 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 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 very 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, including malformed bones of the middle ear (93%) and incomplete cochlea (Mondini defect), which is diagnosed with an MRI scan. In many cases, the external ear can be unique enough to suspect the diagnosis of CHARGE 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 mutation analysis of CHD7 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 (atriventricular) 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 Shprintzen-VCF syndrome (deletion 22q11.2).
Most boys 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). Girls may have small labia. Most children with CHARGE require hormone therapy to achieve puberty due to hypogonadotropic hypogonadism, and their pituitary gonadal axis should be evaluated by a pediatric endocrinologist.
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. All children with CHARGE should have a kidney ultrasound.
Cleft lip and/or cleft palate
About 25% of children with CHARGE 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. Submucous cleft palate (just the muscle, not the bone in the roof of the mouth) may be hard to diagnose.
TEF or EA
About 15-20% of children with CHARGE 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 of these 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 are small after birth. Sometimes this is due to nutrition problems, heart problems or multiple illnesses. Some children with CHARGE 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 hypotonia (weakness). 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 similar to 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 have a small thumb, broad palm with "hockey-stick" palmar crease, and short fingers.
Other Common Findings
These features may be important for management, but not very helpful in making the diagnosis. Brain abnormalities, including small head (microcephaly), hydrocephalus (water on the brain) 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. 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 have an umbilical hernia, omphalocele or limb abnormalities, such as abnormal thumbs or extra fingers.
A few children with CHARGE 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 VCF, children with possible CHARGE and no mutation in CHD7 should have array comparative genomic hybridization testing done. Some children with CHARGE appear to have a poor immune response even, and the presence of hypocalcemia should prompt an immunologic evaluation. Most children with CHARGE syndrome and immunodeficiency have T-cell deficiency.
Many children with CHARGE develop scoliosis, even as relatively young children. This may be due in part to their weak upper body, but a skeletal survey should be carried out to exclude skeletal anomalies, particularly those of the cervical spine.
Developmental Features as Signs of CHARGE Syndrome
Most young children with CHARGE 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 will show significant catch up in later childhood, manifesting normal intellectual abilities, and ending up as 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 remediate their sensory deficits and prevent behavioral problems.
As children with CHARGE 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 may show signs of obsessive-compulsive disorder. Many children with CHARGE 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 is usually a new mutation (change) in the CHD7 gene, or rarely, genomic alterations in the region of chromosome 8 (8q21) where the CHD7 gene is located. CHD7 function is required for the development of the retina and cranial motor neurons. Most cases of CHARGE syndrome occur sporadically, often in association with older paternal age. In rare cases, CHARGE has run in families, either two affected children or a parent and child affected, either because of parental mosaicism for a CHD7 mutation, which results in a parent being mildly affected or not affected at all.
There are no known teratogens (exposures during pregnancy) that have been associated with CHARGE syndrome.
CHARGE syndrome is a rare disorder, affecting 0.1-1.2/10,000 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 than those described in the medical literature. Many cases are misdiagnosed or undiagnosed, especially in children with fewer problems. Although many features of CHARGE are apparent at birth, some features will not become apparent for weeks, months, or perhaps years later. The recurrence risk of CHARGE for parents with one affected child is low, around 2-3 percent. The recurrence risk for an adult with CHARGE to have an affected child may be as high as 50 percent.
Symptoms of the following disorders can be similar to those of CHARGE syndrome. Comparisons may be useful for a differential diagnosis.
DiGeorge sequence, which consists of complex heart defects, immunodeficiency and abnormalities of the thyroid and parathyroid glands, may occur in CHARGE syndrome, with 72% manifesting hypocalcemia and 60% demonstating lymphopenis. Because these features are also seen in 22q11.2 deletion syndrome, children with possible CHARGE should have array comparative hybridization testing if mutation analysis of CHD7 is negative. Some children with CHARGE appear to have poor immune response even without DiGeorge sequence.
A variety of chromosome abnormalities can result in features that overlap with CHARGE. Most have different ear anomalies and facial features, and many of these disorders can be ruled out by array comparative hybridization, which is a more advanced form or chromosome analysis.
Velocardiofacial syndrome (VCF-22q deletion syndrome, Shprintzen syndrome) is far more common than CHARGE syndrome. There are many overlapping features in these two disorders. VCF is characterized by velopharyngeal incompetence (cleft palate and/or swallowing problems), cardiac (heart) defects, and a typical face (long and narrow). Many children with VCF also have DiGeorge sequence. The overwhelming majority of children with VCF have a microdeletion (tiny missing piece) of chromosome 22 (deletion 22q11.2) which can also be detected by a special lab technique called FISH (fluorescent in-situ hybridization).
The heart defects and swallowing problems seen in VCF can be nearly identical to those seen in CHARGE. However, the characteristic ears, face and temporal bone findings are distinctly different, as are the hands (long and slender hands in VCF vs. short and broad in CHARGE; long face in VCF, square face in CHARGE). Only about 5 percent of children with CHARGE have complete DiGeorge sequence as part of CHARGE. Conversely, of all the children with DiGeorge, about 85 percent have VCF with a chromosome 22 deletion, 5 percent have CHARGE and 10 percent have something else. To date, there has not been a single individual with definite CHARGE who had a FISH test that was positive for the 22q11 deletion. (For more information on this disorder, choose Shprintzen-VCF as your search term in the Rare Disease Database).
VACTERL Association is a rare disorder characterized by abnormalities affecting several parts of the body. VACTERL is an acronym that stands for (V)ertebral anomalies, (A)nal atresia, (C)ardiac defects, (T)racheo(E)sophageal fistula, (R)enal and (L)imb anomalies. Vertebral anomalies, limb anomalies and anal atresia are each very common in VACTERL and very rare in CHARGE. The choanal atresia in CHARGE affects the nose, not the rectum/anus. Children with VACTERL are unlikely to have any of the major diagnostic features of CHARGE. Neither do they have the typical physical features (face, ears, hands) associated with CHARGE. In some cases, especially in the newborn period, VACTERL and CHARGE may be difficult to distinguish from each other due to overlapping birth defects. VACTERL is a clinical diagnosis, and there is no lab test to prove it. (For more information on this disorder, choose VACTERL Association as your search term in the Rare Disease Database).
Retinoic acid embryopathy is a very rare disorder caused by exposure of a fetus to retinoic acid (or Accutane, which is used to treat acne) during pregnancy. The ear malformations of this syndrome can be similar to CHARGE ears. However, other features are different. (For more information on this disorder, choose Fetal Retinoid Syndrome as your search term in the Rare Disease Database).
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 listed above. Other similar disorders such as VCF-Shprintzen and VACTERL need to be ruled out as well. Some children clearly have CHARGE syndrome. Molecular Genetic testing is available for mutations in the CHD7 gene associated with the condition, and if this is negative, array comparative hybridization should be done, because in a few cases, there has been submicroscopic genomic alteration of chromosome 8q12.
Although these children have many problems, 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 a number of 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. Others involved in the treatment of children with CHARGE include deaf/blind specialists, occupational therapy, physical therapy and speech therapy.
Appropriate therapies and educational interventions must take into account any hearing and vision loss, which is present. The intelligence of children with CHARGE 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 someone with both vision loss and some hearing loss.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. A team approach is essential for these complex children.
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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Report last updated: 2012/04/09 00:00:00 GMT+0