CHARGE Syndrome is a rare genetic syndrome that produces a constellation of clinical features. The features are described in the name ‘CHARGE’ which stands for:
Coloboma of the eye
Atresia of the Nasal choanae
Retardation of growth and/or development
Another name for this syndrome is Hall-Hittner syndrome
The prevalence of CHARGE syndrome is 0.1-1.2 of10,000 live births. It is the leading cause of congenital deaf-blindness in the U.S. according to the National Consortium of Deaf-Blindness. In 2017, there were 933 children and youth identified as having CHARGE syndrome.
CHARGE syndrome typically occurs spontaneously (i.e. no previous family history) due to a de novo mutation in the CHD7 gene located on chromosome 8q12. In rare cases, it can be inherited in an autosomal dominant pattern. The CHD7 gene provides instructions for making a protein (chromodomain helicase DNA-binding protein) which regulates gene expression by altering chromatin remodeling. Chromatin remodeling alters how tightly DNA is packaged, which affects the rate of gene expression. It was found that 90-95% of patients fulfilling the formal diagnostic criteria for CHARGE syndrome are heterozygous for a CDH7 mutation or deletion. Most CHD7 gene mutations lead to the production of an abnormal CHD7 protein, which breaks down prematurely. A shortage of this protein is thought to disrupt chromatin remodeling and thus gene expression. These changes in gene expression during embryonic development are thought to underlie the signs and symptoms of CHARGE syndrome.
Ophthalmic abnormalities are found in 75-90% of CHARGE patients. The most common abnormality is a coloboma of the eye (not the eyelid). These are typically chorioretinal (intra- and extra- macular) and optic nerve, but can also occur in the iris and lens. In addition to visual impairment, colobomas predispose CHARGE syndrome patients to retinal detachment. Other ophthalmic features that can occur in patients with CHARGE syndrome include microphthalmia, microcornea, cataracts, strabismus, cranial nerve VII palsy, and ptosis. High refractive errors and amblyopia also occur in CHARGE syndrome.
Cardiac malformations are found in 75-85% of patients with CHARGE syndrome. Cardiac defects can include Tetralogy of Fallot, aortic arch interruption, double outlet right ventricle with arch vessel abnormalities, and atrioventricular septal defects (AVSD).
Choanal Atresia and Upper Airway Abnormalities
Approximately 65% of patients with CHARGE syndrome may have obstructed breathing due to choanal atresia at birth. Other upper airway abnormalities that can be seen in CHARGE syndrome include: laryngomalacia, tracheomalacia, tracheoesophageal fistula, and subglottic stenosis.
Genital hypoplasia is a common feature in patients with CHARGE Syndrome. This is secondary to hypogonadotropic hypogonadism. Boys can have micropenis and cryptorchidism. Girls can have reduced clitoral size. Additionally, patients can have renal abnormalities such as renal dysgenesis and duplex kidneys.
Patients may experience variable degrees of sensorineural hearing loss. The most common ear abnormality is absence of the lateral semicircular canals. Dysplasia of the vestibular canal can also occur, resulting in poor balance and delays in walking.
The majority of infants with CHARGE syndrome generally experience growth restriction. In addition to growth abnormalities, most CHARGE patients have impaired cognitive and communication ability. One study showed that 70% of CHARGE syndrome patients have an IQ less than 70. Behaviorally, children with CHARGE syndrome have been reported to engage in social withdrawal, repetitive motor mannerisms, and have difficulty sleeping.
Other clinical findings in CHARGE include cranial nerve dysfunction, endocrine dysregulation, and recurrent infections. A significant majority of infants are found to have difficulty feeding, manifesting as weak sucking and chewing, swallowing difﬁculty, gastro-esophageal reﬂux, and chronic aspiration. These issues are likely due to cranial nerve dysfunction and 90% of such patients require tube feeding at some point. Patients with CHARGE syndrome are also at risk for hypothyroidism and recurrent suppurative ear and chest infections.
- CHARGE syndrome is diagnosed clinically. Two widely utilized diagnostic systems are the Blake and Verloes criteria. Both systems define major and minor criteria consistent with CHARGE syndrome. Major signs are more specific for CHARGE syndrome and include most prominent cranial abnormalities. Minor signs are used to help define CHARGE syndrome by primary, distinct, non-overlapping topographic areas.
- Major signs are: coloboma of the iris or choroid, chloanal atresia, and hypoplastic semicircular canals.
- Minor signs are: rhombencephalic dysfunction, hypothalamo-hypophyseal dysfunction, abnormal middle or external ear, malformation of mediastinal organs, and mental retardation.
- A formal diagnosis of CHARGE syndrome requires 3 major signs or 2 major signs with 2 or more minor signs.
- The diagnosis of partial or incomplete CHARGE syndrome is made with 2 major signs and 1 minor sign.
- Atypical CHARGE diagnosis consists of 2 major signs and no minor signs, or 1 major sign and 3 or more minor signs.
- This methodology includes more CHARGE syndrome diagnoses that were previously classified as “possibly CHARGE syndrome” using previous diagnostic criteria.
- Genetic analysis of the CHD7 gene is often performed in patients with suspected CHARGE syndrome to confirm the diagnosis. Mutations in CHD7 are present in approximately 70-90% of patients clinically diagnosed with CHARGE syndrome. CHD7 mutations are most common in patients meeting formal criteria for CHARGE syndrome, and less common in those diagnosed with atypical or incomplete CHARGE syndrome. Therefore, while the presence of a CHD7 mutation can confirm a diagnosis of CHARGE syndrome, the absence of a mutation cannot definitively rule it out.
- 22q11.2 deletion syndrome
- Oculo‐auriculo‐vertebral spectrum
- VACTERL/VATER association
- Kabuki syndrome
- Teratogen‐related embryopathies
- Abruzzo-Erickson syndrome
- Kallmann syndrome
- Renal coloboma syndrome
- Cat-eye syndrome
- Joubert syndrome
- BOR syndrome
- 5q11.2 micro-deletion syndrome
- Other chromosomal micro-deletion syndromes
Management of children with CHARGE syndrome requires a multidisciplinary team of healthcare professionals to address the life-threatening medical conditions, as well as the developmental and behavioral abnormalities associated with the condition. Patients require early intervention with occupational, speech, and physical therapy, and low vision intervention to ensure that they maximize their vision potential.
A detailed pediatric ophthalmologic examination is critical for documenting the presence, degree, and location of colobomas and identifying any other ocular abnormalities that may be present (eg. refractive errors or ocular surface disease). Performing a visual acuity exam to assess for vision function is also very important. Chorioretinal colobomas are the most common type of coloboma in CHARGE syndrome and can lead to retinal detachment. Treatment for chorioretinal retinal detachment is pars plana vitrectomy using silicone oil (versus gas filling) to reduce recurrent retinal detachment. Prophylactic laser photocoagulation can also be performed in eyes with chorioretinal coloboma to prevent rhegmatogenous retinal detachment.
Other ophthalmic symptoms such as photophobia can be treated with tinted glasses. Cranial nerve abnormalities such as facial nerve palsy may be treated with a lubrication regimen and ultimately surgical intervention.
Behavioral and Developmental Management
Early developmental interventions are crucial. It is recommended that patients be taught sign language as well as expressive language development with the aim of adapting patients to their disabilities and maximizing overall function. It is important to maximize all vision and hearing potential.
A cardiologist should be involved in the care of these patients. Echocardiography should be performed in all children to evaluate for cardiac abnormalities.
Severity and etiology of hearing loss (conductive vs. sensorineural) should be assessed using audiometry. Hearing aids or cochlear implants should be considered depending on severity of deafness.
Management with a gastroenterologist is indicated in CHARGE patients with feeding problems and chronic aspiration. It is important to address the feeding concerns in a timely manner. Gastrostomy or jejunostomy may be indicated to overcome feeding problems in infants.
CHARGE syndrome is a rare genetic syndrome that affects numerous organ systems. The most common ophthalmic manifestation is a coloboma (usually chorioretinal). Diagnosis is based on clinical findings using either the Blake or Verloes criteria. Management involves early intervention by a multidisciplinary team involving various specialists, including pediatric ophthalmologists.
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