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AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: David Tegay, DO, FACMG, Assistant Professor of Pediatrics and Internal Medicine, Clinical Research Scholar, Co-Director, Division of Medical Genetics, Stony Brook University Hospital
David Tegay is a member of the following medical societies: American Society of Human Genetics and Federation of American Societies for Experimental Biology
Editors: Elaine H Zackai, MD, Director of Clinical Genetics Center, Professor of Pediatrics, Department of Pediatrics, Division of Human Genetics and Molecular Biology, University of Pennsylvania, Children's Hospital of Philadelphia; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System; Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
CHARGE syndrome, CHARGE Association, CHD-7 spectrum disorder, coloboma, choanal atresia
Background
The cardinal features of coloboma, heart anomalies, choanal atresia, retardation of growth and development, and genital and ear anomalies clinically define CHARGE syndrome. No single feature is universally present or sufficient for diagnosis, and the severity is variable. Other frequently occurring features of significance include: characteristic face and hand dysmorphology, hypotonia, urinary tract anomalies, orofacial clefting, deafness, and dysphagia and tracheoesophageal anomalies. The clinical diagnosis requires the presence of at least 3 cardinal features, or 2 cardinal features plus at least 3 associated minor characteristics.
CHARGE syndrome is an autosomal dominant condition with genotypic heterogeneity. Most cases are due to mutation or deletion of the chromodomain helicase DNA-binding protein-7 (CHD7) gene, although case reports exist of individuals who meet the clinical criteria for the diagnosis of CHARGE syndrome with a variety of underlying cytogenetic abnormalities (including 22q11.2 deletions) and single gene mutations (including SEMA3E gene mutations).
Pathophysiology
A developmental defect involving the midline structures of the body occurs, specifically affecting the craniofacial structures.
This defect is attributed to arrest in embryologic differentiation in the second month of gestation, when the organs affected are in the formative stages (choanae at 35-38 d postconception, eye at fifth wk, cardiac septum at 32-38 d, cochlea at 36 d, external ear at sixth wk). The prechordal mesoderm is necessary for the development of the mid face, and it exerts an inductive role on the subsequent development of the prosencephalon, the forepart of the brain.
The mechanisms suggested are (1) deficiency in migration of cervical neural crest cells into the derivatives of the pharyngeal pouches and arches, (2) deficiency of mesoderm formation, and (3) defective interaction between neural crest cells and mesoderm resulting in defects of blastogenesis and hence the typical phenotype.
The function of CHD7 during embryologic development remains unclear.
Frequency
International
The estimated birth incidence of CHARGE syndrome is 1 in 8,500-12,000.
Mortality/Morbidity
- Mortality is highest in the neonatal period and early infancy.
- Frequent association of swallowing problems increases the risk of aspiration and contributes to increased mortality and morbidity.
- Criteria for poor survival include the following:
- Bilateral choanal atresia
- Complex cyanotic congenital heart disease
- Central nervous system anomalies
- Esophageal atresia
Race
CHARGE syndrome has a panethnic distribution.
Sex
CHARGE syndrome exhibits autosomal dominant inheritance, and expression is not sex-linked. Therefore, males and females are affected with equal frequency.
Age
CHARGE syndrome is frequently diagnosed in the neonatal or prenatal period because of the presence of multiple congenital anomalies and dysmorphic features.
History
- Prenatal presentation
- Intrauterine growth retardation
- Congenital heart defects
- Orofacial clefting
- Poor fetal movement
- Neonatal presentation
- Small for gestational age
- Dysmorphic features
- Respiratory distress/cyanosis
- Swallowing/feeding difficulty
- Failed newborn hearing screen
- Inability to pass nasogastric tube
- Infantile and childhood presentation
- Failure to thrive
- Developmental delay
- Feeding difficulty
- Poor growth
Physical
The defining features of CHARGE syndrome are coloboma, heart anomalies, choanal atresia, retardation of growth and development, and genital and ear anomalies. Other frequently occurring significant features include: characteristic face and hand dysmorphology, hypotonia, urinary tract anomalies, orofacial clefting, deafness, dysphagia, and tracheoesophageal anomalies. Again, no single feature is universally present or sufficient for the diagnosis of CHARGE syndrome, and the degree of severity varies.
The clinical diagnosis requires the presence of at least 3 cardinal features, or 2 cardinal features plus at least 3 associated minor characteristics.
- Coloboma of the eye (79%): This is usually bilateral and affects the posterior segment of the eye (ie, choroid, retina, optic disc). It rarely involves the iris. Microphthalmia and nystagmus are consistently associated with severe coloboma. Coloboma that does not involve the fovea does not affect vision. Retinal detachment is a frequent complication.
- Heart anomaly (85%): Septal defects (interventricular, interatrial) and conotruncal malformation (aortic valve stenosis, aortic coarctation, interrupted aortic arch) are the most frequent anomalies. Other anomalies include patent ductus arteriosus and tetralogy of Fallot. All variations of complex heart anomalies are reported.
- Choanal atresia/stenosis (57%): Choanal atresia is membranous or bony and bilateral in over 50% of cases, usually presenting in the newborn period with respiratory distress. Choanal atresia is a threat to life because infants cannot establish mouth breathing. A history of polyhydramnios in pregnancy is usually present. Of all features of CHARGE syndrome, choanal atresia, when bilateral, is the most easily ascertainable. Its presence indicates poor prognosis for survival and necessitates multiple complex surgeries for correction. When associated with other anomalies (eg, cyanotic heart disease, tracheoesophageal fistula and/or atresia), most children with bilateral atresia do not survive beyond the first year of life. Unilateral atresia may present as persistent nasal discharge in early childhood.
- Growth retardation (failure to thrive - 80%): Intrauterine growth retardation and growth failure are observed in 75% of patients. Growth failure is noticeable in the first 6 months of life. It is due to endocrine causes (eg, growth hormone deficiency, gonadotrophin deficiency). Feeding difficulty with poor caloric intake may also contribute to growth failure. No correlation exists between the severity of the growth defect and the severity of the component anomalies.
- Mental retardation (70%): Developmental delay is typically present and is often characterized as mild to moderate. More severe developmental delay is often associated with other significant birth defects and a greater degree of later mental retardation. Patients with severe coloboma and inner ear problems are particularly affected. Poor vision and hearing result in the absence of visual and auditory cues that are essential for early motor development, and abnormalities in the vestibular function affect the adoption of upright posture and, thus, lead to delay in motor development.
The need for multiple and prolonged hospitalizations and lack of active management of the sensory deficit can also contribute to developmental delay. These issues must be adequately addressed in a timely fashion, when present, to maximize developmental outcomes. Mental retardation is not universal but is frequent. One should be careful not to diagnose mental retardation until the full extent of sensory deficits are known and corrective measures have been implemented. - Genital hypoplasia (male 70%, female 30%): Males have micropenis and are either cryptorchid or have complete absence of testis. Females have labial hypoplasia that is difficult to identify in the neonatal period. Hypogonadotrophic hypogonadism secondary to pituitary or hypothalamic causes is suggested as the cause, as evidenced by poor response to luteinizing hormone-releasing hormone (LHRH) and human chorionic gonadotropin (HCG) stimulation tests.
- Ear malformations (90-100%): External ear malformation was noted in 100% of patients. Ears may be small, simple, low set, and/or cup shaped; protruding helix may be unraveled. External ear malformations are more abnormal on the side of the facial palsy and may be related to denervation early in the developmental process of the ear.
- Deafness (62%): Usually bilateral and of mixed type. A unique, wedge-shaped audiogram has been described with a descending bone conduction curve intersecting at low frequencies with a flat curve for air conduction. Inner ear abnormalities include partial or complete semicircular canal hypoplasia. Vestibular or cochlear defect leads to sensorineural deafness. Middle ear problems cause conductive hearing loss and are commonly due to ossicular malformations, stapedius tendon abnormality, or serous effusion. CT scan of the temporal bone demonstrates partial or complete semicircular canal hypoplasia.
- Other anomalies found to be consistently associated with CHARGE syndrome are as follows:
- Neurologic anomalies: Cranial nerve palsy (mainly facial nerve but also auditory), glossopharyngeal and vagus nerves, microcephaly, and neonatal brainstem dysfunction, which manifest in the form of feeding difficulty and swallowing difficulty, are found.
- Dysmorphic features: These features include a typically asymmetric square face, malar flattening, unilateral facial nerve paralysis, and micrognathia.
- Hand dysmorphology: This includes brachydactyly and clinodactyly.
- Occasional anomalies reported, but not consistently present, in individuals with CHARGE syndrome are as follows:
- Renal - Hydronephrosis, vesicoureteric reflux
- Larynx - Laryngomalacia, laryngeal clefts
- Esophageal - Atresia, tracheoesophageal fistula
- Skeletal - Hemivertebrae, scoliosis, clinodactyly, syndactyly
- Orofacial clefting - Found in 53% of patients
Causes
CHARGE syndrome is an autosomal dominant condition with genotypic heterogeneity. Most cases are due to mutations of the CHD7 gene (58-71%), although case reports exist of individuals who meet the criteria for the clinical diagnosis of CHARGE syndrome and who have a variety of cytogenetic abnormalities, including 22q11.2 deletions, 14q22-q24.3 inverted duplications, and 9p-, and single gene mutations (including SEMA3E gene mutations).
DiGeorge Syndrome
Smith-Lemli-Opitz Syndrome
Velocardiofacial Syndrome
Other Problems to be Considered
Cat-eye syndrome
Holoprosencephaly spectrum disorders
Isolated coloboma
Isolated choanal atresia
Isolated congenital heart defects
VATER/VACTERL association
Lab Studies
- CHD7 mutation analysis is diagnostic in 58-71% of individuals who meet the clinical criteria for CHARGE syndrome. Genotype-phenotype correlations are being established.
- High-resolution karyotype (chromosome analysis) is used.
- Fluorescent in situ hybridization (FISH) or array–chorionic gonadotropic hormone (CGH) is used to detect submicroscopic copy number variations of the CHD7 and 22q11.2 loci and other submicroscopic chromosomal abnormalities in individuals in whom CHD7 testing is uninformative.
- BUN, creatinine, electrolytes: Evaluate and monitor renal function and exclude hypocalcemia (DiGeorge syndrome).
- LHRH and HCG tests: Perform these tests to evaluate the pituitary gonadal axis in cases of hypogenitalism.
- Growth hormone levels: Obtain growth hormone levels to exclude growth hormone deficiency contributing to growth retardation.
Imaging Studies
- Chest radiography: Perform chest radiography to exclude cardiopulmonary pathology and to document normal lung volume and cardiac shape and size in persons with respiratory distress, especially in the newborn period.
- Cranial ultrasound: Perform this study in the immediate neonatal period to exclude major malformations of the brain.
- Head CT and/or MRI scans, including the temporal bones: Obtain CT and/or MRI scans to exclude cerebral malformation and/or cerebral atrophy and to exclude defective formation of the ossicles of the middle ear. MRI scan of the brain may demonstrate cerebral atrophy, midline brain defects (eg, agenesis of corpus callosum), and forebrain anomalies, particularly arrhinencephaly. CT scan of the temporal bone demonstrates partial or complete semicircular canal hypoplasia. Ideally, evaluate the internal ear in later infancy or early childhood, when the ear is more fully formed.
- Barium swallow: Perform this study to diagnose swallow dysfunction and/or esophageal dysmotility and tracheal aspiration.
- Abdominal ultrasound: Perform abdominal ultrasound to exclude renal anomalies.
- Skeletal survey: Survey the skeleton to exclude skeletal anomalies.
- Echocardiogram: Perform to identify and/or exclude congenital cardiac defects.
Other Tests
- Electroencephalogram: Perform EEG to diagnose seizures.
- Immune system evaluation: Evaluate the immune system to exclude cellular immunodeficiency or lymphopenia and lymphocyte function defect (DiGeorge syndrome overlap).
- ECG: Perform to identify and/or exclude congenital cardiac defects.
- Serial audiometry and auditory brainstem evoked responses
- Document the type and severity of conductive and sensorineural hearing loss.
- A characteristic wedge-shaped response is reported.
- Visual evoked response and electroretinogram
- Identify and document the severity of visual loss.
- Visual evoked response (VER) and electroretinogram (ERG) are abnormal but do not correlate with the extent or the localization of the coloboma.
- Due to cognitive defects, administering tests of visual acuity is difficult; hence, more sophisticated tests (eg, VER, ERG) that do not depend on patient behavior responses are appropriate.
Medical Care
At birth, provide a secure airway, stabilize the patient, exclude major life-threatening congenital anomalies, and transfer the individual with CHARGE syndrome to a specialist center with pediatric otolaryngologist and other subspecialty services.
- If airway establishment does not correct cyanosis in a newborn, congenital heart disease is the most likely cause.
- Individuals with CHARGE syndrome who survive the initial neonatal and infantile period merit vigorous rehabilitation of the sensory function to enable proper psychomotor development.
- Nasogastric feeding is indicated in individuals with swallowing difficulty.
- In the presence of facial palsy, avoid corneal scarring by using artificial tears.
- In males with CHARGE syndrome, androgen therapy has been tried for penile growth.
Surgical Care
Ensure coordination of various procedures in order that operations and investigations requiring sedation or a general anesthetic can be performed at the same time and multiple anesthetic administrations can be avoided.
- Tracheostomy
- Myringotomy and tympanostomy tubes (for otitis media)
- Gastrostomy and fundoplication (may be necessary with feeding difficulty)
Consultations
Genetic consultation is used for diagnosis, counseling, management, and coordination of services.
- Otolaryngology
- Cardiology
- Ophthalmology
- Gastroenterology
- Audiology
- Neurology
- Speech therapy
- Physiotherapy
- Occupational therapy
- Social services
- Special education
Further Outpatient Care
- Long-term coordination of care is necessary.
- Ensure follow-up care and recognition and prevention of complications.
Transfer
- A tertiary hospital with appropriate pediatric subspecialists should coordinate and undertake care.
Complications
- Eye - Corneal ulceration, retinal detachment
Patient Education
- Families of patients with CHARGE syndrome require education regarding the disease manifestations and potential complications.
- A discussion of the genetic basis of the disorder should include recurrence risks (1-2% for unaffected parents, up to 50% for affected individuals).
- Genetic counseling should be made available for individuals at increased risk for affected offspring to explain options in future pregnancies, including prenatal and preimplantation genetic diagnosis.
Medical/Legal Pitfalls
- Mental retardation is not universal. Developmental outcomes can be maximized with early and accurate diagnosis, early intervention and appropriate therapy so that the individuals fullest developmental potential can be realized. Particularly, failure to monitor in an ongoing fashion for visual and auditory disabilities may result in increased developmental delay.
- Various clinics (eg, otolaryngology, neurology, audiology, ophthalmology) individually follow up with many patients. Failure to consider CHARGE syndrome may lead to missing the involvement of other organs, especially eyes and ears and, thus, a delay in correcting those defects.
- Failure to counsel parents concerning prognosis, recurrence risks, and prenatal and preimplantation diagnostic options is a pitfall.
The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Venkataraman Krishnan, MBBS, DCH, MRCP, FAAP, MD to the development and writing of this article.
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CHARGE Syndrome excerpt Article Last Updated: Jul 7, 2006
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