eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

CHARGE Syndrome

Author: David H Tegay, DO, FACMG, Associate Professor of Medicine and Medical Genetics, New York College of Osteopathic Medicine at the New York Institute of Technology; Assistant Professor of Pediatrics, Stony Brook University Medical Center
Coauthor(s): Jamie C Yedowitz, New York College of Osteopathic Medicine of the New York Institute of Technology
Contributor Information and Disclosures

Updated: Nov 13, 2009

Introduction

Background

CHARGE syndrome is an autosomal dominant genetic disorder typically caused by mutations in the chromodomain helicase DNA-binding protein-7 (CHD7) gene.¹  The acronym "CHARGE" denotes the nonrandom association of coloboma, heart anomalies, choanal atresia, retardation of growth and development, and genital and ear anomalies, which are frequently present in various combinations and to varying degrees in individuals with CHARGE syndrome.²  No single feature is universally present or sufficient for the clinical diagnosis of CHARGE syndrome, and numerous guidelines have been published to aid in establishing a likely clinical diagnosis.^2,3,4  

Blake et al suggested that a typical clinical diagnosis of CHARGE syndrome requires the presence of at least 4 major features or 3 major features plus at least 3 minor features.³ Major features include ocular coloboma or microphthalmia, choanal atresia or stenosis, cranial nerve abnormalities, and characteristic auditory and/or auricular anomalies. Minor features include distinctive facial dysmorphology, facial clefting, tracheoesophageal fistula, congenital heart defects, genitourinary anomalies, developmental delay, and short stature. Other frequently associated abnormal findings include characteristic hand dysmorphology, hypotonia, deafness, and dysphagia.^3,5

Although most cases of CHARGE syndrome are due to mutation or deletion of the CHD7 gene, some individuals with CHARGE syndrome harbor disparate pathologic cytogenetic anomalies (including 22q11.2 deletions) or mutations in other genes (including SEMA3E) unrelated to CHD7.^6,7,8,9,10

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 affected organs are in the formative stages (choanae at 35-38 days' gestation, eye at 5 weeks' gestation, cardiac septum at 32-38 days' gestation, cochlea at 36 days' gestation, external ear at 6 weeks' gestation). The prechordal mesoderm is necessary for the development of the mid face and exerts an inductive role on the subsequent development of the prosencephalon, the forepart of the brain.^11,12

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.^11,4

The complete function of CHD7 during embryologic development remains unclear.¹²

Frequency

International

The estimated birth incidence of CHARGE syndrome is 1 in 8,500-12,000.¹³

Mortality/Morbidity

Mortality and morbidity in CHARGE syndrome includes the following:^14,15,16

• 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
  • CNS 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.

Clinical

History

The history in patients with CHARGE syndrome may include the following:^17,5,18,15

• 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 typical defining features of CHARGE syndrome include 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. Numerous guidelines have been published to aid in establishing a likely clinical diagnosis of CHARGE syndrome, requiring various combinations of these features.^2,3,4

• Coloboma of the eye (70-80%): 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 (60-70%): 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 (30-60%): 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 ascertained. 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 approximately 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 between the severity of the growth defect and the severity of the component anomalies is observed.
• Mental retardation (70-75%)
  • 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 90-100% 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.
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  Typical ear malformation

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  Typical ear malformation

• Deafness/hearing Loss (60-90%): 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 Mondini malformation or partial or complete semicircular canal hypoplasia/aplasia. 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
  • 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 observed.
  • 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 (not consistently present)
  • Renal - Hydronephrosis, vesicoureteric reflux
  • Larynx - Laryngomalacia, laryngeal clefts
  • Esophageal - Atresia, tracheoesophageal fistula
  • Skeletal - Hemivertebrae, scoliosis, clinodactyly, syndactyly
  • Orofacial clefting - Found in approximately 30-50% of patients

Causes

CHARGE syndrome is an autosomal dominant condition with genotypic heterogeneity. Most cases (58-71% in unselected CHARGE referrals and as many as 90% of patients who meet criteria for typical CHARGE syndrome) are due to mutations of the CHD7 gene leading to haploinsufficiency.^1,6,17,19

Microdeletions encompassing the entire CHD7 gene or affecting individual CHD7 gene exons occur in a minority of cases.^20,21 One case report detailed CHD7 duplication, which did not result in a CHARGE-like phenotype.²²  Numerous case reports have described individuals clinically diagnosed with CHARGE syndrome who harbor various presumably pathologic cytogenetic abnormalities, including 22q11.2 deletions, 14q22-q24.3 inverted duplications, and 9p-, and single gene mutations (including SEMA3E gene mutation).^7,8,9,10

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