CHARGE Syndrome 

Updated: Jun 12, 2019
Author: Megan Ehlinger Boothe, MD; Chief Editor: Maria Descartes, MD 

Overview

Practice Essentials

CHARGE syndrome is an autosomal dominant genetic disorder typically caused by pathogenic variants in the chromodomain helicase DNA-binding protein-7 (CHD7) gene.[1, 2] The acronym "CHARGE" denotes the nonrandom association of coloboma, heart anomalies, atresia of the choanae, retardation of growth and development, genital anomalies, and ear anomalies (including deafness and vestibular disorders), which are frequently present in various combinations and to varying degrees in individuals with CHARGE syndrome.[3, 4] No single feature is universally present or sufficient for the syndrome's clinical diagnosis; numerous guidelines have been published to aid in the diagnosis.[3, 5, 6, 7]

Blake et al suggested that a typical clinical diagnosis of CHARGE syndrome requires the presence of at least four major features or three major features plus at least three minor features.[5] Major features include the following:

  • Ocular coloboma or microphthalmia
  • Choanal atresia or stenosis
  • Cranial nerve abnormalities
  • Characteristic auditory and/or auricular anomalies

Minor features include the following:

  • Distinctive facial dysmorphology - Asymmetrical, square face; malar flattening; unilateral facial nerve paralysis; micrognathia; low-set, cupped ears
  • Facial clefting
  • Tracheoesophageal fistula
  • Congenital heart defects
  • Genitourinary anomalies
  • Developmental delay

Other frequently associated abnormal findings include characteristic hand dysmorphology (such as hockey-stick palmar creases, square palm, brachydactyly), hypotonia, deafness, and dysphagia.[5, 8, 9, 10]

Changes to diagnostic criteria were proposed by Verloes in 2005 to include three major features or two major features with two supportive criteria. Based on this model, major features included ocular coloboma, choanal atresia or stenosis, and hypoplasia of semicircular canals. Supportive criteria include characteristic outer ear, cranial nerve abnormality, heart or esophagus anomalies, and behavioral or brain abnormalities.[6] Hale et al subsequently proposed additional changes to the diagnostic criteria to include pathogenic CHD7 variants and cleft palate as major features. Their proposal would loosen diagnostic criteria to include two major features with any number of supportive criteria, allowing for a diagnosis of CHARGE syndrome in cases of atypical or more mild phenotypes.[11]

Although most cases of CHARGE syndrome are due to pathogenic variants or deletion of the CHD7 gene, some syndromic individuals harbor disparate pathologic cytogenetic anomalies (including 22q11.2 deletions) or mutations in other genes (including SEMA3E) unrelated to CHD7.[12, 13, 14, 15, 16, 17, 18]

Workup

Laboratory studies in the evaluation of CHARGE syndrome can include the following:

  • CHD7 mutation analysis - Diagnostic in more than 90% of individuals referred with presumptive CHARGE syndrome
  • High-resolution karyotype (chromosome analysis)
  • Blood urea nitrogen (BUN), creatinine, electrolytes
  • Luteinizing hormone-releasing hormone (LHRH) and human chorionic gonadotropin (HCG)
  • Growth hormone levels
  • Complete blood count (CBC) and immunology studies

Imaging studies that can be used in the syndrome’s assessment include the following:

  • Chest radiography
  • Cranial ultrasonography
  • Abdominal ultrasonography
  • Head computed tomography (CT) scanning and/or magnetic resonance imaging (MRI)
  • Barium swallow
  • Skeletal survey
  • Echocardiography

Management

At birth in infants with CHARGE syndrome, provide a secure airway, stabilize the patient, exclude major life-threatening congenital anomalies, and transfer the individual to a specialist center with a pediatric otolaryngologist and other subspecialty services.

Surgeries can include the following:

  • Tracheostomy
  • Myringotomy and tympanostomy tubes - For otitis media
  • Gastrostomy and fundoplication - May be necessary with feeding difficulty

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 midface and exerts an inductive role on the subsequent development of the prosencephalon, the forepart of the brain.[19, 20]  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.[6, 19]  The complete function of CHD7 during embryologic development remains unclear.[20]

Epidemiology

Frequency

International

The estimated birth incidence of CHARGE syndrome is 1 in 10,000 to 1 in 15,000.[21, 10]

Mortality/Morbidity

Mortality in CHARGE syndrome 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.[22, 23]

Factors associated with poor survival include the following[24] :

  • Bilateral choanal atresia
  • Complex cyanotic congenital heart disease
  • CNS anomalies

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.

Prognosis

Mortality in CHARGE syndrome is higher in the first few years of life and occurs most often in infants with severe birth defects. Patients remain medically fragile beyond the first years of life, typically needing frequent hospitalizations due to illness and infection and requiring frequent surgeries. In later childhood through adulthood, more frequent causes of death include aspiration, infection, and obstructive or central sleep apnea.[10]

 

Presentation

History

The history in patients with CHARGE syndrome may include the following.[8, 23, 25, 26] :

Prenatal presentation

This can include the following:

  • Intrauterine growth retardation
  • Congenital heart defects
  • Orofacial clefting
  • Poor fetal movement

Neonatal presentation

This can include the following:

  • Small for gestational age
  • Dysmorphic features - Asymmetrical, square face; malar flattening; unilateral facial nerve paralysis; micrognathia; low-set, cupped ears
  • Respiratory distress/cyanosis
  • Swallowing/feeding difficulty
  • Failed newborn hearing screen
  • Inability to pass nasogastric tube

Infantile and childhood presentation

This can include the following:

  • Failure to thrive
  • Developmental delay
  • Feeding difficulty
  • Poor growth

A retrospective study by Kong and Martin found that out of 23 patients with CHARGE syndrome, 15 (65%) had at least one atopic disorder, with five (22%) having a food allergy; six (26%), a drug allergy; five, a contact allergy; two (9%), allergic rhinitis; and five, asthma. Atopic disorders did not differ significantly with regard to whether a CHD7 pathogenic variant was present.[27]

Physical

CHARGE syndrome is typically a sporadically occurring, autosomal dominant condition. Rarely, it is inherited from a parent; however, the syndrome's expression is so variable that adults may be diagnosed only after a more severely affected child has been diagnosed.

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, anosmia, orofacial clefting, deafness, dysphagia, and tracheoesophageal anomalies. Immune deficiencies have also been reported. [10] The occasional family member may also have features of this disease.[28]

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.[3, 5, 6]

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.[29]

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.

Developmental delay and intellectual disability (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 intellectual disability.

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.

Intellectual disability is not universal but is frequent. There is no correlation between intellectual disability and the severity of birth defects.[10]

One should be careful not to diagnose intellectual disability until the full extent of sensory deficits is 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. See the image below.

Typical ear malformation 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

These include the following:

  • 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

  • Cerebellar vermis hypoplasia - A study by Sohn et al found that five out of 17 patients (29.4%) with CHARGE syndrome had cerebellar vermis hypoplasia, suggesting, according to the investigators, that this may also be a sign of the syndrome;[30] in another study, Yu et al found cerebellar vermis hypoplasia in seven out of 20 of CHARGE syndrome patients (35%) proven to have a CHD7 mutation[31]

  • Dysmorphic features - These features include a typically asymmetrical, square face; malar flattening; unilateral facial nerve paralysis; and micrognathia

  • Hand dysmorphology - This includes brachydactyly and clinodactyly

  • Orofacial clefting - Cleft lip and palate is seen in approximately 30-50% of patients[32]

  • Limb anomalies - Seen in approximately one third of patients; includes hockey-stick palmar creases, square palms, hypoplastic nails, brachydactyly, syndactyly, preaxial polydactyly, and ectrodactyly; tibial aplasia has also been reported[11, 10, 33, 34]

Occasional anomalies (not consistently present)

These include the following:

  • Renal - Hydronephrosis, vesicoureteric reflux

  • Larynx - Laryngomalacia, laryngeal clefts

  • Esophageal - Atresia, tracheoesophageal fistula

  • Skeletal - Hemivertebrae, scoliosis, clinodactyly

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, 12, 25, 35, 28]

Microdeletions encompassing the entire CHD7 gene or affecting individual CHD7 gene exons occur in a minority of cases.[36, 37] If the CHD7 mutation analysis is normal, obtaining studies for del/dup of CHD7 and then an array of comparative genomic hybridization (CGH) are the next steps. A genotype/phenotype correlation has not been identified, although patients harboring missense variants in CHD7 less commonly fulfill the clinical criteria for CHARGE syndrome.[38]

One case report detailed CHD7 duplication, which did not result in a CHARGE-like phenotype.[39] 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.[13, 14, 15, 16]

 

DDx

Diagnostic Considerations

These include the following:

  • 22q11.2 deletion syndrome

  • Cat-eye syndrome

  • Holoprosencephaly spectrum disorders

  • Isolated coloboma

  • Isolated choanal atresia

  • Isolated congenital heart defects

  • Joubert spectrum

  • Kallmann syndrome

  • Kabuki syndrome

  • Renal coloboma syndrome

  • VATER/VACTERL association

Differential Diagnoses

 

Workup

Laboratory Studies

See the list below:

  • CHD7 mutation analysis is diagnostic in more than 90% of individuals referred with presumptive CHARGE syndrome. If the CHD7 sequencing is normal, this should be followed by del/dup analysis and then high-density microarray

  • High-resolution karyotype (chromosome analysis) may be considered if the microarray result was normal.

  • BUN, creatinine, electrolytes - Evaluate and monitor renal function and exclude hypocalcemia (DiGeorge syndrome).

  • Luteinizing hormone-releasing hormone (LHRH) and human chorionic gonadotropin (HCG) - 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.

  • CBC and immunology studies - Immunodeficiency has been reported and is primarily T-cell based but may also be humoral, even appearing like Omenn syndrome.[40, 41]

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 ultrasonography

Perform this study in the immediate neonatal period to exclude major malformations of the brain.

Head CT scanning and/or MRI, including the temporal bones

Perform computed tomography (CT) scanning and/or magnetic resonance imaging (MRI) to exclude cerebral malformation and cerebral atrophy and to exclude defective formation of the ossicles of the middle ear. MRI of the brain may reveal cerebral atrophy, midline brain defects (eg, agenesis of corpus callosum), and forebrain anomalies, particularly arrhinencephaly. CT scanning of the temporal bone reveals partial or complete semicircular canal hypoplasia. Ideally, evaluate the internal ear in later infancy or early childhood, when the ear is more fully formed.

A retrospective CT/MRI scan study by Mahdi and Whitehead of 15 patients with CHARGE syndrome suggested that clival pathology is a universal manifestation of the condition. Thirteen patients (87%) were found on imaging to have either a partial or complete coronal clival cleft, while clival hypoplasia, with no clefting, was identified in the remaining two patients (13%).[42]

Barium swallow

Perform this study to diagnose swallow dysfunction and/or esophageal dysmotility and tracheal aspiration.

Abdominal ultrasonography

Perform abdominal ultrasonography to exclude renal anomalies.

Skeletal survey

Survey the skeleton to exclude skeletal anomalies.

Echocardiography

Perform echocardiography to identify or exclude congenital cardiac defects.

Other Tests

See the list below:

  • 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

    • Regular ophthalmologic visits are important.

    • 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.

 

Treatment

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 a 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. Surgeries can include the following:

  • Tracheostomy

  • Myringotomy and tympanostomy tubes - For otitis media

  • Gastrostomy and fundoplication - May be necessary with feeding difficulty

In patients with CHARGE syndrome who have sensorineural hearing loss, careful treatment planning can lead to auditory benefit. In a study of 10 patients with CHARGE syndrome and 3 patients with CHARGE-like syndrome, 9 patients demonstrated improved responsiveness with cochlear implantation.[43] Thus, cochlear implantation may be indicated after critical assessment.[44]

Consultations

Genetic consultation is used for diagnosis, counseling, management, and coordination of services.

  • Otolaryngology

  • Cardiology

  • Ophthalmology

  • Otolaryngology

  • Gastroenterology

  • Audiology

  • Neurology

  • Speech therapy

  • Orthopedics

  • Physiotherapy

  • Occupational therapy

  • Social services

  • Special education

 

Medication

Medication Summary

Medication is not currently a component of care in CHARGE syndrome. See Treatment.

 

Follow-up

Further Outpatient Care

See the list below:

  • Long-term coordination of care is necessary in patients with CHARGE syndrome.

  • Ensure follow-up care and recognition and prevention of complications.

Transfer

See the list below:

  • A tertiary hospital with appropriate pediatric subspecialists should coordinate and undertake care.

Complications

See the list below:

  • Eye - Corneal ulceration, retinal detachment

Patient Education

See the list below:

  • Families of patients with CHARGE syndrome require education regarding the disease manifestations and potential complications.

  • Discuss the genetic basis of the disorder and include the recurrence risks (1-2% for unaffected parents, as much as 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.

  • Familial cases do occur; although autosomal dominant heritance with variable expression is rare, it does occur.