CHARGE Syndrome

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

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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.

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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]

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