CHARGE Syndrome

Updated: Apr 05, 2016
  • Author: David H Tegay, DO, FACMG; Chief Editor: Maria Descartes, MD  more...
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Overview

Background

CHARGE syndrome is an autosomal dominant genetic disorder typically caused by mutations in the chromodomain helicase DNA-binding protein-7 (CHD7) gene. [1, 2] 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. [3, 4] 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. [3, 5, 6]

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. [5] 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. [5, 7, 8]

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. [9, 10, 11, 12, 13]

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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 mid face and exerts an inductive role on the subsequent development of the prosencephalon, the forepart of the brain. [14, 15]

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, 14]

The complete function of CHD7 during embryologic development remains unclear. [15]

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Epidemiology

Frequency

International

The estimated birth incidence of CHARGE syndrome is 1 in 8,500-12,000. [16]

Mortality/Morbidity

Mortality and morbidity in CHARGE syndrome includes the following: [17, 18, 19]

  • 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.

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