Practice Essentials
CHARGE syndrome is an autosomal dominant genetic disorder characterized by a set of birth defects and caused by mutations in the CHD7 gene, which encodes a protein involved in chromatin remodeling. [1, 2] It was initially identified using the acronym CHARGE, which stands for coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness. [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 have proposed that for a CHARGE syndrome diagnosis to be clinically typical, it should include 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 commonly observed anomalies often include distinctive hand malformations (like hockey-stick palmar creases, square palm, short fingers), hypotonia, deafness, and dysphagia. [5, 8, 9, 10]
Changes to diagnostic criteria were proposed by Verloes in 2005 to include three major features
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
-
Central nervous system (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]
Patient Education
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.
-
Typical ear malformation
