OMIM ID:
CHARGE Syndrome
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Both ocular and systemic abnormalities are highly variable, even within families. Among the most common ocular features are unilateral or bilateral ocular colobomas (80%). These involve the iris most frequently but they may extend into the posterior chamber and rarely involve the optic nerve. A significant number of patients with uveal colobomas have an associated microphthalmia. The lid fissures often slant downward. A few patients have congenital cataracts, optic nerve hypoplasia, persistent hyperplastic vitreous, and strabismus.
Systemic Features
A wide variety of systemic anomalies have been reported. Congenital heart defects (primarily septal) and CNS malformations are among the most common features, reported in 85% and 55% respectively. Tetralogy of Fallot is considered by some to be the most common heart malformation. Growth and mental retardation are found in nearly 100%. The pinnae are often set low and hearing loss is common. Ear anomalies, both internal and external, have been described in 91%, and some degree of conduction and/or sensorineural deafness is present in 62%. Choanal atresia is found in at least 57% of patients. This along with cleft palate and sometimes esophageal atresia or reflux often contributes to feeding difficulties which are common in all age groups. Cranial nerve deficits are seen in 92% of patients and more than one nerve is involved in nearly 3 of 4 patients. The most common cranial nerve defects involve numbers IX, X, VIII, and V. Facial palsies are an especially important feature. Hypogonadotropic hypogonadism and underdevelopment of the external genitalia are often seen, especially in males. One-third of patients have limb anomalies and many have short digits. The facies is considered by some as characteristic with a square configuration, broad forehead, flat midface, and a broad nasal bridge.
Infant and childhood morbidity is high with feeding difficulties a major cause of death.
Genetics
Inheritance
Many cases occur sporadically but family patterns consistent with autosomal dominant inheritance are common as well. Advanced paternal age may be a factor in de novo cases. Sequence variants of multiple types have been reported in the CHD7 gene (8q12.1-q12.2) in more than 90% of familial patients. The gene product is a DNA –binding protein that impacts transcription regulation via chromatin remodeling.
Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) has been considered to be allelic to CHARGE syndrome but may be the same disorder since mutations in CHD7 are responsible and many patients have other features characteristic of the syndrome described here.
Several patients with classical features of the CHARGE syndrome and de novo mutations in the SEMA3E gene (7q21.11) have also been described.
Pedigree
Autosomal dominant
Autosomal dominant disorders require only one mutation for the disease to be expressed. Since an affected parent has two chromosomes, only one of which has the mutant gene, parents can expect that half (50%) of their children will receive that one and inherit the disease. It is common for individuals that inherit the mutation, however, to not have evidence of the disease (nonpenetrance).
Autosomal dominant inheritance leads to a vertical pattern of transmission