CHARGE Syndrome

At a glance

A potentially life-threatening, congenital multiple-malformation syndrome. CHARGE is an acronym that stands for Coloboma, Heart disease, choanal Atresia, mental and growth Retardation, Genital and urinary anomalies, and Ear anomalies with deafness. The prognosis worsens if the disorder is associated with concomitant cyanotic congenital heart disease, central nervous system anomalies, or esophageal atresia.

Synonyms

CHARGE Association; Hall-Hittner Syndrome (both synonyms are now obsolete).

Incidence

Approximately 1:10,000-15,000 live births. No sexual or racial predilection has been reported.

Genetic inheritance

More than 90% of the cases occur sporadically, the remaining cases are familial with autosomal dominant transmission. No genotype-phenotype correlation could be detected and inter- and even intrafamilial expression is highly variable. The defect is caused by mutations (frameshift, nonsense, missense, or splice-site) in the CHD7 (Chromodomain [chromatin organisation modifier] Helicase DNA-Binding Protein 7) gene, which has been mapped to chromosome 8q12.2. The CHD7 protein is involved in the epigenetic regulation of transcription and plays a role in the control of gene expression through chromatin remodeling and thus in early embryonic development. Exposure to teratogenic substances (eg, thalidomide, hydantoin), but also maternal diabetes mellitus had occasionally been blamed to play a causative role, but none of these theories proved to be convincing.

Pathophysiology

CHARGE Syndrome is a midline developmental defect attributed to an arrest in embryologic differentiation during early organogenesis. The mechanism has not been precisely identified, but may include failure of the cervical neural crest cells to differentiate and migrate into the derivatives of the pharyngeal pouches and arches, deficient blastogenesis as a result of defective interaction between mesoderm and neural crest cells, and failure of mesoderm formation.

Diagnosis

None of the features in the CHARGE acronym is universally present. Patients may present in the neonatal period with respiratory distress and feeding difficulties. Delayed manifestation is usually associated with persistent nasal discharge, failure to thrive, audiovisual defects, and developmental delay. Different diagnostic criteria (subdivided into major and minor criteria) have been proposed and used to confirm the diagnosis.