What is the management approach for an individual with a CHD7 (Chromodomain Helicase DNA binding protein 7) mutation?

Management of CHD7 Mutation (CHARGE Syndrome)

Immediate Diagnostic Confirmation and Genetic Counseling

Individuals with CHD7 mutations require immediate referral to a geneticist for comprehensive evaluation, family counseling regarding recurrence risk, and coordination of multidisciplinary care, as intellectual disability occurs in almost all cases and requires early intervention services. 1

• CHD7 mutations cause CHARGE syndrome (Coloboma, Heart defects, Atresia of choanae, Retardation of growth/development, Genital hypoplasia, Ear anomalies), with approximately 50% of patients having congenital heart disease. 1
• Genetic testing should be performed using direct exon sequencing, with multiplex ligation-dependent probe amplification (MLPA) added if initial sequencing is negative, as intragenic deletions may be missed by standard sequencing. 2
• Genetic counseling must address that most CHARGE-causing mutations are de novo truncating variants (nonsense, frameshift), though missense mutations are more common in milder phenotypes like isolated Kallmann syndrome. 3

Cardiac Evaluation and Management

All individuals with confirmed CHD7 mutations must undergo comprehensive echocardiography immediately to screen for tetralogy of Fallot, interrupted aortic arch, truncus arteriosus, patent ductus arteriosus, ventricular septal defect, and atrial septal defect. 1

• Cardiac lesions occur in 50% of CHD7 mutation carriers, with tetralogy of Fallot and interrupted aortic arch being most common. 1
• Patients with complex congenital heart disease require surgical intervention by surgeons with specific training in congenital heart disease, not general cardiac surgeons. 4
• Follow-up frequency depends on lesion complexity: annually for repaired defects with minimal residua, every 6-24 months for moderate complexity, and every 3-12 months for complex lesions. 4
• Endocarditis prophylaxis is mandatory for patients with uncorrected cyanotic heart disease, prosthetic valves, or residual intracardiac shunts at repair sites. 1

Neurodevelopmental Assessment and Early Intervention

Immediate referral to early intervention services (birth to 3 years) is mandatory, as intellectual disability occurs in almost all CHD7 mutation carriers, and developmental screening must begin at diagnosis regardless of age. 1

• Neurodevelopmental evaluation should include assessment by a developmental pediatrician, pediatric neurologist, and pediatric psychologist to address motor, cognitive, language, and social deficits. 1
• Structural brain imaging with MRI should be obtained if microcephaly, seizures, or other neurological symptoms are present, as brain malformations are common. 1
• Referral to physical therapy, occupational therapy, feeding therapy, and speech therapy should occur immediately upon diagnosis, not after developmental delays become apparent. 1

Hearing and Otologic Management

Comprehensive audiologic evaluation and temporal bone CT imaging must be performed immediately at diagnosis, as 97% of CHD7 mutation carriers have hearing loss, with 83% having severe-to-profound loss in at least one ear. 5

• Sensorineural hearing loss is most common, particularly with nonsense or frameshift CHD7 variants causing haploinsufficiency. 5
• Temporal bone imaging reveals structural anomalies in 79% of patients with hearing loss, including vestibulo-cochlear defects and semicircular canal abnormalities. 5, 6
• Early cochlear implantation or hearing aid fitting is critical, as hearing loss directly impacts language development in children already at risk for intellectual disability. 5

Ophthalmologic Evaluation

Comprehensive ophthalmologic examination including dilated fundoscopy must be performed to identify colobomas of the iris or retina, which are prevalent in CHD7 mutations. 6

• Colobomas are a cardinal feature of CHARGE syndrome and require ongoing monitoring for retinal detachment risk. 6

Airway and Respiratory Assessment

Evaluation by pediatric otolaryngology is mandatory to assess for choanal atresia and laryngomalacia, both highly prevalent in CHD7 mutations. 6

• Laryngomalacia occurs frequently and may require surgical intervention if causing significant airway obstruction. 6
• Choanal atresia requires surgical correction and may necessitate tracheostomy in severe cases. 6

Endocrine and Growth Monitoring

Screening for genital hypoplasia and hypogonadotropic hypogonadism should be performed, as CHD7 mutations can cause Kallmann syndrome phenotype with absent puberty. 3

• Growth parameters must be monitored regularly, as growth retardation is a core feature of CHARGE syndrome. 1
• Endocrinology referral is indicated for patients with delayed puberty or genital anomalies. 3

Establishing a Medical Home

A coordinated care model with a designated primary care provider serving as the "medical home" is essential, with the geneticist and cardiologist maintaining close communication and ensuring all specialists have current clinical records. 1, 4

• The medical home provider coordinates developmental surveillance, screening, evaluation, and management across all subspecialties. 1
• Patients should carry copies of relevant medical records, particularly cardiac surgical reports and genetic testing results. 4

Common Pitfalls to Avoid

• Failing to screen for CHD7 mutations in patients with isolated Kallmann syndrome plus deafness or cleft lip/palate, as these represent milder phenotypic expressions of CHD7 mutations. 3
• Assuming normal hearing based on behavioral responses, as severe-to-profound hearing loss is present in 83% of cases and requires objective audiologic testing. 5
• Delaying early intervention services until developmental delays become obvious, as intellectual disability is nearly universal and early intervention improves outcomes. 1
• Using only standard sequencing without MLPA, as intragenic deletions account for a significant proportion of CHD7 mutations and will be missed. 2