What is the recommended prenatal testing strategy for CHARGE syndrome?

Prenatal Testing Strategy for CHARGE Syndrome

Direct Recommendation

When CHARGE syndrome is suspected prenatally based on characteristic ultrasound findings (congenital heart defects, choanal atresia, or ear anomalies), proceed with targeted fetal imaging including detailed 2D/3D ultrasound of external ears, fetal MRI, and temporal bone CT scan, followed by diagnostic testing via amniocentesis or chorionic villus sampling with CHD7 gene sequencing to confirm the diagnosis and optimize delivery planning. 1, 2

Clinical Context and Diagnostic Approach

When to Suspect CHARGE Syndrome Prenatally

CHARGE syndrome should be considered when specific combinations of anomalies are identified on prenatal ultrasound:

• Congenital heart defects (particularly septal defects and conotruncal anomalies such as double outlet right ventricle, tetralogy of Fallot) are present in 70% of cases and often serve as the initial finding 1, 3
• Choanal atresia is detected in 70% of prenatally diagnosed cases 1
• Tracheoesophageal atresia with associated polyhydramnios occurs in 40% 1
• Cleft lip/palate or unexplained polyhydramnios should prompt careful screening 1

Essential Imaging Protocol

The diagnostic keystone for prenatal CHARGE syndrome is identification of inner and external ear anomalies, which are constant features when carefully evaluated: 1

First-Line Ultrasound Assessment

• 2D ultrasound for cardiac anatomy, growth parameters, and major structural anomalies 1
• 3D ultrasound is critical for visualizing external ear malformations, which are present in 100% of cases when carefully evaluated 1, 3
• Specific attention to ear structure and response to acoustic stimulation (non-response is a specific clue) 3

Second-Line Imaging Studies

• Fetal MRI to assess for semicircular canal agenesis, arhinencephaly, and choanal atresia 1, 2
• Temporal bone CT scan to evaluate semicircular canal development and inner ear structures 1

Important caveat: A normal fetal MRI does not exclude CHARGE syndrome, as some features may not be visible prenatally 2

Diagnostic Confirmation Strategy

Genetic Testing Pathway

When CHARGE syndrome is suspected with normal chromosomal microarray:

1. Offer invasive diagnostic testing via chorionic villus sampling (if <15 weeks) or amniocentesis (if ≥15 weeks) 4
2. Request CHD7 gene sequencing specifically, as this confirms diagnosis in the majority of cases 1, 5, 3
3. Consider whole exome sequencing if CHD7 testing is negative but clinical suspicion remains high 3, 6

The chromosomal microarray (CMA) should be performed first to exclude other genetic syndromes, but CMA alone will not detect CHARGE syndrome 4, 1

Differential Diagnosis Considerations

CHARGE syndrome shares overlapping features with other conditions that must be excluded:

• 22q11.2 deletion syndrome (DiGeorge syndrome) presents with similar cardiac defects and thymic hypoplasia 4, 6
• Both conditions can present with increased nuchal translucency in first trimester 4, 6
• MLPA (multiplex ligation-dependent probe amplification) for 22q11.2 deletion should be performed alongside CHD7 testing 6

Timing and Quality Considerations

Optimal Gestational Age Windows

• First trimester (11-14 weeks): Increased nuchal translucency may be the earliest clue, though this is nonspecific 4, 6
• Second trimester (≥20 weeks): Most prenatal features become apparent, including cardiac defects and extracardiac abnormalities 4
• Detailed anatomic survey at 16-20 weeks should include specific evaluation for CHARGE-associated features 4

Critical Pitfalls to Avoid

1. Do not dismiss intrauterine growth restriction as excluding CHARGE syndrome – this was previously considered an exclusion criterion but has been documented in confirmed cases 2

2. Do not rely solely on major anomalies – minor clues such as structurally malformed ears, renal malrotation, or persistent non-response to acoustic stimulation are diagnostically significant 3

3. Do not assume normal karyotype or microarray excludes genetic syndrome – CHARGE requires specific CHD7 gene testing 1, 6

4. Do not delay genetic counseling – families need information about 50% recurrence risk in future pregnancies and variable expressivity 4

Pregnancy Management After Diagnosis

Monitoring Requirements

Pregnancies with confirmed or suspected CHARGE syndrome require:

• Close monitoring for polyhydramnios and potential preterm labor 4, 1
• Serial growth ultrasounds due to risk of intrauterine growth restriction 4, 2
• Fetal echocardiography to monitor cardiac function 4

Delivery Planning

• Location of delivery should be influenced by the diagnosis, with delivery at a tertiary center with immediate access to neonatal intensive care, pediatric cardiology, and ENT surgery 4
• Mode of delivery may be influenced by presence of structural anomalies 4
• Multidisciplinary team should be assembled before delivery including neonatology, cardiology, and genetics 4

Genetic Counseling Essentials

All families with prenatal diagnosis or suspicion of CHARGE syndrome require:

• Discussion of 50% recurrence risk in future pregnancies (autosomal dominant inheritance) 4
• Explanation of variable expressivity – phenotype can range from mild to severe 4
• Options for future pregnancies including preimplantation genetic diagnosis 4
• Parental testing to assess for germline mosaicism, though negative parental testing does not eliminate recurrence risk 4