CHARGE Syndrome: Clinical Features, Diagnosis, and Management
Overview and Genetic Basis
CHARGE syndrome is a genetic disorder caused by autosomal dominant mutations in the CHD7 gene (chromosome 8q12.1), with approximately 67% of clinically diagnosed cases having identifiable CHD7 mutations. 1, 2, 3 The CHD7 protein functions as an ATP-dependent chromatin remodeling protein, and most mutations are de novo, occurring sporadically rather than being inherited. 2, 3
Characteristic Clinical Features
The acronym CHARGE defines the cardinal features:
Major Diagnostic Features
- Coloboma of the eye - present in mutation-positive patients more commonly than mutation-negative cases 1, 4
- Heart defects - occurring in 50-75% of cases, with over-representation of atrioventricular septal defects, conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch), and aortic arch anomalies 1, 5
- Atresia of the choanae - bilateral or unilateral nasal passage obstruction, diagnosed by inability to pass a small rubber catheter through the nose 1
- Retarded growth and development - intellectual disability occurs in almost all cases 1
- Genital abnormalities - genital hypoplasia and urinary tract anomalies 1, 3
- Ear abnormalities and deafness - including characteristic semicircular canal hypoplasia/dysplasia resulting in vestibular areflexia, which is a consistent and distinguishing feature 6, 3, 4
Additional Common Features
- Temporal bone anomalies - semicircular canal hypoplasia is highly characteristic and more common in CHD7 mutation-positive patients 3, 4
- Facial nerve palsy - more prevalent in mutation-positive individuals 3, 4
- Cleft lip/palate 3
- Tracheo-esophageal fistula 3
- Behavioral problems - including autistic-like behavior 3
Diagnostic Approach
Initial Clinical Assessment
When CHARGE syndrome is suspected, immediately assess for the inability to pass a small rubber catheter through the nose (diagnostic for choanal atresia), perform nasal endoscopy, and obtain echocardiography. 1, 7
Genetic Testing
- CHD7 gene sequencing is the primary diagnostic test, identifying mutations in approximately 67% of clinically diagnosed cases 8, 3
- Over 528 unique pathogenic CHD7 alterations have been identified, scattered throughout the gene without clear genotype-phenotype correlations 8, 3
- Most mutations are nonsense, frameshift, or splice-site mutations representing null alleles 2, 3
Imaging Studies
- Echocardiography - mandatory to evaluate for congenital heart defects 7, 5
- Renal and bladder ultrasound - to screen for genitourinary anomalies 7
- Temporal bone imaging - to assess semicircular canal anatomy 4
- CT scan - may be used for detailed evaluation of choanal atresia, though not routinely required 1
Important Diagnostic Pitfall
CHARGE syndrome must be distinguished from 22q11.2 deletion syndrome (DiGeorge syndrome), as they are distinct genetic conditions with different molecular causes (CHD7 mutations versus 22q11.2 deletions) despite some overlapping features. 6, 9 Both can present with cardiac defects and genitourinary abnormalities, but CHARGE has characteristic ear/vestibular findings and coloboma, while 22q11.2 deletion has thymic hypoplasia and hypoparathyroidism. 7, 9
Multidisciplinary Management Recommendations
Immediate Neonatal Management
- For bilateral choanal atresia presenting in neonates, establish airway patency immediately - neonates are obligate nasal breathers and require urgent intervention 1
- Avoid live-attenuated vaccines until T-cell function is assessed, as some CHARGE patients may have thymic abnormalities requiring thymus transplantation 1
Cardiovascular Management
- All CHARGE patients require comprehensive cardiac evaluation and ongoing cardiology follow-up due to the 50-75% prevalence of congenital heart defects 1, 5
- Assess for cardiac-related hepatic congestion in patients with complex cardiac disease, as chronic venous hypertension can lead to cardiac cirrhosis 6
- Perioperative morbidity and mortality are increased due to overlapping cardiovascular and non-cardiovascular comorbidities 5
Surgical Management of Choanal Atresia
- The preferred surgical approach is micro-endoscopic endonasal repair, with 63% of patients requiring only one procedure 1
- Transpalatine approach is reserved for cases with insufficient nasal passage 1
- Long-term follow-up (minimum 12 months) is essential to monitor for restenosis 1
Developmental and Neurodevelopmental Support
- CHARGE syndrome is classified as high-risk for developmental disorders, requiring early developmental surveillance, screening, and intervention within a medical home model 1
- Intellectual disability occurs in almost all cases, necessitating early intervention services 1
- Monitor for behavioral problems including autistic-like features 3
Immunological Considerations
- Screen for T-cell deficiency, as some CHARGE patients may have thymic abnormalities requiring specialized immunological management 1
- Consider antibiotic prophylaxis if recurrent infections occur 1
Genetic Counseling
- Most cases (>90%) are de novo mutations with low recurrence risk for parents, though germline mosaicism has been documented 3
- Affected individuals have a 50% risk of transmitting the mutation to offspring 3
- Parental genetic screening should be performed to confirm sporadic origin 2
Long-term Surveillance
- Coordinate lifelong multidisciplinary care involving cardiology, otolaryngology, ophthalmology, audiology, developmental pediatrics, and genetics 1, 7
- Regular monitoring for growth, development, hearing, vision, and cardiac function 1, 5
- Screen for associated comorbidities throughout the lifespan 1
Clinical Variability and Prognosis
No clear genotype-phenotype correlations exist, with significant clinical variability even among siblings with identical CHD7 mutations. 3 This unpredictability necessitates comprehensive evaluation of each patient regardless of specific mutation type. The broad phenotypic spectrum means that nearly all patients fulfill current diagnostic criteria, but severity varies considerably. 3, 4