CHARGE Syndrome

Epidemiology and Genetics

Epidemiology

• Incidence: 1 in 12,000–15,000 newborns
• Mortality is highest during neonatal period.

Genetics

• Most commonly due to loss of function mutation in CHD7 gene 
  • Produces the CHD7 protein, involved in chromatin remodeling
  • Chromatin remodeling controls the gene expression. 
  • The defective CHD7 protein breaks down prematurely. 
  • Results in a disrupted chromatin remodeling and poor gene expression 
  • Neural crest differentiation into various structures throughout the body is impaired.
• Inheritance pattern: autosomal dominant 
• May be familial, but more often results from de novo (idiopathic) mutations
• Advanced paternal age possibly a risk factor

Clinical Presentation

Characteristic symptoms

CHARGE is an acronym to describe the clinical presentation of this syndrome: 

• C for Coloboma (a hole in the choroid, retina, iris, and/or optic disc)
  • Unilateral or bilateral
  • Impairment of vision depending on the location and size 
  • May also present with microphthalmia
• H for Heart defects (60%–70% of cases) 
  • Coarctation of the aorta
  • Aortic valve stenosis
  • Tetralogy of Fallot
  • Patent ductus arteriosus
• A for Atresia of the choanae (choanal atresia)
  • Bony and/or membranous tissue blocks back of nasal passageway.
  • Inability to pass nasogastric tube is noted.
• R for growth Retardation (60%–70% of cases)
  • Noticeable in the first 6 months of life
  • May be noted in utero
  • Short stature
  • Due to growth hormone (GH) deficiency and a gonadotropin deficiency
• G for Genital abnormalities 
  • Hypogonadotropic hypogonadism
  • Micropenis, cryptorchidism
  • Labial dysplasia
• E for Ear abnormalities (100% of cases)
  • Hypoplastic semicircular canals are pathognomonic.
  • External ear is small, low-set, and square-shaped with protruding helices.
  • Developmental defects of the middle and inner ear → hearing impairment 

Associated conditions

• Additional facial dysmorphic features: square face, facial nerve palsy, malar flattening, micrognathia, orofacial clefting
• Skeletal anomalies such as scoliosis, polydactyly, oligodactyly, or clubfoot
• Tracheoesophageal fistula
• Feeding and swallowing difficulties/under-nutrition
• Neurological anomalies 
• Intellectual disability and developmental delay
• Renal anomalies

Diagnosis

Diagnostic criteria

The diagnosis of CHARGE syndrome can be established if 2 major criteria plus any number of minor criteria are present.

• 4 major criteria (4 Cs):
  1. Coloboma
  2. Choanal atresia or cleft palate
  3. Characteristic external, middle, or inner ear anomalies including hypoplastic semicircular canals
  4. CHD7 variant (pathogenic)
• 7 minor criteria:
  1. Cranial nerve dysfunction including hearing loss
  2. Dysphagia/feeding difficulties
  3. Structural brain anomalies
  4. Developmental delay/intellectual disability/autism
  5. Hypothalamo-hypophyseal dysfunction (including hormonal deficiencies) and genital anomalies
  6. Heart or esophageal malformations
  7. Renal/skeletal/limb anomalies

Laboratory tests

• Complete blood count (CBC)
• Renal function tests
• Hormonal analysis (↓ growth hormone, ↓ gonadotrophins)
• Immunological studies

Imaging studies

• Ultrasonography (US): 
  • Cranial US: done during neonatal period to exclude major brain malformations
  • Abdominal US: to exclude renal abnormalities
• Echocardiography: valvular abnormalities and structural heart defects
• Barium swallow: esophageal dysmotility
• Chest radiographs: to detect cardiopulmonary abnormalities
• Computed tomography (CT) and magnetic resonance imaging (MRI): forebrain anomalies, cerebral atrophy, midbrain defects

Other tests

• Electroencephalogram (EEG)
• Electrocardiogram (ECG)
• Audiometry
• Ophthalmologic exam
• Psychological and educational assessments

Management and Prognosis

Management

Various supportive and corrective treatment options are available. Treatment is tailored to the symptoms and anomalies present. 

• Medical treatment:
  • Oxygen supplementation for cyanotic heart disease
  • Nasogastric feeding for swallowing difficulties
  • Artificial tears for facial palsy to avoid scarring of a cornea
  • Hearing aids/cochlear implants
  • Durable medical equipment such as braces or wheelchairs to help with mobility
  • Androgen therapy given in some cases for penile growth
  • Physical therapy to help with mobility
  • Speech therapy as needed
• Surgical treatment:
  • Tracheostomy (tube placement into the trachea to stabilize air passage)
  • Gastrostomy (tube placement into the stomach for feeding)
  • Myringotomy (tube placement into the tympanic membrane for otitis media)

Prognosis

• Mortality is higher in the neonatal period and early infancy due to:
  • Cyanotic heart disease
  • Bilateral choanal atresia
  • Esophageal atresia 
  • Central nervous system (CNS) anomalies
• Treatment is necessary for survival, but no curative treatments are available.

Differential Diagnosis

• VACTERL association: a disorder that affects multiple body systems in fetal development. VACTERL is the acronym for the constellation of clinical features seen with this condition: Vertebral defects, Anal atresia, Cardiac defects, Tracheoesophageal fistula, Renal anomalies, and Limb abnormalities. The disorder appears to occur sporadically with no clear inheritance pattern. Cognition is not affected. The disorder is a diagnosis of exclusion in the setting of the presence of at least 3 of the above clinical features. Treatment is conservative and surgical based on symptoms and abnormalities. 
• Kallmann syndrome: a genetic condition that causes hypogonadotropic hypogonadism and impaired sense of smell. Mutations in the same gene (CHD7) implicated in CHARGE syndrome have been seen in those with Kallmann syndrome. Given the overlap, individuals with suspected Kallmann syndrome may have similar features to that of CHARGE syndrome, albeit much milder, and should undergo additional screening. Genetic testing with gene sequencing helps with diagnosis and differentiation.