CHARGE syndrome

CHARGE syndrome is an acronym that classically describesa phenotype associated with CHD7 gene mutation originally defined by a combinationconstellation of head and neck, cardiac, CNS, and genitourinary disorderscongenital anomalies:

• C: coloboma
• H: heart defects (congenital heart disease)
• A: atresia (choanal)choanae
• R: retardation ofretarded growth and development
• G: genital and/or urinary abnormalitieshypoplasia
• E: ear abnormalities and/or deafness

Epidemiology

Clinical presentation

CHARGE syndrome is usually suspected at birth once multiple congenital abnormalities are identified. 

Diagnosis

The diagnosis of CHARGE syndrome can be made on clinical grounds ^6,11:

• definite CHARGE syndrome: four4 major characteristics or three3 major characteristics and threeplus 3 minor characteristics
• possible/probable CHARGE syndrome: one-to-two major characteristics and several minor characteristics

Major criteria

1. coloboma (~85(80%): ranges from defect of iris, retina, choroid, or disc, to microphthalmia or anophthalmia
2. choanal atresia/stenosis/stenosis (~55 (45%) (or or cleft palate (25-50%)
3. cranial nerve dysfunction, e.g.anomaly/dysfunction
   • olfactory (90%): hyposmia/anosmia
   • facial (40%): facial palsy (~40%), dysphagia (~80%)
   • CHARGE syndromevestibulocochlear (95-100%): sensorineural deafness
   • glossopharyngeal or vagal (60-80%): velopharyngeal incoordination for suck/swallow
4. characteristic ear anomalies (some or all of the following) (90%)
   • atretic outer earabnormal auricle: short and wide (lop/cup shaped), absent lobule, truncated helix, prominent antihelix
   • ossicular chain malformationmalformations
   • Mondini malformation
   • absent/hypoplastic semicircular canals

Minor criteria

• urogenital abnormalities
  • kidney
    • duplex kidney
    • renal hypoplasia/solitary kidney
  • penis
    • hypospadias
    • penile agenesis
  • scrotum/testes
    • bifid scrotum
    • cryptorchidism
  • vaginal atresia
  • uterine atresia
• congenital heart disease
  • tetralogy of Fallot
  • atrioventricular canal defect
  • double outlet right ventricle
• short stature
• cleft palate +/- lip
• oesophageal atresia / tracheo-oesophageal fistula (~15%) ²
• characteristic facies
• developmental delay

Pathology

CHARGE syndrome is thought to occur due to a disturbance in embryonic differentiation ~35^th to 45^th day of gestation.

Genetics

Most cases are sporadic but there are occasional autosomal dominant forms. Approximately two-thirds of cases are caused by a defect in the CHD7 (chromodomain helicase DNA-binding protein 7) gene on chromosome 8 ^4,7.

Radiographic features

CT

Temporal bone CT reveals the following abnormalities ¹⁰: 

• unpneumatized mastoid (8%)
• high-riding jugular bulb (27%)
• large (>1 mm) emissary veins (30%) or persistent petrosquamosal sinus (13%)
• absent/stenotic oval window (71%)
• absent/stenotic round window (14%)
• dysplastic malleus (1%), incus (11%), and stapes (50%)
• aberrant course of the facial nerve tympanic segment (29%) or mastoid segment (7%)
• aberrant course of the vestibular aqueduct (68%)
• stenotic cochlear aperture (37%)
• semicircular canal aplasia (77%) or dysplasia (20%)
• cochlear incomplete partition type II (8%) or cochlear hypoplasia type III (4%) or type IV (26%)

MRI

HeadBrain MRI reveals the following abnormalities ^7,9:

• temporal bone
  • vestibular dysplasia (100%)
  • semicircular canal dysplasia (100%)
  • internal auditory canal dysplasia (100%)
  • cochlear dysplasia (89%)
  • cochlear nerve deficiency (83%)
  • absent cochlear aperture (44%)
  • enlarged vestibular aqueduct (6%)
• face
  • cleft lip/palate (50%)
  • parotid dysplasia (60%)
  • coloboma (40%)
  • choanal atresia (20%)
• skull base
  • basioccipital hypoplasia (90%)
  • coronal clival cleft (87%)
  • dorsally angulated clivus (70%)
  • J-shaped sella (70%)
  • bony olfactory groove dysplasia (75%)
• brain
  • olfactory nerve hypoplasia (100%)
  • olfactory sulcus dysplasia (100%)
  • brainstem hypoplasia (50%)
  • ventriculomegaly (30%)
  • vermian hypoplasia (20%)

Treatment and prognosis

The prognosis is variable depending on the extent of defects. In sporadic forms, the risk of recurrence is at ~1%.

History and etymology

This constellation of pathology was initially described by B D Hall and independently by H M Hittner in 1979. The term "CHARGE" was first coined by R A Pagon to describe an association between the symptoms and subsequent work isolated a common genetic defect seen in 60% of individuals: the CHD7 defect.