CHARGE syndrome

CHARGE syndrome is a phenotype associated with CHD7 gene mutation originally defined by a constellation of congenital anomalies:

• C: coloboma

• H: heart defects

• A: atresia choanae

• R: retarded growth and development

• G: genital hypoplasia

• E: ear abnormalities and/or deafness

According to updated diagnostic criteria, the most defining features are the 4 Cs:

• coloboma

• choanal atresia

• cranial nerve anomalies (especially olfactory pathway absence)

• characteristic ear anomalies (especially semicircular canal dysplasia/aplasia)

Epidemiology

The incidence is 1-12 per 100,000 births ⁶.

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: 4 major characteristics or 3 major plus 3 minor characteristics

• possible/probable CHARGE syndrome: one or two major characteristics and several minor characteristics

Major criteria

1. coloboma (80%): ranges from defect of iris, retina, choroid, or disc, to microphthalmia or anophthalmia

2. choanal atresia/stenosis (45%) or cleft palate (25-50%)

3. cranial nerve anomaly/dysfunction

   • olfactory (90%): hyposmia/anosmia

   • facial (40%): facial palsy

   • vestibulocochlear (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%)

   • abnormal auricle: short and wide (lop/cup shaped), absent lobule, truncated helix, prominent antihelix

   • ossicular malformations

   • 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 around the 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

All CHARGE patients are indicated to undergo CT of the temporal bone and MRI of the brain, ideally in the same anaesthesia session ¹¹.

CT

Temporal bone CT demonstrates the following abnormalities: 

• middle ear and mastoid

  • dysplastic ossicles with ankylosis (62-93%) ^8,10

    • stapes (50%)

    • incus (11%)

    • malleus (1%)

  • absent stapedius, pyramidal eminence, and sinus tympani (92%) ³

  • aberrant course of the facial nerve (38-88%) ^8,10

  • small middle ear cavity (0-81%) ^8,10

  • unpneumatized mastoid (8%) ¹⁰

  • high-riding jugular bulb (27%) ¹⁰

  • large (>1 mm) emissary veins (30%) or persistent petrosquamosal sinus (12-13%) ^8,10

• inner ear

  • absent/stenotic oval window (71-81%) ^8,10

  • absent/stenotic round window (14-23%) ^8,10

  • aberrant course of the vestibular aqueduct (46-68%) ^8,10

  • dysplastic or hypoplastic vestibule (58%) ⁸

  • semicircular canal aplasia (77-100%) or dysplasia (20%) ^8,10

  • cochlear incomplete partition type II (8%) or cochlear hypoplasia type III (4%) or type IV (26%) ¹⁰

  • atretic/stenotic cochlear aperture (37-77%) ⁸

MRI

Brain MRI demonstrates 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/absence (15-83%) ⁸

  • 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.

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.