CHARGE syndrome

CHARGE syndrome is usually caused by a de novo variant in the CHD7 gene. It can be diagnosed at birth; however, some characteristics may not be evident until the child has grown older. One major criterion and several minor criteria of CHARGE syndrome are needed for a clinical geneticist to make the diagnosis.

CHARGE syndrome is named after some of its common features:

• coloboma and cranial nerve anomalies;
• heart anomalies;
• atresia of the choanae;
• retardation of growth;
• genital underdevelopment; and
• ear anomalies.

Major diagnostic criteria

• Coloboma: Failure to close the eyeball during fetal development, which results in keyhole-shaped pupils and other anomalies of the retina, optic nerve and macula. Microphthalmia (small eyes) and anophthalmia (missing eyes) are severe forms of coloboma. Colobomas are present in 70%–90% of patients with CHARGE syndrome.
• Cranial nerve anomalies: Sensorineural hearing loss due to problems in cranial nerve VIII and dysplasia of the semi-circular canals, swallowing problems due to problems with cranial nerves IX and X, asymmetrical facial palsy due to cranial nerve VII, reduced sense of smell due to cranial nerve I.
• Choanal atresia: Blocked or narrowed passages from the back of the nose to the throat.
• CHARGE ear: Typically short and wide ears with little or no earlobe. The helix may end in the mid-ear and the ears are often floppy due to weak cartilage. Malformation of the bones of the middle ear can be picked up on an MRI.

Minor diagnostic criteria

• Heart anomalies: Present in 75%–80% of cases. The most common are tetralogy of Fallot, ventricular septal anomalies, atrioventricular canal anomalies and aortic arch anomalies.
• Genital anomalies: Most boys with CHARGE have a small penis and undescended testes, and hypospadias can occur. Girls may have small labia.
• Kidney anomalies: These are variable and occur in around 40% of cases.
• Cleft lip/palate: Occurs in around 25% of cases.
• Tracheoesophageal fistula and oesophageal atresia: Occurs in around 15%–20% of cases.
• Poor growth.
• Hypotonia of the trunk.
• Typical facial features: Square face and broad, prominent forehead, arched eyebrows, large eyes, prominent nasal bridge, small nostrils, small mouth, occasionally a small chin. The face is often asymmetrical.
• CHARGE hand: Small thumb, broad palm with ‘hockey stick’ palmar crease, short fingers.
• Other features include developmental delay, scoliosis, brain anomalies and behavioural difficulties.

CHARGE syndrome is usually caused by a de novo variant in the CHD7 gene. Rarely, genomic alterations in the 8q12.2 region may be identified (where the CHD7 gene is located). CHD7 function is required for the development of the retina and cranial motor neurons.

Around 90% of CHARGE patients have pathogenic variants in the CHD7 gene. The pathogenic variants are usually loss of function (frameshift or stop-gain) and can be found throughout the coding region of CHD7. It is worth noting that not every CHD7 variant causes CHARGE and some patients with CHARGE do not have a mutation in CHD7.

Genomic testing offered includes microarray CGH, CHD7 gene sequencing with deletion and duplication testing, and whole exome sequencing.

For diagnosis, other forms of imaging such as echocardiogram, renal ultrasound and middle ear MRI may also be appropriate.

CHARGE syndrome is rare. The fact that it is usually caused by a de novo gene change means that most parents who have an affected child are at very low probability of having another. For a small number of families, gonadal mosaicism leads to an unpredictable but increased chance of recurrence (around 2%–4%).

If an individual with CHARGE syndrome has a child, they have a 50% chance of passing CHARGE on to their offspring.

Currently there is no gene therapy to manage patients with CHARGE syndrome.

Surgical correction of some of the anomalies – such as the heart anomalies, choanal atresia and cleft lip and/or palate – is available. Some children will be offered hormone therapy to correct the genital anomalies caused by hypogonadotropic hypogonadism. Other supportive medical therapies may also be beneficial, and patients are managed in a large multidisciplinary team with physiotherapy, occupational therapy and other specialist input.

For clinicians

• NHS England: National Genomic Test Directory
• NORD Rare Disease Database: CHARGE syndrome

For patients

• CHARGE Family Support Group
• CHARGE Syndrome Foundation