Introduction

CHARGE is an acronym for key features observed in the syndrome. CHARGE stands for:

Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness. The syndrome was first coined in 1981 as a non-random association of abnormalities, occurring together more often than chance alone could explain.¹

The criteria for diagnosis of CHARGE syndrome includes the presence of a collection of key characteristics. The major criteria physicians look for are coloboma, choanal atresia, cranial nerve abnormalities and typical CHARGE ear abnormalities.² 

CHARGE syndrome is a rare genetic disorder, affecting an estimated 1 in 10,000 newborns globally.² The genetic basis of CHARGE syndrome lies in mutations (changes in the DNA sequence) of the CHD7 gene, which encodes the chromodomain helicase DNA-binding protein-7.² Early diagnosis of CHARGE syndrome is crucial, as appropriate management can reduce morbidity rates.² 

In this article, we will explore the core features of this syndrome that make up the CHARGE acronym.

Core features of CHARGE syndrome

Coloboma (C)

Coloboma is an eye defect characterised by an area of missing tissue in the eye. This feature can be unilateral (in one eye) or bilateral (in both eyes). It can either only affect the iris, or extend to include the retina and optic nerve. Henceforth, Coloboma can impair your vision, and in severe cases,may result in blindness. 

Eye abnormalities are reported in approximately 80% of individuals with CHARGE syndrome; symptoms typically consist of microphthalmos (abnormally small eyes) or anophthalmos (complete absence of eye(s)).¹ 

Heart defects (H)

Congenital (present at birth) heart defects occur in 75-80% of individuals with CHARGE syndrome.¹

The most commonly observed defect is tetralogy of Fallot, which is seen in 33% of individuals with CHARGE syndrome. Tetralogy of Fallot is a condition which includes four structural heart abnormalities. This defect makes it harder for your heart to effectively move blood around your body, meaning it's harder for oxygen to be transported around your body.^1,4 

Other frequently seen heart defects include: 

Patent ductus arteriosus (PDA), in which the patent ductus fails to close after birth, creating a persistent opening between the two major blood vessels leading from the heart: the aorta, carrying oxygenated blood and the pulmonary artery, carrying deoxygenated blood. This allows blood with different oxygen levels to mix, potentially disrupting the efficiency of oxygen distribution to body tissues.^1,4

Double outlet right ventricle (DORV) with atrioventricular canal is a rare heart defect in which the aorta and pulmonary artery both arise from the right ventricle, and there is a single valve or opening between the atria and the ventricles. This defect can lead to significant blood flow problems and can present as Tetralogy of Fallot.^1,4

Ventricular septal defect (VSD) occurs when the walls between ventricles, also called the septum, do not fully fuse, leaving a hole. This allows mixing of oxygenated and deoxygenated blood, leading to a decreased efficiency of oxygen transport around the body.^1,4 

Atrial septal defect (ASD) with or without cleft mitral valve describes a hole between the upper heart chambers called atria. This creates an abnormal route of blood flow in the heart, that allows oxygenated blood from the left atrium to flow into the deoxygenated right atrium, signifying that more oxygenated blood moves to the lungs. Some rare ASD cases may have a cleft in the mitral valve (the valve located between the left atrium and left ventricle).^1,4 

While some mild cases of congenital heart defects require no treatment, other cases can require surgical intervention. Complications of heart defects include an abnormal heart rhythm (arrhythmia), stroke if the oxygen/blood flow to the brain is limited, hypertension, cyanosis (blue fingers and toes due to poor blood supply) and heart failure.^1,4

Atresia of the choanae (A)

Atresia of the choanae refers to a narrowing or blockage of nasal passages. This is a primary feature of CHARGE syndrome, thus it is often a key sign that promotes suspicion that a child may have CHARGE syndrome. The choanae atresia may be membranous or bony and can be unilateral (in one nostril) or bilateral (both nostrils). Bilateral can be associated with an increase in newborn mortality, especially if linked to cardiac abnormalities and or tracheoesophageal atresia, a rare condition in which the oesophagus fails to develop properly.¹

Polyhydramnios in pregnancy is seen frequently in individuals carrying a fetus with bilateral posterior choanal atresia, though it may also be present without, likely due to an insufficient swallowing mechanism. Polyhydramnios can also arise if a foetus has atresia of the choanae or swallowing difficulties.³ Chronic middle ear infections and deafness are also associated complications with atresia of the choanae.¹

Retardation of growth/development (R)

‘Retardation’ means delaying or slowing the process of, in individuals with CHARGE syndrome, both growth and development. These delays become more apparent as a child matures. At birth, children with CHARGE syndrome are usually of a healthy weight and height. However, as the child ages, growth delays will start to occur.

A majority of school-aged children with CHARGE syndrome have a short physical stature, placing low for physical growth norms.

Despite that, growth patterns in CHARGE syndrome can vary. For instance, when slower growth rate is linked to cardiac and respiratory problems, compensatory catch-up on growth can allow individuals to eventually reach a ‘normal’ height. Growth in height can occur in CHARGE syndrome adults well into their 20s. Feeding problems with growth can also result in short stature in individuals with CHARGE syndrome. Hence, feeding interventions are required to help prevent growth delays. Occasionally, slower growth may also be attributed to growth hormone deficiency.¹

Mental development can also be slowed in CHARGE syndrome with cognitive functions varying tremendously. Particular behavioural characteristics and autism-spectrum-like disorders are also now recognised features of CHARGE syndrome.¹ 

Genitourinary abnormalities (G)

Abnormalities in genital development are also a characteristic feature in patients who suffer from CHARGE syndrome. Hypogonadotropic hypogonadism, often linked to pubertal arrest/delay, may cause underdevelopment of the external genitalia. 

In males, genital development abnormalities seen with CHARGE can include: 

• a micropenis (abnormally small penis)
• penile agenesis (absence of a penis)
• hypospadias (curved penis)
• cryptorchidism (absence of testicle(s)) 

In females, abnormalities seen in CHARGE syndrome include: 

• atresia of the uterus, cervix and vagina (absence or blockage of the uterine cavity, cervix or vagina)
• hypoplastic labia and clitoris (when the folds of skin around the vagina opening, and clitoris fail to develop)¹

Furthermore, renal (kidney) abnormalities reported in CHARGE syndrome consists of: 

• hydronephrosis (a swollen kidney due to a blockage) 
• underdeveloped and smaller than normal kidneys 
• duplex kidneys (where one kidney has two ureters, the tubes that carry urine to the bladder rather than the usual one) 
• vesicoureteral reflux (urine travelling the wrong way, such as flowing from the bladder back up towards the kidneys)¹

Ear abnormalities / hearing loss (E)

Ear abnormalities seen in CHARGE syndrome include external ear malformations, where individuals suffer from unusually shaped ears. These characteristic CHARGE ear abnormalities are easy to visualise, thus easing the diagnosis process. These abnormalities are caused by a lack of cartilage and innervation, which creates a lop or cup-shaped ear with a small, underdeveloped lobe. 

The extent of hearing loss and deafness in CHARGE syndrome ranges from mild to severe. Facial nerve palsies, a type of cranial nerve abnormality that can be seen in CHARGE syndrome, is also a good predictor of sensorineural hearing loss. Characteristic CHARGE ear abnormalities that can aid in diagnosis may be viewed using a CT or MRI scan, and in particular, include absent semicircular canals.¹

Additional features (Beyond the Acronym)

Cranial nerve abnormalities can form part of the diagnostic criteria for CHARGE syndrome and are often asymmetric. Cranial nerve dysfunctions include: 

• anosmia (loss of smell, absence of the olfactory bulb is associated with CHARGE syndrome)
• facial palsy (weakness of facial muscles due to damaged nerves) 
• swallowing difficulties/gastroesophageal reflux (stomach acid moving back up into the oesophagus) 
• sensorineural hearing loss¹ 

Particular behavioural characteristics may also be observed with CHARGE syndrome. These include motor impairments, low adaptive behaviour skills, and symptoms of autism.¹

Summary

CHARGE syndrome is a complex, multisystem genetic disorder, resulting in a collection of abnormalities occurring together. Presentation of the syndrome varies between individuals and diagnosis typically requires a sufficient collection of major and/or minor CHARGE syndrome features. Recognition of core features is widely useful for diagnosis. The certain characteristics to look out for include: 

• coloboma
• heart defects
• atresia choanae 
• retarded growth and development 
• genital hypoplasia
• ear abnormalities