Overview 

CHARGE syndrome is a rare genetic condition that is present from the time of birth. Usually, this syndrome occurs as a sporadic mutation, meaning it is not inherited from the parents and it transpires for the first time in the family line. According to research, mutations to the CHD7 gene were found in 90% of classic cases of CHARGE syndrome.¹ This gene provides instructions for making a protein that helps control how other genes work during early embryo development.² Consequently, when the CHD7 gene is altered, many structures, such as the eye or heart, do not develop as they should, leading to features seen in CHARGE syndrome. 

The name of the syndrome is an acronym detailing the core features:^1,3

• C: Coloboma (a hole in part of the eye)
• H: Heart defects
• A: Atresia of the choanae (birth defect resulting in the nasal passage becoming blocked by bone or tissue, leading to difficulty breathing and feeding babies)
• R: Growth Retardation (limited/poor growth pre- and post-birth)
• G: Genital anomalies 
• E: Ear malformations and hearing loss

This syndrome is commonly diagnosed in prenatal or newborn screening due to the multiple manifestations of anomalies. Of these anomalies, heart issues are very common; research looking across 68 studies has found that congenital (present from birth) heart defects occur in about 76.6% of patients with CHARGE syndrome.⁴

What types of heart defects are associated with CHARGE Syndrome, and how are they surgically managed?

Research indicates that the heart defects associated with CHARGE syndrome include:

Tetralogy of Fallot 

Tetralogy of Fallot is a condition found in CHARGE syndrome patients, where a group of four associated congenital cardiac abnormalities are present simultaneously:^5,6

1. Ventricular Septal Defects (VSDs): the septal wall between the two lower heart chambers (ventricles) does not form properly, resulting in a hole
2. Pulmonary stenosis: this is where the pulmonary valve within the heart narrows, restricting blood flow to the lungs
3. Overriding aorta: during prenatal development, the aorta is formed to position incorrectly, typically above a damaged wall or ventricular septal defect between the left and right ventricles rather than the left side of the heart
4. Right ventricular hypertrophy: this is the abnormal thickening of the right ventricular muscle. In particular, the blockage of blood flow out of the right ventricle, usually brought on by pulmonary stenosis, causes the right ventricular muscle to enlarge

Surgical management of Tetralogy of Fallot

Usually, surgical interventions for this condition would start within the first year of life. This is to improve blood flow to the lungs and to correct the structural problems associated with this congenital heart defect.⁷

Treatment may involve one or both of the following:⁶

Temporary surgery (palliative repair)

Before major surgery, a number of babies may require a temporary procedure, particularly if they are too fragile for a full operation. Or if they have very narrow pulmonary arteries (blood vessels which carry blood away from the right side of the heart to the lungs), and if they are born prematurely (before 37th week of pregnancy).

• This procedure involves inserting a tiny tube called a shunt between the pulmonary artery and a major artery that branches off the aorta (subclavian artery)
• By opening a new route for the blood to flow to the lungs, this shunt contributes to allowing increased oxygen saturation in the blood
• After the baby goes on to have the full, complete surgical repair, this shunt is later removed

Open-heart surgery (complete repair)

To completely fix the heart, open-heart surgery is required to fix the multiple abnormalities associated with the condition. A surgeon fixes this within multiple steps:

• The VSD can be fixed with a patch which blocks the hole between the two lower heart chambers
• The pulmonary valve is either repaired or replaced completely. Surgeons may cut away thickened muscle to open a pathway for blood (this is in the cases of infundibular stenosis), or if it is too narrow, it will be cut open and enlarged with a patch as well
• Sometimes surgeons will widen the pulmonary arteries to improve blood flow to the lungs

With modern surgical techniques, survival rates following repair are very high, and symptoms go on to improve. Even though it is termed a “complete repair”, patients will need lifelong specialist management from cardiologists and possible follow-up treatment to address valve function or rhythm problems, despite having surgery. This may mean further medication or perhaps even surgery.⁶

Atrial septal defects

Atrial septal defects (ASDs) are abnormalities which occur within the septum, separating the two upper chambers of the heart (the left and right atria (plural of atrium)), observed in CHARGE syndrome patients.⁵ Usually, this manifests as a hole within the septum, which results in an avenue for blood to travel from the left atrium toward the right atrium.⁹

There are three different types of ASDs:⁹

• Secundum ASD: this is the most common form of ASD, where the hole forms within the middle of the atrial septum
• Primum ASD: this is where the hole forms at the lower end of the atrial septum close to the ventricles
• Sinus venosus ASD: this involves a hole malformation at the spot between the right pulmonary vein and the superior vena cava

Surgical Management of Atrial Septal Defects

A surgeon can fix a large ASD through one of two methods:⁹

Endovascular ASD Closure: 

This keyhole procedure is also called cardiac percutaneous ASD closure. It is a method of closing an ASD without requiring a deep skin incision (which occurs in open-heart surgery).

• A catheter (a long, thin tube) is inserted into a prominent vein at the top of the leg and is directed to the heart
• The hole will be closed with a patch that is placed over the ASD, and over time, the patient’s tissue will cover the patch, overlapping securely

Open-heart surgery

• This is an invasive surgery where the ribcage is cut and opened to reveal the heart and the ASD
• The atrial septum hole is covered by a patch attached by the surgeon. Alternatively, the patient's own heart lining, known as the pericardium, or a synthetic substance, can be used to make the patch
• The patch eventually becomes a permanent part of the septum when the heart tissue grows over it

Aortic arch abnormalities

Infants with CHARGE syndrome are also found to have defects in the aortic arch (the curved section of the aorta).^5,10 The malformations in this area can affect how blood flows from the heart to the rest of the body. Common aortic arch abnormalities include: 

• Interrupted aortic arch (IAA):  this is where the aorta is not fully connected and is incomplete, creating a gap in the vessel. Therefore, the blood cannot move through towards the rest of the body, which is life-threatening¹¹
• Coarctation of the aorta (CoA): the aorta has a narrowed section, restricting blood flow. Similarly, this means adequate blood flow towards the rest of the body cannot occur, and as a result, the heart tries to compensate by working harder¹²
• Right-sided aortic arch with aberrant left subclavian artery: this is an anomaly observed when the aortic arch bends to the right side instead of the normal left-sided arching that should be present. This is also found with an abnormally positioned left subclavian artery^10,13

Surgical management of aortic arch abnormalities

Surgical management of IAA is often urgent, very soon after diagnosis, and the surgeon reconnects the two ends of the aorta, sometimes using a patch to cover the gap.¹¹

 For the surgical repair of CoA, the surgeon could repair it through one of three methods:¹⁴

• The narrowed section of the aorta is removed, and the healthy ends are sewn together (end-to-end anastomosis)
• Surgeons may also fix the narrowing of the aorta by widening it using a patch (patch aortoplasty)
• Another surgical option is balloon angioplasty, which is where a surgeon inflates a balloon inside the aorta to widen and restore adequate blood flow to the rest of the body

Typically, if a right-sided aortic arch with an aberrant left subclavian artery is present in an infant, they will be asymptomatic, not requiring surgical treatment. However, if it forms a vascular ring affecting breathing or feeding, then some babies may require surgery to reposition the blood vessels or release the vascular ring. This would prevent their food pipe and windpipe from being squished.¹⁰

Summary

CHARGE syndrome is a genetic disorder that is rare and evident at birth, primarily resulting from mutations within the CHD7 gene, which affects embryonic development with various structural abnormalities. The syndrome arises by exhibiting primary features: Coloboma, malformations of the heart, choanal atresia, growth retardation, genital malformations, and deformities of the ear, along with hearing loss. Heart defects are common, occurring in approximately 76.6% of patients. There are different major conditions which include: Tetralogy of Fallot, atrial septal defects and aortic arch abnormalities. The treatment typically includes surgical interventions in the first year and may be supplemented by palliative procedures temporarily to stabilise weak infants and later corrective open-heart surgery to fully repair structural issues. These abnormalities have a profoundly negative impact on blood flow and require corrective surgical procedures to improve prognosis. Whilst surgery has significantly improved survival, ongoing management by cardiologists is required after corrective surgeries to address possible valve or rhythm-related complications which may follow during the patient's lifetime.