Introduction

CHARGE syndrome is a rare genetic neonatal disorder which affects multiple parts of the child’s body, including vital organs. It affects the heart, eyes, ears, mouth, nerves, nose, and genitals, causing developmental delays.¹

CHARGE stands for:

• Coloboma
• Heart disease
• Atresia of the choanae 
• Retarded growth and/or development
• Genital abnormality
• Ear abnormality, hearing difficulties or deafness

Children with CHARGE syndrome often have specific facial characteristics that are identifiable with the syndrome, including:

• Small-shaped ears
• Drooping of one side of the mouth
• Small/large eyes and a gap in one of the eye structures (such as the iris)
• Square-shaped face
• Small lower jaw
• Nose abnormalities
• Cleft palate or a thin upper lip
• Asymmetrical face

Aetiology

Although hereditary cases of CHARGE syndrome are rare, most cases occur due to new genetic mutations. This condition is specifically linked to the CHD7 gene, which helps create a protein called ‘chromodomain helicase DNA binding protein 7’. This protein is important in the body for several functions, including the development of vital organ systems. When there is a mutation in this gene, CHARGE syndrome occurs, leading to developmental delays and other key symptoms.^2,3

Prevalence

• CHARGE syndrome is known to affect 1 in every 10000 births¹
• Affects both sexes equally¹
• Most known cases of CHARGE syndrome occur randomly, rather than being inherited¹
• A study in 2010 that examined 379 CHARGE syndrome patients found that 67% of them had a CHD7 mutation¹
• There is a 1% recurrence rate (meaning that for most families, the chances of having another child with the syndrome are extremely small)¹

Immunodeficiency as a contributor to morbidity

Having a weakened immune system means that the body has a harder time defending itself from infections or other health issues. This condition is referred to as immunodeficiency, and it comes in  two main forms: 

• Primary immunodeficiency - Present from birth, caused by genetic changes that affect parts of the immune system (usually the T-cells and B-cells). It makes individuals more vulnerable to infections and autoimmune disorders⁴
• Secondary immunodeficiency - Develops later in life due to external factors such as HIV infection or certain medications, such as chemotherapy. Unlike primary immunodeficiency, it is not inherited and can affect anyone at any age, depending on exposure to the triggering factor⁴ 

Immunodeficiency significantly increases the risk of illness and other health concerns. When the immune system is not functioning properly or working at its best, infections or other diseases are more easily contracted, tend to last longer, and are often more severe. This can lead to frequent hospitalisations and long-term health issues, which ultimately affect overall quality of life. For example, in a long-term study of 473 people diagnosed with common variable immune deficiency, 94% of them had a history of infections. A variety of other health issues were also observed:⁵ 

Immune system in CHARGE syndrome

Immunodeficiency in people with CHARGE syndrome can vary widely in severity. A review of existing literature and clinical data on immune dysfunction in CHARGE syndrome identified a total of 59 CHARGE patients. Of those, 61% (36 people) had a confirmed variant in the CHD7 gene, which affected immune function. Additionally, the review found that:⁶  

Common infection risks

People with CHARGE syndrome are more likely to have recurrent infections. This is often due to them having structural differences in their ears, sinuses, and nose, which make them more prone to respiratory infections like bronchitis. Additional factors, such as neurological issues and acid reflux, can further increase the infection risk. 

Beyond the physical challenges, some of these infections may also be related to underlying immune system issues, specifically immunodeficiency. In particular, the thymus (an organ that plays a key role in the development of T-cells, which are cells that fight off infections) may not function properly. This is referred to as thymus-dependent immunity.⁷ 

However, certain infections are especially common in CHARGE patients. Understanding and recognising these trends can help families and healthcare providers to keep a closer eye out and help respond to starting infections quickly. 

Ear infections 

One of the most recognisable features of CHARGE syndrome is the congenital, abnormal ear structures. These abnormalities occur in the middle and inner ears, and may cause ear infections (otitis media) and hearing loss. In particular, Eustachian tube dysfunction, or problems with the Eustachian tube, which helps balance pressure and drain fluid from the ear, are a known cause for these hearing problems in CHARGE syndrome cases.⁸ 

Opportunistic infections

An opportunistic infection is an infection caused by organisms—like bacteria, fungi, viruses, or parasites—that normally do not cause disease in healthy people, but can cause severe illness in individuals with weakened immune systems. Immunodeficiency does not occur in every child with CHARGE syndrome, so when it does happen, it is usually because the thymus gland does not develop or work properly, which then leads to impaired T-cell production. Fewer functioning T-cells means that you are more susceptible to infections.⁹

Respiratory tract infections

These infections are common in CHARGE syndrome, including pneumonia, bronchitis, and sinusitis. They are due to anatomical anomalies, such as the upper airway region, which increases the risk of developing respiratory tract infections.¹⁰ A study examined 50 children with CHARGE syndrome and found that accidental inhalation was a major issue, which caused 10 out of 20 deaths. The majority of children with CHARGE also experience issues with eating and swallowing; due to this, tubes (gastrostomy tube) will most likely be used as a long-term feeding alternative to make sure they receive the required nutrients.¹¹

Summary

CHARGE syndrome is a congenital (birth defect) genetic disorder which is caused by a mutation in the CHD7 gene. It leads to a wide range of health problems and abnormalities that affect different parts of the body. In individuals with CHARGE syndrome, immune problems can vary in severity. However, the structural abnormalities associated with CHARGE syndrome often increase the chances of developing certain infections, and in some cases, the risks can be even higher if immune problems are present.

Early detection and management are crucial for improving long-term outcomes. They also allow healthcare providers to address serious complications, such as airway abnormalities and feeding difficulties, which can often lead to conditions like pneumonia. Overall, early intervention is key to avoiding life-threatening situations, improving quality of life, and ensuring that every aspect of the child’s health and development is supported, given the wide range of symptoms involved in CHARGE syndrome.