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CHARGE syndrome
This rare condition is caused by changes in the CHD7 gene and can lead to a range of challenges, including vision and hearing problems, heart defects, and developmental delay. It typically affects around 1 in 8,500-10,000 babies.
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Overview
CHARGE syndrome is a complex genetic condition that affects many different parts of the body. The name CHARGE is an acronym, originally standing for Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genital abnormalities, and Ear anomalies [PMID:10729220]. However, it is now understood that individuals with CHARGE syndrome can present with a wide range of features, not all of which are always present. The severity of the condition also varies considerably between individuals.
CHARGE syndrome is a rare condition, affecting approximately 1 in 8,500 to 10,000 newborns. It is considered one of the leading causes of congenital (present from birth) anomalies with multiple effects. The condition can significantly impact an individual's health and development from infancy through adulthood.
Symptoms & clinical features
The clinical features of CHARGE syndrome are highly variable, meaning no two individuals will have exactly the same set of challenges. Common signs and symptoms often involve sensory organs, such as the eyes and ears, as well as major organ systems. Eye abnormalities, such as coloboma, where part of the eye structure is missing, are a frequent finding [PMID:10729220]. This can affect vision to varying degrees.
Hearing impairment is also very common, ranging from mild to profound, and can be due to structural problems in the ear or damage to the auditory nerve. Other common features include heart defects, which can range from minor to severe, and choanal atresia or stenosis (narrowing or blockage of the nasal passages), which can cause breathing difficulties, particularly in newborns. Developmental delay affecting motor skills, speech, and learning abilities is also often observed in individuals with CHARGE syndrome. Additional features can include distinctive facial characteristics, feeding difficulties, and problems with growth and hormone regulation.
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Affected organs
CHARGE syndrome can affect a number of organ systems throughout the body. Key areas typically impacted include the eyes, leading to conditions like coloboma or microphthalmia (small eyes). The ears are almost always affected, with abnormalities in the outer, middle, and inner ear structures, contributing to hearing loss. The heart often presents with various congenital heart defects, which may require surgical intervention [PMID:10729220].
Respiratory issues can arise from choanal atresia, affecting the nasal passages. The brain and central nervous system can also be affected, leading to developmental delay and intellectual disability, as well as problems with balance and coordination. The genitourinary system may show abnormalities, particularly in males. Hormonal imbalances, affecting growth and puberty, are also possible due to pituitary gland dysfunction.
Risks & severity
The severity of CHARGE syndrome varies significantly, with some individuals having mild symptoms that allow for greater independence, while others face complex medical challenges requiring lifelong care. The condition is present from birth, and complications such as severe heart defects or breathing problems can be life-threatening in infancy. Challenges with feeding, growth, and sensory impairments can contribute to long-term health concerns.
Lifelong care and support from various medical specialists are often needed to manage the diverse symptoms of CHARGE syndrome. Developmental progress varies widely, but individuals typically benefit from early intervention therapies such as physiotherapy, occupational therapy, and speech and language therapy. Vision and hearing impairments can profoundly impact communication and learning, highlighting the need for early diagnosis and appropriate interventions.
Genetic causes
CHARGE syndrome is overwhelmingly caused by pathogenic variants in the CHD7 gene [PMID:15636087]. The CHD7 gene provides instructions for making a protein called chromodomain helicase DNA binding protein 7. This protein plays a crucial role in regulating gene expression, which is the process by which cells turn genes on and off.
The CHD7 protein achieves this by modifying chromatin, the complex of DNA and proteins that forms chromosomes. By altering chromatin structure, CHD7 influences the accessibility of DNA to the cellular machinery responsible for transcribing genes. When the CHD7 gene has a pathogenic variant, the resulting protein may be non-functional or have reduced activity, disrupting the normal regulation of many genes important for embryonic development. This disruption during early development leads to the wide range of abnormalities observed in CHARGE syndrome.
- CHD7 chromodomain helicase DNA binding protein 7The CHD7 gene provides instructions for a protein involved in chromatin remodelling, crucial for foetal development and implicated in conditions like CHARGE syndrome and Kallmann syndrome.
Inheritance pattern
CHARGE syndrome is typically inherited in an autosomal dominant pattern. This means that only one copy of the altered CHD7 gene in each cell is sufficient to cause the condition. In most cases of CHARGE syndrome, the pathogenic variant occurs spontaneously as a new change (de novo variant) in the affected individual and is not inherited from either parent [PMID:15636087].
If an individual has CHARGE syndrome due to a de novo variant, their parents typically do not carry the altered gene and therefore have a very low risk of having another child with the condition. However, if a parent does carry the pathogenic variant, even without showing significant symptoms themselves (which is rare in CHARGE syndrome but possible with mosaicism), there is a 50% chance for each child to inherit the altered gene. Genetic counselling is important for families to understand the specific inheritance risks.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of CHARGE syndrome is initially based on a collection of clinical features observed in an individual. Healthcare professionals use established clinical criteria, which consider the presence of major and minor characteristics, to suggest a diagnosis. However, confirming the diagnosis involves genetic testing for pathogenic variants in the CHD7 gene.
Genetic testing for CHARGE syndrome, typically looking for pathogenic variants in CHD7, is available through the NHS Genomic Medicine Service (GMS). Referral for genetic testing is usually made by a clinical geneticist or a paediatrician specialist. The relevant NHS Genomic Medicine Service 'R-code' would typically be R77 (Developmental disorders) or R79 (Multisystem disorder). A confirmed genetic diagnosis can provide clarity for families and help guide management and access to appropriate services.
Management & lifestyle
Due to the complex and varied nature of CHARGE syndrome, management involves a multidisciplinary team approach. This typically includes paediatricians, geneticists, cardiologists, ophthalmologists, ENT specialists, and developmental specialists. The focus is on addressing specific symptoms and supporting the individual's development and quality of life.
Interventions may include surgery for heart defects or choanal atresia, hearing aids or cochlear implants for hearing loss, and corrective lenses or other treatments for vision problems. Therapies such as physiotherapy, occupational therapy, and speech and language therapy are crucial for addressing developmental delays. Regular monitoring for potential complications and ongoing support from healthcare professionals and genetic counsellors are essential throughout an individual's life. Management plans are always individualised based on the specific needs of the patient.
UK care pathway
In the UK, individuals suspected of having CHARGE syndrome typically enter the NHS care pathway through a referral to a paediatrician or a clinical geneticist. These specialists can assess the range of symptoms and determine if genetic testing is appropriate. The NHS Genomic Medicine Service provides genetic testing, usually under 'R-codes' such as R77 (Developmental disorders) or R79 (Multisystem disorder), to identify pathogenic variants in the CHD7 gene.
Following a diagnosis, a genetic counsellor plays a vital role in explaining the condition, its inheritance, and the implications for the family. Care coordination is often managed by a paediatrician, with referrals to various specialist teams as needed to address specific organ system involvement.
Frequently asked questions
What does CHARGE syndrome stand for?
CHARGE was originally an acronym for Coloboma, Heart defects, Atresia choanae, Retarded growth/development, Genital/urinary abnormalities, and Ear anomalies. While these are common features, individuals may not have all of them, and 'CHARGE' is now used as the name of the syndrome itself rather than just an acronym.
Is CHARGE syndrome inherited from parents?
Most cases of CHARGE syndrome are caused by a new genetic change (de novo variant) in the CHD7 gene that is not inherited from either parent. In these situations, the risk for parents to have another child with CHARGE syndrome is very low. Genetic counselling can provide specific information about individual family risks.
Can individuals with CHARGE syndrome lead independent lives?
The level of independence varies greatly depending on the severity of the symptoms. Some individuals with milder forms of CHARGE syndrome may achieve significant independence with appropriate support and therapies. Others with more complex needs will require lifelong care and assistance.
What kind of support is available for families with CHARGE syndrome?
Families in the UK can access support through the NHS, which includes multidisciplinary medical teams, therapies, and genetic counselling. There are also patient support groups and charities that offer valuable resources, information, and a community for families affected by CHARGE syndrome.
How is the diagnosis of CHARGE syndrome confirmed?
The diagnosis is typically suspected based on a combination of clinical features. It is confirmed through genetic testing, which looks for pathogenic variants in the CHD7 gene. This testing is available through the NHS Genomic Medicine Service following a referral from a specialist.
References
- Usman N, Sur M. CHARGE Syndrome. 2023. PMID: 32644625
- Hsu P, Ma A, Wilson M. CHARGE syndrome: a review. Journal of paediatrics and child health. 2014. PMID: 24548020
- Blake KD, Prasad C. CHARGE syndrome. Orphanet journal of rare diseases. 2006. PMID: 16959034
- Mustillo PJ, Sullivan KE, Chinn IK. Clinical Practice Guidelines for the Immunological Management of Chromosome 22q11.2 Deletion Syndrome and Other Defects in Thymic Development. Journal of clinical immunology. 2023. PMID: 36648576
- Hudson A, Trider CL, Blake K. CHARGE Syndrome. Pediatrics in review. 2017. PMID: 28044040
- Polito MV, Ferraioli M, Nocilla A. CHARGE syndrome and congenital heart diseases: systematic review of literature. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace. 2023. PMID: 37675914
- Hartshorne TS, Stratton KK, Brown D. Behavior in CHARGE syndrome. American journal of medical genetics. Part C, Seminars in medical genetics. 2017. PMID: 29082623
- Mehr S, Hsu P, Campbell D. Immunodeficiency in CHARGE syndrome. American journal of medical genetics. Part C, Seminars in medical genetics. 2017. PMID: 29159871