Introduction

CHARGE syndrome is a genetic condition characterised by complex issues that usually involve multiple body parts. It is generally considered an extremely rare genetic disorder, with its incidence estimated at around 1 in 10,000 births.¹ The name CHARGE stands for some of the major features of the syndrome, namely: Coloboma, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital abnormalities, and Ear abnormalities.¹ A full understanding of CHARGE syndrome will ensure that early intervention can be carried out which may have a dramatic effect on the patient's outcome.

The most predominant cause of the CHARGE syndrome is the presence of mutations in the DNA-binding protein-7, CHD7 gene.¹ This gene, essentially, codes for a protein, which, at the instance of development, modulates the structure of the chromatin.¹

Causes of charge syndrome

The primary cause of the CHARGE syndrome is due to the presence of mutations in the DNA-binding protein-7, CHD7 gene.¹ This gene codes for a protein, which during development, modulates the structure of chromatin.¹ The mutations in CHD7 involve several body systems; hence, the wide variety of abnormalities that are characteristic of CHARGE syndrome. 67% of all individuals who are clinically diagnosed with CHARGE syndrome have a mutation in this gene.¹

Characteristics of charge syndrome

C - Coloboma defects of the eye

A coloboma is a hole or gap in one of the structures of the eye, most commonly the iris, the retina, the choroid, or the optic nerve.² It results from incomplete closure of the eye during embryonic development.² A coloboma typically leads to impaired vision, which can range from minor vision difficulties to blindness, depending on the size and location of the defect. Other eye abnormalities related to this syndrome include microphthalmia³ in which the size of the eyes is smaller than average and nystagmus, a condition in which the eyes make involuntary movements.

H - Heart defects

Heart defects may be severe to minor and include, amongst others, ASD, VSD, or tetralogy of Fallot.⁴ Some of these heart defects will require surgical correction shortly after birth, while others may be mild and not require surgical intervention. The early detection and management of issues such as those affecting the heart help to offer better survival and quality of life in children with CHARGE.

A – Atresia of the choanae (blocked nasal passages)

This is a condition where the nasal passages are either partially or completely blocked, preventing normal airflow through the nose. In some instances, choanal atresia may be life-threatening and thus warrants immediate surgical intervention. 

R - Retardation of growth and development 

Children with CHARGE syndrome often have expressive delays in growth and development. There is retardation in the chronological timing of acquisition of motor milestones like sitting, crawling, and walking. It manifests as mild to severe, whereby some are able to attain normal intelligence while others need lifelong care; the sooner the developmental intervention, the better the outcome.

G – Genital abnormalities

The most common abnormalities involve the genitalia of males, where there may be underdeveloped undescended testes. Abnormal development of the reproductive organs may also occur in females, though this is less common than in males. This might have implications for fertility, but in any event, monitoring for abnormalities of the genitalia during the growth of a child will be necessary. Hormonal therapy or surgery might be required to correct these abnormalities.

E – Ear abnormalities

One of the more critical sensory problems related to CHARGE syndrome involves hearing loss. Many individuals with CHARGE have unusually formed external ears or missing ears; they also may have middle or inner ear abnormalities that give rise to conductive, sensorineural, or mixed types of hearing loss. All these hearing losses are amenable in part to cochlear implantation, other hearing devices, and early speech intervention in mitigating or minimising their effects on the acquisition of speech and communication.

Diagnosis of charge syndrome

Diagnosis of CHARGE syndrome is complex and involves not only clinical findings but also genetic testing. Early diagnosis provides a very crucial key to the effective management of the condition and improves the prognosis of the child. Diagnosis involves the presence of certain key features supported by advanced imaging and laboratory tests.

Clinical diagnosis

The diagnosis of CHARGE syndrome is usually first made based on temporal bone imaging in conjunction with characteristic clinical features. Based on the typical criteria, a patient could be said to have CHARGE syndrome if he or she presents with three major criteria or four major and three minor criteria.¹ Four major diagnostic criteria remembered by the mnemonic "4 C's" are:

• Coloboma – structural defect of the eye
• Cranial nerve anomalies-hearing, facial movement, and swallowing
• Choanal atresia-atresia of the nasal passages 
• Typical CHARGE ear – anomalies in the shape or structure of the outer, middle, or inner ear

In addition to these major criteria, the following minor characteristics aid in further fine-tuning the diagnosis: Congenital heart defects, like atrial septal defect and ventricular septal defect, Cleft lip or palate.¹

Genetic testing

Prenatal screening of the gene CHD7, which encodes the chromodomain helicase DNA-binding protein¹. 

Laboratory evaluation

Tests in the laboratory to assess the health of a person with CHARGE syndrome are as follows: Complete blood count and renal function tests.¹

Treatment and management of charge syndrome

Management of CHARGE syndrome is complex as many issues have to be addressed. Medical and surgical interventions depend on the condition's symptoms, specific severity, and timing. Early intervention will lead to an improvement in the long-term results.

Medical management

Medical management of CHARGE syndrome is directed at the various congenital anomalies, feeding problems, and sensory impairment.¹ Early consultation with appropriate specialists ensures that all potential health issues are identified early.

Cardiac management: Congenital heart defects are one of the common associations with CHARGE syndrome and require frequent priority.¹ Prostaglandins should be given in all newborns diagnosed with PDA and decreased pulmonary blood flow to maintain patency of the ductus.¹ All infants with suspected CHARGE syndrome need cardiology consultation.

Airway: Breathing difficulties are common in infants with choanal atresia or tracheoesophageal fistula; tracheostomy is often necessary to manage airway obstruction.¹ This chronic difficulty with the airways can be a long-standing problem and thus requires close follow-up, with interventions as necessary.¹

Feeding problems: Children with CHARGE have very frequent feeding difficulties due to swallowing problems and reflux.¹ Many of these children will have a gastrostomy or jejunostomy feeding tube placed in order to feed them appropriately. Feeding therapy may be recommended in an effort to help the child establish oral feeding skills.¹

Hearing Loss: Amplification with hearing aids should be fitted as soon as the hearing loss has been detected.¹ Monthly follow-ups are necessary so that adjustments can be made for growth and any changing needs a child might experience. Cochlear implants have been found in some cases to be effective and an increase in auditory perception. It should be noted that children who are also being fitted with cochlear implants should be taught, in addition, sign language to help in communication alongside speech therapy.

Endocrine Care: Most cases require hormonal treatment to rectify genital anomalies and deficiencies in secondary sexual development.¹ Testosterone treatment can be administered.¹ In the event of a boy's experiencing delayed puberty, supplementary testosterone treatment may be required at puberty. Girls can be subjected to hormone replacement at puberty to induce normal sexual development and to avoid osteoporosis.¹

Surgical interventions

In addition, most children with CHARGE syndrome will require surgical treatment for certain structural anomalies. Surgery of various types and at various times is determined by the different issues that each particular child presents.

Cleft Palate Repair: Individuals diagnosed with cleft lip or palate should be evaluated by an oral maxillofacial surgeon for appropriate timing of surgical repair.¹ This is typically completed in infancy or during early childhood to facilitate feeding and reduce potential delay in speech development.

Cranial Nerve Dysfunction: Some individuals with CHARGE syndrome have facial palsy due to dysfunction of the cranial nerves.¹ This may include an inability to close the eye, and that can lead to scarring of the cornea. The application of artificial tears or other measures to protect the eye is necessary to prevent further damage to the eye.

Long-term care

CHARGE syndrome is a condition that requires intermittent monitoring and management throughout life. Multidisciplinary care by specialists in cardiology, otolaryngology, endocrinology, ophthalmology, and genetics can help manage all aspects of the condition.¹

Genetic Counseling: Regular consultation should be made available with a genetic counsellor/geneticist to discuss the implications of the CHD7 mutation for the family and the risk of future pregnancy.¹

Physical Therapy: It is helpful and recommended to have physical therapy for children with hypotonia and developmental delays as early as possible to facilitate motor development.¹ Occupational and speech therapies may be advised if necessary to further the child's independence and communication skills.

Summary

Diagnosis and management of CHARGE syndrome are very complicated and demanding; their early institution rests upon awareness of its genetic basis, key features, and treatment possibilities. There is great relevance of early diagnosis and early intervention to the timing of the outcome. Ever-advancing medical research and changing treatment methods lighten the prognosis for those with a diagnosis of CHARGE syndrome and give hope to the families of the persons concerned. It allows greater awareness, better management, and support of the condition, furthering understanding of this very rare but impactful disorder.