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CHARGE syndrome is an inherited disorder caused by a mutation in the DNA-binding protein-7 CHD7 gene. CHARGE syndrome is an acronym for coloboma, heart disease, atresia of the choanae, retarded growth and mental development, genital anomalies, and ear malformations and hearing loss. CHARGE syndrome can have high morbidity, but the morbidity can be minimized by early diagnosis and treatment. This activity reviews the pathophysiology, evaluation, and treatment of CHARGE syndrome and highlights the role of the interprofessional team in managing patients and counseling families of patients with this syndrome. Objectives: Explain the etiology and describe the pathophysiology of CHARGE syndrome. Outline the typical presentation and most common physical examination findings associated with CHARGE syndrome. Summarize the important aspects of medical and surgical management of CHARGE syndrome, including occupational, physical, and speech therapy. Review the importance of collaboration and communication amongst the interprofessional team to enhance the delivery of care for patients affected by CHARGE syndrome. Access free multiple choice questions on this topic.

CHARGE syndrome is a rare, autosomal dominant genetic disorder commonly diagnosed during the prenatal or neonatal period due to the identification of numerous dysmorphic and congenital anomalies. The features of CHARGE syndrome were first described independently by Hall and Hittner, and hence, it was initially called Hall-Hittner syndrome. Pagon first described the cardinal anomalies such as coloboma, choanal atresia, heart defects, genital abnormalities, retarded growth, and ear malformation, and coined the term CHARGE syndrome. Diagnosis is now made using the criteria proposed by Blake et al and further modified by Verloes, who highlighted the importance of the 3C triad (coloboma, choanal atresia, abnormal semicircular canals).[1][2] Other criteria include orofacial cleft, distinctive facial appearance, tracheoesophageal fistula, limb abnormalities, and, rarely, immune deficiencies. See Image. CHARGE Syndrome. Mutations in the CHD7 (chromodomain helicase DNA-binding protein) gene on 8q12 result in several structural and physiological abnormalities, including hearing and vision loss, heart defects, and gastrointestinal problems. Among these, gastrointestinal problems have a profound impact throughout an individual's life, leading to increased morbidity and mortality.

Mutations in the CHD7 gene are the most common cause of CHARGE syndrome. In the rare case, it is autosomal dominant, meaning it is inherited from a parent to a child. Most cases arise from de novo mutations, meaning they are not inherited but occur sporadically. Therefore, CHD7 gene abnormalities, which are usually de novo, are present in more than 90% of children who meet the clinical diagnostic criteria. The CHD7 gene encodes a protein that regulates developmental pathways by modulating chromatin organization. Mutations in the CHD7 gene lead to the production of an abnormally nonfunctional, short CHD7 protein, which disrupts gene regulation and causes disordered neural crest development. If these changes occur during the embryonic period, it leads to the development of the typically pleiotropic signs and symptoms of CHARGE syndrome.[3]

CHARGE syndrome is a congenital disorder with an incidence of approximately 1 in 10,000 births. It is not sex-linked, so both males and females are equally affected. Most cases are sporadic and not inherited, but the mean paternal age appears slightly elevated. In 2010, a study of 379 patients with CHARGE syndrome was conducted, followed by CHD7 mutation testing, which showed that 67% of cases were attributable to CHD7 mutations.[4] The recurrence rate is 1%.

Neural crest cells play an essential role in giving rise to derivatives, including bone, pigment cells, smooth muscle, endocrine cells, neurons, glia, and cartilage. Anomalies in neural crest-derived tissues can cause CHARGE syndrome. Deficiency in the migration of cervical neural crest cells into the pharyngeal pouches and arches, failure of mesoderm development, and a defective interface between neural crest cells and mesoderm can subsequently lead to multiple phenotypic abnormalities. Mutations in the DNA-binding protein 7 (CHD7) gene cause CHARGE syndrome, as CHD7 plays a vital role in neural crest development.[5]

CHARGE syndrome is a pleiotropic disorder, including coloboma, heart defects, choanal atresia, retarded growth, genital abnormalities, ear anomalies, and deafness. A consistent feature of CHARGE syndrome is semicircular canal hypoplasia, which leads to vestibular areflexia.[6] Other associated congenital disabilities include bilateral or unilateral iris coloboma, bilateral or unilateral choanal stenosis, or choanal atresia. On physical examination, other abnormalities such as cranial nerve abnormalities, including anosmia, facial palsy (bilateral or unilateral), impaired hearing, and difficulty in swallowing, have been observed. Other features in CHARGE syndrome are abnormal ear shape, cryptorchidism, hypogonadism in both females and males, developmental delay, orofacial clefts, and tracheoesophageal fistula. Specific behavioral problems, such as autistic-like behavior, have also been defined.[7][8] A detailed history and a consideration of prenatal, neonatal, and childhood presentations are required. The prenatal performance needs to be assessed when poor fetal development, intrauterine growth restriction (IUGR), cleft lip or cleft palate, or a congenital heart defect is found in utero. Neonates with CHARGE syndrome have multiple life-threatening medical conditions, such as small for gestational age, inability to pass a nasogastric tube due to choanal atresia, dysmorphic features, and respiratory distress. Feeding difficulties are a significant cause of morbidity in all age groups.

The diagnosis of CHARGE syndrome is initially based on temporal bone imaging and clinical findings. The only gene associated with CHARGE syndrome is CHD7, encoding the chromodomain helicase DNA-binding protein. This sequencing detects pathogenic variants in the maximum number of individuals with typical CHARGE syndrome who meet the following criteria: having the 3 primary characteristics or 4 major and 3 minor characteristics. The major criteria are the 4 C's: coloboma, cranial nerve abnormalities, choanal atresia, and typical CHARGE ear. The minor criteria are heart defects, cleft lip or palate, genital abnormalities, hypotonia, kidney abnormalities, esophageal atresia, poor growth, typical CHARGE face, and typical CHARGE hand. In general, CHD7 analysis in individuals with fewer major components or with typical CHARGE syndrome detects pathogenic variants in approximately 65%-70% of cases.[9] The outline of diagnosis is summarized as clinical presentation, laboratory evaluation, genetic analysis, and imaging studies: Clinical diagnosis: a combination of major and minor diagnostic characteristics, comprising 3 primary features or 4 major and 3 minor characteristics. Laboratory analysis includes a blood workup, such as complete blood count, serum electrolytes, renal function tests, luteinizing hormone-releasing hormone, Human chorionic gonadotropin, blood urea nitrogen, creatinine, growth hormone levels, and immunologic studies. Genetic analysis: Prenatal screening for CHD7 variants is restricted to familial cases and performed via amniocentesis or chorionic or villus sampling at 10–12 and 18–20 weeks’ gestation. Imaging studies: Involves a skeletal survey, abdominal ultrasound, barium swallow, echocardiography, chest x-ray, cranial ultrasound in neonates, and head computed tomography scan and magnetic resonance imaging (MRI).[9]

Patients with CHARGE syndrome require careful medical and surgical management. Management depends on the timing, features, and severity of the presentation. The most common neonatal emergencies in CHARGE syndrome include cyanosis due to congenital heart defects, or bilateral posterior choanal atresia, and, less likely, trachea-esophageal fistula.[1] Therefore, all patients suspected of having CHARGE syndrome should have a cardiology consultation. If the infant has patent ductus arteriosus and limited pulmonary blood flow, prostaglandin should be given to maintain ductal patency. Some cases require tracheostomy to manage chronic airway difficulties, aspiration, or gastroesophageal reflux disease. Children with CHARGE syndrome need extensive medical management of their feeding difficulties, regularly needing jejunostomy or gastrostomy feeding tubes.[10] In children with CHARGE syndrome, intubation may be very difficult. Hence, a pediatric otolaryngologist or anesthesiologist should be present for planned surgical procedures. In patients with facial palsy, corneal scarring can be prevented by the use of artificial tears. Hearing aids should be used as quickly as hearing loss is recognized, with regular follow-up. Regular remolding of the earpieces is required, as ear canals can be narrow initially, and ear cartilage may be insufficient to support a hearing aid. Cochlear implants have been successfully implanted in patients with CHARGE syndrome.[11] Children with CHARGE syndrome who undergo cochlear implantation should be allowed to learn sign language alongside their speech training. For endocrine issues, sex steroid therapy must be used for the descent of the testes and penile growth in males with CHARGE syndrome. Testosterone is given for incomplete and delayed male puberty during adolescence. Females are given hormone replacement therapy if indicated at puberty. The use of sex hormone replacement can prevent osteoporosis. Assessment for cleft palate, together with submucous cleft palate and surgical correction at the appropriate age, must be done by an oral maxillofacial surgeon. Physical examination to evaluate the integrity of the cranial nerve in patients presenting with facial palsy. Ongoing and regular consultation with a genetic counselor or geneticist is recommended.[12]

Differential diagnosis for CHARGE syndrome includes the following: 2 deletion syndrome Isolated coloboma Isolated choanal atresia Isolated congenital heart defects Cat-eye syndrome Joubert spectrum Kabuki syndrome Holoprosencephaly spectrum disorders Renal coloboma syndrome VATER/VACTERL association Kalman syndrome Smith-Lemli-Opitz syndrome DiGeorge syndrome

Patients in the early years of life (infant age) are at high risk, specifically those infants who have severe congenital disabilities, resulting in poor outcomes and, thus, a high morbidity and mortality rate. Patients are most vulnerable in the first year of life and are more prone to having an infection, requiring frequent hospitalization, and needing complex surgeries, including congenital heart surgery. In late childhood through adulthood, more common causes of death include infection, aspiration, and obstructive sleep apnea. Widespread bilateral coloboma resulting in poor vision, brain malformation, and microcephaly leads to a poor prognosis.[13]

Families of patients with CHARGE syndrome need education about the disease manifestations and possible complications. Genetic counseling should be accessible for individuals at increased risk for potentially affected offspring to describe options in future pregnancies, including preimplantation and prenatal genetic diagnosis. Children with CHARGE syndrome can be assessed on a case-by-case basis. Some may require full-time support and individualized programs, and some may need little assistance. An essential step in addressing abnormal behavior is understanding why it occurs and helping the child develop more appropriate interaction strategies. Before a child reaches age 18, care must be transitioned to adult clinicians and specialists who manage the individual in later years.

An interprofessional team that offers a comprehensive, unified approach to service delivery can achieve optimal outcomes for patients with CHARGE syndrome. Early identification of the syndrome and a diagnostic workup to identify individual manifestations helps prevent associated complications. CHARGE syndrome is a heterogeneous condition, and consultation with a geneticist, pediatric cardiologist, pediatric otolaryngologist, or anesthesiologist is essential to make a shared decision that is key to better outcomes. It is necessary to use a cohesive, coordinated care pathway grounded in evidence for the evaluation, planning, and management of all aspects of the disease. The earlier a complication is recognized and managed, the better the prognosis.[14][15]