CHARGE Syndrome

CHARGE syndrome is a rare genetic condition with autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance in which almost all body systems are affected. The acronym CHARGE stands for the constellation of clinical features seen with this condition: Coloboma, Heart defects, Atresia choanae, Growth retardation, Genetic Abnormalities, and E ar AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation abnormalities. Genetic testing confirms the diagnosis. Treatment is symptomatic with management of the airway, heart defects, and feeding ability as the priorities in early life. There is no definitive curative therapy.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Epidemiology and Genetics

Epidemiology

  • Incidence: 1 in 12,000–15,000 newborns
  • Mortality is highest during neonatal period.

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

  • Most commonly due to loss of function mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in CHD7 gene 
    • Produces the CHD7 protein, involved in chromatin remodeling
    • Chromatin remodeling controls the gene expression. 
    • The defective CHD7 protein breaks down prematurely. 
    • Results in a disrupted chromatin remodeling and poor gene expression 
    • Neural crest differentiation into various structures throughout the body is impaired.
  • Inheritance pattern: autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance 
  • May be familial, but more often results from de novo (idiopathic) mutations
  • Advanced paternal age possibly a risk factor

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Clinical Presentation

Characteristic symptoms

CHARGE is an acronym to describe the clinical presentation of this syndrome: 

  • C for Coloboma (a hole in the choroid, retina, iris, and/or optic disc)
    • Unilateral or bilateral
    • Impairment of vision depending on the location and size 
    • May also present with microphthalmia
  • H for Heart defects (60%–70% of cases) 
    • Coarctation of the aorta Coarctation of the aorta Coarctation of the aorta is a narrowing of the aorta between the aortic arch and the iliac bifurcation commonly around the point of insertion of the ductus arteriosus. Coarctation of the aorta is typically congenital and the clinical presentation depends on the age of the patient. Coarctation of the Aorta
    • Aortic valve stenosis
    • Tetralogy of Fallot Tetralogy of Fallot Tetralogy of Fallot is the most common cyanotic congenital heart disease. The disease is the confluence of 4 pathologic cardiac features: overriding aorta, ventricular septal defect, right ventricular outflow obstruction, and right ventricular hypertrophy. Tetralogy of Fallot
    • Patent ductus arteriosus Patent ductus arteriosus The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA)
  • A for Atresia of the choanae (choanal atresia)
    • Bony and/or membranous tissue blocks back of nasal passageway.
    • Inability to pass nasogastric tube is noted.
  • R for growth Retardation (60%–70% of cases)
    • Noticeable in the first 6 months of life
    • May be noted in utero
    • Short stature
    • Due to growth hormone (GH) deficiency and a gonadotropin deficiency
  • G for Genital abnormalities 
    • Hypogonadotropic hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism
    • Micropenis, cryptorchidism Cryptorchidism Cryptorchidism is one of the most common congenital anomalies in young boys. Typically, this asymptomatic condition presents during a routine well-child examination where 1 or both testicles are not palpable in the scrotum. Cryptorchidism
    • Labial dysplasia
  • E for Ear abnormalities (100% of cases)
    • Hypoplastic semicircular canals are pathognomonic.
    • External ear is small, low-set, and square-shaped with protruding helices.
    • Developmental defects of the middle and inner ear → hearing impairment 

Associated conditions

  • Additional facial dysmorphic features: square face, facial nerve palsy, malar flattening, micrognathia, orofacial clefting
  • Skeletal anomalies such as scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis, polydactyly, oligodactyly, or clubfoot
  • Tracheoesophageal fistula Tracheoesophageal fistula Tracheoesophageal fistula is an abnormal connection between the trachea and esophagus. Esophageal Atresia and Tracheoesophageal Fistula
  • Feeding and swallowing difficulties/under-nutrition
  • Neurological anomalies 
  • Intellectual disability and developmental delay
  • Renal anomalies

Diagnosis

Diagnostic criteria

The diagnosis of CHARGE syndrome can be established if 2 major criteria plus any number of minor criteria are present.

  • 4 major criteria (4 Cs):
    1. Coloboma
    2. Choanal atresia or cleft palate cleft palate The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate
    3. Characteristic external, middle, or inner ear anomalies including hypoplastic semicircular canals
    4. CHD7 variant (pathogenic)
  • 7 minor criteria:
    1. Cranial nerve dysfunction including hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    2. Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia/feeding difficulties
    3. Structural brain anomalies
    4. Developmental delay/intellectual disability/autism
    5. Hypothalamo-hypophyseal dysfunction (including hormonal deficiencies) and genital anomalies
    6. Heart or esophageal malformations
    7. Renal/skeletal/limb anomalies

Laboratory tests

  • Complete blood count (CBC)
  • Renal function tests
  • Hormonal analysis (↓ growth hormone, ↓ gonadotrophins)
  • Immunological studies

Imaging studies

  • Ultrasonography (US): 
    • Cranial US: done during neonatal period to exclude major brain malformations
    • Abdominal US: to exclude renal abnormalities
  • Echocardiography: valvular abnormalities and structural heart defects
  • Barium swallow: esophageal dysmotility
  • Chest radiographs: to detect cardiopulmonary abnormalities
  • Computed tomography (CT) and magnetic resonance imaging (MRI): forebrain anomalies, cerebral atrophy, midbrain defects
Severe basal ganglia epvs

Magnetic resonance imaging showing cerebral atrophy from mild (A) to moderate (B) to severe (C) stages

Image: “EPVS” by Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. License: CC BY 4.0

Other tests

  • Electroencephalogram (EEG)
  • Electrocardiogram Electrocardiogram An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) ( ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG))
  • Audiometry
  • Ophthalmologic exam
  • Psychological and educational assessments

Management and Prognosis

Management

Various supportive and corrective treatment options are available. Treatment is tailored to the symptoms and anomalies present. 

  • Medical treatment:
    • Oxygen supplementation for cyanotic heart disease
    • Nasogastric feeding for swallowing difficulties
    • Artificial tears for facial palsy to avoid scarring of a cornea
    • Hearing aids/cochlear implants
    • Durable medical equipment such as braces or wheelchairs to help with mobility
    • Androgen therapy given in some cases for penile growth
    • Physical therapy to help with mobility
    • Speech therapy as needed
  • Surgical treatment:
    • Tracheostomy (tube placement into the trachea Trachea The trachea is a tubular structure that forms part of the lower respiratory tract. The trachea is continuous superiorly with the larynx and inferiorly becomes the bronchial tree within the lungs. The trachea consists of a support frame of semicircular, or C-shaped, rings made out of hyaline cartilage and reinforced by collagenous connective tissue. Trachea to stabilize air passage)
    • Gastrostomy (tube placement into the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach for feeding)
    • Myringotomy (tube placement into the tympanic membrane for otitis media)

Prognosis

  • Mortality is higher in the neonatal period and early infancy due to:
    • Cyanotic heart disease
    • Bilateral choanal atresia
    • Esophageal atresia Esophageal atresia Esophageal atresia is a congenital anomaly in which the upper esophagus is separated from the lower esophagus and ends in a blind pouch. The condition may be isolated or associated with tracheoesophageal fistula, which is an abnormal connection between the trachea and esophagus. Esophageal Atresia and Tracheoesophageal Fistula 
    • Central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (CNS) anomalies
  • Treatment is necessary for survival, but no curative treatments are available.

Differential Diagnosis

  • VACTERL association VACTERL Association VACTERL association is a rare disorder that affects multiple body systems in fetal development. There is no clear genetic cause or inheritance pattern for the development of this disorder. The acronym VACTERL stands for its characteristic anomalies: Vertebral abnormalities, Anal atresia, Cardiac defects, Tracheoesophageal abnormalities, Renal anomalies, and Limb abnormalities. VACTERL Association: a disorder that affects multiple body systems in fetal development. VACTERL is the acronym for the constellation of clinical features seen with this condition: Vertebral defects, Anal atresia, Cardiac defects, Tracheoesophageal fistula, Renal anomalies, and Limb abnormalities. The disorder appears to occur sporadically with no clear inheritance pattern. Cognition is not affected. The disorder is a diagnosis of exclusion in the setting of the presence of at least 3 of the above clinical features. Treatment is conservative and surgical based on symptoms and abnormalities. 
  • Kallmann syndrome Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome: a genetic condition that causes hypogonadotropic hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism and impaired sense of smell. Mutations in the same gene (CHD7) implicated in CHARGE syndrome have been seen in those with Kallmann syndrome Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome. Given the overlap, individuals with suspected Kallmann syndrome Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome may have similar features to that of CHARGE syndrome, albeit much milder, and should undergo additional screening. Genetic testing with gene sequencing helps with diagnosis and differentiation.

References

  1. Van Ravenswaaij-Arts, C. & Martin, Donna M.(2017). New insights and advances in CHARGE syndrome: Diagnosis, etiologies, treatments, and research discoveries. Am J Med Genet C Semin Med Genet. 175(4): 397–406. Published online 2017 Nov 24. doi: 10.1002/ajmg.c.31592
  2. CHARGE Syndrome. Online Mendelian Inheritance in Man (OMIM). Retrieved December 2, 2020. URL:https://www.omim.org/entry/214800#creationDate
  3. Jongmans, M.C., et al.  (2006). CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. 43(4): 306–314.Published online 2005 Oct 14. doi: 10.1136/jmg.2005.036061
  4. Dijk, D. R., Bocca, G., & van Ravenswaaij-Arts, C. M. (2019). Growth in CHARGE syndrome: optimizing care with a multidisciplinary approach. J Multidiscip Healthc.12: 607–620. Published online 2019 Aug 1. doi: 10.2147/JMDH.S175713
  5. Jongmans M.C., van Ravenswaaij-Arts C.M., Pitteloud N., et al. (2009). CHD7 mutations in patients initially diagnosed with Kallmann syndrome–the clinical overlap with CHARGE syndrome. Clinical Genetics. 75(1):65-71. DOI: 10.1111/j.1399-0004.2008.01107.x.
  6. Blake, K. M., Prasad, C. (2015). Orphanet: CHARGE syndrome.  Retrieved December 9, 2020, from https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=138

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