CHARGE Syndrome

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Disease Entity

Disease

CHARGE Syndrome is a rare genetic syndrome that produces a constellation of clinical features. The features are described in the name ‘CHARGE’ which stands for:

Coloboma of the eye

Heart defects

Atresia of the Nasal choanae

Retardation of growth and/or development

Genitourinary malformation

Ear abnormalities[1]

Another name for this syndrome is Hall-Hittner syndrome

Epidemiology

The prevalence of CHARGE syndrome is 0.1-1.2 of10,000 live births. It is the leading cause of congenital deaf-blindness in the U.S. according to the National Consortium of Deaf-Blindness. In 2017, there were 933 children and youth identified as having CHARGE syndrome.[2]

Genetics

CHARGE syndrome typically occurs spontaneously (i.e. no previous family history) due to a de novo mutation in the CHD7 gene located on chromosome 8q12.[3] In rare cases, it can be inherited in an autosomal dominant pattern. The CHD7 gene provides instructions for making a protein (chromodomain helicase DNA-binding protein) which regulates gene expression by altering chromatin remodeling. Chromatin remodeling alters how tightly DNA is packaged, which affects the rate of gene expression.[4] It was found that 90-95% of patients fulfilling the formal diagnostic criteria for CHARGE syndrome are heterozygous for a CDH7 mutation or deletion.[5] Most CHD7 gene mutations lead to the production of an abnormal CHD7 protein, which breaks down prematurely.[4] A shortage of this protein is thought to disrupt chromatin remodeling and thus gene expression. These changes in gene expression during embryonic development are thought to underlie the signs and symptoms of CHARGE syndrome.

Clinical Features

Ophthalmic Abnormalities

Ophthalmic abnormalities are found in 75-90% of CHARGE patients.[6] The most common abnormality is a coloboma of the eye (not the eyelid). These are typically chorioretinal (intra- and extra- macular) and optic nerve, but can also occur in the iris and lens. In addition to visual impairment, colobomas predispose CHARGE syndrome patients to retinal detachment.[7] Other ophthalmic features that can occur in patients with CHARGE syndrome include microphthalmia, microcornea, cataracts, strabismus, cranial nerve VII palsy, and ptosis.[8] High refractive errors and amblyopia also occur in CHARGE syndrome.

Cardiac Abnormalities

Cardiac malformations are found in 75-85% of patients with CHARGE syndrome.[9] Cardiac defects can include Tetralogy of Fallot, aortic arch interruption, double outlet right ventricle with arch vessel abnormalities, and atrioventricular septal defects (AVSD).[10]

Choanal Atresia and Upper Airway Abnormalities

Approximately 65% of patients with CHARGE syndrome may have obstructed breathing due to choanal atresia at birth.[11] Other upper airway abnormalities that can be seen in CHARGE syndrome include: laryngomalacia, tracheomalacia, tracheoesophageal fistula, and subglottic stenosis.[12]

Genitourinary Abnormalities

Genital hypoplasia is a common feature in patients with CHARGE Syndrome. This is secondary to hypogonadotropic hypogonadism.[13] Boys can have micropenis and cryptorchidism. Girls can have reduced clitoral size.[14] Additionally, patients can have renal abnormalities such as renal dysgenesis and duplex kidneys.[15]

Auditory Abnormalities

Patients may experience variable degrees of sensorineural hearing loss.[16] The most common ear abnormality is absence of the lateral semicircular canals. Dysplasia of the vestibular canal can also occur, resulting in poor balance and delays in walking.[17]

Developmental Abnormalities

The majority of infants with CHARGE syndrome generally experience growth restriction.[18] In addition to growth abnormalities, most CHARGE patients have impaired cognitive and communication ability. One study showed that 70% of CHARGE syndrome patients have an IQ less than 70.[19] Behaviorally, children with CHARGE syndrome have been reported to engage in social withdrawal, repetitive motor mannerisms, and have difficulty sleeping.[20]

Other Abnormalities

Other clinical findings in CHARGE include cranial nerve dysfunction, endocrine dysregulation, and recurrent infections. A significant majority of infants are found to have difficulty feeding, manifesting as weak sucking and chewing, swallowing difficulty, gastro-esophageal reflux, and chronic aspiration. These issues are likely due to cranial nerve dysfunction and 90% of such patients require tube feeding at some point.[21] Patients with CHARGE syndrome are also at risk for hypothyroidism[22] and recurrent suppurative ear and chest infections.[23]

Diagnosis

  • CHARGE syndrome is diagnosed clinically. Two widely utilized diagnostic systems are the Blake and Verloes criteria.[1] Both systems define major and minor criteria consistent with CHARGE syndrome. Major signs are more specific for CHARGE syndrome and include most prominent cranial abnormalities. Minor signs are used to help define CHARGE syndrome by primary, distinct, non-overlapping topographic areas.
    • Major signs are: coloboma of the iris or choroid, chloanal atresia, and hypoplastic semicircular canals.
    • Minor signs are: rhombencephalic dysfunction, hypothalamo-hypophyseal dysfunction, abnormal middle or external ear, malformation of mediastinal organs, and mental retardation.
    • A formal diagnosis of CHARGE syndrome requires 3 major signs or 2 major signs with 2 or more minor signs.
    • The diagnosis of partial or incomplete CHARGE syndrome is made with 2 major signs and 1 minor sign.
    • Atypical CHARGE diagnosis consists of 2 major signs and no minor signs, or 1 major sign and 3 or more minor signs.
    • This methodology includes more CHARGE syndrome diagnoses that were previously classified as “possibly CHARGE syndrome” using previous diagnostic criteria.[24]
  • Genetic analysis of the CHD7 gene is often performed in patients with suspected CHARGE syndrome to confirm the diagnosis. Mutations in CHD7 are present in approximately 70-90% of patients clinically diagnosed with CHARGE syndrome. CHD7 mutations are most common in patients meeting formal criteria for CHARGE syndrome, and less common in those diagnosed with atypical or incomplete CHARGE syndrome.[25][5] Therefore, while the presence of a CHD7 mutation can confirm a diagnosis of CHARGE syndrome, the absence of a mutation cannot definitively rule it out.

Differential diagnosis

  • 22q11.2 deletion syndrome
  • Oculo‐auriculo‐vertebral spectrum
  • VACTERL/VATER association
  • Kabuki syndrome
  • Teratogen‐related embryopathies[1][9]
  • Abruzzo-Erickson syndrome
  • Kallmann syndrome
  • Renal coloboma syndrome
  • Cat-eye syndrome
  • Joubert syndrome
  • BOR syndrome
  • 5q11.2 micro-deletion syndrome
  • Other chromosomal micro-deletion syndromes

Management

Management of children with CHARGE syndrome requires a multidisciplinary team of healthcare professionals to address the life-threatening medical conditions, as well as the developmental and behavioral abnormalities associated with the condition. Patients require early intervention with occupational, speech, and physical therapy, and low vision intervention to ensure that they maximize their vision potential.

Ophthalmologic Management

A detailed pediatric ophthalmologic examination is critical for documenting the presence, degree, and location of colobomas and identifying any other ocular abnormalities that may be present (eg. refractive errors or ocular surface disease). Performing a visual acuity exam to assess for vision function is also very important. Chorioretinal colobomas are the most common type of coloboma in CHARGE syndrome and can lead to retinal detachment. Treatment for chorioretinal retinal detachment is pars plana vitrectomy using silicone oil (versus gas filling) to reduce recurrent retinal detachment.[26] Prophylactic laser photocoagulation can also be performed in eyes with chorioretinal coloboma to prevent rhegmatogenous retinal detachment.[27]

Other ophthalmic symptoms such as photophobia can be treated with tinted glasses. Cranial nerve abnormalities such as facial nerve palsy may be treated with a lubrication regimen and ultimately surgical intervention.[1]

Behavioral and Developmental Management

Early developmental interventions are crucial. It is recommended that patients be taught sign language as well as expressive language development with the aim of adapting patients to their disabilities and maximizing overall function.[28] It is important to maximize all vision and hearing potential.

Cardiology Management

A cardiologist should be involved in the care of these patients. Echocardiography should be performed in all children to evaluate for cardiac abnormalities.[1]

Otolaryngology Management

Severity and etiology of hearing loss (conductive vs. sensorineural) should be assessed using audiometry. Hearing aids or cochlear implants should be considered depending on severity of deafness.

Gastrointestinal Management

Management with a gastroenterologist is indicated in CHARGE patients with feeding problems and chronic aspiration. It is important to address the feeding concerns in a timely manner. Gastrostomy or jejunostomy may be indicated to overcome feeding problems in infants.[21]

Conclusion

CHARGE syndrome is a rare genetic syndrome that affects numerous organ systems. The most common ophthalmic manifestation is a coloboma (usually chorioretinal). Diagnosis is based on clinical findings using either the Blake or Verloes criteria. Management involves early intervention by a multidisciplinary team involving various specialists, including pediatric ophthalmologists.

Additional Resources

  • CHARGE syndrome: National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): Health Conditions; 2019 Feb. CHARGE syndrome; [reviewed 2017 Feb; cited 2019 Nov 27]; Available from: https://ghr.nlm.nih.gov/condition/charge-syndrome Accessed February 24, 2021.

References

  1. 1.0 1.1 1.2 1.3 1.4 Hsu P, Ma A, Wilson M, et al. CHARGE syndrome: a review. J Paediatr Child Health. 2014;50(7):504-11.
  2. “The 2017 National Child Count of Children and Youth who are Deaf-Blind.” NCDB: The National Consortium on Deaf-Blindness. 2018
  3. Vissers LE, Van ravenswaaij CM, Admiraal R, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004;36(9):955-7.
  4. 4.0 4.1 https://ghr.nlm.nih.gov/condition/charge-syndrome#. Last accessed April 4, 2020.
  5. 5.0 5.1 Bergman JEH, Janssen N, Hoefsloot LH, Jongmans MCJ, Hofstra RMW, van Ravenswaaij-Arts CMA. CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype. J Med Genet. 2011;48:334–42.
  6. Russell-Eggitt IM, Blake KD, Taylor DS, Wyse RK. The eye in the CHARGE association. Br. J. Ophthalmol. 1990; 74: 421–6.
  7. Mcmain K, Blake K, Smith I, et al. Ocular features of CHARGE syndrome. J AAPOS. 2008;12(5):460-5.
  8. Nishina S, Kosaki R, Yagihashi T et al. Ophthalmic features of CHARGE syndrome with CHD7 mutations. Am J Med Genet A 2012; 158A: 514–18.
  9. 9.0 9.1 Blake KD, Prasad C. CHARGE syndrome. Orphanet J Rare Dis. 2006;1:34.
  10. Wyse RK, al-Mahdawi S, Burn J, Blake K. Congenital heart disease in CHARGE association. Pediatr Cardiol 1993; 14: 75–81.
  11. Leclerc JE, Fearon B. Choanal atresia and associated anomalies. Int J Pediatr Otorhinolaryngol. 1987;13(3):265-72.
  12. Morgan D, Bailey M, Phelps P, Bellman S, Grace A, Wyse R. Ear-nose-throat abnormalities in the CHARGE association. Arch Otolaryngol Head Neck Surg. 1993;119(1):49-54.
  13. Wheeler PG, Quigley CA, Sadeghi-Nejad A, Weaver DD.Hypogonadism and CHARGE association. Am J Med Genet 2000; 94: 228–31.
  14. Jongmans MCJ, Admiraal RJ, van der Donk KP et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. 2006; 43: 306–14.
  15. Lalani SR, Hefner MA, Belmont JW, Davenport SL. CHARGE syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews. Seattle, WA: University of Washington, 1993–2013.
  16. Holcomb MA, Rumboldt Z, White DR. Cochlear nerve deficiency in children with CHARGE syndrome. Laryngoscope 2013;123:793–6.
  17. Admiraal RJ, Huygen PL. Vestibular areflexia as a cause of delayed motor skill development in children with the CHARGE association. Int J Pediatr Otorhinolaryngol. 1997;39:205–22.
  18. Husu E, Hove HD, Farholt S et al. Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome. Clin Genet. 2013; 83: 125–34.
  19. Salem-Hartshorne N, Jacob S. Adaptive behavior in children with CHARGE syndrome. Am J Med Genet. A 2005; 133A: 262–7.
  20. Smith IM, Nichols SL, Issekutz K, Blake K, Canadian Paediatric Surveillance P. Behavioral profiles and symptoms of autism in CHARGE syndrome: preliminary Canadian epidemiological data. Am J Med Genet. A 2005; 133A: 248–56.
  21. 21.0 21.1 White DR, Giambra BK, Hopkin RJ, Daines CL, Rutter MJ. Aspiration in children with CHARGE syndrome. Int J Pediatr Otorhinolaryngol. 2005; 69: 1205–9.
  22. Asakura Y, Toyota Y, Muroya K et al. Endocrine and radiological studies in patients with molecularly confirmed CHARGE syndrome. J Clin Endocrinol Metab. 2008;93:920–4.
  23. Gennery AR, Slatter MA, Rice J et al. Mutations in CHD7 in patients with CHARGE syndrome cause T-B + natural killer cell + severe combined immune deficiency and may cause Omenn-like syndrome. Clin Exp Immunol. 2008;153:75–80.
  24. Verloes A. Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A. 2005;133A(3):306-8.
  25. Aramaki M, Udaka T, Kokasi R, et al. Phenotype spectrum of CHARGE syndrome with CHD7 mutations. J Pediatr. 2006;118: 410-414.
  26. Gopal L, Badrinath SS, Sharma T, et al. Surgical management of retinal detachments related to coloboma of the choroid. Ophthalmology. 1998;105(5):804-9.
  27. Uhumwangho OM, Jalali S. Chorioretinal coloboma in a paediatric population. Eye (Lond). 2014;28(6):728-33.
  28. Bernstein V, Denno LS. Repetitive behaviors in CHARGE syndrome:differential diagnosis and treatment options. Am J Med Genet. 2005;133A: 232–9