CHARGE Syndrome

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Article initiated by:
Angelo Sarmiento, Eric Jiaming Zhang
All contributors:
Kai R. Seely, BS, Stephen C. Dryden, M.D., Jesse Wesberry, Stephen C. Dryden, M.D., S. Grace Prakalapakorn, MD, MPH, Eniolami O. Dosunmu, MD, Carla J. Osigian, MD
Assigned editor:
Carla J. Osigian, MD
Review:
Assigned status Up to Date
 by Carla J. Osigian, MD on September 23, 2025.


CHARGE Syndrome
DiseasesDB
32233
ICD-10
[1]87.8
OMIM
214800
MeSH
D058747


Disease Entity

Disease

CHARGE syndrome (historically also called Hall–Hittner syndrome) is a multisystem genetic disorder classically summarized by the acronym C H A R G E: Coloboma of the eye; Heart defects; Atresia of the nasal choanae (or choanal stenosis); Retardation of growth and/or development; Genitourinary anomalies; and Ear abnormalities (including external ear malformation and sensorineural hearing loss).

After the discovery of CHD7 mutations as the underlying genetic basis, the recognized clinical spectrum of CHARGE syndrome was broadened to include features such as cranial nerve abnormalities, vestibular dysfunction, cleft lip and/or palate, hypothyroidism, tracheoesophageal malformations, neurological anomalies, seizures, and renal defects.[1][2]

Epidemiology

Reported birth prevalence estimates vary because of differences in diagnostic criteria and case ascertainment. Recent estimates indicate that CHARGE has an incidence of approximately 1 in 10000 births. Prevalence figures continue to be refined as genetic testing identifies milder or atypical CHD7-related phenotypes.[3]

Genetics

The CHD7 gene (chromodomain helicase DNA-binding protein 7), located on chromosome 8q12, is the primary gene implicated in CHARGE syndrome. Most pathogenic variants in CHD7 arise de novo, although when inherited, the condition follows 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. Pathogenic variants in CHD7 often result in a truncated, nonfunctional protein, disrupting transcriptional control and impairing neural crest development. When these disruptions occur during embryogenesis, they give rise to the broad and multisystem features characteristic of CHARGE syndrome.[3]

Among individuals meeting formal clinical diagnostic criteria, CHD7 pathogenic variants are identified in the majority of cases (historically cited as ~70–90%, depending on the cohort and criteria used). The advent of broader genomic testing (including multigene panels and exome sequencing) has clarified that CHD7 pathogenic variants also present with partial or atypical phenotypes. This broader recognition has prompted some investigators to use the term ‘CHD7 disorder’ to encompass these variable manifestations.[4][1]

Clinical Features

Ophthalmic manifestations

Ophthalmic abnormalities are found in 75-90% of CHARGE patients.[5] Coloboma (typically chorioretinal and/or optic nerve involvement; sometimes iris or lens) is the most characteristic ocular anomaly and may cause severe visual impairment. Colobomas also increase the lifetime risk of retinal detachment in these patients. [6] Other ocular findings include microphthalmia, microcornea, cataracts, strabismus, cranial nerve palsies affecting ocular motility, ptosis, high refractive error, and amblyopia.[7]

Cardiac anomalies

Cardiac malformations are found in 75-85% of patients with CHARGE syndrome.[8] Cardiac defects include a wide spectrum of congenital abnormalities, including Tetralogy of Fallot, aortic arch interruption, double outlet right ventricle with arch vessel abnormalities, and atrioventricular septal defects (AVSD).[9]

Choanal and airway anomalies

Approximately 65% of patients with CHARGE syndrome may have obstructed breathing due to choanal atresia at birth.[10] Other upper airway abnormalities that can be seen in CHARGE syndrome include: orofacial cleft, laryngomalacia, tracheomalacia, tracheoesophageal fistula, and subglottic stenosis.[11]

Genitourinary and endocrine

Genital hypoplasia is a common feature in patients with CHARGE Syndrome. This is secondary to hypogonadotropic hypogonadism.[12] Boys can have micropenis and cryptorchidism. Girls can have reduced clitoral size.[13] Additionally, patients can have renal abnormalities such as renal dysgenesis and duplex kidneys.[14]

Auditory and vestibular

Ear malformations including hypoplasia of the semicircular canals, and mixed or sensorineural hearing loss are characteristic. Vestibular hypoplasia/dysplasia contributes to balance impairment and delayed motor milestones.[15] [16]

Neurodevelopment and growth

The majority of infants with CHARGE syndrome generally experience growth restriction.[17] In addition to growth abnormalities, most CHARGE patients have impaired cognitive and communication ability. Behaviorally, children with CHARGE syndrome have been reported to engage in social withdrawal, repetitive motor mannerisms, and have difficulty sleeping.[18]

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.[19] Patients with CHARGE syndrome are also at risk for hypothyroidism[20] and recurrent suppurative ear and chest infections.[21]

Diagnosis

CHARGE syndrome remains primarily a clinical diagnosis, but modern advances in genetics have broadened the diagnostic framework. While the classic criteria (Blake 1998, Verloes 2005, Hale 2016) remain widely cited, more recent publications emphasize a broader “CHD7 disorder” spectrum, recognizing that patients with pathogenic CHD7 variants may present with incomplete or atypical features that do not fulfill older criteria. Consequently, many recommend integrating both clinical features and molecular testing to classify CHD7-related phenotypes.[1] [22]

Genetic testing is strongly recommended in suspected cases, especially when only partial clinical criteria are met, as approximately 70–90% of clinically diagnosed patients harbor a CHD7 mutation or deletion. Importantly, the absence of a CHD7 variant does not exclude the diagnosis, given phenotypic variability and the possibility of undetected changes. In cases where CHD7 testing is negative but clinical suspicion remains high, extended testing may be considered, including multigene panels, exome or RNA/splice analysis, and chromosomal microarray.

Differential diagnosis

  • 22q11.2 deletion syndrome
  • Oculo‐auriculo‐vertebral spectrum
  • VACTERL/VATER association
  • Kabuki syndrome
  • Teratogen‐related embryopathies[2][8]
  • 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.

General, developmental, and rehabilitative care

Early intervention (physical, occupational, speech therapy), individualized education plans, and sensory habilitation (hearing amplification, low-vision services, sign language where appropriate) are foundational to optimize developmental outcomes. Regular surveillance for endocrine deficits, growth, and pubertal progression is recommended.

Ophthalmologic Management

Early and serial ophthalmic examinations with attention to refractive error, amblyopia prevention, cataract assessment, and documenting the presence, degree, and location of colobomas are essential. Because chorioretinal colobomas carry an elevated risk of rhegmatogenous retinal detachment, prophylactic laser retinopexy to the borders of sizeable colobomas can be considered in selected eyes to reduce detachment risk. [23] When detachment occurs, pars plana vitrectomy (often with long-term tamponade such as silicone oil) is commonly performed, though outcomes are variable and surgery is technically challenging in small/abnormal eyes.[24]

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.[2]

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.[2]

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.[19]

Genetics and counseling

Genetic testing confirms diagnosis in most clinically typical cases; families should be offered genetic counseling given the usually de novo nature of pathogenic variants but rare possibility of parental mosaicism or autosomal dominant transmission.

Conclusion

CHARGE syndrome is a complex multisystem disorder most often attributable to pathogenic variants in CHD7. Advances in genetic testing over the past decade have broadened the recognized phenotypic spectrum and refined diagnostic approaches, underscoring the heterogeneity of this condition. Ophthalmic involvement, most notably chorioretinal coloboma, remains a hallmark feature with significant implications for vision and quality of life. Optimal care requires early, coordinated, and multidisciplinary management to address the diverse medical, developmental, and sensory challenges faced by affected individuals.

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 van Ravenswaaij-Arts CM, Hefner M, Blake K, et al. CHD7 Disorder. 2006 Oct 2 [Updated 2025 Aug 14]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.
  2. ↑ 2.0 2.1 2.2 2.3 Hsu P, Ma A, Wilson M, et al. CHARGE syndrome: a review. J Paediatr Child Health. 2014;50(7):504-11.
  3. ↑ 3.0 3.1 Usman N, Sur M. CHARGE Syndrome. [Updated 2023 Mar 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.
  4. ↑ 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.
  5. ↑ Russell-Eggitt IM, Blake KD, Taylor DS, Wyse RK. The eye in the CHARGE association. Br. J. Ophthalmol. 1990; 74: 421–6.
  6. ↑ Mcmain K, Blake K, Smith I, et al. Ocular features of CHARGE syndrome. J AAPOS. 2008;12(5):460-5.
  7. ↑ 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.
  8. ↑ 8.0 8.1 Blake KD, Prasad C. CHARGE syndrome. Orphanet J Rare Dis. 2006;1:34.
  9. ↑ Wyse RK, al-Mahdawi S, Burn J, Blake K. Congenital heart disease in CHARGE association. Pediatr Cardiol 1993; 14: 75–81.
  10. ↑ Leclerc JE, Fearon B. Choanal atresia and associated anomalies. Int J Pediatr Otorhinolaryngol. 1987;13(3):265-72.
  11. ↑ 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.
  12. ↑ Wheeler PG, Quigley CA, Sadeghi-Nejad A, Weaver DD.Hypogonadism and CHARGE association. Am J Med Genet 2000; 94: 228–31.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Holcomb MA, Rumboldt Z, White DR. Cochlear nerve deficiency in children with CHARGE syndrome. Laryngoscope 2013;123:793–6.
  16. ↑ 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.
  17. ↑ Husu E, Hove HD, Farholt S et al. Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome. Clin Genet. 2013; 83: 125–34.
  18. ↑ 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.
  19. ↑ 19.0 19.1 White DR, Giambra BK, Hopkin RJ, Daines CL, Rutter MJ. Aspiration in children with CHARGE syndrome. Int J Pediatr Otorhinolaryngol. 2005; 69: 1205–9.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ Hale CL, Niederriter AN, Green GE, Martin DM. 2016. Atypical phenotypes associated with pathogenic CHD7 variants and a proposal for broadening CHARGE syndrome clinical diagnostic criteria. Am J Med Genet Part A 170A: 344–354.
  23. ↑ Uhumwangho OM, Jalali S. Chorioretinal coloboma in a paediatric population. Eye (Lond). 2014;28(6):728-33.
  24. ↑ 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.
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