CHARGE syndrome

CHARGE syndrome
"Lop ear" phenotype characteristic of a person with CHARGE syndrome, along with her cochlear implant.
SpecialtyPediatrics

CHARGE syndrome (formerly known as CHARGE association) is a rare syndrome caused by a genetic disorder. First described in 1979, the acronym "CHARGE" came into use for newborn children with the congenital features of coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness.[1] These features are no longer used in making a diagnosis of CHARGE syndrome, but the name remains. About two thirds of cases are due to a CHD7 mutation. CHARGE syndrome occurs only in 0.1–1.2 per 10,000 live births; as of 2009 it was the leading cause of congenital deafblindness in the US.[2]

Signs and symptoms

The clinical presentation of this condition is consistent with, but not limited to, the following:[3]

  • Anophthalmia
  • Aortic arch aneurysm
  • Attention deficit
  • Cleft of scrotum
  • Cleft palate
  • External ear malformation
  • Hearing impairment
  • Iris coloboma
  • Micropenis

Genetics

CHARGE syndrome was formerly referred to as CHARGE association, which indicates a non-random pattern of congenital anomalies that occurs together more frequently than one would expect on the basis of chance. Very few people with CHARGE will have 100% of its known features. In 2004, mutations on the CHD7 gene (located on Chromosome 8) were found in 10 of 17 patients in the Netherlands, making CHARGE an official syndrome.[4] A 2006 US study of 110 individuals with CHARGE syndrome showed that 60% of those tested had a mutation of the CHD7 gene.[5]

In 2010, a review of 379 clinically diagnosed cases of CHARGE syndrome, in which CHD7 mutation testing was undertaken found that 67% of cases were due to a CHD7 mutation.[6] CHD7 is a member of the chromodomain helicase DNA-binding (CHD) protein family that plays a role in transcription regulation by chromatin remodeling.[7]

Diagnosis

Fundus image a,b) indicate chorioretinal colobomata of optic discs and macula -arrows

The diagnosis of CHARGE syndrome is often difficult, because it is rare. The syndrome spans many disciplines, and as such, can be diagnosed by a pediatrician, family medicine physician, oral and maxillofacial surgeon, ENT specialist, ophthalmologist, endocrinologist, cardiologist, urologist, developmental specialist, radiologist, geneticist, physiotherapist, occupational therapist, speech therapist, or orthopedic specialist.

Although genetic testing positively identifies nearly two thirds of children with CHARGE syndrome, diagnosis is still largely clinical. The following signs were originally identified in children with this syndrome, but are no longer used in to make the diagnosis alone.

Genetic testing

Genetic testing for CHARGE syndrome involves specific genetic testing for the CHD7 gene. The test is available at most major genetic testing laboratories. Insurance companies sometimes do not pay for such genetic tests, though this is changing rapidly as genetic testing is becoming standard across all aspects of medicine. CHARGE syndrome is a clinical diagnosis, which means genetic testing is not required in order to make the diagnosis. Rather, the diagnosis can be made based on clinical features alone.

Screening other organ systems

Once the diagnosis is made based on clinical signs, it is important to investigate other body systems that may be involved. For example, if the diagnosis is made based on the abnormal appearance of the ears and developmental delay, it is important to check the child's hearing, vision, heart, nose, and urogenital system. Ideally, every child newly diagnosed with CHARGE syndrome should have a complete evaluation by an ENT specialist, audiologist, ophthalmologist, pediatric cardiologist, developmental therapist, and pediatric urologist.

Treatment

Children with CHARGE syndrome may have a number of life-threatening medical conditions; with advances in medical care, these children can survive and can thrive with the support of a multidisciplinary team of medical professionals. Therapies and education must take into consideration hearing impairment, vision problems, and any others. Early intervention, such as occupational, speech-language, and physical therapy, to improve static posture, ambulation, and self-care skills is important. The intelligence of children with multiple health impairments, such as combined deafblindness, can be underestimated in the absence of early intervention.

Education

Children with CHARGE syndrome will vary greatly in their abilities in the classroom: some may need little support, while some may require full-time support and individualized programs. Taking each of the various affected body systems into account is vital to the success of the child in the educational setting.

An important step in dealing with abnormal behavior is understanding why it is occurring and helping the child learn more appropriate methods of communicating.

Epidemiology

The incidence is estimated to range from 0.1–1.2 per 10,000 live births, though the true incidence is unknown.[8] As of 2005, the highest prevalence was found in Canada and estimated at 1 in 8,500 live births.[9]

History

B.D. Hall first described the CHARGE association in a 1979 journal paper of about 17 children who had been born with choanal atresia.[10] During the same year, H.M. Hittner described 10 children who had choanal atresia as well as coloboma, congenital heart defect, and hearing loss.[11] Using both coloboma or choanal atresia and some of the other related characteristic malformations, R. A. Pagon first coined the acronym CHARGE in 1981 to emphasize that this cluster of associated malformations occurred together.[1] It came to be recognised as a syndrome within the umbrella of the CHARGE association, a set of apparently random signs occurring together. Since the signs seen in CHARGE are caused by a genetic anomaly, its name was eventually changed to 'CHARGE syndrome'.

References

  1. 1 2 Pagon RA, Graham JM, Zonana J, Yong SL (1981). "Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association". J. Pediatr. 99 (2): 223–7. doi:10.1016/S0022-3476(81)80454-4. PMID 6166737.
  2. ↑ "The 2008 National Child Count of Children and Youth who are Deaf-Blind" (PDF). The National Consortium on Deaf-Blindness. 2009. p. 30. Archived from the original (PDF) on 2012-03-15.
  3. ↑ "CHARGE syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 11 July 2021. Retrieved 23 October 2021.
  4. ↑ Vissers, L. E.; van Ravenswaaij, C. M.; Admiraal, R.; Hurst, J. A.; de Vries, B. B.; Janssen, I. M.; et al. (2004). "Mutations in a new member of the chromodomain gene family cause CHARGE syndrome". Nature Genetics. 36 (9): 955–957. doi:10.1038/ng1407. PMID 15300250.
  5. ↑ Lalani, S.R.; Safiullah, A.M.; Fernbach, S.D.; et al. (2006). "Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation". Am. J. Hum. Genet. 78 (2): 303–14. doi:10.1086/500273. PMC 1380237. PMID 16400610.
  6. ↑ Zentner, G.E.; Layman, W.S.; Martin, D.M.; Scacheri, P.C. (2010). "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome". Am. J. Med. Genet. A. 152 (3): 674–686. doi:10.1002/ajmg.a.33323. PMC 2918278. PMID 20186815.
  7. ↑ Janssen, N.; Bergman, J.E.; Swertz, M.A.; Tranebjaerg, L.; Lodahl, M.; Schoots, J.; Hofstra, R.M.; van Ravenswaaij-Arts, C.M.; Hoefsloot, L.H. (August 2012). "Mutation update on the CHD7 gene involved in CHARGE syndrome". Human Mutation. 33 (8): 1149–1160. doi:10.1002/humu.22086. PMID 22461308.
  8. ↑ Blake, KD; Prasad, C (Sep 7, 2006). "CHARGE syndrome". Orphanet Journal of Rare Diseases. 1: 34. doi:10.1186/1750-1172-1-34. PMC 1586184. PMID 16959034.
  9. ↑ Issekutz, KA; Graham JM Jr; Prasad, C; Smith, IM; Blake, KD (Mar 15, 2005). "An epidemiological analysis of CHARGE syndrome: preliminary results from a Canadian study". American Journal of Medical Genetics Part A. 133A (3): 309–17. doi:10.1002/ajmg.a.30560. PMID 15637722.
  10. ↑ Hall BD (1979). "Choanal atresia and associated multiple anomalies". J. Pediatr. 95 (3): 395–8. doi:10.1016/S0022-3476(79)80513-2. PMID 469662.
  11. ↑ Hittner HM, Hirsch NJ, Kreh GM, Rudolph AJ (1979). "Colobomatous microphthalmia, heart disease, hearing loss, and mental retardation--a syndrome". Journal of Pediatric Ophthalmology and Strabismus. 16 (2): 122–8. PMID 458518.
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