CHARGE Syndrome 

  • Author: David H Tegay, DO, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Nov 13, 2009
 

Background

CHARGE syndrome is an autosomal dominant genetic disorder typically caused by mutations in the chromodomain helicase DNA-binding protein-7 (CHD7) gene.[1] The acronym "CHARGE" denotes the nonrandom association of coloboma, heart anomalies, choanal atresia, retardation of growth and development, and genital and ear anomalies, which are frequently present in various combinations and to varying degrees in individuals with CHARGE syndrome.[2] No single feature is universally present or sufficient for the clinical diagnosis of CHARGE syndrome, and numerous guidelines have been published to aid in establishing a likely clinical diagnosis.[2, 3, 4]

Blake et al suggested that a typical clinical diagnosis of CHARGE syndrome requires the presence of at least 4 major features or 3 major features plus at least 3 minor features.[3] Major features include ocular coloboma or microphthalmia, choanal atresia or stenosis, cranial nerve abnormalities, and characteristic auditory and/or auricular anomalies. Minor features include distinctive facial dysmorphology, facial clefting, tracheoesophageal fistula, congenital heart defects, genitourinary anomalies, developmental delay, and short stature. Other frequently associated abnormal findings include characteristic hand dysmorphology, hypotonia, deafness, and dysphagia.[3, 5]

Although most cases of CHARGE syndrome are due to mutation or deletion of the CHD7 gene, some individuals with CHARGE syndrome harbor disparate pathologic cytogenetic anomalies (including 22q11.2 deletions) or mutations in other genes (including SEMA3E) unrelated to CHD7.[6, 7, 8, 9, 10]

Next

Pathophysiology

A developmental defect involving the midline structures of the body occurs, specifically affecting the craniofacial structures.

This defect is attributed to arrest in embryologic differentiation in the second month of gestation, when the affected organs are in the formative stages (choanae at 35-38 days' gestation, eye at 5 weeks' gestation, cardiac septum at 32-38 days' gestation, cochlea at 36 days' gestation, external ear at 6 weeks' gestation). The prechordal mesoderm is necessary for the development of the mid face and exerts an inductive role on the subsequent development of the prosencephalon, the forepart of the brain.[11, 12]

The mechanisms suggested are (1) deficiency in migration of cervical neural crest cells into the derivatives of the pharyngeal pouches and arches, (2) deficiency of mesoderm formation, and (3) defective interaction between neural crest cells and mesoderm, resulting in defects of blastogenesis and hence the typical phenotype.[11, 4]

The complete function of CHD7 during embryologic development remains unclear.[12]

Previous
Next

Epidemiology

Frequency

International

The estimated birth incidence of CHARGE syndrome is 1 in 8,500-12,000.[13]

Mortality/Morbidity

Mortality and morbidity in CHARGE syndrome includes the following:[14, 15, 16]

  • Mortality is highest in the neonatal period and early infancy.
  • Frequent association of swallowing problems increases the risk of aspiration and contributes to increased mortality and morbidity.
  • Criteria for poor survival include the following:
    • Bilateral choanal atresia
    • Complex cyanotic congenital heart disease
    • CNS anomalies
    • Esophageal atresia

Race

CHARGE syndrome has a panethnic distribution.

Sex

CHARGE syndrome exhibits autosomal dominant inheritance, and expression is not sex-linked. Therefore, males and females are affected with equal frequency.

Age

CHARGE syndrome is frequently diagnosed in the neonatal or prenatal period because of the presence of multiple congenital anomalies and dysmorphic features.

Previous
Proceed to Clinical Presentation
 
 
Contributor Information and Disclosures
Author

David H Tegay, DO, FACMG  Associate Professor of Medicine and Medical Genetics, New York College of Osteopathic Medicine at the New York Institute of Technology; Assistant Professor of Pediatrics, Stony Brook University Medical Center

David H Tegay, DO, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Osteopathic Association, American Society of Human Genetics, and Federation of American Societies for Experimental Biology

Disclosure: Nothing to disclose.

Coauthor(s)

Jamie C Yedowitz  New York College of Osteopathic Medicine of the New York Institute of Technology

Disclosure: Nothing to disclose.

Specialty Editor Board

Elaine H Zackai, MD  Professor of Pediatrics, Professor of Obstetrics and Gynecology, Professor of Pediatrics in Human Genetics, University of Pennsylvania School of Medicine; Director, Clinical Genetics Center, University of Pennsylvania; Senior Physician and Director of Clinical Genetics, The Children's Hospital of Philadelphia

Elaine H Zackai, MD is a member of the following medical societies: American Cleft Palate/Craniofacial Association, American College of Medical Genetics, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine

Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Leonard G Feld, MD, PhD, MMM, FAAP  Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center

Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. Vissers LE, van Ravenswaaij CM, Admiraal R, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. Sep 2004;36(9):955-7. [Medline].

  2. [Guideline] Pagon RA, Graham JM Jr, Zonana J, Yong SL. Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. J Pediatr. Aug 1981;99(2):223-7. [Medline].

  3. [Guideline] Blake KD, Davenport SL, Hall BD, Hefner MA, Pagon RA, Williams MS. CHARGE association: an update and review for the primary pediatrician. Clin Pediatr (Phila). Mar 1998;37(3):159-73. [Medline].

  4. [Guideline] Verloes A. Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A. Mar 15 2005;133A(3):306-8. [Medline].

  5. Jones KL. CHARGE association. In: Smith's Recognizable Patterns of Human Malformation. 5th ed. WB Saunders Co; 1997:668-70.

  6. Aramaki M, Udaka T, Kosaki R, Makita Y, Okamoto N, Yoshihashi H. Phenotypic spectrum of CHARGE syndrome with CHD7 mutations. J Pediatr. Mar 2006;148(3):410-4. [Medline].

  7. Clementi M, Tenconi R, Turolla L, Silvan C, Bortotto L, Artifoni L. Apparent CHARGE association and chromosome anomaly: chance or contiguous gene syndrome. Am J Med Genet. Nov 1 1991;41(2):246-50. [Medline].

  8. North KN, Wu BL, Cao BN, Whiteman DA, Korf BR. CHARGE association in a child with de novo inverted duplication (14)(q22-->q24.3). Am J Med Genet. Jul 17 1995;57(4):610-4. [Medline].

  9. Lev D, Nakar O, Bar-Am I, Zudik A, Watemberg N, Finkelstien S. CHARGE association in a child with de Novo chromosomal aberration 46, X,der(X)t(X;2)(p22.1;q33) detected by spectral karyotyping. J Med Genet. Dec 2000;37(12):E47. [Medline].

  10. Lalani SR, Safiullah AM, Molinari LM, Fernbach SD, Martin DM, Belmont JW. SEMA3E mutation in a patient with CHARGE syndrome. J Med Genet. Jul 2004;41(7):e94. [Medline].

  11. Williams MS. Speculations on the pathogenesis of CHARGE syndrome. Am J Med Genet A. Mar 15 2005;133A(3):318-25. [Medline].

  12. Sanlaville D, Etchevers HC, Gonzales M, et al. Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development. J Med Genet. Mar 2006;43(3):211-317. [Medline].

  13. Issekutz KA, Graham JM Jr, Prasad C, Smith IM, Blake KD. An epidemiological analysis of CHARGE syndrome: preliminary results from a Canadian study. Am J Med Genet A. Mar 15 2005;133A(3):309-17. [Medline].

  14. Kallen K, Robert E, Mastroiacovo P, et al. CHARGE Association in newborns: a registry-based study. Teratology. Dec 1999;60(6):334-43. [Medline].

  15. Blake KD, Russell-Eggitt IM, Morgan DW, Ratcliffe JM, Wyse RK. Who's in CHARGE? Multidisciplinary management of patients with CHARGE association. Arch Dis Child. Feb 1990;65(2):217-23. [Medline].

  16. Tellier AL, Cormier-Daire V, Abadie V, et al. CHARGE syndrome: report of 47 cases and review. Am J Med Genet. Apr 13 1998;76(5):402-9. [Medline].

  17. Jongmans MC, Admiraal RJ, van der Donk KP, et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. Apr 2006;43(4):306-14. [Medline].

  18. Davenport SL, Hefner MA, Mitchell JA. The spectrum of clinical features in CHARGE syndrome. Clin Genet. Apr 1986;29(4):298-310. [Medline].

  19. Lalani SR, Safiullah AM, Fernbach SD, et al. Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation. Am J Hum Genet. Feb 2006;78(2):303-14. [Medline].

  20. Bergman JE, de Wijs I, Jongmans MC, Admiraal RJ, Hoefsloot LH, van Ravenswaaij-Arts CM. Exon copy number alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome. Eur J Med Genet. Sep-Oct 2008;51(5):417-25. [Medline].

  21. Udaka T, Okamoto N, Aramaki M, Torii C, Kosaki R, Hosokai N. An Alu retrotransposition-mediated deletion of CHD7 in a patient with CHARGE syndrome. Am J Med Genet A. Apr 1 2007;143(7):721-6. [Medline].

  22. Monfort S, Roselló M, Orellana C, Oltra S, Blesa D, Kok K, et al. Detection of known and novel genomic rearrangements by array based comparative genomic hybridisation: deletion of ZNF533 and duplication of CHARGE syndrome genes. J Med Genet. Jul 2008;45(7):432-7. [Medline].

  23. Writzl K, Cale CM, Pierce CM, Wilson LC, Hennekam RC. Immunological abnormalities in CHARGE syndrome. Eur J Med Genet. Sep-Oct 2007;50(5):338-45. [Medline].

  24. Gennery AR, Slatter MA, Rice J, Hoefsloot LH, Barge D, McLean-Tooke A, 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. Jul 2008;153(1):75-80. [Medline].

  25. Arndt S, Laszig R, Beck R, et al. Spectrum of Hearing Disorders and Their Management in Children With CHARGE Syndrome. Otol Neurotol. Oct 16 2009;[Medline].

 
Previous
Next
 
Typical ear malformation
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.