CHARGE association is a nonrandom occurrence of con- genital malformations including Coloboma, Heart disease, Atresia of choana, Retarded growth and/or CNS anomalies, Genitourinary defects and/or hypogonadism, and Ear anom- alies and/or deafness. The association was first reported by Hall in 1979 in 17 children with multiple congenital anomalies who were ascertained because of choanal atresia. However, the acronym was coined by Pagon in 1981. The prevalence is esti- mated to be 1 in 10,000.
GENETICS/BASIC DEFECTS
1. Sporadic in most cases
2. Possible polytropic developmental field defect involving neural crest cells or the neural tube itself
3. A possible genetic causation a. Increased paternal age b. Rare familial cases
c. A high concordance rate in monozygotic twins d. A de novo gene mutation
e. Parent-to-child transmission suggesting autosomal dominant inheritance
f. Recurrences among siblings to normal parents sug- gesting possible germ cell line mosaicism
g. Submicroscopic chromosome anomaly
i. Different chromosome anomalies reported in patients with a pattern of malformations reminis- cent of CHARGE association
ii. Recently, de novo overlapping microdeletions were identified in 8q12 in patients with CHARGE syndrome by array-based compara- tive genomic hybridization
4. Sequence analysis of genes residing within 8q12 critical region revealed mutations in the CHD7 gene (a novel member of the chromodomain gene family) in a number of CHARGE patients without microdeletions
CLINICAL FEATURES
1. Major criteria a. Eye anomalies
i. Coloboma (80–90%) of the iris, choroid disc and optic nerve
ii. Microphthalmia/anophthalmia
iii. Secondary retinal detachments and cataracts iv. Total or partial vision loss
v. Superior palpebral ptosis, epicanthus, and tele- canthus
b. Choanal Atresia (50–60%) c. Ear anomalies/deafness (90%)
i. External ears a) Asymmetry b) Posteriorly rotated c) Dystopia
d) Prominent e) Increased width
f) Decreased height g) Cup-shaped
h) ‘Snipped-off’ helical fold
i) Prominent antihelix discontinuous with the antitragus
j) Triangular concha k) Small or absent lobes ii. Middle ears
a) Chronic serous otitis media approaching 100%
b) Eustachian tube anomalies associated with choanal atresia or palatal cleft
c) Ossicular malformations d) Conductive hearing loss iii. Inner ears
a) Cochlear defects
b) Sensorineural hearing loss iv. Temporal bone malformations d. Cranial nerve dysfunction (70–90%)
i. Cranial nerve I: anosmia
ii. Cranial nerve VII: unilateral or bilateral facial palsy
iii. Cranial nerve VIII: sensorineural deafness and vestibular problems
iv. Cranial nerves IX and/or X: velopharyngeal incoordination and swallowing problems 2. Minor criteria
a. Heart disease (cardiovascular malformations) (75–85%) i. Conotruncal defects (e.g., tetralogy of Fallot) ii. AV canal defects
iii. Aortic arch anomalies iv. Others
b. Growth and mental Retardation (70–100%) i. Growth deficiency
ii. Short stature
iii. Delayed motor milestones iv. Hypotonia
v. Mental retardation c. Genital anomaly (70–80%)
i. Males: micropenis, cryptorchidism, delayed/
incomplete pubertal development
ii. Females: hypoplastic labia, delayed/incomplete pubertal development
d. Orofacial cleft
i. Cleft lip/palate (15–20%) ii. Laryngeal cleft
e. Tracheoesophageal fistula/esophageal atresia (15–20%) f. Distinctive face (70–80%)
i. Broad forehead ii. Square face iii. Facial asymmetry 149
CHARGE Association
150 CHARGE ASSOCIATION
iv. Ptosis
v. Arched eyebrows
vi. Shallow supraorbital ridges vii. Iris coloboma
viii. High nasal bridge ix. Full nasal tip
x. Microretrognathia xi. Cleft lip/palate
xii. Laterally protruding ears
xiii. Prognathism, prominent mandibular mentum, and generalized facial narrowing with advancing age xiv. Occasional broad or webbed neck with sloping
shoulders 3. Occasional findings
a. Thymic/parathyroid hypoplasia: DiGeorge sequence without chromosome 22q11 deletion (rare)
b. Renal anomalies (15–25%) i. Dysgenesis
ii. Horseshoe/ectopic kidney iii. Hydronephrosis
c. Hand anomalies
i. Polydactyly, ectrodactyly, thumb hypoplasia (rare)
ii. Altered palmar flexion creases (50%) d. General appearance
i. Webbed neck (rare)
ii. Sloping shoulders (occasional)
iii. Accessory or hypoplastic nipples (rare) e. Abdominal defects
i. Omphalocele (rare) ii. Umbilical hernia (15%) f. Spine anomalies (rare)
i. Scoliosis ii. Hemivertebrae g. CNS malformations
i. Midline defects (corpus callosum agenesis, arhi- nencephaly, septal agenesis, meningoencephalo- cele, partial vermis agenesis) (22%)
ii. Asymmetry (cerebral, ventricular, cerebellar) (18%)
iii. Hindbrain anomalies (brain stem hypotrophy demonstrated by CT scan or MRI, vermian age- nesis) (14%)
DIAGNOSTIC INVESTIGATIONS
1. Audiology, tympanometry, BAER, and CT of temporal bones for evaluation of hearing loss
2. Dilated fundoscopic exam for colobomas
3. Nasal pharyngeal feeding tube passage and CT scan of upper airway for evaluation of choanal atresia
4. Echocardiography for cardiovascular malformations 5. Ultrasound for renal anomalies
6. CT scan and/or MRI for brain malformations
7. Chromosome analysis for associated chromosomal anomalies
8. Molecular genetic analysis for CHD7 gene mutation
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: not increased unless a parent is affected with autosomal dominant disorder
b. Patient’s offspring: not increased unless the patient has an autosomal dominant disorder
2. Prenatal diagnosis
a. Ultrasonography: difficult unless in the pregnancy at risk b. CHD7 gene mutation analysis of fetal cells obtained from CVS and amniocentesis for the family at risk may be available clinically in the near future
3. Management
a. Feeding problems/failure to thrive i. Use of antispasmodics ii. Nissen fundoplication iii. Gastrostomy tube for feeding b. Developmental delay/mental retardation
i. Early infant intervention ii. Special education
c. Respiratory problems: may require tracheostomy for aspiration of secretions
d. Choanal stenosis/atresia
i. Airway stabilization and circulatory support ii. Requires surgical opening for the posterior
choanae by placing stents to keep the nasal pas- sages open if there is obstructed breathing iii. Choanoplasty
e. Congenital heart defects: corrective surgery when indicated
f. Colobomas: requires ophthalmologic care g. External ear anomalies/hearing loss
i. Hearing aids for deafness
ii. Surgery for ear canal and temporal bone abnor- malities
h. Management of other associated anomalies
REFERENCES
Amiel J, Attié-Bitach T, Marianowski R, et al.: Temporal bone anomaly pro- posed as a major criteria for diagnosis of CHARGE syndrome. Am J Med Genet 99:124–127, 2001.
Awrich PD, Flannery DB, Robertson L, et al.: CHARGE association anomalies in siblings [abstract]. Am J Med Genet 34:80A, 1982.
Blake KD, Davenport SL, hall BD, et al.: CHARGE association: an update and review for the primary pediatrician. Clin Pediatr 37:159–173, 1998.
Chestler RJ, France TD: Ocular findings in CHARGE syndrome. Six case reports and a review. Ophthalmology 95:1613–1619, 1988.
Clementi M, Tenconi R, Turolla L, et al.: Apparent CHARGE association and chromosome anomaly: chance or contiguous gene syndrome. Am J Med Genet 41:246–250, 1991.
De Krijger RR, Mooy CM, Van Hemel JO, et al.: CHARGE association-related ocular pathology in a newborn with partial trisomy 19q and partial mono- somy 21q, from a maternal translocation (19;21)(q13.1;q22.3). Pediatr Dev Pathol 2:577–581, 1999.
Dhooge L, Lemmerling M, Lagache M, et al.: Otological manifestations of CHARGE association. Ann Otol Rhinol Laryngol 107(pt 1):935–941, 1998.
Edwards BM, Van Riper LA, Kileny Pr: Clinical manifestations of CHARGE association. Int J Pediatr Otorhinolaryngol 33:23–42, 1995.
Edwards BM, Kileny PR, Van Riper LA: CHARGE syndrome: a window of opportunity for audiologic intervention. Pediatrics 110:119–126, 2002.
Graham JM Jr: A recognizable syndrome within CHARGE association: Hall- Hittner syndrome. Am J Med Genet 99:120–123, 2001.
CHARGE ASSOCIATION 151
Hall BD: Choanal atresia and associated multiple anomalies. J Pediatr 95:395–398, 1979.
Harris J, ‘Robert E, Kallen B: Epidemiology of Choanal atresia with special reference to the CHARGE association. Pediatrics 99:363–367, 1997.
Hittner HM, Hirsch NJ, Kreh GM, et al.: Colobomatous microphthalmia, heart disease, hearing loss, and mental retardation—a syndrome. J Pediatr Ophthalmol Strabismus 16:122–128, 1979.
Hurst JA, Meinecke P, Baraitser M: Balanced t(6;8)(6p8p6q8q) and the CHARGE association. J Med Genet 28:54–55, 1991.
Kaplan LC: Choanal atresia and its associated anomalies. Further support for the CHARGE association. Int J Pediatr Otorhinolaryngol 8:237–242, 1985.
Lubinsky MS: Properties of associations: identity, nature, and clinical criteria, with a commentary on why CHARGE and Goldenhar are not associa- tions. Am J Med Genet 49:21–25, 1994.
Metlay LA, Smythe PS, Miller ME: Familial CHARGE association: clinical report with autopsy findings. Am J Med Genet 26:577–581, 1999.
Mitchell JA, Giangiacomo J, Hefner MA, et al.: Dominant CHARGE associa- tion. Ophthalmol Paediatr Genet 6:271–276, 1985.
Morgan DW, Bailey CM, Phelps P, et al.: Ear-nose-throat abnormalities in the CHARGE association. Arch Otolaryngol Head Neck Surg 119:49–54, 1993.
Murofoshi T, Ouvrier RA, Parker GD, et al.: Vestibular anomalies in CHARGE association. Ann Otol Rhinol Laryngol 106:129–134, 1997.
North KN, Wu BL, Cao BN, et al.: CHARGE association in a child with de novo inverted duplication (14)(q22>q24.3). Am J Med Genet 57:610–614, 1995.
Pagon RA, Graham JM Jr, Zonana J, et al.: Coloboma, congenital heart disease, and Choanal atresia with multiple anomalies: CHARGE association. J Pediatr 99:223–227, 1981.
Russell-Eggitt JM, Blake KD, Taylor DSL, et al.: The eye in CHARGE associ- ation. Br J Ophthalmol 74:421–426, 1990.
Sanlaville D, Romana SP, Lapierre JM, et al.: A CGH study of 27 patients with CHARGE association. Clin Genet 62:135–138, 2002.
Siebert JR, Graham JM, MacDonald C: pathological features of the CHARGE association: support for involvement of the neural crest. Teratology 31:331–336, 1985.
Tellier AL, Lyonnet S, Cormier-Daire V, et al.: Increased paternal age in CHARGE association. Clin Genet 50:548–550, 1996.
Tellier AL, Theopile D, Bonner D, et al.: CHARGE association: report of 47 cases with genotypic analysis of chromosomes 7q36 and 22q11. Am J Hum Genet 59 (suppl):100A, 1996.
Telllier AL, Cormier-Daire V, Abadie V, et al.: CHARGE association: report of 47 cases and review. Am J Med Genet 76:402–409, 1998.
Tellier AL, Amiel J, Delezoide AL, et al.: Expression of the PAX2 gene in human embryos and exclusion in the CHARGE syndrome. Am J Med Genet 93:85–88, 2000.
Thelin JW, Mitchell JA, Hefner MA: CHARGE syndrome: part II. Hearing loss. Int J Pediatr Otorhinolaryngol 12:145–163, 1986.
Vissers LELM, van Ravenswaaij CMA, Admiraal R, et al.: Mutations in a novel member of the chromodomain gene family cause CHARGE syn- drome. American Society of Human Genetics 54th Annual Meeting, Abstract #1, 2004.
Warburg M: Ocular colobomata and multiple congenital anomalies: the CHARGE association. Ophthalmol Paediatr Genet 6:31–36, 1983.
Wiener-Vacher SR, Amanou L, Denixe P, et al.: Vestibular function in children with the CHARGE association. Arch Otolaryngol Head Neck Surg 125:342–347, 1999.
152 CHARGE ASSOCIATION
Fig. 1. A boy with typical CHARGE association at ages 11 (front view) and 15 (lateral view). The patient had bilateral colobomas, choanal atresias, growth and mental retardation, hypogonadism, and ear anomalies with hearing loss.
