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CHARGE Syndrome

CHARGE Association

CHARGE syndrome is characterized by the association of coloboma, heart anomalies, choanal atresia, retardation of growth and development, genital and ear anomalies.


Presentation

Patients with CHARGE syndrome are usually identified in infancy or early childhood when multiple congenital anomalies are found. Many of these defects are diagnosed in the neo-natal period and require immediate surgical intervention because they are life-threatening. Congenital heart defects occur in 75 to 80% of patients [2].

Most individuals with CHARGE syndrome have distinctive facial features. These may include [9] [11]:

  • a square-shaped face
  • facial asymmetry, a difference in the appearance between the right and left sides of the face
  • low-set and abnormal appearing ears
  • antimongoloid slant of the eyes
  • anteverted nares [11]

The occurrence of one or more of the major features increases the suspicion of CHARGE syndrome. Patients with one of the major abnormalities should be evaluated for all the other major and minor anomalies [10] [11].

Major Criteria (Frequency (%))

Minor Criteria (Frequency (%))

In older individuals, bilateral posterior choanal atresia is predictive of the presence of the other three major criteria and of aortic arch anomalies.

Children with CHARGE may develop behavioral difficulties. These have been described as autistic-like and obsessive-compulsive. Attention deficit disorders and tic disorders may also be present [12]. Multi-sensory impairments, communication frustrations, and physical pain all have been blamed in the behavior disorders.

Dutch
  • Twenty-seven Dutch and 19 Australian patients (aged 16 months-18 years) with genetically confirmed CHARGE syndrome were included. The low-dose adrenocorticotropin (ACTH) test was used to assess CAI in the Dutch cohort.[ncbi.nlm.nih.gov]
  • Information and advice for physicians, general practitioners and dentists " These are now available in English here (translation of 2011 Dutch guidelines). CHARGE syndrome (OMIM 214800) is a variable multiple congenital anomaly syndrome.[rug.nl]
  • Additional medical information was extracted from the patient files and the database of the Dutch Expertise Centre for CHARGE syndrome.[journals.plos.org]
  • Johnson [ 37 ] have also associated CHD7 mutations with CHARGE association by mapping a balanced chromosome translocation in affected monozygotic twins, thus confirming the earlier findings of the Dutch team.[ncbi.nlm.nih.gov]
Cyanotic Congenital Heart Disease
  • 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.[emedicine.medscape.com]
Alopecia
  • Severe immunodeficiency with CHARGE syndrome has been noted only rarely Omenn syndrome is a rare autosomal recessive form of SCID with erythroderma, hepatosplenomegaly, lymphadenopathy and alopecia.[ncbi.nlm.nih.gov]
Antimongoloid Slant
  • These may include: a square-shaped face facial asymmetry, a difference in the appearance between the right and left sides of the face low-set and abnormal appearing ears antimongoloid slant of the eyes anteverted nares The occurrence of one or more of[symptoma.com]
Low Set Ears
  • Ear abnormalities and deafness – most children with CHARGE syndrome have some level of hearing impairment, varying from mild to profound, along with underdeveloped or low-set ears.[gosh.nhs.uk]
  • The most common external ear anomalies include low-set ears, asymmetric ears, or small or absent ear lobes. The degree of hearing loss varies from mild to severe.[encyclopedia.com]
Psychomotor Retardation
  • In this report, we describe a patient with a typical phenotype characterized by psychomotor retardation, hypertrichosis, facial asymmetry, synophria, failure to thrive, developmental delay and gastro-esophageal reflux, carrying a de novo 6.04Mb interstitial[ncbi.nlm.nih.gov]
Cryptorchidism
  • This boy was known to have CHARGE syndrome with multiple congenital anomalies, including coloboma, ventricular septal defect, choanal atresia, growth and mental retardation, bilateral cryptorchidism, dysplasia of the right ear, cleft lip, and hydrocephalus[ncbi.nlm.nih.gov]
  • The patient showed several phenotypic features of the syndrome, associated with a prepubertal state and cryptorchidism; hypogonadotrophic hypogonadism with undetectable testosterone levels not responsive to hCG testing and severe osteoporosis were ascertained[ncbi.nlm.nih.gov]
  • […] of these cases showed ossicle anomalies and four patients had downward displacement of the facial nerve (FN) toward the promontory; five patients showed delayed development; four of these children had cardiovascular malformations; three patients had cryptorchidism[ncbi.nlm.nih.gov]
  • […] eart defects (typically tetralogy of Fallot, patent ductus arteriosus, or ventricular or atrial septal defect), a tresia of the choanae, r enal anomalies and retardation of growth and/or development, g enital anomalies in males such as small penis or cryptorchidism[medical-dictionary.thefreedictionary.com]
  • […] ossicular chain malformation Mondini malformation absent/hypoplastic semicircular canals Minor criteria urogenital abnormalities kidney duplex kidney renal hypoplasia / solitary kidney penis hypospadias penile agenesis scrotum/testicles bifid scrotum cryptorchidism[radiopaedia.org]
Microphallus
  • Abnormalities of genitalia in males include an underdeveloped penis (micropenis or microphallus) and testicles that fail to descend to the scrotum (cryptorchidism). In females, there may be overgrowth or underdevelopment of the labia or clitoris.[encyclopedia.com]
  • Microphallus, penile agenesis, hypospadias, chordee, cryptorchidism, bifid scrotum, atresia of uterus, cervix and vagina, hypoplastic labia and clitoris are reported genital anomalies in this syndrome.[ncbi.nlm.nih.gov]

Workup

In 2004, the CHD7 gene mutation on Chromosome 8 was found to be responsible for CHARGE syndrome in 60-67% of cases [3] [6]. Though genetic testing is helpful in identifying individuals with the disorder, it is not conclusive. The cost of the test may be prohibitive. Therefore, the diagnosis of the disorder is usually made by the clinical finding of the major and minor features of the disorder.

Further workup depends on the presenting anomalies. All patients suspected of having CHARGE syndrome should be evaluated for all the major and minor features of the disorder. Referral should be made to appropriate specialists, when abnormalities are found. Further workup will follow as needed.

Early identification of abnormalities and intervention is imparative to the management , treatment, and prevention of morbidity and mortality in individuals with CHARGE syndrome.

Treatment

Children with CHARGE syndrome require intensive medical management as well as numerous surgical interventions. They also need multidisciplinary follow up. Specific treatment depends on the associated anomalies. Early identification of oral, nasal, ophthalmic, and cardiac abnormalities and immediate intervention are essential for the best prognosis and physical and developmental outcomes.

One significant issue in all patients with CHARGE is the feeding adaptations needed by these children. This issue requires early aggressive intervention to prevent growth retardation and respiratory complications [11].

Behavior problems have become more common in individuals with CHAGE and require special educational and physical/developmental therapeutic services [4] [6].

Early interventions, such as occupational and physical therapy, are very important to decrease the possibility of developmental delay. Management should be by a multidisciplinary team, [13] as these children can thrive with the support of a team of medical professionals.

Prognosis

Prognosis for individuals with CHARGE syndrome is dependent on the type and severity of the anomalies involved. Early infancy mortality rates are 10% to 20%.

Survival rates have improved with new cardiac treatments [11]. For those who survive through early childhood, life expectancy is usually normal [7]. Infants with bilateral choanal atresia, cardiac defects and renal malformations have a high mortality rate [7].

Feeding difficulties are a major cause of morbidity for individuals of all ages. Among individuals who die in later childhood and adulthood, gastro-esophageal reflux was present in 100% of the cases and pneumonia the most common cause of death [7].

Etiology

CHARGE syndrome is identified solely on the presence of the major anomalies occurring together. Recently mutations in the CHD7 gene have been identified in individuals with CHARGE syndrome [3] [4]. However, the gene is found in only 60% of patients with the disorder.

CHARGE syndrome results from a mutation or deletion of the CHD7 gene on Chromosome 8 [3] [4]. CHARGE syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene from one parent is sufficient to cause the disorder. However most cases seem to result from new mutations in the CHD7 gene, where neither parent has the abnormal gene. The disorder, therefore, occurs in families with no history of the disorder [5].

Since, one-third of individuals with CHARGE syndrome do not have an identified mutation in the CHD7 gene, researchers suspect there are other genetic and environmental factors that may be involved in these individuals [6].

Epidemiology

The reported incidence of CHARGE syndrome is approximately 0.1 per 10,000 live births [1] [2]. Incidence does not appear to be influenced by race, gender, or ethnicity.

There is a very small increased incidence in families with disease and in monozygotic twins. This supports a genetic origin [3].
There is a slightly higher mean paternal age at conception for infants born with the disorder. No other environmental or social factors have been found.

Sex distribution
Age distribution

Pathophysiology

All the abnormalities associated with CHARGE syndrome are due to embryotic defects in craniofacial structures. The structures involved all are formed in the second month of gestation. This is a formative stage in the development of these organs [7].

Mutations in the CHD7 gene produce an abnormally short, nonfunctional CHD7 protein. This abnormal protein results in the physical anomalies of CHARGE syndrome [3] as it causes generalized disruption of the interaction of mesenchymal–epithelium (mesenchyme, mesoderm, and ectoderm and endoderm) [8].

The major anomalies related to CHARGE syndrome are:
Coloboma refers to a key-hole shaped defect in one of the structures of the eye: iris, retina, choroid, or optic disc. People with coloboma may have no vision problems or may be blind, depending on the affected structures and severity [2] [9] [10] [11].
Heart defects, most commonly Tetrology of Fallot, Patent Ductus Arteriosus, and Ventral Septal Defects, all of which involve the cardiac endothelium [2].

Choanal atresia is the blockage of the back of the nasal passage (choana) by abnormal bony or soft tissue (membranous). It can be unilateral or bilateral [2].

Retardation of development is primarily due to sensorimotor distruptions related to abnormalities of the eyes, ears, and cranial nerves [1] [11].

Genital abnormalities, delayed sexual development, and growth retardation can be attributed to altered pituitary gland function [2] [9].

Ear anomalies occur in the external, middle, and inner ear. The most common ear anomaly is the abnormal appearance of bowl-shaped and concave ears, known as "lop ears" [9] [10]. Abnormalities of the middle and inner ear commonly cause deafness. Inner ear abnormalities may cause defects in balance and motor skills.

Prevention

There are no guidelines for prevention of CHARGE syndrome.

Summary

CHARGE syndrome is an autosomal dominant genetic disorder which is associated with multiple congenital anomalies.

CHARGE is an acronym for the most common features of the disorder: Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genital defects, and Ear abnormalities [1].

Various combinations of the anomalies may be present and may occur to varying degrees. No single feature is always present. Clinical diagnosis of CHARGE syndrome requires the presence of four of the major defect, or three major features and one minor characteristic [2].

Patient Information

What is CHARGE syndrome?

CHARGE syndrome is a rare genetic disorder that causes one or more birth defects. A birth defect is a health condition that is present at birth and may change the shape or function of one or more parts of the body.

The defects in CHARGE syndrome develop during early fetal development and affect multiple body systems. They can cause significant health problems, body development, or in how the body works.

The term CHARGE comes from the first letter of some of the more common defects seen in these children:
(C) = coloboma (a hole in a part of the eye) and/or cranial nerve defects, (80%)
(H) = heart defects, (75-85%)
(A) = atresia of the choanae, blocked nasal/breathing passages (50-60%)
(R) = retardation of growth and development (70-80%)
(G) = genital underdevelopment, delayed sexual development (38%)
(E) = ear abnormalities and hearing loss (62-90%)

What causes CHARGE syndrome?

The cause of CHARGE is usually a mutation (change) in the CHD7gene on Chromosome 8. Most cases result from a new mutation occurring in people with no history of the disorder in their family. This disorder does not appear to be passed down from parent to child.

How is Charge syndrome diagnosed?

Diagnosis of CHARGE syndrome is based on the presence of three or more of the major abnormalities identified by its name. Most children with CHARGE syndrome also have characteristic facial features that include:

  • a square-shaped face
  • facial asymmetry, a difference in the appearance of the right and left sides of the face
  • low-set and oddly formed ears
  • slanted eyes
  • outward flaring nostrils

What does a diagnosis of CHARGE syndrome mean for a child?

The symptoms of CHARGE syndrome vary greatly from child to child. The prognosis and amount of disability depends entirely on the defects involved. Children with heart, oral, and renal defects may need immediate surgery to correct defects that are life threatening.

Early diagnosis, treatment, and intervention are very important for every child diagnosed with CHARGE syndrome. Development of an individual plan of care, for the individual child is essential to assure the best prognosis and optimum health and development for the child.

Many children with CHARGE syndrome have hearing and vision problems. These children will require specialized educational programs. The incidence of cognitive delays in children with CHARGE syndrome is probably 50% or less. Some children with CHARGE syndrome have specific learning disabilities and behavioral problems. Many adults with CHARGE syndrome live independently and develop normal intelligence.

Behavior problems are common in children with CHARGE syndrome. These may be due largely to vision and hearing losses, difficulties with communication, and delayed motor skills. Early intervention with these deficiencies may be helpful in preventing and controlling the behaviors.

How is CHARGE syndrome treated?

Treatment for CHARGE syndrome depends on the specific anomalies involved. Identification in the new-born period is essential to address life-threatening disorders. Children with CHARGE derive the greatest benefit from early intervention and specialized educational programs that address hearing and vision deficits, movement, and sensorimotor interventions.

What does a parent of a child with CHARGE syndrome need to do?

A parent of a child with CHARGE syndrome should take a role in planning for your child’s care. They should ask question of all the healthcare professionals involved, request referral to specialists, and insist on speech and hearing evaluations as early as possible.

In order to ensure an educational program that will allows the child to reach his or her full potential parents need to take on the role of advocate. Children with CHARGE syndrome vary greatly in their abilities in the classroom. Some may need very little support, while others require full-time support and individualized programs.

References

Article

  1. Pagon RA, Graham JM, Zonana J, Young SL. 1981. Coloboma, congenital heart disease and choanal atresia with multiple anomalies: CHARGE association. J Pediatr 99: 223–227.
  2. Blake KD, Davenport SLH, Hall BD, Hefner MA, Pagon RA, Williams MS, Lin AE, Graham JM Jr. 1998. CHARGE association: An update and review for the primary pediatrician. Clin Pediatr 37: 159–174.
  3. Lalani SR, Safiullah AM, Fernbach SD, 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.
  4. 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.
  5. Zentner GE, Layman WS, Martin DM, Scacheri PC. Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome. Am J Med Genet A. Mar 2010;152A(3):674-86.
  6. Vissers LELM, van Ravenswaaij CMA, Admiraal R, Hurst JA, de Vries BBA, Janssen IM, van der Vliet XX, Huys EHLPG, de Jong PJ, Hamel BCJ, Schoenmakers EFPM, Brunner HG, Veltman JA, van Kessel AG. 2004. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 36: 955–957.
  7. Issekutz KA, Graham JM, Prasad C, Smith IM, Blake KD. An epidemiological analysis of CHARGE syndrome: Preliminary results from a Canadian study. Am. J. Med. Genet. 2005, 133A: 309–317. doi: 10.1002/ajmg.a.30560
  8. Williams MS. Speculations on the pathogenesis of CHARGE syndrome. Am. J. Med. Genet., 133A: 318–325.
  9. Searle LC, Graham JM, Prasad C, Blake KD. CHARGE syndrome from birth to adulthood: An individual reported on from 0 to 33 years. Am. J. Med. Genet. 2005, 133A: 344–349.
  10. Blake KD, Prasad C. CHARGE syndrome. Orphanet journal of rare diseases 1: 34. Sep 7, 2006.
  11. Thelin JW, Swanson LA. CHARGE Syndrome: multiple congenital anomalies including disorders of all senses and speech, language, feeding, swallowing, and behavior. The ASHA Leader, 11(14), 6-7. (2006, Oct. 17).
  12. Smith IM, Nichols SL, Issekutz K, Blake K. Behavioral profiles and symptoms of autism in CHARGE syndrome: Preliminary Canadian epidemiological data. Am. J. Med. Genet. 2005, 133A: 248–256. doi: 10.1002/ajmg.a.30544
  13. Hefner MA,  Davenport SLH. CHARGE syndrome: A management manual for parents, Version 2.1 2002. Columbia, MO: CHARGE Syndrome Foundation

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Last updated: 2018-06-22 09:44