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CHARGE Syndrome

, MD, , MS, , MD, PhD, and , MD, CM.

Author Information
, MD
Assistant Professor, Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas
, MS
Genetic Counselor and Clinical Associate Professor, Department of Pediatrics
Saint Louis University School of Medicine
Saint Louis, Missouri
, MD, PhD
Professor, Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas
, MD, CM
Sensory Genetics/Neurodevelopment
Bloomington, Minnesota

Initial Posting: ; Last Update: February 2, 2012.

Summary

Disease characteristics. CHARGE is a mnemonic for coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies. CHARGE syndrome is characterized by the following:

  • Unilateral or bilateral coloboma of the iris, retina-choroid, and/or disc with or without microphthalmos (80%-90% of individuals)
  • Unilateral or bilateral choanal atresia or stenosis (50%-60%)
  • Cranial nerve dysfunction resulting in hyposmia or anosmia, unilateral or bilateral facial palsy (40%), impaired hearing, and/or swallowing problems (70%-90%)
  • Abnormal outer ears, ossicular malformations, Mondini defect of the cochlea and absent or hypoplastic semicircular canals (>90%)
  • Cryptorchidism in males and hypogonadotrophic hypogonadism in both males and females
  • Developmental delay
  • Cardiovascular malformations (75%-85%)
  • Growth deficiency (70%-80%)
  • Orofacial clefts (15%-20%)
  • Tracheoesophageal fistula (15%-20%)

Neonates with CHARGE syndrome often have multiple life-threatening medical conditions. Feeding difficulties are a major cause of morbidity in all age groups.

Diagnosis/testing. The diagnosis of CHARGE syndrome is based on clinical findings and temporal bone imaging. CHD7, encoding the chromodomain helicase DNA binding protein, is the only gene currently known to be associated with CHARGE syndrome. Sequence analysis of the CHD7 coding region detects mutations in most individuals with typical CHARGE syndrome (i.e., having the four major characteristics or three major and three minor characteristics). Overall, CHD7 analysis in individuals with either typical CHARGE syndrome or a milder phenotype (i.e., fewer major characteristics) detects mutations in about 65%-70% of cases.

Management. Treatment of manifestations: Neonates require immediate evaluation of the airway, feeding, heart, and hearing. Management involves: tracheostomy and surgical correction of choanal atresia as needed; a multidisciplinary approach to feeding therapy including specialists in speech-language pathology, occupational therapy, and nutrition and gastrostomy as needed; routine care for heart defects; and hearing aids and hearing habilitation as soon as hearing loss is documented. Psychological/school evaluations should be performed by a team that includes specialists in deaf/blindness when dual sensory loss is present.

Prevention of secondary complications: Special attention to potential airway problems associated with anesthesia.

Surveillance: Regular ophthalmologic and audiologic evaluations; testing for hypogonadotropic hypogonadism if puberty has not occurred by age 13-14 years.

Genetic counseling. CHARGE syndrome, caused by mutation of CHD7, is inherited in an autosomal dominant manner. Most individuals diagnosed with CHARGE syndrome represent simplex cases (i.e., a single occurrence in a family). If a parent of the proband has CHARGE syndrome or has a CHD7 mutation, the risk to the sibs of inheriting the mutation is 50%. If neither parent is affected, the empiric risk to sibs of a proband is approximately 1%-2%, most likely attributable to germline mosaicism. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing CHD7 mutation has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

Diagnostic criteria for CHARGE syndrome, a multiple malformation syndrome, are based on a combination of major and minor diagnostic characteristics. (CHARGE stands for coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies.)

As described by Blake et al [1998], and modified by Amiel et al [2001] and Verloes [2005], the major diagnostic characteristics of CHARGE syndrome are the following:

  • Definite CHARGE syndrome. Individuals with all four major characteristics (Table 1) or three major and three minor characteristics (Table 2)
  • Probable/possible CHARGE syndrome. Individuals with one or two major characteristics and several minor characteristics

Major characteristics are those that are common in CHARGE syndrome and relatively uncommon in other syndromes (see Table 1).

Table 1. Major Diagnostic Characteristics of CHARGE Syndrome

CharacteristicsManifestationsFrequency
Ocular colobomaColoboma of the iris, retina, choroid, disc; microphthalmos80%-90%
Choanal atresia or stenosis 1, 2Unilateral/bilateral: bony or membranous atresia/stenosis50%-60%
Cranial nerve dysfunction or anomalyI: hyposmia or anosmiaFrequent
VII: facial palsy (unilateral or bilateral)>40%
VIII: hypoplasia of auditory nerveFrequent
IX/X: swallowing problems with aspiration70%-90%
Characteristic CHARGE syndrome earOuter ear: short, wide ear with little or no lobe, "snipped off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (see Figure 13 80%-100%
Middle ear: ossicular malformations 4
Mondini defect of the cochlea 5
Temporal bone abnormalities; absent or hypoplastic semicircular canals 5

1. Cleft palate may substitute for this characteristic in some individuals.

2. The diagnosis is confirmed by non-enhanced CT scan in axial sections.

3. Davenport et al [1986b]

4. The combination of ossicular malformations and inner ear defects can result in a mixed (conductive and sensorineural) hearing loss with a wedge-shaped audiogram.

5. Most commonly determined by CT of the temporal bones

Minor characteristics are common in CHARGE syndrome but are either less specific to CHARGE syndrome (e.g., heart defects), more difficult to evaluate consistently (e.g., characteristic CHARGE syndrome face), or not readily apparent in infancy (see Table 2).

Table 2. Minor Diagnostic Characteristics of CHARGE Syndrome

CharacteristicsManifestationsFrequency
Genital hypoplasiaMales: micropenis, cryptorchidism
Females: hypoplastic labia
50%-60%
Males and females: delayed puberty secondary to hypogonadotropic hypogonadismFrequent
Developmental delay 1Delayed milestones, hypotonia≤100%
Cardiovascular malformationIncluding conotruncal defects (e.g., tetralogy of Fallot), AV canal defects, and aortic arch anomalies75%-85%
Growth deficiencyShort stature, usually postnatal with or without growth hormone deficiency70%-80%
Orofacial cleftCleft lip and/or palate15%-20%
Tracheoesophageal (TE) fistulaTE defects of all types15%-20%
Distinctive facial featuresSquare face with broad prominent forehead, prominent nasal bridge and columella, flat midface (see Figure 2270%-80%

1. May be primarily the result of illness, dual sensory impairment, and vestibular dysfunction

2. Davenport et al [1986a]

Occasional findings include the following:

  • DiGeorge sequence
  • Omphalocele or umbilical hernia
  • Bony scoliosis or hemivertebrae
  • Renal anomalies including dysgenesis, horseshoe/ectopic kidney
  • Hand anomalies including polydactyly, altered palmar flexion creases (see Figure 3), atypical split hand/split foot deformity
  • Additional features including short webbed neck, sloping shoulders, and nipple anomalies
Figure 3

Figure

Figure 3. Typical CHARGE hand: square hand, short fingers, finger-like thumb, hockey-stick palmar crease

Testing

Cytogenetic analysis. The majority of individuals with CHARGE syndrome have a normal karyotype; on rare occasions, variable chromosomal abnormalities are seen. The following chromosome abnormalities that disrupt CHD7 (locus 8q12) have been reported:

Molecular Genetic Testing

Gene. CHD7, encoding the chromodomain helicase DNA-binding protein, is the only gene in which mutations are known to cause CHARGE syndrome [Vissers et al 2004].

Clinical testing

Table 3. Summary of Molecular Genetic Testing Used in CHARGE Syndrome

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
CHD7Sequence analysisSequence variants 2>90% in typical cases fulfilling Blake’s diagnostic criteria 4
65%-70% for all typical and suspected cases combined 5
Deletion / duplication testing 3Large contiguous-gene deletions; exonic or whole-gene deletionsRare 6

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.

4. Bergman et al [2011]

5. Jongmans et al [2006], Aramaki et al [2006], Zentner et al [2010]

6. Aramaki et al [2006], Vuorela et al [2007]. In 54 individuals in whom no CHD7 mutation was identified by sequence analysis, Bergman et al [2008] found CHD7 exon deletions in 1.9% (1/54).

Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at www.eurogentest.org [Blake et al 2011; see full text].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

  • The diagnosis is primarily established by clinical findings.
  • Molecular testing for CHD7 confirms the diagnosis in the majority of cases.
  • Array CGH study can be considered to exclude 22q11.2 deletion and other cytogenetic abnormalities, with associated phenotype overlapping with CHARGE syndrome.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Morbidity and mortality. Neonates with CHARGE syndrome often have multiple life-threatening medical conditions. Blake et al [1990] reported poor survival if one or more of the following were present: cyanotic cardiac lesions, bilateral posterior choanal atresia, and tracheoesophageal fistula. In another study, poor life expectancy correlated with male gender, central nervous system (CNS) malformation, bilateral choanal atresia, and tracheoesophageal fistula [Tellier et al 1998]. Issekutz et al [2005] reported high mortality in infants with atrioventricular septal defects and in infants with a combination of ventriculomegaly and brain stem/cerebellar anomalies (13%). Feeding difficulties were also found to be a major cause of morbidity at all ages.

Choanal atresia. At birth, bilateral choanal atresia causes respiratory distress requiring immediate resuscitation. Unilateral choanal atresia may go undiagnosed until the child presents with persistent unilateral rhinorrhea.

Heart defects are present in 75%-85% of individuals with CHARGE syndrome and are often complex. Many types of heart defects occur; conotruncal anomalies (tetralogy of Fallot, interrupted aortic arch, perimembranous ventricular septal defect, double-outlet right ventricle, and truncus arteriosus), AV canal defects, and aortic arch anomalies (vascular ring, aberrant subclavian artery) are described frequently. Other common structural defects include ASD, VSD, and PDA.

Esophageal atresia or tracheoesophageal fistula occurs in approximately 15%-20% of infants with CHARGE syndrome and can further exacerbate feeding difficulties and respiratory distress in the first few days of life. Preoperatively, the greatest risk to the infant is aspiration. Early diagnosis with appropriate clinical management greatly improves survival.

Swallowing problems. Feeding can be associated with coughing, choking, nasal regurgitation, aspiration, and/or gastroesophageal reflux [Dobbelsteyn et al 2005]. Aspiration and swallowing dysfunction are common in children with CHARGE syndrome and are primarily the result of cranial nerve IX/X abnormalities often complicated by choanal atresia or cleft palate.

Flexible endoscopic evaluation of swallowing (FEES) and/or video swallow study (VSS) often show pooling, premature spillage, poor hypopharyngeal motility, or laryngeal penetration [White et al 2005]. A large number of children require nasogastric or gastric (G-tube) feeding, often for several years. Swallowing may eventually improve spontaneously; however, some adults continue to avoid foods that are difficult to swallow.

Gastroesophageal reflux is common.

Airway problems are primarily the result of a structural defect such as choanal atresia but can also be secondary to aspiration of gastric contents caused by swallowing incoordination and gastroesophageal reflux. Without interventions such as Nissen fundoplication and gastrostomy and tracheostomy, recurrent pneumonia and long-term lung damage can result.

Facial palsy. Unilateral or bilateral facial palsy is present in almost 50% of individuals with CHARGE syndrome. Bilateral facial palsy results in lack of facial expression, which may hinder interpersonal communication.

Colobomata are found in one or both eyes in 80%-90% of individuals with CHARGE syndrome. Asymmetry in the size and extent of involvement of the eyes is frequent. Iris colobomas do not interfere with vision but may predispose to light sensitivity. A uveo-retinal coloboma commonly extends posteriorly to the optic nerve, which may be severely dysplastic and reduce vision. The macula may be involved, most commonly in eyes that are moderately to severely microphthalmic, further compromising vision. Any uveo-retinal coloboma increases the risk of retinal detachment because of the thin marginal adhesion to the edge of the retinal pigment epithelium.

Hearing loss is one of the most common features of CHARGE syndrome. Hearing loss can vary from mild to profound (see Hereditary Hearing Loss and Deafness Overview). The hearing loss can be difficult to quantify, requiring multiple brain stem audio evoked response (BAER) tests over several months. Thelin et al [1986] reported a characteristic wedge-shaped audiometric pattern of mixed hearing loss and verified that hearing loss is progressive in some individuals [Thelin & Fussner 2005]. The presence of facial paralysis was found to predict reliably the presence of sensorineural hearing loss [Edwards et al 2002].

The sensorineural component of the hearing loss is often associated with a Mondini malformation of the cochlea. Hypoplasia of the auditory nerve has also been described.

The conductive component of the hearing loss may result from malformed or absent ossicles, fixation of the ossicular chain to the wall of the tympanic cavity, absence of the stapedius muscle, absence of the oval window, and obliteration of the round window [Dhooge et al 1998, Morimoto et al 2006]. The conductive component may fluctuate with middle ear disease.

Chronic recurrent otitis media is common.

Vestibular abnormalities. With appropriate imaging, abnormalities of the semicircular canals are found in as many as 95% of affected individuals [Lemmerling et al 1998, Tellier et al 1998, Wiener-Vacher et al 1999, Abadie et al 2000, Bauer et al 2002, Morimoto et al 2006].

Absence or hypoplasia of the semicircular canals impairs balance, especially when combined with visual loss. The resulting poor balance contributes to delays in motor development.

Genitourinary abnormalities. Approximately 50%-60% of males have genital hypoplasia manifesting as micropenis and cryptorchidism. Wheeler et al [2000] suggested that central hypogonadism is responsible not only for the genital hypoplasia in males, but also for the lack of secondary sexual development in both males and females. Hypogonadotropic hypogonadism, evidenced by lack of pubertal development and/or abnormally low serum concentrations of LH and FSH, was reported in all nine individuals in this study.

Renal anomalies, including solitary kidney, hydronephrosis, and renal hypoplasia, occur in approximately 25%-40% of children with CHARGE syndrome [Blake et al 1998, Ragan et al 1999].

Growth retardation. Children with CHARGE syndrome usually have normal birth weight and birth length. By late infancy, linear growth usually declines from the normal curve.

In a study of 25 children with normal nutritional status age five years and older, Pinto et al [2005] reported normal growth hormone (GH) secretion in 22 and GH deficiency in three. The three with GH deficiency had height more than 3 SD below the mean, growth rate less than 4 cm/year, insufficient response to two GH stimulation tests, and IGF-I levels greater than 2 SD below the mean for age and pubertal stage.

Immunodeficiency. DiGeorge sequence can be occasionally seen in CHARGE syndrome, resulting in mild to severe T-cell deficiency [Writzl et al 2007].

Limb/bone abnormalities. Limb abnormalities are observed in more than one third of individuals with CHARGE syndrome [Brock et al 2003]. Although no consistent pattern is observed, the more commonly reported anomalies include hypoplastic nails, clinodactyly (fifth finger, second toe), polydactyly, contractures, brachydactyly, missing digits, club foot, tibial anomalies, and joint hyperflexibility. Hip dislocation, missing ribs, and abnormal vertebrae have also been described.

Scoliosis is common [Doyle & Blake 2005]. During childhood, it is often neuromuscular in origin.

Dental anomalies include protruding jaw, overbite, hypodontia of permanent dentition, and poor mineralization of the enamel [Stromland et al 2005].

Sinusitis may be a major problem in childhood and in older children is often caused by “silent” gastroesophageal reflux. Sinusitis is a frequent cause of severe pain, often manifested by sudden changes in behavior, including apparently aggressive behaviors.

Brain abnormalities. Reported central nervous system anomalies include arrhinencephaly, corpus callosum agenesis and posterior fossa anomalies [Tellier et al 1998]. Anomalies of the olfactory tracts and bulbs varying from moderate hypoplasia to complete aplasia causing olfactory deficiency have been reported in numerous studies [Chalouhi et al 2005, Pinto et al 2005].

The course of the facial nerve is often anomalous [Morimoto et al 2006].

Developmental delay. Children with CHARGE syndrome usually show marked delays in motor development. Prolonged hospitalization, truncal hypotonia with ligamentous laxity, decreased visual acuity, hearing impairment, and vestibular disturbance all contribute to this delay. Many infants show poor head control and often move using a combat crawl, pushing with their feet in the supine position or by using a five-point crawl (using the head for additional support). When walking is initiated, gait is often unsteady.

In one report, mean age for head holding was five months, sitting independently 14.8 months, and walking unaided 33 months [Tellier et al 1998].

Speech/language delay. Language development is often delayed because of hearing loss and further exacerbated by reduced vision that impairs lip reading and perception of body language cues.

Cognitive development and psychological assessment. Delayed motor and/or language development cannot be used to predict cognitive potential of affected individuals [Raqbi et al 2003, Brown 2005, Hartshorne et al 2005b].

Assessment of cognitive abilities is difficult because of lack of standardized tools to evaluate individuals with both visual and hearing impairment. Raqbi et al [2003] showed that the intellectual performance of individuals with CHARGE syndrome ranged from major learning disability with no speech and poor communication to almost normal. They demonstrated that despite marked delay in motor milestones in children ages birth to three years, intellectual outcome in 50% was satisfactory. Only 25% of the studied group had a poor intellectual outcome. Raqbi et al [2003] also showed that microcephaly, brain malformation, and extensive bilateral coloboma resulting in reduced vision were the only findings predictive of poor intellectual outcome. The results suggest that for approximately half of children with CHARGE syndrome, motor and speech/language delay is mainly secondary to multiple sensory deficits and not to CNS dysfunction.

Salem-Hartshorne & Jacob [2005] showed that the range of adaptive behavior scores (ABES) in individuals with CHARGE syndrome is broader and higher than previously reported. Those children with better walking skills and fewer medical problems scored higher on this scale than children with poorer walking skills and more medical problems. In this study, one half of the individuals obtained a standard score higher than 70 on the ABES at follow-up. Thirteen percent scored above a standard score of 90.

Many adults with CHARGE syndrome are known to live independently and many are currently attending college, or are college graduates with advanced degrees [Hartshorne et al 2005b; Hefner & Davenport, personal observations].

Behavioral profile includes repetitive, obsessive-compulsive, aggressive, and self-abusive behaviors [Bernstein & Denno 2005, Hartshorne et al 2005a, Hartshorne et al 2005b, Smith et al 2005]. Attention-deficit hyperactivity disorder (ADHD) is also seen in many individuals with CHARGE syndrome [Hartshorne & Cypher 2004]. Many behaviors regarded as aberrant or disruptive are attempts at communication about pain, unease, or frustration [Brown 2005, Salem-Hartshorne & Jacob 2005].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations exist [Jongmans et al 2006, Lalani et al 2006, Sanlaville et al 2006].

Most individuals with the combination of coloboma, choanal atresia, and hypoplastic semicircular canals (three major signs identified by Verloes [2005]) have mutations in CHD7 [Lalani et al 2006, Jongmans et al 2006].

Penetrance

To date, penetrance in those with CHD7 mutations is 100%; i.e., all individuals who are heterozygous for a CHD7 mutation have some features of CHARGE syndrome.

Nomenclature

For individuals who fit the diagnostic criteria for CHARGE syndrome or have CHD7 mutations, “CHARGE association” is not an appropriate term.

Although the earliest descriptions of what is now known as CHARGE syndrome were published by Hall and Hittner, the term “Hall-Hittner syndrome” has not been a common designation for this syndrome.

Prevalence

CHARGE syndrome occurs in at least one in 10,000 births. Issekutz et al [2005] suggest occurrence in one in 8,500 births.

No teratogen or exposure is known to increase the risk for CHARGE syndrome.

Differential Diagnosis

The 22q11.2 deletion syndrome (del 22q11.2) is characterized by congenital heart disease, particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch type IB, perimembranous ventricular septal defect, double outlet right ventricle, and truncus arteriosus); palatal abnormalities, particularly velopharyngeal incompetence (VPI), submucosal cleft palate, and cleft palate; characteristic facial features; and learning difficulties. Additional findings include immune deficiency, hypocalcemia, significant feeding problems, renal anomalies, hearing loss (both conductive and sensorineural), laryngotracheoesophageal anomalies, growth hormone deficiency, autoimmune disorders, seizures (without hypocalcemia), and skeletal abnormalities. The 22q11.2 deletion syndrome is diagnosed in individuals with a submicroscopic deletion of chromosome 22 detected by fluorescence in situ hybridization (FISH) using DNA probes from the DiGeorge chromosomal region (DGCR).

Several clinical features of 22q11.2 deletion syndrome overlap with CHARGE syndrome; however, the facial features seen in these disorders are distinct. Abnormalities of the semicircular canals that are common in CHARGE syndrome are rarely seen in 22q11.2 deletion syndrome. Feeding difficulties typically last longer in children with CHARGE syndrome than 22q11.2 deletion syndrome.

Kallmann syndrome. Although mutations in CHD7 have been reported in individuals with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia or hyposmia), these individuals have additional features characteristic of CHARGE syndrome and thus, CHARGE syndrome is the most appropriate diagnosis for such individuals [Jongmans et al 2008].

VACTERL association is a combination of vertebral anomalies, anal atresia, cardiac anomalies, tracheoesophageal fistula or esophageal atresia, and renal and limb anomalies. VACTERL association generally differs from CHARGE syndrome by the absence of colobomas, choanal atresia, characteristic ear deformity, and cranial nerve anomalies. The temporal bone anomaly frequently seen in CHARGE syndrome is rarely reported in VACTERL. VACTERL usually occurs sporadically. The cause is unknown.

Kabuki syndrome. Ming et al [2003] reported that phenotypic overlap between CHARGE syndrome and Kabuki syndrome (cleft palate, heart defects, occasional coloboma, growth retardation) can sometimes lead to the consideration of CHARGE syndrome in individuals with Kabuki syndrome. However, the typical facial features in Kabuki syndrome (long palpebral fissures with eversion of lateral third of lower eyelids, sparse eyebrows, and large prominent ears (all of which become more prominent with age) and prominent fingertip pads are distinct from those in CHARGE syndrome. A mutation in MLL2 is identified in about 56%-76% of individuals with a clinical diagnosis of Kabuki syndrome [Hannibal et al 2011, Li et al 2011, Micale et al 2011, Paulussen et al 2011].

Renal coloboma syndrome (papillorenal syndrome), caused by mutations in PAX2, is characterized by retinal/optic nerve colobomas, kidney abnormalities, and occasional hearing loss. Individuals with a PAX2 mutation do not have the multiple congenital anomalies seen in CHARGE syndrome. No individual with a clinical diagnosis of CHARGE syndrome has been found to have a mutation in PAX2 [Tellier et al 2000].

Cat-eye syndrome, characterized by the combination of coloboma of the iris and anal atresia with fistula, preauricular tags and/or pits, and frequent occurrence of heart and renal malformations, is caused by inv dup(22)(q11) (presence of a supernumerary bisatellited chromosome 22 that often has two centromeres). Individuals with cat-eye syndrome do not fulfill the clinical diagnostic criteria for CHARGE syndrome.

Joubert syndrome with bilateral chorioretinal coloboma is characterized by interstitial fibrosis of the kidney leading to renal insufficiency, hepatic fibrosis, neonatal tachypnea, cerebellar vermis aplasia/ hypoplasia, and polydactyly. 'Molar tooth' sign on neuroimaging is diagnostic of Joubert syndrome. The characteristic radiologic features and the absence of other major diagnostic characteristics of CHARGE syndrome distinguish this condition from CHARGE syndrome. Mutations in at least ten genes are known to cause Joubert syndrome; inheritance is autosomal recessive.

Branchiootorenal (BOR) syndrome, caused by EYA1 mutation, is a syndrome of deafness, external ear deformity, lateral semicircular canal hypoplasia, and renal malformation. The absence of branchial fistulae and cysts and other major criteria of CHARGE syndrome distinguish BOR syndrome from CHARGE syndrome.

Choanal atresia can be an isolated birth defect or occur as part of a syndrome. Other conditions in which choanal atresia occurs:

Retinoic embryopathy secondary to prenatal AccutaneTM exposure. Exposure to AccutaneTM during any time within the first trimester produces malformations associated with abnormal migration of neural crest cells. Malformations include microtia/anotia, micrognathia, cleft palate, conotruncal heart defects and aortic-arch abnormalities, thymic defects, retinal or optic nerve abnormalities, and central nervous system malformations [Lammer et al 1985]. Although some overlap, especially the conotruncal cardiac malformations, is seen with CHARGE syndrome, infants with retinoic embryopathy do not meet diagnostic criteria for CHARGE syndrome.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with CHARGE syndrome, the following evaluations are recommended:

  • Dilated ophthalmologic examination by pediatric ophthalmologist to determine the type and extent of the coloboma and associated findings such as strabismus, refractive error, or central vision impairment (CVI); when possible, clinical testing of visual fields
  • Cardiac evaluation for cardiovascular anomalies
  • Assessment for unilateral or bilateral choanal atresia and/or stenosis by nasal endoscopy or CT scan
  • ENT and audiologic evaluation:
    • In infants, brain stem auditory evoked response (BAER) to evaluate hearing as soon as the infant is medically stable
    • In older children and adults, hearing evaluation as appropriate for age and developmental status

      See Deafness and Hereditary Hearing Loss Overview for discussion of types of audiologic evaluation.
  • CT scan of the temporal bones to evaluate for middle ear and inner ear defects
  • Evaluation for cleft palate, including submucous cleft palate
  • Assessment of cranial nerve function by physical examination for evidence of facial palsy and by swallowing studies
  • Evaluation for esophageal atresia or tracheoesophageal (TE) fistula with posteroanterior and lateral plain chest radiographs and radiographic visualization of a rigid nasogastric tube that fails to pass from the mouth to the stomach (Contrast-enhanced studies may be necessary to identify or locate a fistula.)
  • Renal ultrasound examination
  • Genetics consultation

Treatment of Manifestations

Management of children with CHARGE syndrome requires coordinated multidisciplinary care:

  • Airway can be compromised from choanal atresia, TE fistula, aspiration pneumonias, tracheomalacia, or an aberrant subclavian vessel impinging on the trachea. Studies have shown that 15%-60% of individuals with CHARGE syndrome require tracheostomy [Roger et al 1999, White et al 2005].
  • Heart defects are managed as in any individual with a congenital heart defect.
  • Choanal atresia. Surgical correction by means of transnasal, transpalatal, or sublabial routes or airway bypass by tracheotomy or endotracheal intubation is usually necessary early in life. Multiple surgeries are often required to maintain the nasal airway.
  • Feeding/swallowing dysfunction. In infancy, feeding can be compromised by oral-motor and/or sensory deficits. A multidisciplinary approach to therapy with specialists in speech-language pathology, occupational therapy, and nutrition can help promote early oral exploration and prevent or minimize oral defensiveness. For children with a G-tube, oral stimulation needs to be maintained to reduce future oral sensitivity/aversion.
  • Gastroesophageal reflux can be significant enough to cause aspiration, often requiring Nissen fundoplication and G-tube insertion. Silent reflux should be considered in the evaluation of recurrent sinusitis.
  • Renal evaluation. Renal ultrasound examination is recommended in all children. Evaluation for urinary tract infection is recommended in cases of unexplained fever or irritability in children unable to communicate.
  • Endocrine evaluation. Early referral for endocrinology consultation is appropriate, especially if linear growth is falling from the normal curve in spite of adequate nutrition and normalized cardiac status. Some of these children may have growth hormone deficiency, which requires growth hormone replacement therapy.

    Individuals with hypogonadotropic hypogonadism may be considered for hormone replacement therapy for induction of puberty and for general health reasons including prevention of osteoporosis.
  • Coloboma. Tinted glasses or a dark visor can be helpful for the photophobia that often accompanies iris colobomas.

    Parents, therapists, and teachers need to take into account visual field defects resulting from retinal coloboma and central visual defects resulting from optic nerve involvement and macular coloboma. For example, visual stimuli and sign language may need to be presented in child's lower visual field.

    For eyes with visual potential, cycloplegic refraction and spectacle correction may be necessary, since substantive refractive errors of mildly or even moderately micro-ophthalmic eyes have been observed.

    Retinal detachment, a potential complication of retinal coloboma, can result in total blindness; therefore, any change in vision status should be treated as a medical emergency.
  • Hearing loss. Hearing loss should be assumed until proven otherwise. Hearing aids and hearing habilitation (which may include sign language in addition to the auditory and speech training) should be started as soon as hearing loss is documented. Many children benefit from bone conduction aids or (especially at school) an FM system. Head bands can be used to help keep the hearing aids in place if the ear cartilage is floppy or if the tape that secures the aid to the scalp is ineffective.

    PE tube placement for chronic serous otitis is common and often needs to continue until adolescence.

    Cochlear implants have been successful in providing sound awareness and even speech recognition in the presence of cochlear abnormalities. Bauer et al [2002] reported successful completion of cochlear implantation and measurable benefit in five individuals with CHARGE syndrome. Of note, variations in the temporal bone anatomy can lead to technical challenges and risk to the facial nerve during implantation. In some individuals, an aberrant course of the facial nerve may be a contraindication for cochlear implant [Bauer et al 2002].
  • Communication. Establishing an appropriate system of communication is more difficult in the presence of both hearing loss and vision loss than in the presence of hearing loss alone. Depending on the degrees of hearing and vision loss, communication may start with touch cues, followed by object cues and proceeding to auditory/oral and/or sign language. Communication training initiated by age three years is critical to the eventual development of symbolic communication [Thelin & Fussner 2005].
  • Deaf-blind service referral. Children with CHARGE syndrome who have combined vision and hearing loss can be considered “deafblind,” an important designation used for qualifying for educational resources in many states. Of note, “deafblind” does not imply total hearing loss or total vision loss: most children with CHARGE syndrome have some residual vision and/or hearing but are still classified as “deafblind.”

    Referral to deafblind education services (e.g., the Deafblind Project within the state of residence) should be made as early as possible after birth so that the parents and project personnel can begin to plan together. A growing body of evidence indicates that normal language development can occur if hearing habilitation is started prior to age six months for hearing-impaired children, whether or not they are visually impaired. Assistance of the Deafblind team to provide consultation to the early childhood education team is highly recommended since many educators and speech therapists have little or no experience with dual sensory loss.
  • Psychological/school evaluations should be performed by a team that includes specialists in deafblindness when dual sensory loss is present. If a deafblind specialist is not available when a psychologist does an evaluation, a vision educator can show the tester where to place materials and whether the lighting and contrast of the printed materials is adequate. A hearing educator can help place the child for optimal hearing and/or do sign language interpretation.
  • Dental procedures, when necessary, may be performed under general anesthesia.
  • Low muscle tone and poor balance predispose children to rapid exhaustion. Many children need adjustments to the classroom or therapy setting to allow for better truncal support. Frequent rest breaks may be needed. Many children can work for longer periods if allowed to do so in a supine position [Williams & Hartshorne 2005].

    Unpublished data suggest that hippotherapy (horseback riding) can be a helpful adjunct to physical therapy to prevent scoliosis as it requires frequent shifts in truncal muscular control — as do karate and other programs that promote good balance. Myofacial release can improve posture and flexibility.
  • Sleep cycles are frequently disturbed even in those without significant visual impairments. Occasionally, sleep studies show obstructive apnea. If the cause is unknown, melatonin has been helpful for some children while others with severe visual impairment may need other medications to regulate sleep.
  • Chronic constipation usually does not respond to simple measures such as increased fluid intake. GI consultation is often indicated.
  • Obsessive-compulsive disorder. Behavioral therapy combined with stress reduction is sometimes helpful alone, but treatment with medications can be a useful adjunct.
  • Pervasive developmental disorder. While the behaviors may mimic autism, there are differences [Hartshorne et al 2005a]. Sensory processing issues are likely implicated. Management by behavior therapy, stress reduction, and sometimes medication is indicated.
  • Attention-deficit hyperactivity disorder. In many instances, establishing an appropriate method of communication and providing adequate stimulation for exploration in a safe environment are more helpful than medication.
  • Increased pain threshold may predispose children to behaviors that are incorrectly interpreted by others as aggressive. Understanding this is critical to devising appropriate interventional strategies.

Prevention of Secondary Complications

Facial palsy. Because the facial nerves are often ectopic, an MRI to determine the location of the facial nerves is appropriate before craniofacial surgery or cochlear implantation is considered.

Anesthesia. The airway problems associated with anesthesia in individuals with CHARGE syndrome can be attributed to choanal atresia, cleft lip and palate, and other upper-airway problems observed in approximately half of individuals with CHARGE syndrome. The soft cartilage and resultant floppy trachea add to potential anesthesia risk. Neurogenic incoordination of swallow and closure of the epiglottis may complicate the postoperative course, especially with repeated general anesthetics. If possible, procedures should be combined to reduce the overall use of anesthesia.

Surveillance

Regular ophthalmologic evaluations are appropriate to follow changes in acuity and risks for retinal detachment and/or cataract. Monitoring nonverbal infants and children who are unable to report subjective loss of vision can permit timely detection of retinal detachment and appropriate surgical repair where necessary.

Frequent retesting of hearing by a pediatric audiologist may be necessary to determine the exact type and extent of hearing loss and to assess the success of hearing habilitation.

Frequent clinical and radiologic dental evaluations should be performed.

Wheeler et al [2000] recommended that LH and FSH be obtained between age two and three months, or by age 13-14 years if puberty has not occurred. If there is reason to suspect hypogonadotropic hypogonadism, a gonadotropin-releasing hormone (GnRH) stimulation test may be helpful.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Prophylaxis for retinal detachment is not appropriate.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CHARGE syndrome typically occurs in a single individual in a family, although rare familial cases inherited in an autosomal dominant manner have been described [Mitchell et al 1985, Lalani et al 2006, Delahaye et al 2007, Jongmans et al 2008, Vuorela et al 2008].

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with CHARGE syndrome do not have an affected parent. In rare instances, one parent may have mild features, including more than one major characteristic, in addition to minor criteria, such as a cardiovascular malformation [Bergman et al 2011].
  • A proband with CHARGE syndrome usually has the disorder as the result of a new gene mutation.
  • If a parent has any features of CHARGE syndrome, molecular genetic testing is appropriate if a CHD7 mutation has been identified in the proband.

Note: Although almost all individuals diagnosed with CHARGE syndrome are the only affected individuals in the family, the family history may appear to be negative because of failure to recognize the mild features of the disorder in family members.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has a CHD7 mutation, the risk to the sibs of inheriting the mutation is 50%.
  • If neither parent is affected, the empiric risk to sibs of a proband is approximately 1%-2%, attributable to germline mosaicism.
  • Because CHARGE syndrome caused by a CHD7 mutation typically occurs as the result of a de novo mutation, the risk to the sibs of a proband is small. However, several sib pairs born to unaffected parents have been reported [Jongmans et al 2006, Lalani et al 2006] with likely germline mosaicism, confirmed in a report by Pauli et al [2009].
  • The presence of two major characteristics along with multiple congenital anomalies in a sib of a proband should prompt complete evaluation for CHARGE syndrome. Molecular genetic testing of the sib is appropriate if a CHD7 mutation has been identified in the proband.

Offspring of a proband

  • Severely affected individuals with CHARGE syndrome do not reproduce.
  • Each child of a mildly affected individual with CHARGE syndrome has a 50% chance of inheriting the mutation.
  • The severity of CHARGE syndrome in a parent does not predict the severity of CHARGE syndrome in the offspring. Variable expression has been observed in the familial cases.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent has the disease-causing mutation in CHD7, his or her family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are mildly affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal molecular testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. Some of the clinical findings in CHARGE syndrome, including polyhydramnios, heart defects, cleft lip/palate, CNS anomalies, and kidney and gastrointestinal anomalies, may be apparent on targeted level II ultrasound examination in the second trimester. Sanlaville et al [2006] proposed performing focused fetal ultrasound and/or brain MRI for detection of external ear anomalies, choanal atresia, semicircular canal agenesis, and arrhinencephaly for a higher prenatal detection rate of CHARGE syndrome. If CHARGE syndrome is suspected, 4D ultrasound of the ears may be helpful.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • CHARGE Syndrome Foundation
    141 Middle Neck Road
    Sands Point NY 11050
    Phone: 800-442-7604 (toll-free); 516-684-4720
    Fax: 516-883-9060
    Email: info@chargesyndrome.org
  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • National Consortium on Deaf-Blindness (NCDB)
    Bibliography and links to state deafblind project resources
    345 North Monmouth Avenue
    Monmouth OR 97361
    Phone: 800-438-9376 (toll-free); 800-854-7013 (TTY)
    Fax: 503-838-8150
    Email: info@nationaldb.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • SeeHear Newsletter
    A Quarterly Newsletter For Families And Professionals On Visual Impairments And Deafblindness.
    Texas School for the Blind and Visually Impaired
    1100 West 45th Street
    Austin TX 78756
    Phone: 800-872-5273 (toll-free); 512-454-8631; 512-206-9451 (TDD)
    Fax: 512-206-9450

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. CHARGE Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for CHARGE Syndrome (View All in OMIM)

214800CHARGE SYNDROME
608892CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 7; CHD7

Normal allelic variants. CHD7 is 188 kb in size and consists of 37 coding exons.

Pathologic allelic variants. The majority of mutations are nonsense and frameshift, and are distributed throughout the gene. Missense mutations are also reported, although relatively infrequently [Aramaki et al 2006, Jongmans et al 2006, Lalani et al 2006, Wincent et al 2008].

Normal gene product. CHD7 encodes a 2997-residue protein. It belongs to a superfamily of proteins called chromodomain helicase DNA binding protein, with two N-terminal chromodomains, a SNF2-like ATPase/helicase domain and a DNA-binding domain. Chromatin remodeling is one of the mechanisms by which gene expression is regulated developmentally. CHD7 is orthologous to Drosophila kismet, which has been shown to facilitate an early step in transcriptional elongation by Pol II [Srinivasan et al 2008].

Abnormal gene product. In the majority of the affected individuals, haploinsufficiency of CHD7 is likely the underlying basis of CHARGE syndrome.

References

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Suggested Reading

  1. American Journal of Medical Genetics. Articles on CHARGE syndrome from the 6th International Charge Conference. Available at www​.chargesyndrome.org. 2005. Accessed 1-30-12.
  2. Hefner M, Davenport SLH, eds. CHARGE syndrome: a management manual for parents. Version 2.1. Columbia, MO: CHARGE Syndrome Foundation, Inc. Available online. 2002. Accessed 1-30-12.
  3. Moss K. Looking at self-stimulation in the pursuit of leisure or I'm okay, you have a mannerism. SeeHear Vol 5, no 3. TSBVI Deafblind Outreach. Available online. 1993. Accessed 1-30-12.

Chapter Notes

Acknowledgments

Thanks to David Weaver for assistance in procuring articles.

Revision History

  • 2 February 2012 (me) Comprehensive update posted live
  • 22 September 2009 (me) Comprehensive update posted live
  • 6 June 2007 (cd) Revision: mutation scanning added
  • 2 October 2006 (me) Review posted to live Web site
  • 14 April 2005 (jwb) Original submission
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