CHARGE syndrome is characterized by a pattern of congenital anomalies including choanal atresia and malformations of the heart, inner ear, and retina (summary by Kallen et al., 1999).
An analysis by Harris et al. (1997) of choanal atresia-associated malformations, present in 47% of the infants studied without chromosome anomalies, indicated that a weak, nonrandom association can be demonstrated between the malformations of the CHARGE complex. If ... An analysis by Harris et al. (1997) of choanal atresia-associated malformations, present in 47% of the infants studied without chromosome anomalies, indicated that a weak, nonrandom association can be demonstrated between the malformations of the CHARGE complex. If the definition of CHARGE is the presence of 3 or more malformations, then of the 444 infants identified, 7% belonged to the CHARGE constellation. Harris et al. (1997) concluded that for the term CHARGE to be meaningful, it should be restricted to infants with multiple malformations and choanal atresia and/or coloboma, combined with other cardinal malformations (heart, ear, and genital), for a total of at least 3 cardinal malformations; growth retardation, especially low birth weight, should not be used in the definition. Verloes (2005) proposed diagnostic criteria for CHARGE syndrome. The 3 major signs were coloboma, choanal atresia, and semicircular canal anomalies, and the 5 minor signs were rhombencephalic abnormalities, hypothalamo-hypophyseal dysfunction, external/middle ear malformations, mediastinal visceral malformations, and mental retardation. Blake et al. (2008) stated that cranial nerve involvement is now considered 1 of the 4 major criteria for a clinical diagnosis of CHARGE syndrome. The other 3 key diagnostic indicators are coloboma, choanal atresia, and characteristic ear anomalies.
Choanal atresia (see 608911) is a feature of the CHARGE association: coloboma of the eye; heart anomaly; atresia, choanal; retardation of mental and somatic development; microphallus; ear abnormalities and/or deafness (Pagon et al., 1981). Facial palsy, cleft palate, ... Choanal atresia (see 608911) is a feature of the CHARGE association: coloboma of the eye; heart anomaly; atresia, choanal; retardation of mental and somatic development; microphallus; ear abnormalities and/or deafness (Pagon et al., 1981). Facial palsy, cleft palate, and dysphagia are commonly associated. The first descriptions of this syndrome were provided by Hall (1979) and Hittner et al. (1979). Hall (1979) reported a constellation of nonrandomly associated malformations occurring with choanal atresia. Hittner et al. (1979) reported 10 individuals, including a mother and child, with colobomatous microphthalmia, heart disease, abnormalities of the external ear with associated hearing loss, and mental retardation. They noted that multiple other anomalies may be associated. Koletzko and Majewski (1984) described 6 patients with choanal atresia and additional malformations and reviewed 11 previously reported cases. Their findings validated the CHARGE association but suggested the inclusion of orofacial clefts and esophageal atresia as main features. A certain degree of dysmorphism (low-set and dysplastic ears, retrogenia, antimongoloid slant of palpebral fissures, anteverted nares) was observed in each of their 6 patients. Infants with bilateral choanal atresia plus cardiac defects and those with choanal atresia plus renal malformations had a high mortality rate. Recurrence risk is low. Davenport et al. (1986) described 15 cases, 9 sporadic and 6 familial. They concluded that CHARGE is a recognizable pattern of malformations and a true syndrome rather than an association. They pointed to external ear malformations (see their photographs) and a 'wedge-shaped' audiogram that may be unique features valuable in diagnosis. Mixed conductive and sensorineural deafness causes an audiogram with a descending bone conduction curve intersecting at low frequencies with a flat curve for air conduction. Congenital facial paralysis occurs in few other conditions. Feeding difficulties are striking even in the absence of cleft palate or tracheoesophageal fistula. Metlay et al. (1987) reported a patient with CHARGE syndrome as manifested by coloboma of the optic nerve head, congenital heart defect (ASD, VSD, and parachute mitral valve), choanal atresia, severe growth retardation, genital hypoplasia, abnormal ears, cleft lip and palate, and pectus carinatum. He died at 19 months of age. His mother was short and had hearing impairment, choanal atresia, and a coloboma of the left iris. Reported familial cases were tabulated. Tetralogy of Fallot is the most frequent type of heart defect reported in the CHARGE association (Cyran et al., 1987). Ivarsson et al. (1988) reported supravalvular and peripheral pulmonary stenosis in a patient with CHARGE association who also had an atrial septal defect. Oley et al. (1988) described 14 boys and 6 girls, including monozygotic twins, who all had at least 4 of the 7 major features included in the mnemonic CHARGE. All had ear anomalies or deafness or both and either coloboma or choanal atresia or both. All the boys had evidence of hypogonadism. Many had a characteristic facial appearance: unusually shaped ears, unilateral facial palsy, square face, malar flattening, and pinched nostrils. All were sporadic cases. Hurst et al. (1989) reported a brother and sister who had atrial septal defect and ventricular septal defect, short stature, microcephaly, developmental delay, and similar dysmorphic facial appearance. The boy had bilateral choanal hypoplasia and stenosis, and Hurst et al. (1989) suspected that the girl had mild choanal stenosis because she had problems in feeding and sucking in the first few months of life. Bialer and Brown (1990) argued that the diagnosis was indeed the CHARGE association in the case of the sibs reported by Hurst et al. (1989). Meinecke et al. (1989) described the rare association of cutaneous syndactyly and nail hypoplasia with the more frequent features of the CHARGE syndrome. Blake et al. (1990) reviewed the clinical experience of 50 patients with CHARGE syndrome. Lin et al. (1990) reviewed 136 patients from the literature and added 8 more. In 47 of these, either a postmortem examination or a computerized axial tomography of the head had been performed. Of the 47, 26 (55%) had definite central nervous system malformations, predominantly forebrain anomalies, particularly arhinencephaly and holoprosencephaly. The presence of CNS malformation was most strongly associated with choanal atresia. Van Meter and Weaver (1996) reported 2 infants (a male and a female) with significant overlap of symptoms of CHARGE association and Goldenhar anomaly (164210). In addition, both infants had plagiocephaly and torticollis, and the boy had cleft lip, heminostril, and tracheoesophageal fistula. The authors suggested that deficiency in migration of neural crest cells, deficiency of mesodermal formation, or defective interaction between neural crest cells and mesoderm may explain the pathogenesis of these defects of blastogenesis. Tellier et al. (1998) evaluated 47 CHARGE patients for the frequency of major anomalies, namely, coloboma (79%), heart malformation (85%), choanal atresia (57%), growth and/or mental retardation (100%), genital anomalies (34%), ear anomalies (91%), and/or deafness (62%). In addition, they commented on anomalies observed frequently in neonates and infants with the CHARGE syndrome, including minor facial anomalies, neonatal brainstem dysfunction with cranial nerve palsy, and internal ear anomalies such as semicircular canal hypoplasia, which was found in each patient that could be tested. Criteria for poor survival were thought to include male gender, central nervous system and/or esophageal malformations, and bilateral choanal atresia. A significantly higher mean paternal age at conception together with concordance in monozygotic twins and the existence of rare familial cases supported the role of genetic factors such as de novo dominant mutation or subtle submicroscopic chromosome rearrangement. The G of the CHARGE association represents genital hypoplasia, which is typically recognized only in males (micropenis/cryptorchidism). On the basis of 9 individuals with CHARGE association, Wheeler et al. (2000) identified hypogonadotropic hypogonadism, manifested by hypogenitalism and gonadotropins at or below minimal detectable levels at ages when these hormones should be readily measurable. The authors suggested that central hypogonadism is responsible not only for the genital hypoplasia in male patients but also for the lack of secondary sexual development in patients of both sexes. Measurement of serum luteinizing hormone (see 152780) and follicle-stimulating hormone (see 136530) in infants may help establish the diagnosis; these determinations in teenagers with CHARGE association can result in early diagnosis of hypogonadotropic hypogonadism, allowing for treatment of hormonal deficiencies and minimization of potential secondary psychosocial and medical problems. Sanlaville et al. (2006) examined 10 fetuses from pregnancies that were terminated due to severe malformations seen on ultrasound; all of the fetuses had truncating mutations of the CHD7 gene. They identified 3 constant features: anomalies of the external ear, agenesis or hypoplasia of the semicircular canals, and arhinencephaly. Features occurring in at least 7 of 10 cases included genital anomalies, thymic hypoplasia, ocular coloboma, CNS anomalies other than arhinencephaly, choanal atresia or cleft palate, and heart defects. Sanlaville et al. (2006) concluded that semicircular canal agenesis and arhinencephaly are highly predictive diagnostic criteria for CHARGE syndrome, and suggested that they be added to the major diagnostic criteria for the disorder. Vervloed et al. (2006) studied associations between behavior and medical problems in 27 patients with CHARGE syndrome and found that of all medical conditions, only the presence or absence of heart defects and cardiac surgery could differentiate between the patients with regard to the number of behavioral problems. Long hospital stays were associated with less problem behavior. Cerebral and heart problems did not result in longer hospital stays, whereas esophageal reflux did. The study did not confirm a significant association between medical conditions and autism found in previous studies. Vervloed et al. (2006) noted that while heart surgery and hospitalization may be protective factors, related variables such as reduced vitality or altered parent-child interactions after heart surgery may be the actual cause. Delahaye et al. (2007) reported 2 unrelated families with dominant transmission of CHARGE syndrome due to pathogenic CHD7 mutations. In both families, the syndrome was phenotypically identified in 1 parent with very mild signs only after the diagnosis of their affected children, who had severe manifestations. Although detailed studies were not performed, the authors suggested that somatic mosaicism may have occurred in the parents. The report emphasized the intrafamilial variability of the syndrome. By analyzing physician-completed questionnaires based on 99 CHARGE patients in Canada, Blake et al. (2008) found that 92% of patients exhibited symptoms of at least 1 cranial nerve anomaly, and 72% had involvement of more than 1. Involvement of CN IX and X was the most common (68.7%), followed by CN VIII auditory (56.6%), CN V (55.6%), CN VII (31.3%), and CN VIII vestibular (22.2%). Blake et al. (2008) suggested that involvement of some of these nerves may underlie the sucking, chewing, and swallowing difficulties often observed in patients with CHARGE syndrome. In 3 of 36 patients with an initial clinical diagnosis of Kallmann syndrome, Jongmans et al. (2009) identified de novo heterozygous mutations in the CHD7 gene. Further evaluation of the 3 patients showed that each had additional clinical features consistent with CHARGE syndrome, including deafness, tooth agenesis, dysmorphic ears, coloboma, and short stature. Jongmans et al. (2009) concluded that patients with anosmia and/or hypogonadotropic hypogonadism should be screened for additional clinical features of CHARGE syndrome. Layman et al. (2009) noted that olfactory defects and olfactory bulb hypoplasia have been previously reported in individuals with CHARGE syndrome. In 5 of 8 individuals with CHARGE due to confirmed CHD7 mutations, they found severe defects in olfaction on the Brief Smell Identification Test (BSIT). Of note, 3 CHARGE patients with mutation in exon 33 of the CHD7 gene did well on the olfaction test, scoring at or near normal. In 3 members of a Finnish family with CHARGE syndrome, Vuorela et al. (2008) identified a nonsense mutation in the CHD7 gene (608892.0017). The male infant proband and a male fetus from a second pregnancy both had absence of the olfactory bulbs in addition to other features consistent with CHARGE syndrome. The male infant, who died at 3 months of age, also had marked isomerism of the liver with significant symmetry of the right side-appearing lobes and a midline gallbladder, as well as extrahepatic bile duct obstruction and significant hyporotation of the intestines. Their father, in whom the mutation was found in peripheral blood lymphocytes and in buccal cells, had minimal findings, with left-sided conductive hearing loss, a dysplastic, cup-shaped right external ear, slightly asymmetric face, and nonspecific degenerative retinal lesion of the right eye. Vuorela et al. (2008) concluded that a healthy or nearly healthy parent of a CHARGE child may carry a CHD7 mutation, which has implications for genetic counseling.
Using an improved method of array comparative genomic hybridization (CGH), Vissers et al. (2004) reported a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 in 2 individuals with CHARGE syndrome. Sequence analysis of genes located in this region ... Using an improved method of array comparative genomic hybridization (CGH), Vissers et al. (2004) reported a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 in 2 individuals with CHARGE syndrome. Sequence analysis of genes located in this region detected mutations in CHD7 (see, e.g., 608892.0001-608892.0004) in 10 of 17 individuals with CHARGE syndrome who did not have microdeletions, thus accounting for the disease in most affected persons. An individual with CHARGE syndrome with an apparently balanced chromosome 8 translocation had been reported by Hurst et al. (1991). Lalani et al. (2006) sequenced the CHD7 gene in 110 individuals who had received a clinical diagnosis of CHARGE syndrome, and detected mutations in 64 (58%). Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations, coloboma of the eye, and facial asymmetry, often caused by seventh cranial nerve abnormalities. Microarray gene expression analysis showed a signature pattern of gene expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutations from controls. Jongmans et al. (2006) identified mutations in the CHD7 gene in 69 of 107 patients with clinical features suggestive of CHARGE syndrome. The authors stated that there were no genotype-phenotype correlations in this cohort and noted that there were differences in clinical presentation even in sib pairs with identical mutations (see 608892.0008). Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism. Udaka et al. (2007) assessed exon copy number using multiplex PCR/liquid chromatography (MP/LC) in 13 classic CHARGE patients in whom screening by DHPLC had failed to identify point mutations or small insertions/deletions in the CHD7 gene. They found a de novo deletion in 1 patient (608892.0010); the authors stated that this was the first CHARGE patient to have exonic deletion of CHD7. Van de Laar et al. (2007) reported 3 unrelated patients with several major features of CHARGE syndrome, 1 of whom fulfilled the diagnostic criteria proposed by Verloes (2005), who also presented severe limb anomalies, including monodactyly, tibia aplasia, and bifid femora. Three different heterozygous truncating mutations in the CHD7 gene were detected, respectively (see, e.g., 608892.0016). Van de Laar et al. (2007) suggested that limb defects should be added to the spectrum of manifestations of CHARGE syndrome. Kim et al. (2008) analyzed the CHD7 gene in 197 patients with Kallmann syndrome or normosmic hypogonadotropic hypogonadism (see HH5; 612370) and identified 7 sporadic heterozygous mutations in 3 KS patients and 4 IHH patients, respectively (see, e.g., 608892.0012-608892.0015). A missense mutation (608892.0012) that was found in a male patient with IHH, cleft lip, and cryptorchidism had previously been reported by Delahaye et al. (2007) in a mother and 2 sons from a family with both typical and atypical CHARGE syndrome phenotypes, and a splice site mutation (608892.0013) in a female KS patient with cleft lip and palate and hearing loss had previously been reported by Jongmans et al. (2008) in 2 brothers with 'relatively mild' CHARGE syndrome. Kim et al. (2008) concluded that both normosmic IHH and Kallmann syndrome due to CHD7 mutations are mild allelic variants of CHARGE syndrome. Bergman et al. (2008) excluded copy number alterations of the CHD7 gene as a major cause of CHARGE syndrome. Among 54 patients suspected of having the disorder in whom CHD7 mutations were not found, multiplex ligation-dependent probe amplification (MLPA) analysis detected only 1 (1.9%) who had a large CHD7 gene alteration, which was a partial deletion encompassing exons 13 to 38. Wincent et al. (2008) identified CHD7 mutations in 18 (64%) of 28 Swedish index patients with CHARGE syndrome. Thirteen of the mutations were novel, and 3 (17%) were large deletions. The changes were de novo in all 15 cases in which parental samples were available for testing. No clear genotype/phenotype correlations were observed. - Mutation in the SEMA3E Gene In a patient originally described by Martin et al. (2001) with CHARGE syndrome and a de novo balanced translocation involving chromosomes 2 and 7, Lalani et al. (2004) mapped the translocation breakpoints and identified the semaphorin-3E gene within 200 kb of the breakpoint on 7q21.11. Screening of patients with CHARGE syndrome for mutations in the SEMA3E gene revealed a de novo mutation in an unrelated patient (S703L; 608166.0001). The mutation was not found in either parent or in 338 ethnically matched control chromosomes. - Exclusion Studies Since PAX2 (167409) gene expression occurs in primordia affected in CHARGE association, Tellier et al. (2000) analyzed the PAX2 gene in 34 patients fulfilling diagnostic criteria for CHARGE. The authors used 2 polymorphisms to look for deletions, and SSCP of the 12 exons to look for nucleotide variations. No disease-causing mutations were identified, suggesting that mutation of the PAX2 gene is not a common cause of CHARGE association. The authors suggested that the expression pattern of PAX2 is consistent with the possibility that unidentified PAX2 downstream targets and effectors could be candidate genes for CHARGE.
With an estimated birth incidence of 1 in 12,000, CHARGE syndrome is a common cause of congenital anomalies (Kallen et al., 1999).
In a national surveillance study in Canada, Issekutz et al. (2005) found that the ... With an estimated birth incidence of 1 in 12,000, CHARGE syndrome is a common cause of congenital anomalies (Kallen et al., 1999). In a national surveillance study in Canada, Issekutz et al. (2005) found that the national incidence of CHARGE syndrome was 3.5 in 100,000 live births, but the incidence in the Atlantic provinces of Newfoundland, Labrador, and the Maritime Provinces, was as high as 1 in 8,500 live births.
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.)...
DiagnosisClinical DiagnosisDiagnostic 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 characteristicsMajor 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 SyndromeView in own windowCharacteristicsManifestationsFrequencyOcular 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 anosmiaFrequentVII: facial palsy (unilateral or bilateral)>40%VIII: hypoplasia of auditory nerveFrequentIX/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 1) 3 80%-100%Middle ear: ossicular malformations 4Mondini defect of the cochlea 5Temporal bone abnormalities; absent or hypoplastic semicircular canals 51. 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 bonesMinor 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 SyndromeView in own windowCharacteristicsManifestationsFrequencyGenital hypoplasiaMales: micropenis, cryptorchidism Females: hypoplastic labia50%-60%Males and females: delayed puberty secondary to hypogonadotropic hypogonadismFrequentDevelopmental 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 2) 270%-80%1. May be primarily the result of illness, dual sensory impairment, and vestibular dysfunction2. Davenport et al [1986a]Occasional findings include the following:DiGeorge sequenceOmphalocele or umbilical herniaBony scoliosis or hemivertebraeRenal 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 anomaliesFigureFigure 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:Balanced chromosomal translocation t(6;8)(6p8p;6q8q) [Hurst et al 1991]De novo balanced chromosomal rearrangement t(8;13)(q11.2;q22) [Johnson et al 2006]Interstitial deletion of 8q11.2-q13 [Arrington et al 2005]Molecular Genetic TestingGene. 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 testingTable 3. Summary of Molecular Genetic Testing Used in CHARGE SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCHD7Sequence analysisSequence variants 2>90% in typical cases fulfilling Blake’s diagnostic criteria 465%-70% for all typical and suspected cases combined 5ClinicalDeletion / duplication testing 3Large contiguous-gene deletions; exonic or whole-gene deletionsRare 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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 StrategyTo confirm/establish the diagnosis in a probandThe diagnosis is primarily established by clinical findings.Molecular testing for CHD7 confirms the diagnosis in the majority of cases. Sequence analysis is the first test of choice.If no mutation is identified by sequence analysis, deletion/duplication analysis by a variety of methods (see Table 3, footnote 3) can be performed to identify large contiguous-gene deletions and exonic or whole-gene deletions. 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.Genetically Related (Allelic) DisordersGao et al [2007] reported polymorphisms in CHD7, associated with susceptibility to idiopathic scoliosis.
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....
Natural HistoryMorbidity 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].
No clear genotype-phenotype correlations exist [Jongmans et al 2006, Lalani et al 2006, Sanlaville et al 2006]....
Genotype-Phenotype CorrelationsNo 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].
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)....
Differential DiagnosisThe 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:Chromosome abnormalitiesCraniosynostosis syndromes (see FGFR-related craniosynostosis)Treacher Collins syndromePrenatal exposure to methimazoleRetinoic 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with CHARGE syndrome, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 fieldsCardiac evaluation for cardiovascular anomaliesAssessment for unilateral or bilateral choanal atresia and/or stenosis by nasal endoscopy or CT scanENT and audiologic evaluation:In infants, brain stem auditory evoked response (BAER) to evaluate hearing as soon as the infant is medically stableIn 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 defectsEvaluation for cleft palate, including submucous cleft palateAssessment of cranial nerve function by physical examination for evidence of facial palsy and by swallowing studiesEvaluation 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 examinationGenetics consultationTreatment of ManifestationsManagement 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 ComplicationsFacial 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.SurveillanceRegular 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.OtherProphylaxis for retinal detachment is not appropriate.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDCHD78q12.1-q12.2Chromodomain-helicase-DNA-binding protein 7CHD7Data 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) View in own window 214800CHARGE SYNDROME 608892CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 7; CHD7Normal 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.