CHARGE SYNDROME

Alternative titles; symbols

CHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION HALL-HITTNER SYNDROME; HHS Phenotype Gene Relationships
Location 7q21.11 8q12.1-q12.2 Phenotype CHARGE syndrome CHARGE syndrome Phenotype MIM number 214800 214800 SEMA3E CHD7

Gene/Locus

Clinical Synopsis

TEXT

A number sign (#) is used with this entry because of evidence that most individuals with CHARG chromodomain helicase DNA-binding protein-7 (CHD7; 608892) There is also evidence that the phenotype may be caused by mutation in the semaphorin-3E gene Kallmann syndrome (HH5; 612370) is an allelic disorder with a less severe but overlapping phenotype.

Clinical Features

Choanal atresia (see 608911) is a feature of the CHARGE association: coloboma of the eye; heart anomaly somatic development; microphallus; ear abnormalities and/or deafness (Pagon et al., 1981). Facial palsy

associated. The first descriptions of this syndrome were provided by Hall (1979)and Hittner et al. (19 nonrandomly associated malformations occurring with choanal atresia. Hittner et al. (1979) reported 10 ind colobomatous microphthalmia, heart disease, abnormalities of the external ear with associated hearing lo multiple other anomalies may

Koletzko and Majewski (1984) described 6 patients with choanal atresia and additional malformations and r findings validated the CHARGE association but suggested the inclusion of orofacial clefts and esophageal dysmorphism (low-set and dysplastic ears, retrogenia, antimongoloid slant of palpebral fissures, anteverted na Infants with bilateral choanal atresia plus cardiac defects and those with choanal atresia plus renal malform risk is

Davenport et al. (1986) described 15 cases, 9 sporadic and 6 familial. They concluded that CHARGE is a reco syndrome rather than an association. They pointed to external ear malformations (see their photographs) a unique features valuable in diagnosis. Mixed conductive and sensorineural deafness causes an audiogram intersecting at low frequencies with a flat curve for air conduction. Congenital facial paralysis occurs in f striking even in the absence of cleft palate

Metlay et al. (1987) reported a patient with CHARGE syndrome as manifested by coloboma of the optic ner

and parachute mitral valve), choanal atresia, severe growth retardation, genital hypoplasia, abnormal ears, c died at 19 months of age. His mother was short and had hearing impairment, choanal atresia, and a coloboma tabulated. Tetralogy of Fallot is the most frequent type of heart defect reported in the CHARGE asso (1988) reported supravalvular and peripheral pulmonary stenosis in a patient with CHARGE associat

Oley et al. (1988) described 14 boys and 6 girls, including monozygotic twins, who all had at least 4 of the CHARGE. All had ear anomalies or deafness or both and either coloboma or choanal atresia or both. All the had a characteristic facial appearance: unusually shaped ears, unilateral facial palsy, square face, malar flatte cases.

Hurst et al. (1989) reported a brother and sister who had atrial septal defect and ventricular septal defect, delay, and similar dysmorphic facial appearance. The boy had bilateral choanal hypoplasia and stenosis, and mild choanal stenosis because she had problems in feeding and sucking in the first few months of life. Bialer was indeed the CHARGE association in the case of the sibs rep

Meinecke et al. (1989) described the rare association of cutaneous syndactyly and nail hypoplasia with t syndrome.

Blake et al. (1990) reviewed the clinical experience of 50 patients with CHARGE syndrome. Lin et al. (199 and added 8 more. In 47 of these, either a postmortem examination or a computerized axial tomography of

(55%) had definite central nervous system malformations, predominantly forebrain anomalies, particularly presence of CNS malformation was most strongly associat

Tellier et al. (1996) found a significant increase in mean paternal age at birth of 41 CHARGE patients (33 population (30.8 +/- 5 years), suggesting the possible role of a dominant mutation or a subtle chromo significantly different in patients

Van Meter and Weaver (1996) reported 2 infants (a male and a female) with significant overlap of sympto anomaly (164210). In addition, both infants had plagiocephaly and torticollis, and the boy had cleft lip, hem authors suggested that deficiency in migration of neural crest cells, deficiency of mesodermal formation, or de and mesoderm may explain the pathogenesis of these

Tellier et al. (1998) evaluated 47 CHARGE patients for the frequency of major anomalies, namely, colobom atresia (57%), growth and/or mental retardation (100%), genital anomalies (34%), ear anomalies (91%) commented on anomalies observed frequently in neonates and infants with the CHARGE syndrome, includin dysfunction with cranial nerve palsy, and internal ear anomalies such as semicircular canal hypoplasia, wh tested. Criteria for poor survival were thought to include male gender, central nervous system and/or esop

atresia. A significantly higher mean paternal age at conception together with concordance in monozygotic t

supported the role of genetic factors such as de novo dominant mutation or subtle sub

The G of the CHARGE association represents genital hypoplasia, which is typically recognized only in mal of 9 individuals with CHARGE association, Wheeler et al. (2000) identified hypogonadotropic hypogo gonadotropins at or below minimal detectable levels at ages when these hormones should be readily mea hypogonadism is responsible not only for the genital hypoplasia in male patients but also for the lack of seco sexes. Measurement of serum luteinizing hormone (see 152780) and follicle-stimulating hormone (see diagnosis; these determinations in teenagers with CHARGE association can result in early diagnosis of hy treatment of hormonal deficiencies and minimization of potential secondary p

Sanlaville et al. (2006) examined 10 fetuses from pregnancies that were terminated due to severe malformati truncating mutations of the CHD7 gene. They identified 3 constant features: anomalies of the external ear canals, and arhinencephaly. Features occurring in at least 7 of 10 cases included genital anomalies, thymic h other than arhinencephaly, choanal atresia or cleft palate, and heart defects. Sanlaville et al. (2006) conc arhinencephaly are highly predictive diagnostic criteria for CHARGE syndrome, and suggested that they be disorder.

Vervloed et al. (2006) studied associations between behavior and medical problems in 27 patients with CHA conditions, only the presence or absence of heart defects and cardiac surgery could differentiate between behavioral problems. Long hospital stays were associated with less problem behavior. Cerebral and heart pro

whereas esophageal reflux did. The study did not confirm a significant association between medical studies. Vervloed et al. (2006) noted that while heart surgery and hospitalization may be protective factors, altered parent-child interactions after heart surgery may

Delahaye et al. (2007) reported 2 unrelated families with dominant transmission of CHARGE syndrome d families, the syndrome was phenotypically identified in 1 parent with very mild signs only after the diagnos manifestations. Although detailed studies were not performed, the authors suggested that somatic mosaicism emphasized the intrafamilial variability of

By analyzing physician-completed questionnaires based on 99 CHARGE patients in Canada, Blake et al. symptoms of at least 1 cranial nerve anomaly, and 72% had involvement of more than 1. Involvement of C

followed by CN VIII auditory (56.6%), CN V (55.6%), CN VII (31.3%), and CN VIII vestibular (22.2%). B of some of these nerves may underlie the sucking, chewing, and swallowing difficulties often obser

In 3 of 36 patients with an initial clinical diagnosis of Kallmann syndrome, Jongmans et al. (2009) identi CHD7 gene. Further evaluation of the 3 patients showed that each had additional clinical features cons deafness, tooth agenesis, dysmorphic ears, coloboma, and short stature. Jongmans et al. (2009) con

hypogonadotropic

hypogonadism

should

be

screened

for

additional

clinical

Layman et al. (2009) noted that olfactory defects and olfactory bulb hypoplasia have been previously reported 5 of 8 individuals with CHARGE due to confirmed CHD7 mutations, they found severe defects in olfaction o Of note, 3 CHARGE patients with mutation in exon 33 of the CHD7 gene did well on the o

In 3 members of a Finnish family with CHARGE syndrome, Vuorela et al. (2008) identified a nonsense mut male infant proband and a male fetus from a second pregnancy both had absence of the olfactory bulbs CHARGE syndrome. The male infant, who died at 3 months of age, also had marked isomerism of the liver appearing lobes and a midline gallbladder, as well as extrahepatic bile duct obstruction and significant hy whom the mutation was found in peripheral blood lymphocytes and in buccal cells, had minimal finding

dysplastic, cup-shaped right external ear, slightly asymmetric face, and nonspecific degenerative retin (2008) concluded that a healthy or nearly healthy parent of a CHARGE child may carry a CHD7 mutation, wh

Other Features

Writzl et al. (2007) reported 2 unrelated infants with genetically confirmed CHARGE syndrome who also h Studies in 1 patient showed no proliferative response to phytohemagglutinin. Both patients also had hypo hypoplastic thymus. Both patients died within the first month of life. A literature review found 15 patients w had immune defects. Most of these patients had a T cell-specific defect and thymic aplasia or hypoplasia wi Ig levels, indicating a humoral defect. Writzl et al. (2007) concluded that newborns with CHARGE syndr

Van de Laar et al. (2007) reported 3 unrelated patients with several major features of CHARGE syndrome

proposed by Verloes (2005), who also presented severe limb anomalies, including monodactyly, tibia ap (2007) suggested that limb defects should be added to the spectrum of man

Alazami et al. (2008) reported a girl, born of consanguineous Saudi Arabian parents, with CHARGE syn CHD7 gene. The patient had typical features of the disorder, including coloboma, patent ductus arteriosu retardation, and hearing loss with cup-shaped ears. She had dysmorphic facial features. In addition, she had r tibia, and near bifurcation of the right distal femur. The mother had been exposed to ciprofloxacin for 2 wee may have contributed to the severity of the phenotype. However, Alazami et al. (2008) concluded that anom another feature of the disorder, and suggested that the 'E' in CHARGE

Burkitt Wright et al. (2009) reported an infant girl diagnosed with CHARGE syndrome on the basis of choana coarctation of the aorta, facial asymmetry, ear abnormalities, and retinal colobomata. She later manifested sev she was noted to have right radial aplasia and absent thumb. The left arm was of normal length, but the left suggesting mild abnormalities. Radiographs of the right arm showed absent radius and pollux, severely b analysis identified a de novo heterozygous frameshift mutation in the CHD7 gene, resulting in haploinsuffic their report and that of Van de Laar et al. (2007), who described CHARGE syndrome patients with severe aplasia, and bifid femora, suggested that limb defects should be added to the spectrum of manifestations of CH

Population Genetics

With an estimated birth incidence of 1 in 12,000, CHARGE syndrome is a common cause of co

In a national surveillance study in Canada, Issekutz et al. (2005) found that the national incidence of CHAR but the incidence in the Atlantic provinces of Newfoundland, Labrador, and the Maritime Provinces, was as h

Pathogenesis

Bajpai et al. (2010) demonstrated that, in both humans and Xenopus, CHD7 (608892) is essential for the for a transient cell population that is ectodermal in origin but undergoes a major transcriptional reprogram differentiation potential and ability to migrate throughout the body, giving rise to craniofacial bones and pigmentation, and cardiac structures. Bajpai et al. (2010) demonstrated that CHD7 is essential for activation

including SOX9 (608160), TWIST (601622), and SLUG (602150). In Xenopus embryos, knockdown of inactive form recapitulates all major features of CHARGE syndrome. In human neural crest cells, CHD7 a remodelers occupy a neural crest-specific distal SOX9 enhancer and a conserved genomic element located u during embryogenesis CHD7 and PBAF cooperate to promote neural crest gene expression and cell migrat work identified an evolutionarily conserved role for CHD7 in orchestrating neural crest gene expression pro control of distal elements by chromatin remodelers, illuminated the pathoembryology of CHARGE syndrome in the regulation of cell motility.

Diagnosis

An analysis by Harris et al. (1997) of choanal atresia-associated malformations, present in 47% of the infa indicated that a weak, nonrandom association can be demonstrated between the malformations of the CHARG

the presence of 3 or more malformations, then of the 444 infants identified, 7% belonged to the CHARGE that for the term CHARGE to be meaningful, it should be restricted to infants with multiple malforma combined with other cardinal malformations (heart, ear, and genital), for a total of at least 3 cardinal malfo birth weight, should not be used

Verloes (2005) proposed diagnostic criteria for CHARGE syndrome. The 3 major signs were colobom anomalies, and the 5 minor signs were rhombencephalic abnormalities, hypothalamo-hypophyseal dysfu mediastinal visceral malformations, and

Blake et al. (2008) stated that cranial nerve involvement is now considered 1 of the 4 major criteria for a cli other 3 key diagnostic indicators are coloboma, choanal atresia, and characteristic ear anomalies.

Cytogenetics

Kushnick et al. (1992) reported an infant girl with the findings of CHARGE association, a 46,XY karyotype, DNA probe was also found. Emanuel et al. (1992) found evidence of microdeletion in the 22q11.2 reg syndrome. This contrasted with microdeletion in 14 of 15 cases of velocardiofacial syndrome (192430) and cardiac malformations (217095). Devriendt et al. (1998) described the case of a female child with features coloboma, large ventricular septal defect, external ear abnormalities, severe growth retardation, and

submicroscopic deletion in 22q11 detected by means of fluorescence in situ hybridization. Since there were f cat-eye syndrome, the presence of a more complex rearrangement of 22q, with a

North et al. (1995) described a 4.5-year-old girl with CHARGE association who had a de novo inverted d included iris colobomas, ventricular septal defect, soft tissue choanal atresia, intellectual impairment, apparently low-set ears, and upslanting palpebral fissures. Family history was unremarkable and parent (1995) compared the findings in their case with those in 5 reported cases of 14q duplication. Although non other findings were such as to suggest that a gene or genes causing some of the anomalies of CHARGE assoc

Hurst et al. (1991) reported a girl with CHARGE syndrome and an apparently balanced chromosome 8 trans tetralogy of Fallot, unilateral choanal atresia, abnormalities of the external ears, bilateral sensorineural tracheoesophageal fistula. Parental karyotypes were normal.

Inheritance
Lalani et al. (2006) presented 5 pedigrees with CHARGE syndrome illustrating 4 familial cases and an

mutations were identified in a family with affected brother and sister, in the monozygotic twins, and in a fami In the case of the affected brother and sister, parental gona

Jongmans et al. (2008) reported 5 unrelated families with CHARGE syndrome confirmed by genetic ana (608892.0011) showed clear parent-to-child transmission, with the parent being less severely affected than unaffected father was found to be somatic mosaic for a mutation that was present in both affected children. families, but no mutations were identified in the parents, suggesting germline mosaicism. There was wide members with the same mutation.

Molecular Genetics

Using an improved method of array comparative genomic hybridization (CGH), Vissers et al. (2004 microdeletion on chromosome 8q12 in 2 individuals with CHARGE syndrome. Sequence analysis of genes CHD7 (608892) in 10 of 17 individuals with CHARGE syndrome who did not have microdeletions, thus persons. An individual with CHARGE syndrome with an apparently balanced chromosome 8 translocatio

Lalani et al. (2006) sequenced the CHD7 gene in 110 individuals who had received a clinical diagnosis of CH 64 (58%). Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malfo asymmetry, often caused by seventh cranial nerve abnormalities. Microarray gene expression analysis sho differences that distinguished the individuals with CHARGE syndrome with

Jongmans et al. (2006) identified mutations in the CHD7 gene in 69 of 107 patients with clinical features sug stated that there were no genotype-phenotype correlations in this cohort and noted that there were differences identical mutations (see 608892.0008). Somatic mosaicism was detected in the unaffected mother of a sib mosaicism.

Udaka et al. (2007) assessed exon copy number using multiplex PCR/liquid chromatography (MP/LC) in 13 c by DHPLC had failed to identify point mutations or small insertions/deletions in the CHD7 gene. Th (608892.0010); the authors stated that this was the first CHARGE patient to

Van de Laar et al. (2007) reported 3 unrelated patients with several major features of CHARGE syndrome proposed by Verloes (2005), who also presented severe limb anomalies, including monodactyly, tibia heterozygous truncating mutations in the CHD7 gene were detected, respectively (see, e.g.,608892.0016). V defects should be added to the spectrum of manifestation

Kim et al. (2008) analyzed the CHD7 gene in 197 patients with Kallmann syndrome or normosmic hypogon

and identified 7 sporadic heterozygous mutations in 3 KS patients and 4 IHH patients, respectively (see, e mutation (608892.0012) that was found in a male patient with IHH, cleft lip, and cryptorchidism had previous a mother and 2 sons from a family with both typical and atypical CHARGE syndrome phenotypes, and a sp KS patient with cleft lip and palate and hearing loss had previously been reported by Jongmans et al. (2008) syndrome. Kim et al. (2008) concluded that both normosmic IHH and Kallmann syndrome due to CHD7 mu syndrome.

Bergman et al. (2008) excluded copy number alterations of the CHD7 gene as a major cause of CHARGE having the disorder in whom CHD7 mutations were not found, multiplex ligation-dependent probe amplifica who had a large CHD7 gene alteration, which was a partial deletion

Wincent et al. (2008) identified CHD7 mutations in 18 (64%) of 28 Swedish index patients with CHARG novel, and 3 (17%) were large deletions. The changes were de novo in all 15 cases in which parental s genotype/phenotype correlations were Mutation in the

In a patient originally described by Martin et al. (2001) with CHARGE syndrome and a de novo balanced 7, Lalani et al. (2004) mapped the translocation breakpoints and identified the semaphorin-3E gene within 20 of patients with CHARGE syndrome for mutations in the SEMA3E gene revealed a de novo mutation in an mutation was not found in either parent or in 338 ethnically Exclusion

Since PAX2 (167409) gene expression occurs in primordia affected in CHARGE association, Tellier et al. (2 fulfilling diagnostic criteria for CHARGE. The authors used 2 polymorphisms to look for deletions, and S variations. No disease-causing mutations were identified, suggesting that mutation of the PAX2 gene is no

The authors suggested that the expression pattern of PAX2 is consistent with the possibility that unidentif could be candidate genes for CHARGE.

Animal Model

Bosman et al. (2005) identified Chd7 mutations in 9 mouse lines generated by N-ethyl-N-nitrosourea ( expression of Chd7 in early development of the mouse in organs affected in CHARGE syndrome, includi vascular system. Closer inspection of heterozygous mutant mice revealed a range of defects with reduced pen septal defects of the heart, hemorrhages, prenatal death, vulva and clitoral defects, and keratoconjunctivi features of CHARGE

Layman et al. (2009) found that Chd7 +/- mice had a loss of odor-evoked electroolfactogram responses, s dysfunctional olfactory epithelium. Chd7 expression was high in basal olfactory epithelial neural stem c

sensory neurons. Chd7-deficient mice exhibited smaller olfactory bulbs, reduced olfactory sensory neuron despite apparently normal functional cilia and sustentacular cells. Significant reductions in the proliferati olfactory sensory neurons in the mature Chd7 +/- olfactory epithelium suggested critical roles for Chd7 in reg

History

The syndrome reported by Abruzzo and Erickson (1977), and cited as an instance of familial CHARGE synd et al. (1987), was demonstrated by Abruzzo and Erickson (1989) to be a separate, probably X-linked disorder See Also: Davenport et al. (1989); Dirlewanger (1966); Goldson et al. (1986); Wyse et al. (1993)

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