Neonatal Presentations of CHARGE Syndrome and VATER

Neonatal Presentations of CHARGE Syndrome and VATER/VACTERLAssociationJulie Kaplan and Louanne HudginsNeoReviews 2008;9;e299-e304DOI: 10.1542/neo.9-7-e299The online version of this article, along with updated information and services, islocated on the World Wide Web at:http://neoreviews.aappublications.org/cgi/content/full/neoreviews;9/7/e299NeoReviews is the official journal of the American Academy of Pediatrics. A monthly publication,it has been published continuously since 2000. NeoReviews is owned, published, and trademarkedby the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,Illinois, 60007. Copyright © 2008 by the American Academy of Pediatrics. All rights reserved.Online ISSN: 1526-9906.Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010

Article geneticsNeonatal Presentations ofCHARGE Syndrome and VATER/VACTERL AssociationJulie Kaplan, MD,*Louanne Hudgins, MD*Author DisclosureDrs Kaplan andHudgins havedisclosed no financialrelationships relevantto this article. Thiscommentary does notcontain a discussionof an unapproved/investigative use of acommercial product/device.Objectives After completing this article, readers should be able to:1. Describe the difference between a syndrome and an association.2. Recognize the phenotype of CHARGE syndrome as it presents in the newborn period.3. Recognize the phenotype of VACTERL association as it presents in the newborn period.4. Construct a differential diagnosis based on some of the common findings in thesedisorders.5. Initiate a plan for diagnostic evaluation and management for these two disorders.AbstractNeonatologists often care for newborns who have multiple congenital anomalies. Thespecific diagnosis has implications for the infant’s clinical management. In this article,we examine the neonatal presentations of CHARGE syndrome and VATER/VACTERL association. Once the features of these two entities are recognizedclinically, the appropriate diagnostic evaluations can be initiated.IntroductionIn evaluating a newborn who has multiple congenital anomalies, the specific diagnosis hasimplications for management and recurrence risk. An association originally was defined bythe International Group in 1982 as a “nonrandom occurrence in two or more individualsof multiple congenital anomalies not known to be a polytypic defect, sequence orsyndrome.” In general, associations do not have a known genetic cause, are not associatedwith developmental disabilities, and have a low recurrence risk for parents and the affectedindividual. A syndrome, on the other hand, generally refers to a pattern of congenitalanomalies that can be explained by a common developmental or genetic cause, often isassociated with developmental disabilities, and can have significant recurrence risk for theparents or the affected individual.The field of molecular genetics has seen remarkable advances in the past decade, and themolecular causes for various genetic conditions recently have been elucidated. CHARGEsyndrome is an example of a genetic disorder that was referred to previously as anassociation until a molecular cause was discovered. VATER/VACTERL still is referred toas an association; the acronym describes anomalies that occur together more often than bychance alone, but there is currently no known pathogenetic cause.CHARGE SyndromeIn 1979, Hall described 17 children who had multiple congenital anomalies, all of whomhad choanal atresia. Also in 1979, Hittner and associates described 10 children who hadcoloboma, congenital heart disease, and hearing loss. The acronym CHARGE initially wascoined by Pagon and colleagues in 1981 and was defined as including Coloboma, Heartdefect, Atresia choanae, Retarded growth and development, Genital hypoplasia, and Earanomalies/deafness. Because a common pathogenetic basis was discovered in 2004, theassociation now is referred to as CHARGE syndrome. CHARGE syndrome has a prevalenceof 1 per 10,000 to 1 per 15,000, and although it is an autosomal dominant disorder,most cases represent simplex cases (the first case discovered in a family).*Division of Medical Genetics, Stanford University, Stanford, Calif.NeoReviews Vol.9 No.7 July 2008 e299Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010

geneticsCHARGE and VATER/VACTERLClinical FindingsColobomas are present in 80% to 90% of patients whohave CHARGE syndrome, and retinal colobomas aremore common than iris colobomas (Fig. 1). Retinalinvolvement can affect the optic nerve or macula, leadingto impaired visual acuity. Severe chorioretinal colobomascan be associated with microphthalmia. Newborns inwhom CHARGE syndrome is suspected should receivean ophthalmologic evaluation for retinal colobomas andbe monitored by ophthalmology with an eye examinationevery 6 months.Heart defects are often complex and found in 75% to85% of those who have CHARGE syndrome. Althoughcardiac defects can vary substantially, conotruncal anomalies(tetralogy of Fallot, double-outlet right ventricle,truncus arteriosus, and perimembranous ventricular septaldefect) and aortic arch anomalies (interrupted aorticarch, vascular ring, and aberrant subclavian artery) comprise38% to 40% of the defects seen in CHARGE syndrome.Other common defects include atrioventricularcanal defects, atrial septal defects, ventricular septal defects,and patent ductus arteriosus.Choanal atresia is a blockage in the passages betweenthe nasal cavity and the nasopharynx. Affected individualsmay have a complete blockage (choanal atresia) or apartial blockage (choanal stenosis), and the blockage maybe unilateral or bilateral. Whereas bilateral choanal atresiacauses significant respiratory distress in the newborn,unilateral choanal atresia or choanal stenosis may not bedetected in the newborn period; the older child who haschoanal stenosis or unilateral choanal atresia may presentwith persistent rhinorrhea or infections. Choanal atresiaor stenosis is present in 50% to 60% of patients who haveCHARGE syndrome and should focus the clinician’sattention on involvement of other organ systems, such asthe eye and heart. Individuals who have bilateral posteriorchoanal atresia often have a prenatal history of polyhydramnios,believed to be due to an insufficient swallowingmechanism. The inability to pass a nasogastrictube should alert the clinician to the possibility of choanalatresia, but computed tomography (CT) scan of thenasopharynx and nasal cavity is necessary to evaluate thequality of the blockage. Bilateral choanal atresia is amedical emergency that should be corrected surgically assoon as possible. Chronic otitis media and deafness arepotential complications of choanal atresia.Infants affected with CHARGE syndrome typicallyhave normal growth parameters at birth, but their lineargrowth tends to decline by late infancy. Some childrenhave been found to have growth hormone deficiency,but growth deceleration frequently is due to cardiac,Figure 1. Retinal coloboma.respiratory, or feeding problems. Early intervention forfeeding difficulties is important.Most children who have CHARGE syndrome showmarked delays in motor development. Such delays can bedue to prolonged hospitalizations, truncal hypotoniawith ligamentous laxity, decreased visual acuity, or vestibulardisturbances. Language development often is delayedas well due to hearing loss. Other individuals mayhave central nervous system abnormalities that can includearrhinencephaly; holoprosencephaly; hypoplasia ofthe cerebellum, inferior cerebellar vermis, and brainstem;cerebellar heterotopias; and absence of the septum pellucidum.Due to the variable nature of the developmentaldelay, the extent of the delay should not be used topredict cognitive function. Cognitive function may rangefrom learning disabilities to profound mental retardation.Genital hypoplasia is present in about 50% to 60% ofmales who have CHARGE syndrome and can manifest asmicrophallus, hypospadias, cryptorchidism, chordee, andbifid scrotum. Female genital hypoplasia may be moredifficult to recognize externally, but hypoplastic labia andclitoris and atresia of the uterus, cervix, and vagina havebeen reported. Renal anomalies have been reported in25% to 40% of individuals and include unilateral renalagenesis, hydronephrosis, renal hypoplasia, duplex kidneys,and vesicoureteral reflux. Hypogonadotropic hypogonadismcan occur in males and females and is associatedwith delays in puberty and low concentrations ofluteinizing hormone and follicle-stimulating hormone.Ear anomalies occur in approximately 90% of childrenand can involve the outer, middle, or inner ear. Thetypical “CHARGE ear” is protuberant, short, and wide,with a hypoplastic lobule, prominent antihelix, and tri-e300 NeoReviews Vol.9 No.7 July 2008Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010

geneticsCHARGE and VATER/VACTERLangular concha (Fig. 2). Middle ear anomalies includeossicular malformations, an abnormal or absent ovalwindow, and absent stapedius muscle. Among the innerear anomalies are aplastic or hypoplastic semicircularcanals, and the Mondini defect (decreased number ofturns to the cochlea) is present in up to 95% of affectedindividuals and can be detected by CT scan of the temporalbones. Temporal bone abnormalities also may bepresent. The combination of ossicular malformations andinner ear defects frequently results in a mixed (conductiveand sensorineural) hearing loss that can range frommild to profound.Although not described in the original acronym, cranialnerve (CN) anomalies also are common and now areincluded among the major diagnostic criteria (Table).Such anomalies usually are asymmetric and can involveCN I, resulting in hyposmia or anosmia (an absentor hypoplastic olfactory bulb is highly indicative ofCHARGE); CN V, resulting in the incoordination ofsucking, chewing, and swallowing; CN VII, resulting infacial paralysis that is usually unilateral (Fig. 3); CN VIII,resulting in sensorineural hearing loss; and CN IX/X/XI, resulting in dysfunctional swallowing, gastroesophagealreflux, and velopharyngeal aspiration.A clinical diagnosis of CHARGE syndrome can bemade based on the major and minor diagnostic criteria(Table) defined by Blake and associates in 1998. Thepresence of all four major criteria (choanal atresia,coloboma, characteristic ears, and cranial nerve anomalies)or three major and three minor characteristics indicatesa diagnosis of CHARGE syndrome. The diagnosisshould be considered strongly in any neonate who exhibitsone of the major diagnostic criteria, and evaluation forabnormalities in other organ systems involved inCHARGE should be initiated.Figure 2. Hypoplastic lobule, prominent antihelix, and trangularconcha characteristic of the typical “CHARGE ear.”Genetic TestingIn 2004, Vissers and colleagues identified a molecularcause for CHARGE syndrome. The responsible gene isCHD7 (chromodomain helicase DNA-binding protein7); the encoded protein regulates gene expression byaltering chromatin structure and plays a critical role inembryogenesis. Clinical testing is currently available, andthe mutation detection frequency is approximately 60%to 65%.Despite the availability of mutation analysis,CHARGE syndrome remains a clinical diagnosis. In theneonatal period, the presence of iris or retinal coloboma,choanal atresia, characteristic ears, hearing loss, facialnerve palsy, or congenital heart defects should alert thephysician to the possible diagnosis. The evaluations initiatedin the neonatal intensive care unit should includean ophthalmology examination, echocardiography, earnose-throatevaluation, renal ultrasonography, and hearingscreen. The most sensitive diagnostic study, whichhas implications for management, is a CT scan of thetemporal bones. Approximately 95% of affected patientshave abnormalities of the inner and middle ear, includingthe Mondini defect, aplasia or hypoplasia of the semicircularcanals, and ossicular malformations. A highresolutionkaryotype should be performed to rule out achromosomal abnormality as the cause of multiple malformations.CHD7 analysis may be helpful in cases wherethe diagnosis is not clear, especially if the family is interestedin prenatal diagnosis for future pregnancies. Insimplex cases, the recurrence risk for the parents is low,but prenatal testing can be offered to the family if there isa known mutation to rule out the unlikely event ofgermline mosaicism. The individual who has CHARGEsyndrome has a 50% risk of having an affected child witheach pregnancy.VATER/VACTERL AssociationIn contrast to CHARGE syndrome, VATER (orVACTERL) association does not have a known molecularcause. VATER association initially was described byQuan and Smith in 1973, and the acronym describes thecomponents: Vertebral defects, Anal atresia, Tracheo-Esophageal fistula with esophageal atresia, and Radialand Renal dysplasia. Kaufman (1973) and Nora andNora (1975) subsequently added “C” for cardiac defectsand “L” for limb defects to broaden the acronym toVACTERL.NeoReviews Vol.9 No.7 July 2008 e301Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010

geneticsCHARGE and VATER/VACTERLTable. Diagnostic Criteria of CHARGE SyndromeFeature Manifestations FrequencyMajor Diagnostic Criteria (4 Cs)ColobomaChoanal Atresia/stenosisCranial Nerve DysfunctionCharacteristic Ear AnomaliesMinor Diagnostic CriteriaCardiovascular MalformationsColoboma of the retina, iris, choroid, and disc;microphthalmiaUnilateral or bilateral, membranous or bony, stenosis oratresiaOlfactory tract anomalies, unilateral or bilateral facial palsy,sensorineural hearing loss, velopharyngeal incoordinationOuter: Short, wide, hypoplastic lobule, prominent antihelix,triangular conchaMiddle: Ossicular malformationsInner: Aplastic or hypoplastic semicircular canals, MondinidefectTemporal bone abnormalities80% to 90%50% to 60%75% to 95%Most commonly conotruncal defects, atrioventricular canal 75% to 85%defects, and aortic arch abnormalitiesGenital HypoplasiaMales: Microphallus, cryptorchidism50% to 60%Females: Hypoplastic labiaBoth: Hypogonadotropic hypogonadismDevelopmental Delay Delayed motor milestones, delayed language, hypotonia 100%Growth DeficiencyShort stature (usually postnatal), occasional growth hormone 70% to 80%deficiencyOrofacial Cleft Cleft lippalate 15% to 20%Tracheoesophageal Fistula All types 15% to 20%Distinctive Facial FeaturesSquare face with broad prominent forehead, prominent nasalbridge and columella, flat midface70% to 80%Occasional AbnormalitiesRenal AnomaliesSpinal AnomaliesHand AnomaliesNeck/Shoulder AnomaliesGastrointestinalUnilateral renal agenesis, horseshoe kidney, hydronephrosis,renal hypoplasia, duplex kidney, vesicoureteral refluxScoliosis, kyphosis, osteoporosis, hemivertebraePolydactyly, altered palmar flexion creases, atypical splithand/split foot deformity, clinodactyly, camptodactyly,cutaneous syndactylyShort/webbed neck, Sprengel deformityOmphalocele, umbilical hernia90%Clinical FindingsVertebral defects that have been described in VACTERLassociation include hemivertebrae, congenital scoliosis,hypersegmentation defects, and sacral dysgenesis; thoracolumbarhemivertebrae have been reported most frequently.Anal atresia or stenosis requires prompt surgicalconsultation and intervention. A wide range of cardiacanomalies have been described in the VACTERL association,although septal defects appear to be most common.Tracheoesophageal fistula or esophageal atresiaoccurs in approximately 1 in 3,500 births and is associatedwith other anomalies in about 50% of cases. Renalanomalies include renal agenesis, ureteropelvic junctionobstruction, and severe reflux. Limb defects tend toinvolve the upper limbs more often than the lower limbs;with upper limb involvement, the radial bones are affectedmore frequently than the ulnar bones. Radialaplasia, deviation of the hand, absence of the thumb,hypoplastic and rudimentary thumb, and preaxial polydactylyhave been described.Individuals who have VACTERL association usuallydo not have dysmorphic facial features, abnormalities ofgrowth, or mental deficiency. Therefore, VACTERL is adiagnosis of exclusion that should not be made until atleast 1 year of age, when growth and development can beconfirmed to be normal.The differential diagnosis in the newborn periodincludes CHARGE syndrome, 22q11 deletion syndrome,and Townes-Brocks syndrome. Infants who haveCHARGE syndrome can have cardiac defects, tracheoesophagealfistula, vertebral anomalies, and renal anomalies.If the diagnosis of CHARGE syndrome is consid-e302 NeoReviews Vol.9 No.7 July 2008Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010

geneticsCHARGE and VATER/VACTERLis usually sporadic. VACTERL-H is associated with apoorer prognosis in terms of survival and mental handicap.Overlap in the features associated withVACTERL-H and Fanconi anemia has been reported inseveral cases. Fanconi anemia is an autosomal recessivedisorder of DNA repair that leads to bone marrow failurein childhood and increased risk of malignancy; diagnosiscan be made using chromosomal breakage studies. In2005, Faivre and associates recommended chromosomalbreakage studies in cases of VACTERL-H and cases ofVACTERL in which the infant has dysmorphic features,skin pigmentation abnormalities, growth retardation, ormicrocephaly.Figure 3. Unilateral facial paralysis caused by an anomaly ofcranial nerve VII.ered, a CT scan of the temporal bones should beobtained to look for the suggestive middle and inner eardefects. The phenotype of 22q11 deletion syndrome isextremely variable; cardiac and renal anomalies are common,but anomalies in almost every organ system havebeen reported. Newborns who have a 22q11 deletionfrequently exhibit a distinctive facial appearance (laterallybuilt-up nasal bridge, small mouth, and short palpebralfissures), long fingers and toes, and possibly hypocalcemia.A fluorescence in situ hybridization study for22q11.2 deletion can be ordered to exclude this diagnosis.Townes–Brocks syndrome is characterized by thetriad of imperforate anus, dysplastic ears (with or withoutpits or tags and hearing loss), and thumb anomalies(triphalangeal thumbs, preaxial polydactyly, or hypoplasticthumbs). Affected infants also may have cardiac andrenal anomalies. This syndrome should be considereddue to the considerable overlap in phenotype. Clinicallyavailable genetic testing for Townes-Brocks syndromehas a detection rate of 70% to 75%.Multiple case reports have linked hydrocephalus withVACTERL association (VACTERL-H). VACTERL-Hmay represent a distinct syndrome because both autosomalrecessive and X-linked patterns of inheritancehave been described. In contrast, VACTERL associationGenetic TestingIf VACTERL association is considered, evaluations inthe neonatal period should include echocardiography,renal ultrasonography, radiographs of the spine, radiographsof the extremities if abnormalities are noted onexamination, and an ophthalmologic evaluation. Inaddition, high-resolution chromosome analysis and agenetics consultation should be obtained to excludeother genetic causes. The recurrence risk for parents andfor the individual is low, and the cause is unknown,although VACTERL is related to maternal diabetes inthe minority of cases.SummaryAlthough CHARGE syndrome and VACTERL associationhave several features in common, the distinctionbetween these two entities affects management, prognosis,and recurrence risk. In addition, a broad differentialdiagnosis needs to be considered in any patient whohas features of VACTERL association because this is adiagnosis of exclusion. A genetics evaluation should beconsidered for any newborn who has multiple congenitalanomalies.Suggested ReadingBlake KD, Devenport SL, Hall BD, et al. CHARGE association: anupdate and review for the primary pediatrician. Clin Pediatr.1998;37:159–173Blake KD, Hartshorne TS, Lawand C, Dailor AN, Thelin JW.Cranial nerve manifestations in CHARGE syndrome. Am J MedGenet. 2008;146A:585–592Blake KD, Prasad C. CHARGE syndrome. Orphanet J Rare Dis.2006;1:34Corsello G, Maresi E, Corrao AM, et al. VATER/VACTERLassociation: clinical variability and expanding phenotype includinglaryngeal stenosis. Am J Med Genet. 1992;44:813–815NeoReviews Vol.9 No.7 July 2008 e303Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010

geneticsCHARGE and VATER/VACTERLCox PM, Gibsin RA, Morgan N, Brueton LA. VACTERL withhydrocephalus in twins due to Fanconi anemia (FA): mutationin the FAC gene. Am J Med Genet. 1997;68:86–90Faivre L, Portnoi MF, Pals G, et al. Should chromosome breakagestudies be performed in parents with VACTERL association?Am J Med Genet. 2005;137:55–58Hall BD. Choanal atresia and associated multiple anomalies. J Pediatr.1979;95:395–398Hittner HM, Hirsch NJ, Kreh GM, Rudolph AJ. Colobomatousmicrophthalmia, heart disease, hearing loss, and mentalretardation—a syndrome. J Pediatr. 1979;16:122–128Jongmans MC, Admiraal RJ, van der Donk KP, et al. CHARGEsyndrome: the phenotypic spectrum of mutation in the CHD7gene. J Med Genet. 2006;43:306–314Kallen K, Mastroiacovo P, Castilla EE, Robert E, Kallen B. VATERnon-random association of congenital malformations: studybased in data from four malformation registers. Am J MedGenet. 2001;101:26–32Kaufman RL. Birth defects and oral contraceptives. Lancet. 1973;1:1396Lalani SR, Hefner M, Belmont JW, Davenport SLH. CHARGEsyndrome. GeneReviews at Genetests: Medical Genetics InformationResource. 2007. Available at: www.genetests.orgNora AH, Nora JJ. A syndrome of multiple congenital anomaliesassociated with teratogenic exposure. Arch Environ Health.1975;30:17–21Quan L, Smith DW. The VATER association. J Pediatr. 1973;82:104–107Raqbi F, Bihan CL, Morisseau-Durand MP, Dureau P, Lyonnet S,Abadie V. Early prognostic factors for intellectual outcome inCHARGE syndrome. Dev Med Child Neurol. 2003;45:483–488Russell-Eggitt IM, Blake KD, Taylor DSI, Wyse RKH. The eye inthe CHARGE association. Br J Ophthalmol. 1990;74:421–426Shaw-Smith C. Oesophageal atresia, tracheo-oesophageal fistula,and the VACTERL association: review of genetics and epidemiology.J Med Genet. 2006;43:545–554Temtamy SA, Miller JD. Extending the scope of the VATERassociation: definition of the VATER syndrome. J Pediatr.1974;85:345–349Vissers L, Ravenswaaij C, Admiraal R, et al. Mutations in a newmember of the chromodomain gene family cause CHARGEsyndrome. Nature Genet. 2004;36:955–957NeoReviews Quiz7. A syndrome is a pattern of congenital anomalies that can be explained by a genetic abnormality, often isassociated with developmental disability, and can have a significant recurrence risk for the parents or theaffected individual. The clinical manifestations of a syndrome often are classified as major and minordiagnostic criteria. Of the following, the major diagnostic criterion with the highest frequency ofoccurrence for CHARGE syndrome is:A. Cardiovascular malformation.B. Choanal atresia.C. Cranial nerve dysfunction.D. Genital hypoplasia.E. Intrauterine growth restriction.8. An association is a pattern of congenital anomalies that does not have a known genetic cause, rarely leadsto developmental disability, and has a low recurrence risk for the parents or the affected individual.VACTERL association is a typical example of an association of congenital anomalies. Of the following, thecongenital anomaly most characteristic of VACTERL association is:A. Facial dysmorphism.B. Mondini inner ear defect.C. Tetralogy of Fallot.D. Thoracolumbar hemivertebrae.E. Triphalangeal thumbs.e304 NeoReviews Vol.9 No.7 July 2008Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010

Neonatal Presentations of CHARGE Syndrome and VATER/VACTERLAssociationJulie Kaplan and Louanne HudginsNeoReviews 2008;9;e299-e304DOI: 10.1542/neo.9-7-e299Updated Information& ServicesPermissions & LicensingReprintsincluding high-resolution figures, can be found at:http://neoreviews.aappublications.org/cgi/content/full/neoreviews;9/7/e299Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at:http://neoreviews.aappublications.org/misc/Permissions.shtmlInformation about ordering reprints can be found online:http://neoreviews.aappublications.org/misc/reprints.shtmlDownloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010