Neonatal Presentations of CHARGE Syndrome and VATER

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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
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Neonatal Presentations of CHARGE Syndrome and VATER

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