Neonatal Presentations of CHARGE Syndrome and VATER

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