Updates on the care and genetics of children with CHARGE SyndromeSeema - PDF document

Updates on the care and genetics of children with CHARGE SyndromeSeema R. Lalani, MDAssociate ProfessorDepartment of Molecular and Human GeneticsBaylor College of Medicine, Houston, TX ObjectivesRecognize the features of CHARGE

syndromeIdentify the medical concerns in CHARGE syndrome CHARGE syndromeoloboma, eart defects, choanal tresia, etarded growth and development, enital abnormalities, and ar anomalies/deafness Occurs in one in 10,000 births How

does a parent describe CHARGE syndrome? Imagine for a moment, a baseball cap on your head pulled all the way over your eyes, so that your only vision is your side vision. Imagine for a minute hearing the sounds around you at a

whisper so that you have to strain to hear every word. Imagine every morsel you ingest being declared a featbecause it requires the concentration of every brain cell. Now imagine living like this for the rest of your life. If t

hat does not define a hero then what does? Clinical features of children with CHARGE syndrome CharacteristicsManifestationsFrequencyOcular olobomaColoboma of the iris, retina, choroid, disc; microphthalmoshoanal atresia or sten

osis Unilateral/bilateral: bony/membranous,atresia/stenosisranial nerve dysfunction or anomalyI: Hyposmia or anosmiaFrequentVII: Facial palsy (unilateral or bilateral)VIII: Hypoplasia of auditory nerveFrequentIX/X: Swallo

wing problems with aspirationharacteristic CHARGE syndrome earOuter ear: Short, wide ear with little or no lobe, often protrude, usually asymmetricMiddle ear: Ossicular malformationsMondini defect of the cochlea Temporal bone a

bnormalities; absent or hypoplastic semicircular canalsBlakes Major Diagnostic Criteria CharacteristicsManifestationsFrequencyGenital hypoplasiaMales: Micropenis, cryptorchidism; Females: Hypoplastic labiaBoth: Delayed pubertyD

evelopmental delayDelayed milestones, hypotonia≤100%Cardiovascular malformationIncluding conotruncal defects(e.g., tetralogy of Fallot), AV canal defects, and aortic arch anomaliesGrowth deficiencyShort stature, usually postn

atal with or without growth hormone deficiencyOrofacial cleftCleft lip and/or palateTracheoesophagealfistulaTE defects of all typesDistinctive facial featuresSquare face with broad prominent forehead, prominent nasal bridge and

columella, flat midface Blakes Minor Diagnostic Criteria DiagnosisDefinite CHARGE syndrome. Individuals with all four majorcharacteristics or three major and three minorcharacteristics Probable/Possible CHARGE syndromeIndividu

als withone or two major characteristics and several minor characteristics. We have about 20,000 plus genesHuman genome has about 3 billion lettersOnly 1.5 % of that are functional players geneVissers et al. (2004) reported mu

tations in CHD7 gene in individuals with CHARGE syndrome CHDgenes play an important role in regulating early embryonic development and cell cycle control by affecting chromatin structure and gene expression CHD7mutation(Misspel

ling)The majority of children with CHARGE syndrome have a mutation in the CHD7 geneIn the majority of individuals, the mutation is not inherited from a parentThe empiric risk of having another child with CHARGE syndrome is abou

t 1%2% when parents are unaffectedIf a parent is affected, then the risk of having another child with CHARGE syndrome is 50% What does it mean when CHD7sequencing is normal in CHARGE diagnosis? There can be DELETION of the CHD

7gene rather than misspelling! The entire CHD7gene is missing, along with other genesCHD7 Chromosomal microarray analysis in a 2week old infantDeletion of CHD7on chromosome 8 Heart defectCleft palateSmall right kidneyHearing l

ossInner ear abnormalitiesNo colobomas Familial cases? There are rare familial cases in which a parent or a sibling may also be affected There is significant intrafamilial variability associated with CHD7 mutations CHA 166R23

19SR2319S ColobomaHearing lossDelayed pubertyColobomaHearing lossEar malformation CHA 19 VSD, ASD, PDAColobomaChoanal atresiaTE fistulaR1069X R1069X TOFColobomaCleft lip/palate Management of children with CHARGE syndromeAirwayc

an be compromised due to many reasons:Choanal atresia, TE fistula, aspiration pneumonias, and tracheomalacia (about 15%60% of individuals with CHARGE syndrome require tracheostomy) Heart defects: managed as in any individual wi

th a congenital heart defectChoanal atresia:Multiple surgeries for often required for correctionwww.genereviews.org Management of children with CHARGE syndromeColobomas: Visual field defects can result from retinal coloboma an

d central visual defects resulting from optic nerve involvement. Sign language may need to be presented in child's lower visual fieldHearing loss should be assumed until proven otherwise. Hearing aids and hearing habilitation (

which may include sign language) should be started as soon as hearing loss is documented. Cochlear implants have been successful in a subset of childrenDeafblind service referral www.genereviews.org Management of children with

CHARGE syndromeFeeding/swallowing dysfunction. A multidisciplinary approach is needed with specialists in speechlanguage pathology, occupational therapy, and nutrition For children with Gtube, oral stimulation needs to be maint

ained to reduce future oral sensitivity/aversionwww.genereviews.org Management of children with CHARGE syndromeRenal: Kidney evaluation is recommended in all children with CHARGE syndromeEndocrinology: Referral for decelerating

linear growth; GH treatment may be needed; hypogonadotropic hypogonadism www.genereviews.org ConclusionsCHARGE syndrome is a recognizable genetic condition characterized by a specific combination of congenital anomaliesThe maj

ority of children with CHARGE syndrome have a de novo mutation in the CHD7geneA multidisciplinary team is required for management of complex problems in children with CHARGE syndrome CHARGE syndrome FoundationParental support g