Neonatal Presentations of CHARGE Syndrome and VATER

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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
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Neonatal Presentations of CHARGE Syndrome and VATER

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