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Common Dysmorphic Syndromes in the NICU Nader Bishara and Carol L. Clericuzio NeoReviews 2008;9;e29-e38 DOI: 10.1542/neo.9-1-e29

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/cgi/content/full/neoreviews;9/1/e29

NeoReviews is the official journal of the American Academy of . A monthly publication, it has been published continuously since 2000. NeoReviews is owned, published, and trademarked by 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 Common Dysmorphic Syndromes in the NICU Nader Bishara, MD,* Objectives After completing this article, readers should be able to: Carol L. Clericuzio, MD† 1. Recognize the phenotypes of selected dysmorphic conditions encountered in the neonatal intensive care unit. Author Disclosure 2. Describe appropriate medical management, /recurrence risk information, and Drs Bishara and prenatal diagnostic options for the disorders. Clericuzio did not 3. Delineate the clinical applications of routine and high-resolution chromosome studies, disclose any financial fluorescence in situ hybridization, and array comparative genomic hybridization. relationships relevant 4. Explain how to use three Internet-based databases (PubMed, OMIM, GeneReviews) to to this article. help diagnose and treat infants who have dysmorphic conditions.

Abstract Neonatologists are responsible for the care of newborns who have a wide variety of critical illnesses, including complications of multiple congenital anomalies. This review article provides an overview of state-of-the art information on the diagnosis and management of a number of genetic disorders frequently encountered in the neonatal intensive care unit (NICU). The latest diagnostic tool for children who have unknown syndromes (array comparative genomic hybridization) as well as Internet-based search engine databases that can be accessed from the NICU are examined.

Introduction The fields of perinatal and neonatal medicine have seen remarkable advances in the past 3 or 4 decades, particularly in regard to the diagnosis and management of genetic disorders. Improvements in amniocentesis, chorionic villous sampling (CVS), and high-resolution three-dimensional ultrasonographic imaging are some of the advances. High-resolution chromosome studies, fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH) are some of the tools that have increased the ability to diagnose genetic disorders. Genetic conditions have an impact on physical health, but also have psychological and social implications for the patient and his or her family. It is essential to understand the general aspects of genetic disorders encountered in the perinatal and neonatal periods and the tools available for diagnosis. Those who have an affected child often are faced with difficult family planning decisions because the diagnosis may affect future pregnancies. Depending on the diagnosis, parents may be faced with choices regarding prenatal testing and pregnancy termination.

Lethal or Semilethal Multiple Malformation Syndromes 18 – Trisomy 18 and other trisomy syndromes are associated with increased maternal age. Trisomy 18 is the second most common autosomal trisomy syndrome seen in liveborn children, with an average incidence of 1 per 3,000. Typically, affected infants are small for gestational age and have a history of maternal polyhydramnios. Multiple maternal serum marker screening can detect many cases of trisomy 18 prenatally. Characteristic facial

*Division of , Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM. †Division of Clinical Genetics/Dysmorphology, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM.

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Figure 1. Small-for-gestational age infant who has trisomy 18, showing short palpebral fissures, hypertrichosis of the forehead, short sternum, clenched hands, hypoplastic genitalia, and malformed foot. The infant also had cardiac and renal anomalies. features include , prominent occiput, small Other birth defects include holoprosencephaly, both typical mouth and jaw, low-set and malformed ears, short pal- and nontypical clefting, cardiac anomalies (most commonly pebral fissures, and mild hypertrichosis of the forehead ventricular septal defect), omphalocele, postaxial polydac- and back (Fig. 1). The hands are often clenched with tyly, cystic dysplastic kidneys, cutis aplasia, and “rocker- overlapping fingers, and the sternum usually is short. bottom” feet with prominent calcanei. Cardiac defects are common but typically nonlethal. The condition is associated with profound mental The neonatal course is complicated by poor sucking abilities, necessitating nasogastric tube feedings. How- ever, even with adequate caloric intake, infants usually fail to thrive. They exhibit after the initial hypotonic neonatal phase. More than 50% die within the first week after birth, although 10% are still alive by 1 year of age. Trisomy 18 is considered a semilethal syndrome because of this small but definite number of survivors beyond 1 year. Diagnosis can be confirmed by a 48-hour culture of lymphocytes in the cytogenetics laboratory. Overnight FISH can yield a more rapid result if the infant is medi- cally unstable, but a karyotype always ultimately is re- quired to rule out a translocation. The recurrence risk is 1%, and future pregnancies can be tested by CVS or amniocentesis.

Trisomy 13 – Figure 2. Interphase amniocyte fluorescence in situ hybridiza- Trisomy 13 is the third most common autosomal trisomy tion (FISH) of a female who has trisomy 13 showing three blue (Fig. 2), with an incidence of 1 per 10,000. Liveborn infants hybridization signals for centromeres and two typically have normal birthweights but have microcephaly. red hybridization signals for centromeres. e30 NeoReviews Vol.9 No.1 January 2008 Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010 genetics dysmorphology

Triploidy Triploidy is the presence of 69 chromosomes (Fig. 3). Fetuses that survive exhibit severe growth re- striction and typically have syndac- tyly and clubfeet (Fig. 4). Chromo- some studies from either placental or fetal tissue should be obtained for confirmation. The recurrence risk is not increased for future preg- nancies.

Osteogenesis Imperfecta Type II Osteogenesis imperfecta type II is a lethal skeletal dysplasia and is the Figure 3. 69,XXX triploidy karyotype. most severe type of osteogenesis retardation, and the median survival for affected infants is 7 days. Most infants die within the neonatal period, although as with trisomy 18, 10% are still alive by 1 year of age. Diagnosis, recurrence risk, and prenatal diagnosis are the same as for trisomy 18.

Figure 4. A 23-week triploid fetus who exhibits severe growth Figure 5. Osteogenesis imperfecta type II. Note the “ribbon- restriction and syndactyly. like” fractured long bones and deficient skull ossification.

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Patients rarely survive beyond the neonatal period due to the severe CNS and renal defects as well as pulmonary hypoplasia (due to com- pression of the fetal lungs by the large kidneys). The recurrence risk is 25%, and prenatal diagnosis can be made by fetal ultrasonography or DNA analysis for known .

Nonlethal Multiple Malformation Syndromes Trisomy 21 is the most com- Figure 6. An infant who has Meckel-Gruber syndrome exhibits occipital encephalocele mon pattern of malformations in and enlarged abdomen due to polycystic kidneys. humans, with an incidence of 1 per 800. Like other , it is asso- imperfecta subtypes. It is due to a defect in the that ciated with increased maternal age. Down syndrome is code for type I procollagen (COL1A1 and COL1A2). characterized by generalized , brachycephaly Most cases are sporadic mutations and have a recurrence with mild microcephaly, upslanting palpebral fissures, risk of up to 6% due to gonadal mosaicism in one of the epicanthal folds, and small ears. The hands are relatively parents. The condition is characterized by short limbs, short, with hypoplasia of the mid-phalanx of the fifth ribbonlike long bones (Fig. 5), and multiple fractures, finger and clinodactyly, single transverse palmar creases, most commonly seen in utero with callus formation. The and wide gap between first and second toes. Cardiac ribs are beaded, and the long bones are markedly de- defects occur in 40% of patients and include endocardial formed. Craniofacial features include large fontanelles, deficient calvarial ossification, shallow orbits, blue sclerae, and low nasal bridge. Most infants are either stillborn or die in the neonatal period, primarily from respiratory failure due to pulmonary hypoplasia and frag- ile ribs or due to central nervous system (CNS) malfor- mations or hemorrhages. Prenatal diagnosis is by fetal ultrasonography or DNA analysis for known procollagen mutations.

Meckel-Gruber Syndrome Meckel-Gruber syndrome is a rare autosomal recessive disorder characterized by large polycystic kidneys, post- axial polydactyly, and occipital encephalocele (Fig. 6).

Figure 8. Excess posterior nuchal skinfolds in Turner syn- Figure 7. Pedal edema in . drome. e32 NeoReviews Vol.9 No.1 January 2008 Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010 genetics dysmorphology

cushion defects, ventricular septal defect, patent ductus Turner Syndrome arteriosus, and atrial septal defect. Turner syndrome (TS) should be suspected in female In all cases of suspected trisomies, routine chromo- infants who have evidence of fetal edema (Fig. 7), such as some analysis should be ordered. Ninety-five percent of excess posterior nuchal skin folds (Fig. 8) or dorsal patients have nondisjunction trisomy 21. The recurrence edema of the feet with small nails. Females who have risk is 1% until exceeded by the maternal age-related risk critical aortic stenosis due to bicuspid aortic valve or (maternal age 40 y). Parents do not need to undergo coarctation of the aorta also should undergo karyo- karyotyping unless there is a translocation chromosome, typing. Affected infants often are small at birth. TS is in which case the recurrence risk depends on whether one caused by the partial or complete absence of one of the of the parents carries the translocation chromosome. X chromosomes. Half are , eg, 45,X/46,XX. Rou- Approximately 1% of infants who have Down syndrome tine chromosome studies should be obtained for diagno- have mosaic trisomy 21, a mixture of normal and trisomic sis, and if TS is diagnosed, an additional 200 cells should cells, and the recurrence risk for this defect is the same as be screened with X and FISH probes to for typical nondisjunction trisomy 21. Prenatal diagnosis rule out the presence of a Y chromosome. Medical man- is performed by CVS or amniocentesis. Although first agement involves cardiology evaluation for bicuspid aor- and second trimester maternal screening is offered to all tic valve, coarctation of the aorta, valvular aortic stenosis, pregnant women, this does not replace diagnostic studies and mitral valve prolapse. Renal ultrasonography is indi- for couples at high risk. cated because 40% of affected infants have renal anoma-

Figure 9. The upper left two chromosome 7s have no , as indicated by the presence of the two pink signals indicating hybridization of the ELN probe. The green probes are control probes. In contrast, the lower left (from a different patient), has no pink hybridization signal, indicating an ELN deletion, which is diagnostic of . The right two panels represent the results of an array comparative genomic hybridization (aCGH) of both patients. On the upper right, genomic material along the length of chromosome 7 shows no significant deviation from baseline, ie, no loss or gain of genomic material. On the lower right, the red arrow indicates a deficiency of genomic material at the ELN , diagnostic of Williams syndrome. Data slide courtesy of Kate Rauen, MD, PhD.

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Figure 10. Genetic mechanisms leading to Prader-Willi syndrome (PWS). Note that the 15q11–13 critical PWS region normally is imprinted (turned-off) in the maternal chromosome, indicated by the black bar. lies such as horseshoe . There is no increased risk for future pregnancies. TS is suspected prenatally when fetal nuchal cystic hygroma or edema/hydrops is identi- fied.

5p- Syndrome (Cri du chat) 5p- syndrome should be suspected in infants who are small for gestational age, exhibit microcephaly with a round face and with downward slant of the palpebral fissures, and have single palmar transverse creases. Affected infants often have a characteristic catlike cry in infancy due to hypotonia and laryngeal abnormal- ities. Most patients have moderate-to-severe mental re- tardation. In contrast to cytogenetic evaluation for sus- pected trisomies, a high-resolution rather than routine chromosome study should be obtained. The high- resolution study is required to look for small genomic duplications or deletions; routine resolution is less ex- pensive and adequate to determine the number of chro- mosomes. If high-resolution chromosomes appear nor- mal, but clinical suspicion remains high, FISH for 5p should be requested. De novo deletions are responsible Figure 11. Infant who has Beckwith-Wiedeman syndrome, for 85% of cases, and 15% are due to parental transloca- exhibiting macrosomia, macroglossia, and a repaired ompha- tions. Therefore, in all cases, parents should be offered locele. This infant subsequently developed hepatoblastoma. e34 NeoReviews Vol.9 No.1 January 2008 Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010 genetics dysmorphology

Figure 12. Postmortem picture of Pfeiffer syndrome. Note the cloverleaf skull and broad medially deviated thumb and great toe. chromosome analysis. Prenatal diagnosis by CVS or am- Hence, the syndrome descriptions reflect the phenotypic niocentesis is available for pregnancies at risk. variability of this very common chromosomal deletion. Current practice is to evaluate all patients who have Microdeletion Syndromes congenital heart for this deletion. When sus- Microdeletion syndromes are recognizable disorders pected, high-resolution chromosome studies and FISH caused by chromosomal deletions that span several genes for del 22q11.2 should be ordered. The laboratory needs and frequently are too small to be detected by conven- to know the indication for the study, eg, congenital heart tional and high-resolution cytogenetic methods. Molec- defect and cleft palate. Parents of affected infants should ular cytogenetic techniques, including FISH and aCGH, be offered the FISH deletion study because 7% have been are used to diagnose these conditions. found to carry the deletion, and recurrence risk is depen- dent on whether the deletion is de novo (very low risk) or VELOCARDIOFACIAL/DIGEORGE (DEL 22Q11.2) SYNDROME. due to parental deletion (50% risk for future pregnan- Originally, this condition had two independent syn- cies). Prenatal diagnosis is accomplished by CVS or am- drome descriptions. In 1965, DiGeorge described un- niocentesis, and the FISH testing must be specifically derdevelopment of the and parathyroids that requested. caused neonatal , conotruncal cardiac de- fects (eg, interrupted aortic arch, and WILLIAMS SYNDROME (DEL 7Q11.23). Williams syn- ), broad facies, minor ear anomalies, drome is characterized by growth restriction; character- and feeding problems. In 1981, the cause was found to istic facial features, including broad forehead, periorbital be deletion of at q11.2. In 1978, fullness, long philtrum, and wide mouth; supravalvular Sphrintzen described a syndrome that encompassed cleft aortic stenosis; and idiopathic hypercalcemia in 15% of palate, with a long narrow face, affected patients. Diagnosed patients should undergo tubular nose with round tip, ventricular septal defect, renal ultrasonography and evaluation for feeding difficul- and growth and learning deficiency. This syndrome is ties. Williams syndrome is caused by a deletion of the inherited as an autosomal dominant condition and in (ELN) and others at 7q11.23. When suspected, high- 1992 also was found to be due to the 22q11.2 deletion. resolution chromosome studies and FISH for del 7q11.23

Table. Distinguishing Clinical Features of FGFR-related Craniosynostosis Syndromes

Disorder Hands Thumbs Feet Great Toe Crouzon Normal Normal Normal Normal Pfeiffer Variable syndactyly Broad and medially deviated Variable syndactyly Broad and medially deviated Apert Bone syndactyly May be fused to fingers Bone syndactyly May be fused to toes

Modified from www.genetests.org—see Suggested Reading.

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should be ordered. Virtually all deletions are de novo, and parental studies usually are not indicated. The microdeletion in Williams syndrome also can be detected by aCGH and FISH (Fig. 9). The aCGH study has the power to detect smaller genomic imbalances than high-resolution chromosome studies and allows for screening of the entire genome. In Figure 9, the array results for chromosome 7 only are depicted, but com- mercially available arrays cover the entire genome.

Imprinting Disorders Normally, each gene is represented by two copies or alleles inherited from each parent at the time of fertilization, and they function equally well whether maternally or paternally inherited. However, less than 1% of genes are imprinted, meaning that there is a parent-of-origin difference in gene expression. Several recognizable disorders are due to errors in imprinted genes. In the neonatal setting, the two most common imprinting disorders are Prader-Willi and Beckwith-Wiedemann syndromes.

PRADER-WILLI SYNDROME (PWS). PWS is character- ized by severe neonatal hypotonia, undescended testes/ hypoplastic scrotum, and severe feeding difficulties that require intervention. Females may show hypoplastic labia Figure 13. Typical presentation of VATER association, with minora. Other findings include almond-shaped eyes, nar- left radial ray deficiency, vertebral anomalies, anal atresia, and row bifrontal diameter, and thick saliva. PWS is due to lower limb defects. The patient also had congenital heart the absence of the paternally contributed genes at disease and a single kidney. 15q11–13, which can arise by three different mecha- nisms (Fig. 10). Some 70% of cases are due to a paternal deletion at 15q11–13. Maternal , ie, two chromosomes from the same parent, accounts for 25% of cases. Abnormal persistence of the im- print on the paternal accounts for the remaining 5%. Diagnosis of PWS is confirmed by a DNA methylation study, which looks for the presence of ap- propriately imprinted maternal and paternal 15 chromosomes. Absence of a paternally imprinted 15 is diag- nostic of PWS, regardless of the mechanism. Because FISH for del 15q11–13 detects only 70% of af- fected infants, DNA methylation is the preferred diagnostic test. Karyotype also is ordered routinely to Figure 14. Bilateral thumb abnormalities in a patient who has Fanconi anemia syndrome rule out translocations. The recur- after stem cell transplant for . She originally was diagnosed with VATER rence risk usually is low, although its association on the basis of vertebral anomalies, radial ray defects, and renal anomaly. determination can be complicated, e36 NeoReviews Vol.9 No.1 January 2008 Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010 genetics dysmorphology

and genetic consultation is recommended if the family Bilateral coronal craniosynostosis or cloverleaf skull is the wishes to learn the risk for future pregnancies. (Editor’s characteristic cranial feature in all (Fig. 12). The syn- Note: See also NeoReviews. 2005;6:e559–e566.) dromes are distinguished by the limb findings (Table). Cleft palate or choanal atresia may result in upper airway BECKWITH-WIEDEMANN SYNDROME (BWS). BWS is obstruction. Proptosis is common and may lead to expo- a congenital overgrowth syndrome characterized by sure keratopathy. Spinal radiographs are needed to eval- macroglossia, hemihyperplasia, abdominal wall defects uate for vertebral anomalies and computed tomography (omphalocele or umbilical hernia), , ear scan or magnetic resonance imaging are required to lobe creases, and posterior helical pits (Fig. 11). The assess for hydrocephalus. Most patients need treatment diagnosis is based on the presence of three of the clinical at a craniofacial center by the age of 2 to 3 months. findings noted previously. Six known mechanisms lead to Recurrence risk depends on whether one of the parents is BWS, involving a handful of imprinted genes at 11p15.5, affected, in which case the recurrence risk is 50%. Prena- including paternal IGF2, which usually is overexpressed. tal diagnosis by fetal ultrasonography or molecular anal- Molecular studies are available in clinical laboratories, ysis for known mutations is available. and all children should undergo a high-resolution chro- mosome study to evaluate for a familial translocation. VATER/VACTERRL Association Approximately 20% of individuals who have BWS have a VATER/VACTERRL is an acronym for the nonrandom familial that can be detected by molecular association of vertebral, anal, cardiovascular anomalies, analysis. The recurrence risk is low, except for familial tracheoesophageal fistula, renal or radial anomalies, and translocation and mutations. Prenatal diagnosis includes other limb anomalies (Fig. 13). Three anomalies gener- fetal ultrasonography and molecular/cytogenetic analy- ally are required to make the diagnosis. The condition sis for families who have those abnormalities. BWS oc- usually is nonhereditary and nongenetic, although it is curs with increased frequency in pregnancies achieved by seen with increased frequency in infants of woman who in vitro fertilization. have insulin-dependent diabetes. Because the same Because 5% to 10% of children who have BWS develop anomalies can be seen in Fanconi anemia syndrome (FA) malignant kidney (Wilms), liver, or adrenal tumors, recog- (Fig. 14), it is very important to consider this diagnosis, nition of this syndrome is important to establish the tumor particularly if a radial ray defect is present. FA is an screening protocol. Abdominal ultrasonography and mea- autosomal recessive cancer syndrome diagnosed by chro- surement of serum alpha-fetoprotein (AFP) at diagnosis mosomal breakage studies. Consultation with clinical and every 3 months until age 4 years plus subsequent genetics is recommended if there are any concerns re- quarterly abdominal ultrasonography until 8 years of age is garding the diagnosis of FA. recommended. Normal AFP values at birth are extremely high, and reference values should be consulted. Suggested Reading CORNELIA DE LANGE SYNDROME. Cornelia de Lange Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. 2nd syndrome is characterized by pre- and postnatal growth ed. Wilmington, De: Wiley-Liss; 2004 restriction and a distinctive facial appearance that in- de Revel TJ, Devriendt K, Fryns JP, Vermeesch JR. What’s new in cludes arched eyebrows and synophrys, long eyelashes, karyotyping? The move towards array comparative genomic hybridisation (CGH). Eur J Pediatr. 2007;166:637–643 anteverted nares, long philtrum, and thin upper lip with Faivre L, Portnoı¨MF, Pals G, et al. Should chromosome breakage a central peak. Affected individuals may have upper limb studies be performed in patients with VACTERL association? Am J deficiencies, including oligodactyly. Virtually all infants Med Genet. 2005;137:55–58 have gastroesophageal reflux and feeding difficulties. Jessica MJ, Laurie AD. Genetic syndromes determined by alter- A number of affected patients have mutations in the ations in pathways. NeoReviews. 2007;8: e120–e126 NIPBL gene. More than 99% of cases are sporadic with Jones KL, ed. Smith’s Recognizable Patterns of Human Malforma- low recurrence risk, although rare autosomal dominant tion. 6th ed. Philadelphia, Pa: WB Saunders; 2005 families have been reported. Online Mendelian Inheritance in Man, OMIM.TM Available at: http://www.ncbi.nlm.nih.gov/omim/ FGFR-related Craniosynostosis Syndromes: Robin NH, Falk MJ, Haldeman-Englert CR. FGFR-related cranio- synostosis syndromes. In: GeneReviews at GeneTests: Medical Crouzon, Pfeiffer, and Apert Genetics Information Resource (database online). © University Most individuals who have these disorders have new of Washington, Seattle. 1997–2007. Available at http:// autosomal dominant mutations in the FGFR2 gene. www.genetests.org. Accessed October 2007

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NeoReviews Quiz

9. A newborn female, who weighs 2,800 g at an estimated gestational age of 37 weeks, has clinical findings of occipital encephalocele, postaxial polydactyly, enlarged abdomen from polycystic kidneys, and hypoplastic lungs. A lethal or semilethal multiple malformation syndrome is suspected. Of the following, the most likely diagnosis in this infant is: A. Edwards syndrome. B. Meckel-Gruber syndrome. C. Osteogenesis imperfecta type II. D. Patau syndrome. E. Triploidy.

10. A newborn male, who weighs 1,800 g at an estimated gestational age of 38 weeks, has clinical findings of microcephaly with a rounded face, hypertelorism with downward slant of palpebral fissures, and single palmar transverse creases. The infant has a peculiar cry suggestive of laryngeal hypotonia and abnormalities. A nonlethal multiple malformation syndrome is suspected. Of the following, the karyotype in this infant is most likely to show an abnormality of chromosome: A. 5. B. 13. C. 18. D. 21. E. X.

11. A newborn female, who weighs 1,680 g at an estimated gestational age of 36 weeks, has a broad forehead, periorbital fullness, long philtrum, and wide mouth. An array comparative genomic hybridization test shows deletion of the elastin gene and of other genes on chromosome 7q11.23. A is suspected. Of the following, the most likely in this infant is: A. Interrupted aortic arch. B. Supravalvular aortic stenosis. C. Tetralogy of Fallot. D. Truncus arteriosus. E. Ventricular septal defect.

12. Normally, each gene is represented by two alleles inherited from each parent at the time of fertilization, and they function equally well, whether maternal or paternal in origin. However, less than 1% of genes are imprinted, meaning that there is a parent-of-origin difference in gene expression. Disorders resulting from such errors in gene expression are called imprinting disorders. Of the following, the most common imprinting disorder in neonates is: A. Beckwith-Wiedemann syndrome. B. Cornelia de Lange syndrome. C. DiGeorge syndrome. D. Fanconi anemia syndrome. E. Pfeiffer syndrome.

e38 NeoReviews Vol.9 No.1 January 2008 Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010 Common Dysmorphic Syndromes in the NICU Nader Bishara and Carol L. Clericuzio NeoReviews 2008;9;e29-e38 DOI: 10.1542/neo.9-1-e29

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