Common Dysmorphic Syndromes in the NICU

DOI: 10.1542/neo.9-1-e29 2008;9;e29-e38 NeoReviews

Nader Bishara and Carol L. Clericuzio Common Dysmorphic Syndromes in the NICU

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Common DysmorphicSyndromes in the NICUNader Bishara, MD,*

Carol L. Clericuzio, MD†

Author Disclosure

Drs Bishara and

Clericuzio did not

disclose any financial

relationships relevant

to this article.

Objectives After completing this article, readers should be able to:

1. Recognize the phenotypes of selected dysmorphic conditions encountered in theneonatal intensive care unit.

2. Describe appropriate medical management, prognosis/recurrence risk information, andprenatal diagnostic options for the disorders.

3. Delineate the clinical applications of routine and high-resolution chromosome studies,fluorescence in situ hybridization, and array comparative genomic hybridization.

4. Explain how to use three Internet-based databases (PubMed, OMIM, GeneReviews) tohelp diagnose and treat infants who have dysmorphic conditions.

AbstractNeonatologists are responsible for the care of newborns who have a wide variety ofcritical illnesses, including complications of multiple congenital anomalies. Thisreview article provides an overview of state-of-the art information on the diagnosis andmanagement of a number of genetic disorders frequently encountered in the neonatalintensive care unit (NICU). The latest diagnostic tool for children who have unknownsyndromes (array comparative genomic hybridization) as well as Internet-based searchengine databases that can be accessed from the NICU are examined.

IntroductionThe fields of perinatal and neonatal medicine have seen remarkable advances in the past 3or 4 decades, particularly in regard to the diagnosis and management of genetic disorders.Improvements in amniocentesis, chorionic villous sampling (CVS), and high-resolutionthree-dimensional ultrasonographic imaging are some of the advances. High-resolutionchromosome studies, fluorescence in situ hybridization (FISH), and array comparativegenomic hybridization (aCGH) are some of the tools that have increased the ability todiagnose genetic disorders.

Genetic conditions have an impact on physical health, but also have psychological andsocial implications for the patient and his or her family. It is essential to understand thegeneral aspects of genetic disorders encountered in the perinatal and neonatal periods andthe tools available for diagnosis. Those who have an affected child often are faced withdifficult family planning decisions because the diagnosis may affect future pregnancies.Depending on the diagnosis, parents may be faced with choices regarding prenatal testingand pregnancy termination.

Lethal or Semilethal Multiple Malformation SyndromesTrisomy 18 – Edwards Syndrome

Trisomy 18 and other trisomy syndromes are associated with increased maternal age.Trisomy 18 is the second most common autosomal trisomy syndrome seen in livebornchildren, with an average incidence of 1 per 3,000. Typically, affected infants are small forgestational age and have a history of maternal polyhydramnios. Multiple maternal serummarker screening can detect many cases of trisomy 18 prenatally. Characteristic facial

*Division of Neonatology, 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.

Article genetics

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features include microcephaly, prominent occiput, smallmouth and jaw, low-set and malformed ears, short pal-pebral fissures, and mild hypertrichosis of the foreheadand back (Fig. 1). The hands are often clenched withoverlapping fingers, and the sternum usually is short.Cardiac defects are common but typically nonlethal.

The neonatal course is complicated by poor suckingabilities, necessitating nasogastric tube feedings. How-ever, even with adequate caloric intake, infants usuallyfail to thrive. They exhibit hypertonia after the initialhypotonic neonatal phase. More than 50% die within thefirst week after birth, although 10% are still alive by 1 yearof age. Trisomy 18 is considered a semilethal syndromebecause of this small but definite number of survivorsbeyond 1 year.

Diagnosis can be confirmed by a 48-hour culture oflymphocytes in the cytogenetics laboratory. OvernightFISH 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 is1%, and future pregnancies can be tested by CVS oramniocentesis.

Trisomy 13 – Patau SyndromeTrisomy 13 is the third most common autosomal trisomy(Fig. 2), with an incidence of 1 per 10,000. Liveborn infantstypically have normal birthweights but have microcephaly.

Other birth defects include holoprosencephaly, both typicaland nontypical clefting, cardiac anomalies (most commonlyventricular septal defect), omphalocele, postaxial polydac-tyly, cystic dysplastic kidneys, cutis aplasia, and “rocker-bottom” feet with prominent calcanei.

The condition is associated with profound mental

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.

Figure 2. Interphase amniocyte fluorescence in situ hybridiza-tion (FISH) of a female who has trisomy 13 showing three bluehybridization signals for chromosome 13 centromeres and twored hybridization signals for X chromosome centromeres.

genetics dysmorphology

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retardation, and the median survival for affected infants is7 days. Most infants die within the neonatal period,although as with trisomy 18, 10% are still alive by 1 yearof age. Diagnosis, recurrence risk, and prenatal diagnosisare the same as for trisomy 18.

TriploidyTriploidy is the presence of 69chromosomes (Fig. 3). Fetuses thatsurvive exhibit severe growth re-striction and typically have syndac-tyly and clubfeet (Fig. 4). Chromo-some studies from either placentalor fetal tissue should be obtainedfor confirmation. The recurrencerisk is not increased for future preg-nancies.

Osteogenesis ImperfectaType II

Osteogenesis imperfecta type II is alethal skeletal dysplasia and is themost severe type of osteogenesisFigure 3. 69,XXX triploidy karyotype.

Figure 4. A 23-week triploid fetus who exhibits severe growthrestriction and syndactyly.

Figure 5. Osteogenesis imperfecta type II. Note the “ribbon-like” fractured long bones and deficient skull ossification.




imperfecta subtypes. It is due to a defect in the genes thatcode for type I procollagen (COL1A1 and COL1A2).Most cases are sporadic mutations and have a recurrencerisk of up to 6% due to gonadal mosaicism in one of theparents. The condition is characterized by short limbs,ribbonlike long bones (Fig. 5), and multiple fractures,most commonly seen in utero with callus formation. Theribs are beaded, and the long bones are markedly de-formed. Craniofacial features include large fontanelles,deficient calvarial ossification, shallow orbits, bluesclerae, and low nasal bridge. Most infants are eitherstillborn or die in the neonatal period, primarily fromrespiratory failure due to pulmonary hypoplasia and frag-ile ribs or due to central nervous system (CNS) malfor-mations or hemorrhages. Prenatal diagnosis is by fetalultrasonography or DNA analysis for known procollagenmutations.

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

Patients rarely survive beyond theneonatal period due to the severeCNS and renal defects as well aspulmonary hypoplasia (due to com-pression of the fetal lungs by thelarge kidneys). The recurrence risk is25%, and prenatal diagnosis can bemade by fetal ultrasonography orDNA analysis for known mutations.

Nonlethal MultipleMalformation Syndromes

Trisomy 21Down syndrome is the most com-mon pattern of malformations inhumans, with an incidence of 1 per800. Like other trisomies, it is asso-

ciated with increased maternal age. Down syndrome ischaracterized by generalized hypotonia, brachycephalywith mild microcephaly, upslanting palpebral fissures,epicanthal folds, and small ears. The hands are relativelyshort, with hypoplasia of the mid-phalanx of the fifthfinger and clinodactyly, single transverse palmar creases,and wide gap between first and second toes. Cardiacdefects occur in 40% of patients and include endocardial

Figure 6. An infant who has Meckel-Gruber syndrome exhibits occipital encephaloceleand enlarged abdomen due to polycystic kidneys.

Figure 7. Pedal edema in Turner syndrome.Figure 8. Excess posterior nuchal skinfolds in Turner syn-drome.




cushion defects, ventricular septal defect, patent ductusarteriosus, and atrial septal defect.

In all cases of suspected trisomies, routine chromo-some analysis should be ordered. Ninety-five percent ofpatients have nondisjunction trisomy 21. The recurrencerisk is 1% until exceeded by the maternal age-related risk(maternal age 40 y). Parents do not need to undergokaryotyping unless there is a translocation chromosome,in which case the recurrence risk depends on whether oneof the parents carries the translocation chromosome.Approximately 1% of infants who have Down syndromehave mosaic trisomy 21, a mixture of normal and trisomiccells, and the recurrence risk for this defect is the same asfor typical nondisjunction trisomy 21. Prenatal diagnosisis performed by CVS or amniocentesis. Although firstand second trimester maternal screening is offered to allpregnant women, this does not replace diagnostic studiesfor couples at high risk.

Turner SyndromeTurner syndrome (TS) should be suspected in femaleinfants who have evidence of fetal edema (Fig. 7), such asexcess posterior nuchal skin folds (Fig. 8) or dorsaledema of the feet with small nails. Females who havecritical aortic stenosis due to bicuspid aortic valve orcoarctation of the aorta also should undergo karyo-typing. Affected infants often are small at birth. TS iscaused by the partial or complete absence of one of theX chromosomes. Half are mosaic, eg, 45,X/46,XX. Rou-tine chromosome studies should be obtained for diagno-sis, and if TS is diagnosed, an additional 200 cells shouldbe screened with X and Y chromosome FISH probes torule out the presence of a Y chromosome. Medical man-agement involves cardiology evaluation for bicuspid aor-tic valve, coarctation of the aorta, valvular aortic stenosis,and mitral valve prolapse. Renal ultrasonography is indi-cated because 40% of affected infants have renal anoma-

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




lies such as horseshoe kidney. There is no increased riskfor future pregnancies. TS is suspected prenatally whenfetal nuchal cystic hygroma or edema/hydrops is identi-fied.

5p- Syndrome (Cri du chat)5p- syndrome should be suspected in infants who aresmall for gestational age, exhibit microcephaly with around face and hypertelorism with downward slant ofthe palpebral fissures, and have single palmar transversecreases. Affected infants often have a characteristic catlikecry 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 routinechromosome study should be obtained. The high-resolution study is required to look for small genomicduplications 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 5pshould be requested. De novo deletions are responsiblefor 85% of cases, and 15% are due to parental transloca-tions. Therefore, in all cases, parents should be offered

Figure 10. Genetic mechanisms leading to Prader-Willi syndrome (PWS). Note that the 15q11–13 critical PWS region normally isimprinted (turned-off) in the maternal chromosome, indicated by the black bar.

Figure 11. Infant who has Beckwith-Wiedeman syndrome,exhibiting macrosomia, macroglossia, and a repaired ompha-locele. This infant subsequently developed hepatoblastoma.




chromosome analysis. Prenatal diagnosis by CVS or am-niocentesis is available for pregnancies at risk.

Microdeletion SyndromesMicrodeletion syndromes are recognizable disorderscaused by chromosomal deletions that span several genesand frequently are too small to be detected by conven-tional and high-resolution cytogenetic methods. Molec-ular cytogenetic techniques, including FISH and aCGH,are used to diagnose these conditions.

VELOCARDIOFACIAL/DIGEORGE (DEL 22Q11.2) SYNDROME.Originally, this condition had two independent syn-drome descriptions. In 1965, DiGeorge described un-derdevelopment of the thymus and parathyroids thatcaused neonatal hypocalcemia, conotruncal cardiac de-fects (eg, interrupted aortic arch, truncus arteriosus andtetralogy of Fallot), broad facies, minor ear anomalies,and feeding problems. In 1981, the cause was found tobe deletion of chromosome 22 at q11.2. In 1978,Sphrintzen described a syndrome that encompassed cleftpalate, Pierre Robin sequence with a long narrow face,tubular nose with round tip, ventricular septal defect,and growth and learning deficiency. This syndrome isinherited as an autosomal dominant condition and in1992 also was found to be due to the 22q11.2 deletion.

Hence, the syndrome descriptions reflect the phenotypicvariability of this very common chromosomal deletion.

Current practice is to evaluate all patients who havecongenital heart disease for this deletion. When sus-pected, high-resolution chromosome studies and FISHfor del 22q11.2 should be ordered. The laboratory needsto know the indication for the study, eg, congenital heartdefect and cleft palate. Parents of affected infants shouldbe offered the FISH deletion study because 7% have beenfound to carry the deletion, and recurrence risk is depen-dent on whether the deletion is de novo (very low risk) ordue to parental deletion (50% risk for future pregnan-cies). Prenatal diagnosis is accomplished by CVS or am-niocentesis, and the FISH testing must be specificallyrequested.

WILLIAMS SYNDROME (DEL 7Q11.23). Williams syn-drome is characterized by growth restriction; character-istic facial features, including broad forehead, periorbitalfullness, long philtrum, and wide mouth; supravalvularaortic stenosis; and idiopathic hypercalcemia in 15% ofaffected patients. Diagnosed patients should undergorenal ultrasonography and evaluation for feeding difficul-ties. Williams syndrome is caused by a deletion of the elastin(ELN) gene and others at 7q11.23. When suspected, high-resolution chromosome studies and FISH for del 7q11.23

Figure 12. Postmortem picture of Pfeiffer syndrome. Note the cloverleaf skull and broad medially deviated thumb and great toe.

Table. Distinguishing Clinical Features of FGFR-related CraniosynostosisSyndromes

Disorder Hands Thumbs Feet Great Toe

Crouzon Normal Normal Normal NormalPfeiffer Variable syndactyly Broad and medially deviated Variable syndactyly Broad and medially deviatedApert Bone syndactyly May be fused to fingers Bone syndactyly May be fused to toes

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




should be ordered. Virtually all deletions are de novo,and parental studies usually are not indicated.

The microdeletion in Williams syndrome also can bedetected by aCGH and FISH (Fig. 9). The aCGH studyhas the power to detect smaller genomic imbalances thanhigh-resolution chromosome studies and allows forscreening of the entire genome. In Figure 9, the arrayresults for chromosome 7 only are depicted, but com-mercially available arrays cover the entire genome.

Imprinting DisordersNormally, each gene is represented by two copies or allelesinherited from each parent at the time of fertilization, andthey function equally well whether maternally or paternallyinherited. However, less than 1% of genes are imprinted,meaning that there is a parent-of-origin difference in geneexpression. Several recognizable disorders are due to errorsin imprinted genes. In the neonatal setting, the two mostcommon imprinting disorders are Prader-Willi andBeckwith-Wiedemann syndromes.

PRADER-WILLI SYNDROME (PWS). PWS is character-ized by severe neonatal hypotonia, undescended testes/hypoplastic scrotum, and severe feeding difficulties thatrequire intervention. Females may show hypoplastic labiaminora. Other findings include almond-shaped eyes, nar-row bifrontal diameter, and thick saliva. PWS is due tothe absence of the paternally contributed genes at15q11–13, which can arise by three different mecha-nisms (Fig. 10). Some 70% of cases are due to a paternaldeletion at 15q11–13. Maternal uniparental disomy, ie,

two chromosomes from the sameparent, accounts for 25% of cases.Abnormal persistence of the im-print on the paternal chromosome15 accounts for the remaining 5%.

Diagnosis of PWS is confirmedby a DNA methylation study,which looks for the presence of ap-propriately imprinted maternal andpaternal 15 chromosomes. Absenceof a paternally imprinted 15 is diag-nostic of PWS, regardless of themechanism. Because FISH for del15q11–13 detects only 70% of af-fected infants, DNA methylationis the preferred diagnostic test.Karyotype also is ordered routinely torule out translocations. The recur-rence risk usually is low, although itsdetermination can be complicated,

Figure 13. Typical presentation of VATER association, withleft radial ray deficiency, vertebral anomalies, anal atresia, andlower limb defects. The patient also had congenital heartdisease and a single kidney.

Figure 14. Bilateral thumb abnormalities in a patient who has Fanconi anemia syndromeafter stem cell transplant for leukemia. She originally was diagnosed with VATERassociation on the basis of vertebral anomalies, radial ray defects, and renal anomaly.




and genetic consultation is recommended if the familywishes to learn the risk for future pregnancies. (Editor’sNote: See also NeoReviews. 2005;6:e559–e566.)

BECKWITH-WIEDEMANN SYNDROME (BWS). BWS isa congenital overgrowth syndrome characterized bymacroglossia, hemihyperplasia, abdominal wall defects(omphalocele or umbilical hernia), hypoglycemia, earlobe creases, and posterior helical pits (Fig. 11). Thediagnosis is based on the presence of three of the clinicalfindings noted previously. Six known mechanisms lead toBWS, involving a handful of imprinted genes at 11p15.5,including paternal IGF2, which usually is overexpressed.Molecular studies are available in clinical laboratories,and all children should undergo a high-resolution chro-mosome study to evaluate for a familial translocation.Approximately 20% of individuals who have BWS have afamilial mutation that can be detected by molecularanalysis. The recurrence risk is low, except for familialtranslocation and mutations. Prenatal diagnosis includesfetal ultrasonography and molecular/cytogenetic analy-sis for families who have those abnormalities. BWS oc-curs with increased frequency in pregnancies achieved byin vitro fertilization.

Because 5% to 10% of children who have BWS developmalignant kidney (Wilms), liver, or adrenal tumors, recog-nition of this syndrome is important to establish the tumorscreening protocol. Abdominal ultrasonography and mea-surement of serum alpha-fetoprotein (AFP) at diagnosisand every 3 months until age 4 years plus subsequentquarterly abdominal ultrasonography until 8 years of age isrecommended. Normal AFP values at birth are extremelyhigh, and reference values should be consulted.

CORNELIA DE LANGE SYNDROME. Cornelia de Langesyndrome is characterized by pre- and postnatal growthrestriction and a distinctive facial appearance that in-cludes arched eyebrows and synophrys, long eyelashes,anteverted nares, long philtrum, and thin upper lip witha central peak. Affected individuals may have upper limbdeficiencies, including oligodactyly. Virtually all infantshave gastroesophageal reflux and feeding difficulties.A number of affected patients have mutations in theNIPBL gene. More than 99% of cases are sporadic withlow recurrence risk, although rare autosomal dominantfamilies have been reported.

FGFR-related Craniosynostosis Syndromes:Crouzon, Pfeiffer, and Apert

Most individuals who have these disorders have newautosomal dominant mutations in the FGFR2 gene.

Bilateral coronal craniosynostosis or cloverleaf skull is thecharacteristic cranial feature in all (Fig. 12). The syn-dromes are distinguished by the limb findings (Table).Cleft palate or choanal atresia may result in upper airwayobstruction. Proptosis is common and may lead to expo-sure keratopathy. Spinal radiographs are needed to eval-uate for vertebral anomalies and computed tomographyscan or magnetic resonance imaging are required toassess for hydrocephalus. Most patients need treatmentat a craniofacial center by the age of 2 to 3 months.Recurrence risk depends on whether one of the parents isaffected, in which case the recurrence risk is 50%. Prena-tal diagnosis by fetal ultrasonography or molecular anal-ysis for known mutations is available.

VATER/VACTERRL AssociationVATER/VACTERRL is an acronym for the nonrandomassociation of vertebral, anal, cardiovascular anomalies,tracheoesophageal fistula, renal or radial anomalies, andother limb anomalies (Fig. 13). Three anomalies gener-ally are required to make the diagnosis. The conditionusually is nonhereditary and nongenetic, although it isseen with increased frequency in infants of woman whohave insulin-dependent diabetes. Because the sameanomalies can be seen in Fanconi anemia syndrome (FA)(Fig. 14), it is very important to consider this diagnosis,particularly if a radial ray defect is present. FA is anautosomal recessive cancer syndrome diagnosed by chro-mosomal breakage studies. Consultation with clinicalgenetics is recommended if there are any concerns re-garding the diagnosis of FA.

Suggested ReadingCassidy SB, Allanson JE, eds. Management of Genetic Syndromes. 2nd

ed. Wilmington, De: Wiley-Liss; 2004de Revel TJ, Devriendt K, Fryns JP, Vermeesch JR. What’s new in

karyotyping? The move towards array comparative genomichybridisation (CGH). Eur J Pediatr. 2007;166:637–643

Faivre L, Portnoı̈ MF, Pals G, et al. Should chromosome breakagestudies be performed in patients with VACTERL association? Am JMed Genet. 2005;137:55–58

Jessica MJ, Laurie AD. Genetic syndromes determined by alter-ations in genomic imprinting pathways. NeoReviews. 2007;8:e120–e126

Jones KL, ed. Smith’s Recognizable Patterns of Human Malforma-tion. 6th ed. Philadelphia, Pa: WB Saunders; 2005

Online Mendelian Inheritance in Man, OMIM.TM Available at:http://www.ncbi.nlm.nih.gov/omim/

Robin NH, Falk MJ, Haldeman-Englert CR. FGFR-related cranio-synostosis syndromes. In: GeneReviews at GeneTests: MedicalGenetics Information Resource (database online). © Universityof Washington, Seattle. 1997–2007. Available at http://www.genetests.org. Accessed October 2007




NeoReviews Quiz

9. A newborn female, who weighs 2,800 g at an estimated gestational age of 37 weeks, has clinical findingsof occipital encephalocele, postaxial polydactyly, enlarged abdomen from polycystic kidneys, andhypoplastic 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 findingsof microcephaly with a rounded face, hypertelorism with downward slant of palpebral fissures, and singlepalmar transverse creases. The infant has a peculiar cry suggestive of laryngeal hypotonia andabnormalities. A nonlethal multiple malformation syndrome is suspected. Of the following, the karyotypein 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 broadforehead, periorbital fullness, long philtrum, and wide mouth. An array comparative genomic hybridizationtest shows deletion of the elastin gene and of other genes on chromosome 7q11.23. A microdeletionsyndrome is suspected. Of the following, the most likely congenital heart defect 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 genesare imprinted, meaning that there is a parent-of-origin difference in gene expression. Disorders resultingfrom such errors in gene expression are called imprinting disorders. Of the following, the most commonimprinting disorder in neonates is:

A. Beckwith-Wiedemann syndrome.B. Cornelia de Lange syndrome.C. DiGeorge syndrome.D. Fanconi anemia syndrome.E. Pfeiffer syndrome.




DOI: 10.1542/neo.9-1-e29 2008;9;e29-e38 NeoReviews

Nader Bishara and Carol L. Clericuzio Common Dysmorphic Syndromes in the NICU

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