Congenital Diaphragmatic Defects and AssociatedSyndromes, Malformations, and ChromosomeAnomalies: A Retrospective Study of 60 Patients andLiterature Review

Gregory M. Enns,1 Victoria A. Cox,1 Ruth B. Goldstein,2 David L. Gibbs,3 Michael R. Harrison,3 andMahin Golabi1*1Department of Pediatrics, University of California, San Francisco, California2Department of Radiology, University of California, San Francisco, California3Fetal Treatment Center, University of California, San Francisco, California

Congenital diaphragmatic defects (CDDs)may occur in malformation syndromes ofvaried causes. Syndromic cases of CDDs dueto chromosomal defects, autosomal reces-sive, autosomal dominant, or X-linked in-heritance have been described. In order todetermine the frequency and nature of syn-dromes, malformations, and chromosomeabnormalities associated with CDDs, we re-viewed the records of all patients with CDDsevaluated over a 4-year period. During the4-year interval, a total of 60 patients wasevaluated. Of these, 29 had a therapeutic orspontaneous abortion, and 31 received post-natal care. On prenatal ultrasonography, 20of 60 (33%) of patients with CDDs had addi-tional anomalies. Additional anomalies, be-sides CDDs, were present in 15 of 31 (48%) ofliveborn patients on newborn evaluation. Intotal, 16 patients with multiple anomalieswere evaluated. Of these, 12 of 16 (75%) hadadditional abnormalities detected by prena-tal ultrasonography. The 4 of 16 (25%) with-out additional anomalies on prenatal sonog-raphy had multiple anomalies found neona-tally, lethal multiple pterygium syndromebeing diagnosed in one case. Prenatal chro-mosome analysis was performed in 7 of 16patients, and all had postnatal karyotypes.All initial karyotypes were normal. Tetra-somy 12p was documented on postnatal fi-broblast analysis in one case who had per-

cutaneous umbilical blood sampling(PUBS). Syndromes diagnosed postnatallyin 7 of 16 patients (44%) include: Fryns syn-drome (2), Simpson-Golabi-Behmel syn-drome (2), tetrasomy 12p (1), Brachmann-deLange syndrome (1), and lethal multiple pte-rygium syndrome (1). We were unable tomake a specific diagnosis in 9 of 16 patients(56%) with multiple malformations. In pa-tients with CDDs, a normal prenatal karyo-type, especially if obtained by PUBS, and ab-sence of other detected abnormalities by fe-tal ultrasonography, do not exclude thepresence of other major anomalies, includ-ing chromosome abnormalities and severemultiple malformation syndromes. Am. J.Med. Genet. 79:215–225, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: congential diaphragmatic de-fects; syndromes; chromo-some anomalies; malforma-tions; prenatal diagnosis

INTRODUCTION

Congenital diaphragmatic defects (CDDs) are rela-tively common malformations, with an estimatedprevalence of 1/2,000 to 1/3,000 [Butler and Claireaux,1962; David and Illingworth, 1976; Harrison and deLorimer, 1981; Philip et al., 1991; Torfs et al., 1992].Posterolateral defects account for approximately 96%of cases, with 84% being left-sided, 13% right-sided,and 2% bilateral. Complete agenesis of the diaphragmhas been reported rarely, although Cunniff et al. [1990]found a 6% prevalence in a review of 102 cases. Thereported male-to-female ratio has varied from 0.6 to1.58 [David and Illingworth, 1976; Puri and Gorman,1984; Benjamin et al., 1988; Philip et al., 1991; Torfs etal., 1992].

Contract grant sponsor: National Institutes of Health; Contractgrant number: GM07085.

Current address of D.L.G. is Department of Surgery, Massa-chusetts General Hospital, Boston, Massachusetts.

*Correspondence to: Mahin Golabi, M.D., M.P.H., UCSF, Box0706, San Francisco, CA 94143-0706.

Received 20 April 1998; Accepted 17 June 1998

American Journal of Medical Genetics 79:215–225 (1998)

© 1998 Wiley-Liss, Inc.

Overall mortality in patients with CDDs is high at 50to 100% [Harrison et al., 1978; Harrison and deLorimer, 1981; Wiener, 1982; Adzick et al., 1989; Cun-niff et al., 1990; Philip et al., 1991; Sharland et al.,1992; Manni et al., 1994]. Polyhydramnios, diagnosisbefore gestational age 25 weeks, and the presence ofcardiovascular malformations have been associatedwith increased mortality [Butler and Claireaux, 1962;Greenwood et al., 1976; Adzick et al., 1985, 1989; Sim-son and Eckstein, 1985; Cunniff et al., 1990; Fauza andWilson, 1994]. Howe et al. [1996] found 50% survival inpatients with normal chromosomes and no otheranomalies. Although survival has increased since theimplementation of extracorporate membrane oxygen-ation (ECMO), among survivors morbidity can be high,with up to 75% having developmental delay [Mc-Gahren et al., 1997]. Fetal surgery also has potential todecrease mortality, but results to date have not beenuniformly promising [Harrison et al., 1997].

Isolated CDDs have been considered to representsporadic malformations with low recurrence risk, withfamilial cases representing ø2% [Tibboel and Gaag,1996]. However, familial cases of CDDs have been de-scribed, with autosomal recessive [David et al., 1979;Arad et al., 1980; Mishalany and Gordo, 1986; Hitch etal., 1989; Harris et al., 1993; Bird et al., 1994a; Faragand Wilson, 1994; Gibbs et al., 1997], autosomal dom-inant [Crane, 1979; de Meeus et al., 1997], X-linkedrecessive [Crane, 1979; Toriello and Higgins, 1985;Martin et al., 1992], and X-linked dominant [Bird et al.,1994a; Parvari et al., 1994] inheritance. In some popu-lations, multifactorial inheritance best explains the oc-currence of CDDs [Crane, 1979; Wolff, 1980], and arecurrence risk of 2% has been estimated [Norio et al.,1984; Narayan et al., 1993]. The aggregate reportsfrom case and population studies suggest that a pro-portion of CDDs are familial, but the actual incidenceof familial defects remains unknown.

CDDs also occur in multiple malformation syn-dromes and associations (Tables I–III). Chromosomal

anomalies and teratogens have been invoked to explainthe occurrence of CDDs as well (Tables IV, V). Up to73% of patients with nonsyndromic CDDs have beenreported to have associated nonpulmonary malforma-tions [Bollman et al., 1995]. The exact frequency ofCDDs associated with multiple congenital anomaly(MCA) syndromes or chromosome abnormalities is un-known. In a study of 102 liveborn patients, Cunniff etal. [1990] estimated that CDDs are associated withMCA syndromes at least 14% of the time. The associa-tion with aneuoploidies is between 10 and 34% [Adzicket al., 1989; Thorpe-Beeston et al., 1989; Philip et al.,1991; Donnenfeld et al., 1993; Bollmann et al., 1995;Howe et al., 1996], with trisomy 18 being reported mostcommonly [David and Illingworth, 1976; Puri and Gor-man, 1984; Benacerraf and Adzick, 1987; Cunniff et al.,1990]. The actual incidence of syndromes and chromo-some anomalies with CDDs is difficult to elucidate, es-pecially because of ascertainment bias inherent in moststudies.

We performed a retrospective study of all patientsreferred to the University of California, San Francisco(UCSF) Division of Medical Genetics and Fetal Treat-ment Center over a 4-year period, and reviewed theliterature, to understand better the relationship be-tween CDDs and specific syndrome diagnoses, associ-ated malformations, and chromosome anomalies.

PATIENTS AND METHODS

We reviewed the records of all patients with CDDsevaluated by the UCSF Division of Medical Geneticsand Fetal Treatment Center over a 4-year period (1992to 1996). A total of 70 patients with CDDs was initiallyreferred to the UCSF Fetal Treatment Center forevaluation. Thirty delivered and received postnatalcare at UCSF; 23 underwent elective pregnancy termi-nation; 5 had spontaneous abortions; and 12 were lostto follow-up, giving a final total of 58 patients evalu-ated by the Fetal Treatment Center. All 58 patients,

TABLE I. Syndromes More Frequently Associated With Congenital Diaphragmatic Hernia*

Syndrome Inheritance Findings References

Fryns syndrome AR Coarse face, broad nasal bridge, distaldigital hypoplasia, Dandy-Walkermalformation, agenesis of corpuscallosum

Bamforth et al. [1992]; Bird et al.[1994a], Cunniff et al. [1990], Fryns etal. [1979], McPherson et al. [1993],Tibboel and Gaag [1996]

Wiedemann-Beckwithsyndrome

AD Macrosomia, omphalocele, macroglossia,ear creases

Bird et al. [1994a], David andIllingworth [1976], Thorburn et al.[1970], Turleau et al. [1984]

Brachman-de Langesyndrome

Sporadic Microbrachycephaly, synophyrs, thin,downturned upper lip, micromelia

Bird et al. [1994a], Cunniff et al. [1990,1993], Turleau et al. [1984]

Simpson-Golabi-Behmel syndrome

XR Macrosomia, hypertelorism,macrostomia, postaxial polydactyly,umbilical/inguinal hernias

Bird et al. [1994a], Chen et al. [1993]

Donnai syndrome AR Absent corpus callosum, hypertelorism,myopia, coloboma, sensorineuraldeafness, omphalocele, malrotation

Donnai and Barrow [1993]

Denys-Drashsyndrome

AD Male pseudohermaphroditism, nephroticsyndrome, Wilms tumor

Devriendt et al. [1995], Tibboel and Gagg[1996]

Perlman syndrome AR Macrosomia, nephroblastomatosis, Wilmstumor, CHD, hypospadias, polysplenia,visceromegaly

Bird et al. [1994a], Greenberg et al.[1988]

*AR, autosomal recessive; AD, autosomal dominant; CHD, congenital heart disease; XR, x-linked recessive.

216 Enns et al.

including 30 patients who received postnatal care bythe UCSF Fetal Treatment Center, and the 28 patientswith a pregnancy outcome of termination, had prenatalultrasonography. Only 6 of the 28 patients (21%) witha pregnancy outcome of termination had prenatal ul-trasonography at UCSF, the remainder having studiesat various outside institutions. Twenty-four of the 28patients (86%) with a pregnancy outcome of spontane-ous or therapeutic abortion had a chromosome analysison cultured amniocytes. Three of the 28 patients (11%)with a pregnancy outcome of termination had an au-topsy.

Of the 30 patients who received postnatal care atUCSF by the Fetal Treatment Center, 14 were referredto Genetics for further evaluation because of the pres-ence of additional anomalies. Two further patientswere evaluated by Genetics at other institutions, butwere not seen by the UCSF Fetal Treatment Center,giving a total of 16 patients with CDDs evaluated byGenetics (and a total of 60 patients evaluated by Ge-netics and the Fetal Treatment Center combined). Oneof the patients seen only by Genetics was liveborn, andthe other was evaluated after elective termination, fol-lowing the detection of multiple anomalies on sonogra-phy. All 16 patients seen by Genetics had prenatal ul-trasonography. Of these, seven had initial chromosomeanalysis by amniocentesis, one underwent chorionicvillus sampling (CVS), one had percutaneous umbilicalblood sampling (PUBS), and seven did not have a pre-natal karyotype. All had postnatal blood karyotyping.The one patient evaluated only by Genetics after elec-tive termination had an autopsy.

RESULTSPrenatal and Postnatal Patients Evaluated by

the Fetal Treatment Center

Of the 29 patients with a pregnancy outcome of spon-taneous or therapeutic abortion (including one patientseen by Genetics alone), six (21%) had sonographicanomalies in addition to CDDs, including hypertelor-ism, bilateral cleft palate, cystic hygroma, cystic ade-nomatoid malformation, possible lung sequestration,heart defect (mitral valve atresia or double outlet rightventricle), two-vessel umbilical cord, chordee, and am-biguous genitalia. Twenty-four of the 29 patients (83%)had chromosome analysis, with normal results in allexcept one, who was found to have a chromosome 7deletion [46,XY, −7+der(7)t(2;7)(p25.3;q34)mat].Twenty-five of 29 patients (86%) had a left diaphrag-matic defect and 3 of 28 (11%) had a right defect. Onepatient had phenotypic characteristics of trisomy 18,but chromosome analysis was refused. Three of fourpatients who underwent autopsy had no other anoma-lies, besides CDDs, reported on prenatal ultrasonogra-phy. However, all had additional anomalies detected onautopsy. The anomalies found at autopsy were broadnasal bridge, apparently low-set ears, hypoplastic man-dible, thymus hypoplasia, esophageal atresia, heartdisease (D-transposition of the great arteries, pulmonicatresia, and AV canal defect), cleft right lobe of liver,short left upper limb, and digital syndactyly. The au-topsy case that had additional anomalies, besides CDD,

detected on ultrasonography was seen by Genetics anda diagnosis of Simpson-Golabi-Behmel syndrome wasmade on the basis of phenotypic appearance.

Of the 31 liveborn patients who received postnatalcare (including one patient seen only by Genetics), 15(48%) had additional anomalies besides CDDs andwere referred to Genetics, and 16 (52%) were consid-ered to have an isolated CDD. Because Genetics did notevaluate the latter group, the presence or absence ofsubtle minor anomalies, or a syndromic diagnosis, can-not be commented on in these patients.

Postnatal Patients Evaluated by Genetics

Twelve of 16 patients (75%) who had prenatal ultra-sonography and were evaluated by Genetics postna-tally had abnormalities on sonography in addition toshowing CDDs. The following sonographic anomalies,in order of frequency, were reported: polyhydramnios(5), hydronephrosis (4), inferior vermis hypoplasia (2),nuchal thickening/cystic hygroma (2), cleft lip (2), two-vessel umbilical cord (2), prominent ventricles (1), ab-normal facial profile (1), abnormal genitalia (1), andintra-uterine growth retardation (IUGR) (1). No prena-tal ultrasound anomalies, other than CDD, were foundin four patients (25%). These four patients all had ad-ditional anomalies detected postnatally, lethal mul-tiple pterygium syndrome being diagnosed in one case.

Of the 16 patients evaluated by Genetics, all hadnormal prenatal karyotypes and lymphocyte postnatalkaryotypes. PUBS was performed on one patient and anormal karyotype was found. (The peripheral lympho-cyte karyotype was also normal.) However, a postnatalskin biopsy performed for fibroblast chromosomeanalysis demonstrated tetrasomy 12p, after a charac-teristic phenotype was seen on neonatal examination.

All 16 patients evaluated by genetics had significantminor or multiple congenital anomalies. Syndromes di-agnosed by Genetics postnatally in 7 of 16 patients(44%) include Fryns syndrome (2), Simpson-Golabi-Behmel syndrome (2), tetrasomy 12p (1), Brachmann-de Lange syndrome (1), and lethal multiple pterygiumsyndrome (1). We were unable to make a specific diag-nosis in 9 of 16 patients (56%). The findings in theseundiagnosed cases included blepharophimosis, flat na-sal bridge, ear abnormalities, congenital heart defects,renal anomalies, digital anomalies, anteriorly placedanus, and hypospadias (Table VI). Three of 16 patients(19%) evaluated by Genetics had a right diaphragmatichernia (one with Brachmann-de Lange syndrome, onewith Fryns syndrome, and one undiagnosed patientwith multiple congenital anomalies), with the remain-der having left defects.

Combined Characteristics of PatientsEvaluated by the Fetal Treatment Center

and Genetics

In total, 20 of 60 patients (33%) with CDDs had ad-ditional anomalies detected on prenatal ultrasonogra-phy. In comparison, the subgroup of patients havingprenatal ultrasonography performed at UCSF had ad-ditional anomalies detected in 11 of 20 cases (55%). Ofthe total 60 patients evaluated, additional anomalies

Congenital Diaphragmatic Defects 217

TABLE II. Rare Syndromes Associated With CDDs*

Syndrome Inheritance Findings References

Absent lefthemidiaphragm–arhinincephaly–cardiacmalformations

AR Hydrocephalus, VSD, hypoplastic nails,hypospadias

Fitch et al. [1978]

Agenesis of corpuscallosumhydrocephaly–diaphragmatichernia–hydrops fetalis

AR Enlarged lateral ventricles Lurie and Kletsky [1990]

Blastogenesis dominant 1 AD Agenesis of corpus callosum, lateralitydefects, CHD, urologic anomalies,urolithiasis

de Meeus et al. [1997]

Brachycephaly–deafnesscataracts-mentalretardation

?AR Down syndrome-like face, short stature,skeletal anomalies

Gripp et al. [1996]

CHARGE syndrome Sporadic Coloboma, heart defect, atresia choanae,retarded growth, genital hypoplasia,ear anomalies

Tibboel and Gaag [1996], Torfset al. [1992]

Collodion baby ?AR Ectropion, eclabium, crumpled pinnae,lamelllar ichthyosis

Torfs et al. [1992]

Congenitalhydrocephalus–shortstature–obesity–hypogenitalism

XR Developmental delay, low-set, posteriorlyangulated ears

Sengers et al. [1985]

Craniofrontonasalsyndrome

?AD/XD Frontonasal dysplasia, craniosynostosis,hypertelorism, bifid/broad nose, shawlscrotum, hypospadias

Morris et al. [1987]

Cutis laxa Heterogeneous Loose skin/joints, umbilical hernia Agha et al. [1978]Diaphragmatic hernia

and epidermolysisbullosa

AR Epidermolysis bullosa Dudin and Thalji [1991]

Diaphragmatichernia–pulmonaryagenesis–hydrocephalus

AR Absent corpus callosum, acqueductalstenosis, absent pulmonary artery,acessory adrenal gland

Bieber et al. [1991]

Ectrodactyly–diaphragmatichernia–congenitalheart disease–agenesisof corpus callosum

Unknown VSD Saal and Bulas [1995]

Fraser syndrome AR Cryptophthalmus, ear anomalies,syndactyly, genital anomalies

Tibboel and Gaag [1996]

Goltz-Gorlin syndrome XD Focal dermal hypoplasia, teethhypoplasia, skeletal malformations,syn/ectrodactyly

Bird et al. [1994a], Kunze et al.[1979], Tibboel and Gaag[1996]

Holt-Oram syndrome AD Upper limb defect, ASD/VSD Howe et al. [1996]Hydrolethalus syndrome AR Hydrocephalus, microphthalmia,

micrognathia, ‘‘key-hole’’ foramenmagnum, cleft lip/palate, CHD,polydactyly

Bird et al. [1994a]

Kabuki syndrome AD/?microdeletion Everted lower eyelids, ear anomalies,CHD, renal anomalies

Silengo et al. [1996]

Lethal multiplepterygium syndrome

AR Multiple pterygia, hypertelorism, cardiachypoplasia, skeletal anomalies

Froster et al. [1997]

Limb–body wall defect ?AD/AR Multiple midline defects, occipital defect,cleft palate, horseshoe kidney,omphalocele

Bird et al. [1994a]

Malepseudohermaphroditismcongenital heartdefect–horseshoekidney–diaphragmatichernia

Unknown Bicornuate uterus, septate/double vagina,rhabdomyomatous dysplasia

Maaswinkel-Mooij andStovkis-Brantsma [1992],Toriello and Higgins [1992]

Maxillonasaldysplasia–diaphragmatichernia–genitalanomalies

Unknown Binder anomaly, mitral valve prolapse,cervical/rib anomalies, genitalanomalies

Toriello et al. [1988]

218 Enns et al.

were further detected in 7 of 20 (35%) of those withnormal prenatal ultrasonography, aside from CDDs,upon evaluation by Genetics or autopsy. Because only 4of 29 patients (14%) with a pregnancy outcome of ter-mination had an autopsy, the incidence of additionalanomalies in this group cannot be accurately calcu-lated. If the patients with a pregnancy outcome of ter-mination are excluded, 15 of 31 patients (48%) werefound to have additional anomalies besides CDDs.

DISCUSSION

Multiple congenital anomalies were present in all 16patients with CDDs evaluated by Genetics. Multiplecongenital anomaly syndromes were diagnosed in 7 of16 patients (44%). Because our study was retrospectivewith ascertainment bias, we are unable to comment onthe actual incidence of syndromes associated withCDDs. Syndromes that appear to be relatively fre-quently associated with CDD, on literature review andbased on our experience, are listed in Table I. Table IIlists rare syndromes, including single cases, that haveCDDs as a part of their phenotype. Well-known geneticsyndromes/associations with single or few reports of anassociation with CDDs, where the association with

TABLE III. Etiologically Heterogeneous Sequences andAssociations With CDDs

Sequence/association References

Agenesis of pancreas Voldsgaard et al. [1994]Blepharophimosis sequence Wolstenholme et al. [1994]Caudal dysgenesis (anomaly) Bird et al. [1994a], Tibboel

and Gaag [1996]Cervical neural crest injury McCredie and Reid [1978]Klippel-Feil anomaly Bird et al. [1994a], Tibboel

and Gaag [1996]Laterality (asplenia/

polysplenia) sequenceBenjamin et al. [1988], Bird

et al. [1994a], Cunniff et al.[1990], Tibboel and Gaag[1996]

Midline developmental fielddefect

Czeizel [1981], Martin et al.[1992], Toriello and Higgins[1995]

Myelodysplasia complex Benjamin et al. [1988]Pentalogy of Cantrell Cantrell et al. [1958], Carmi

and Boughman [1992]Poland anomaly Bamforth et al. [1992],

Tibboel and Gaag [1996]Robin sequence Bird et al. [1994a], Tibboel

and Gaag [1996]Splenogonadal fusion Gouw et al. [1985]

TABLE II. (Continued)

Syndrome Inheritance Findings References

Micrognathia–cleftpalate–shortneck–vertebralanomalies–mentalretardation

AD Facial asymmetry, low-set ears, cleftpalate, laryngomalacia

Mathieu et al. [1993]

Microphthalmia withlinear skin defects(MLS)

XR Oncocytic cardiomyopathy, arrhythmias,ocular defects

Bird et al. [1994b]

MIDAS syndrome XR Microphthalmia, dermal aplasia,sclerocorneae, agenesis of corpuscallosum

Happle et al. [1993]

Multiple herniae ?AR Cervical lung herniation, hiatus hernia,inguinal hernia, bladder diverticula

Zaglul and Odita [1995]

Nasopharyngealteratoma–Dandy–Walker malformation–diaphragmatic hernia

Unknown Dysplastic ears, cleft palate,micrognathia, CHD

Aughton et al. [1990]

PAGOD syndrome AR Pulmonary artery hypoplasia,agonadism, omphalocele, dextrocardia,sex reversal

Kennerknecht et al. [1993]

Polycystickidneys–microcephaly–dysmorphicfacies–brachymelia–congenital heartdefects

AR Hypertelorism, large ears, cleft palate,situs inversus, genital hypoplasia

Gillessen-Kaesbach et al. [1993]

Radial raydefects–omphalocele–diaphragmatichernia-hepatic cyst

Unknown Gershoni-Baruch et al. [1990]

Split-hand-obstructiveurinaryanomalies–spinabidifa-diaphragmaticdefect

AD Czeizel and Losonci [1987]

Thoracoabdominalsyndrome

XD Ventral midline defects, CHD Bird et al. [1994a], Parvari etal. [1994]

*AR, autosomal recessive; AD, autosomal dominant; XR, x-linked recessive; XD, x-linked dominant; CHD, congenital heart disease; ASD, atrial septaldefect; VSD, ventricular septal defect.

Congenital Diaphragmatic Defects 219

TABLE IV. Chromosome Anomalies Reported With CDDs

Chromosome anomaly References

Monosomy/trisomy/aneuploidy45, X (Ullrich-Turner syndrome) Benjamin et al. [1988], Bollmann et al. [1995], Cunniff et al. [1990], David and Illingworth

[1976], Tibboel and Gaag [1996]Trisomy 2p Lurie et al. [1995]Partial trisomy 5 Bollmann et al. [1995], Tibboel and Gaag [1996]Trisomy 11p15 (Wiedemann-Beckwith syndrome) Turleau et al. [1984]Trisomy 13 Benjamin et al. [1988], Fauza and Wilson [1994], Thorpe-Beeston et al. [1989]Trisomy 18 Adzick et al. [1989], Benacerraf and Adzick [1987], Benjamin et al. [1988], Bollmann et al.

[1995], Cunniff et al. [1990], David and Illingworth [1976], Fauza and Wilson [1994], Howeet al. [1996], Manni et al. [1994], Philip et al. [1991], Tibboel and Gaag [1996]

Trisomy 20p Bird et al. [1994a], David and Illingworth [1976], Tibboel and Gaag [1996]Trisomy 21 Adzick et al. [1989], Benacerraf and Adzick [1987], David and Illingworth [1976], Greenwood

et al. [1996], Harris et al. [1993], Honore et al. [1993], Manni et al. [1994], Tibboel andGaag [1996]

Trisomy 22 Kim et al. [1992], Ladonne et al. [1996]47, XX, +mar Torfs et al. [1992]47, XY +mar16 Howe et al. [1996]47, XY +18, inv(2)(p11.2;q13) Tibboel and Gaag [1996]Mosaic trisomy Fauza and Wilson [1994]46, XY/47, XY +14 Howe et al. [1996]Triploidy 69, XXX Thorpe-Beeston et al. [1989]Tetrasomy 12p Adzick et al. [1989], Bergoffen et al. [1993], Donnenfeld et al. [1993], Fauza and Wilson [1994],

McPherson et al. [1993], Tibboel and Gaag [1996]Teraploidy 21 Adzick et al. [1989], Benacerraf and Adzick [1987], Fauza and Wilson [1994], Tibboel and

Gaag [1996]Deletions/translocations

Chromosome 146, XY, del(1)(pter-q32.3<q42.3-qter) Youssoufian et al. [1988]del (1)(q32-q42) Bird et al. [1994a], Tibboel and Gaag [1996]dup (1)(q24-31.2) Bird et al. [1994a]46, XY/46, XY, dup(1)(q24q31.2) Clark and Fenner-Gonzales [1989]46, XY, t(1;15)(q41;q21.2) Smith et al. [1994]46, XY, t(1;21)(q32;q22)pat Howe et al. [1996]t(1;21) Philip et al. [1991], Tibboel and Gaag [1996]der(1) Benjamin et al. [1988]

Chromosome 346, XY, del(3)(q21q23) Wolstenholme et al. [1994]del(3) Tibboel and Gaag [1996]46, XY, der, t(3;8)(p23;p23.1) Tibboel and Gaag [1996]

Chromosome 44p- Bird et al. [1994a], Howe et al. [1996]

Chromosome 6del 6q23-ter Bird et al. [1994a], Shen-Schwarz et al. [1989]46, XY, t(6;8)(q24;q23) Howe et al. [1996]

Chromosome 746, XY,-7+der(7)t(2;7)(p25.3;q34)mat Current study46, XY, 7q-(q32) Torfs et al. [1992]7q- Fauza and Wilson [1994]ctb(7)(q31.3) Bonneau et al. [1991]

Chromosome 846, XY, del(8)(p23.1) Howe et al. [1996]del(8) Thorpe-Beeston et al. [1989]Balanced 8;14(q24;q21) Philip et al. [1991]46, XX, t(8;13)(q22.3;q22) Temple et al. [1994]46, XX, t(8;15)(q22.3;q15) Temple et al. [1994]r4, 7q+, del(8), +mar Tibboel and Gaag [1996]

Chromosome 946, XY, -9+t(5q;9p) Tibboel and Gaag [1996], Torfs et al. [1992]46, XY, -9+der(9)t(9;11)(p24;p12)pat Donnenfeld et al. [1993]46, XY, -9+der(9)t(9;11)(p24;p13) Tibboel and Gaag [1996]

Chromosome 10Balanced 10;X translocation Cunniff et al. [1990]

Chromosome 1246, XY, del(12) Howe et al. [1996]Balanced 12;15 translocation Fauza and Wilson [1994]

Chromosome 1313q- Benjamin et al. [1988]

Chromosome 14Abnormal 14 centromere Fauza and Wilson [1994]

Chromosome 1546, XY, del(15)(q24-qter) Kristoffersson et al. [1987]46, XX, -15, +der(15)t(15;17)(q24.3:q23.3) Howe et al. [1996]47, XY, t(15;21)(p12;p12) Tibboel and Gaag [1996]

X Chromosomedel Xp22.2-pter (MIDAS syndrome) Happle et al. [1993]46, X, del (X) (p22.1) Plaja et al. [1994]

220 Enns et al.

CDDs may be serendipitous, or a low-frequency asso-ciation, include Apert syndrome [Bird et al., 1994a;Tibboel and Gaag, 1996], C trigonocephaly [Addor etal., 1995], DiGeorge syndrome [McGahren et al., 1997],Oculo-auriculo-vertebral (OAV) spectrum [Greenwoodet al., 1974; David and Illingworth, 1976; Bird et al.,1994a; Tibboel and Gaag, 1996], Stickler syndrome[Benjamin et al., 1988; Bird et al., 1994a; Tibboel andGaag, 1996], Rubinstein-Taybi syndrome [Benjamin etal., 1988; Bird et al., 1994a; Tibboel and Gaag, 1996],and tuberous sclerosis [Ohri et al., 1980]. We recognizethat the division of syndromes into separate tables maybe somewhat arbitrary. However, as a first approxima-tion, these lists may aid the clinician in bedside diag-nosis. In the future, when more is known about thecauses of CDDs and further population studies of syn-dromes associated with CDDs are made, a more quan-titative listing, with actual incidence values, should bepossible.

Up to 73% of patients with CDDs have been reportedto have associated nonpulmonary malformations [Boll-man et al., 1995], with most studies reporting approxi-mately 25 to 50% of patients as having additionalanomalies [Butler and Claireaux, 1962; David and Ill-ingworth, 1976; Greenwood et al., 1976; Puri and Gor-man, 1984; Simson and Eckstein, 1985; Benacerraf andAdzick, 1987; Benjamin et al., 1988; Adzick et al., 1989;Hitch et al., 1989; Cunniff et al., 1990; Fauza and Wil-son, 1994]. In past studies, malformations of the cen-tral nervous system were seen in 5 to 75% of patients,of the cardiovascular system in 4 to 63%, the genito-urinary system in 5 to 27%, and the gastrointestinalsystem in 1 to 20% [Butler and Claireaux, 1962; Davidand Illingworth, 1976; Greenwood et al., 1976; Benja-min et al., 1988; Hitch et al., 1989; Philip et al., 1991;Torfs et al., 1992; Bollman et al., 1995]. Subcostoster-nal diaphragmatic defects (Morgagni type) are rare,but these patients may also have significant additionalanomalies [Pokorny et al., 1984]. In our study, 9 of 16patients (56%) with CDDs with associated anomaliesdid not have syndromic diagnoses. Additional malfor-mations were present, however, with 6 of 9 (67%) hav-ing congenital heart disease, 5 of 9 (56%) having gas-trointestinal anomalies (anterior anus, intestinal mal-

rotation, cleft liver), 2 of 9 (22%) having genitourinaryanomalies (hypospadias, cryptorchidism), and 1 of 9(11%) having a primary brain malformation (agenesisof corpus callosum and gray matter heterotopias pres-ent together in one patient). When the liveborn pa-tients with CDDs not evaluated by Genetics are com-

TABLE V. Possible Teratogenic Causes of CDDs

Teratogen References

Drugs/toxins‘‘Antiadipositum’’ Wolff [1980]Nitrofen Tibboel and Gaag [1996]Phenmetrazine Powell and Johnstone [1962],

David and Illingworth [1976]Polybrominated

diphenylsTibboel and Gaag [1996]

Quinine David and Illingworth [1976]Thalidomide Hobolth [1962], David and

Illingworth [1976]Vitamin A Lipson et al. [1993]Warfarin Normann and Stray-Pedersen

[1989]Deficiency states

Vitamin A deficiency Tibboel and Gaag [1996]Viral infections

Influenza Conover and Roessmann [1990]

TABLE VI. Summary of Associated Malformations in PatientsWith CDD Evaluated by Genetics Without a Specific Syndromic

Diagnosis (n 4 9)*

MalformationNo. of

affected patients

‘‘Dysplastic’’ ears 6Congenital heart disease 6

Ventricular septal defect (2)Tetralogy of Fallot (1)Patent ductus arteriosus (1)Truncus arteriosus (1)Total anomalous pulmonary venous return (1)

Hyperconvex/hypoplastic nails 6Shallow supraorbital ridges 5Flat nasal bridge 5Blepharophimosis 4Micrognathia 4Webbed neck 4Digital anomalies 4

Brachydactyly (1)Camptodactyly (1)Clinodactyly (1)Syndactyly (1)

Anterior anus 3Sparse hair 2Hypertelorism 2Epicanthic folds 2Lower canthal folds 2Bulbous nasal tip 2Small mouth 2Short neck 2Abnormal hair 2Hypoplastic nipples 2Abnormal thorax 2Dysplastic nails 2Hydrops/edema 2Agenesis of corpus callosum 1Heterotopias 1Microcephaly 1Prominent occiput 1Frontal bossing 1‘‘Coarse’’ face 1Synophrys 1Hypotelorism 1Telecanthus 1Downslanting palpebral fissures 1Ptosis 1Short nose 1Midface hypoplasia 1Smooth philtrum 1Everted lower lip 1Cystic hygroma 1Wideset nipples 1Umbilical hernia 1Malrotation 1Cleft liver 1Hypospadias 1Cryptorchidism 1Abnormal palmar creases 1

*Genetics evaluated 16 patients in total; 7 of 16 (44%) had a syndromicdiagnosis and 9 of 16 (56%) had multiple associated malformations, but asyndromic diagnosis was not made. The associated malformations of thelatter group are shown above.

Congenital Diaphragmatic Defects 221

bined, 15 of 31 (48%) were found to have additionalanomalies besides CDDs.

Despite numerous reports of patients with CDDs, thecauses of CDDs have not been fully elucidated. Al-though several reports of CDDs have documented te-ratogen exposure (Table V), a direct causative effecthas not been proven [Bos et al., 1994]. Most diaphrag-matic hernias are posterolateral anomalies that arisefrom defective formation and/or defective fusion of thepleuroperitoneal membrane [Moore, 1982]. Diaphrag-matic agenesis is relatively rare, occurring in ø1–6% of

CDDs [Cunniff et al., 1990; Tibboel and Gaag, 1996],and its pathogenesis is also unknown. Although dia-phragmatic agenesis may have a different pathogen-esis than diaphragmatic hernias, and there have beenfamilial cases in which only diaphragmatic agenesis ispresent [Norio et al., 1984; Toriello and Higgins, 1985;Bird et al., 1994a; Gibbs et al., 1997], both disordersmay exist in the same sibship [Arad et al., 1980; Wolff1980; Farag et al., 1994]. In the summary tables(Tables I–V), a distinction was not made between con-genital diaphragmatic hernia and diaphragmatic agen-esis, because many reports did not emphasize the dif-ference.

Historically, CDDs have been primarily consideredas isolated, usually sporadic, events. However, therehave been increasing reports of familial cases [Crane,1979; Arad et al., 1980; Toriello and Higgins, 1985;Hitch et al., 1989; Martin et al., 1992; Farag et al.,1994; Bird et al., 1994a; Parvari et al., 1994; de Meeuset al., 1997], syndromic cases (Tables I, II), ‘‘associa-tions’’ (Table III), and cases associated with chromo-somal defects (Table IV). In 1958, Cantrell et al. de-scribed a condition with five anomalies affecting themidline [Cantrell et al., 1958]. Czeizel found that mid-line anomalies, including neural tube defects, oralclefts, omphalocele, and diaphragmatic hernia, wereassociated with one another far more frequently thanexpected by chance [Czeizel, 1981]. Soon thereafter,Opitz and Gilbert introduced the concept of the midlineas a developmental field [Opitz and Gilbert, 1982].Thereafter, a population study found that most midlinedefects were statistically associated with other midlinedefects [Khoury et al., 1989]. Several further reportshave described CDDs associated with various midlineanomalies, with possible autosomal recessive [Fitch etal., 1978; Lurie and Kletsky, 1990; Bieber et al., 1991;Bird et al., 1994b], X-linked recessive [Toriello andHiggins, 1985; Carmi et al., 1990; Martin et al., 1992],or X-linked dominant [Parvari et al., 1994] inheritance,giving support to the theory that a number of develop-mental genes are responsible for controlling the forma-tion of the midline ‘‘field.’’ A number of recognizablepatterns of malformation syndromes associated withCDDs also have midline defects as prominent compo-nents of their phenotype, including Fryns syndrome,Wiedemann-Beckwith syndrome, Simpson-Golabi-Behmel syndrome, Donnai syndrome, and Perlmansyndrome (Tables I, VII). It is possible that midlinedevelopmental genes are affected in these syndromesas well. Other interesting, but unexplained, associa-tions with CDDs include macrosomia [Turleau et al.,1984; Sengers et al., 1985; Greenberg et al., 1988; Chenet al., 1993], male pseudohermaphroditism [Arad et al.,1980; Maaswinkel-Mooij and Stovkis-Brantsma, 1992;Toriello and Higgins, 1992; Kennerknecht et al., 1993;Devriendt et al., 1996], linear skin defects [Kunze etal., 1979; Happle et al., 1993; Bird et al., 1994b], andlimb defects [Kunze et al., 1979; Czeizel and Losconi,1987; Gershoni-Baruch et al., 1990; Chen et al., 1993;Cunniff et al., 1993; Gillessen-Kaesbach et al., 1993;Bird et al., 1994a; Howe et al., 1996; Froster et al.,1997] (Table VII). Until the genes responsible for thesephenotypes have been identified and had their function

TABLE VII. Syndromes and Associations With CDDsClassified According to a Specific Major Anomaly*

Midline Defects (general)Donnai syndromeFryns syndromeLimb–body wall defectMidline developmental field defectRadial ray defects–omphalocele–diaphragmatic

hernia–hepatic cystSimpson-Golabi-Behmel syndromeThoracoabdominal syndromeWeidemann-Beckwith syndrome

Midline defects (CNS)Absent left hemidiaphragm–arhinincephaly–cardiac

malformationsAgenesis of corpus callosum–hydrocephaly–diaphragmatic

hernia–hydrops fetalisBlastogenesis Dominant 1Diaphragmatic hernia–pulmonary agenesis–hydrocephalusDonnai syndromeEctrodactyly–diaphragmatic hernia–congenital heart

disease–agenesis of corpus callosumFryns syndromeMIDAS syndromeMidline developmental field defect

Linear skin defectsGoltz-Gorlin syndromeMicrophthalmia with linear skin defects (MLS)MIDAS syndrome

MacrosomiaPerlman syndromeSimpson-Golabi-Behmel syndromeWiedemann-Beckwith syndrome

Male pseudohermaphroditismDenys-Drash syndromeMale pseudohermaphroditism–congenital heart

defect–horseshoe kidney–diaphragmatic herniaPAGOD syndrome

Limb defectsBrachmann-de Lange syndromeBrachycephaly–deafness–cataracts–mental retardationEctrodactyly–diaphragmatic hernia–congenital heart

disease–agenesis of corpus callosumFraser syndromeFryns syndromeGoltz-Gorlin syndromeHolt-Oram syndromeHydrolethalus syndromeLethal multiple pterygium syndromePolycystic kidneys–microcephaly–brachymelia–congenital

heart defectsRadial ray defects–omphalocele–diaphragmatic

hernia–hepatic cystSimpson–Golabi–Behmel syndromeSplit hand–obstructive urinary anomalies–spina

bifida–diaphragmatic defect

*For references for the listed syndromes and associations, refer to Tables I,II, and III.

222 Enns et al.

fully ascertained, the significance of these associationsis uncertain.

The aggregate data clearly show that there are casesof isolated or syndromic CDDs that are inherited. Chro-mosome analysis and a careful search for additionalanomalies, both by prenatal sonography and postnatalevaluation, should be performed in cases of CDD. Adetailed family history also should be obtained. DespiteCDDs being the only finding on prenatal sonogram in 3of 14 patients, these patients were found to have mul-tiple anomalies on postnatal evaluation. In addition,despite normal prenatal karyotypes and postnatal lym-phocytic karyotypes, one patient was found to have tet-rasomy 12p on analysis of skin fibroblasts. This patienthad PUBS performed for assessment of the karyotypeprenatally. Cytogenetic discrepancies between PUBSand amniocentesis for chromosome analysis in a case ofcongenital diaphragmatic hernia associated with tetra-somy 12p have been documented previously, with tet-rasomy 12p not being detected on PUBS analysis [Don-nenfeld et al., 1993]. However, another recent reportrecommended PUBS for prenatal karyotyping in casesof CDD [Howe et al., 1996]. Given our experience andpast reports of cytogenetic discrepancy between PUBSand amniocentesis for prenatal karyotyping, westrongly recommend amniocentesis for prenatal karyo-typing in all cases of CDD. Although CDDs can be de-tected early in the second trimester [Thorpe-Beeston etal., 1989], prenatal ultrasonography is not infallible,and may miss other anomalies. We detected additionalanomalies in 7 of 20 patients (35%) with normal pre-natal sonograms, aside from CDDs, after postnatalevaluation by Genetics or autopsy. Although only fourpatients were autopsied, all had additional anomaliesdetected. We suggest that an autopsy should bestrongly encouraged after a spontaneous or therapeuticabortion of a fetus with CDD, in order to detect poten-tial additional anomalies that may have diagnostic orcounseling implications. We advise caution in gene-tic counseling in cases of CDD detected prenatally,because a normal prenatal karyotype, especially if ob-tained by PUBS, and absence of other detected anoma-lies by fetal ultrasonography, do not exclude the pres-ence of other major anomalies, chromosome abnormali-ties, or a syndromic diagnosis.

ACKNOWLEDGMENTS

G.M.E. was supported, in part, by NIH TrainingGrant GM07085.

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