Anomalous right pulmonary artery origins inassociation with the fetal valproate syndrome

C N Mo, E J Ladusans

AbstractTwo cases are reported of fetal valproatesyndrome in association with anomalousright pulmonary artery origin. Both diag-noses were confirmed following cardiaccatheterisation as echocardiography alonewas inadequate to define the anatomy.Anomalous right pulmonary artery originis extremely rare making a chance associ-ation with fetal valproate syndrome veryunlikely. We recommend that anomalouspulmonary artery origin is borne in mindin patients with valproate syndrome un-dergoing cardiac assessment, particularlyas this may be a diYcult diagnosis to makeon echocardiography.(J Med Genet 1999;36:83–84)

Keywords: valproate syndrome; hemitruncus

The incidence of both major and minorcongenital abnormalities is increased amonginfants of mothers with epilepsy comparedwith the general population.1 This could be theresult of maternal seizures leading to periods ofhypoxia during pregnancy, intrinsic maternalfactors leading to an inherited predisposition tomalformations, and teratogenic eVects ofanticonvulsants.2 It is now recognised thatthere is a specific fetal syndrome associatedwith maternal valproate use, comprising typicaldysmorphic features and often involving majororgan system anomalies.2–8

We describe two infants born to motherswho were treated with sodium valproatemonotherapy throughout pregnancy. They hadtypical features of fetal valproate syndrome andboth had rare abnormalities of pulmonaryartery origin.

Case reportsCASE 1

A male infant presented at the age of 1 weekwith dusky spells and poor feeding. He was alsonoted to have a cardiac murmur. He was bornto a family in which epilepsy was verypredominant; his mother, her father, and twocousins were aVected. His mother was treatedwith sodium valproate throughout pregnancyat a dose of 1.4 g daily. The birth had beenuneventful; he was born by normal vaginaldelivery at term with a birth weight of 3340 g.

He had dysmorphic features typical of fetalvalproate syndrome. These consisted of a high,prominent forehead with midline bossing,upturned nose, low set ears with a straightupper helical border, large eyes, large, widefontanelles, and small feet with prominent ballsand heels. Subsequent investigations included

chest radiography showing a right oligaemiclung, electrocardiography indicating right ven-tricular hypertrophy and right axis deviation,and echocardiography showing situs solitus,right ventricular hypertrophy, and that the ori-gin of the right pulmonary artery could not bedefined. Cardiac catheterisation showed thatthe right pulmonary artery was disconnectedfrom the main pulmonary artery and was fedby small collateral vessels from the descendingaorta The left pulmonary artery was anatomi-cally normal but had suprasystemic pressurewithin it. There was also a large patent ductusarteriosus. Karyotype was normal 46,XY.

At the age of 21⁄2 months he underwentreconstructive surgery to reconnect the rightpulmonary artery to the main pulmonaryartery and to ligate the PDA. Following theoperation, clinical improvement was seen andradiologically there was reperfusion of the rightlung. Echocardiography confirmed resolutionof the pulmonary hypertension. He unfortu-nately died two months later of unrelatedcauses.

CASE 2

A male infant was born at 38 weeks’ gestationto a mother taking 1 g sodium valproate dailythroughout pregnancy. The birth was normaland birth weight was 2700 g. He presented atthe age of 20 days with poor feeding and asso-ciated breathlessness. He had a cluster ofdysmorphic features, including flat nasalbridge, short nose and anteverted nares, long,shallow philtrum, antimongoloid slant to thepalpebral fissures, and downturned angles ofthe mouth, which confirmed fetal valproatesyndrome. He also had bilateral talipes equino-varus, microcephaly, dysplastic proximalphalanges of the index fingers, and unusualbilateral iris defects. Cardiovascular examina-tion showed a systolic murmur and he wasclinically in cardiac failure. Chest radiographyshowed pulmonary plethora, more pronouncedon the right. ECG showed inferior QRScomplex abnormalities and biventricular volt-age increase. Echocardiography showed mod-erately severe tricuspid regurgitation indicatinghigh pulmonary pressure, the left pulmonaryartery arising normally from the main pulmo-nary artery but the right pulmonary arteryarising directly from the aorta (hemitruncus).The pulmonary valve itself appeared dysplasticand stenosed; there was gross right ventricularhypertrophy. These findings were confirmed atcardiac catheterisation (fig 1). This infant alsohad a normal 46,XY karyotype.

Initially control of heart failure was achievedthrough diuretics and then at the age of 2months he underwent surgery to relieve the

J Med Genet 1999;36:83–84 83

Department ofPaediatric Cardiology,Royal ManchesterChildren’s Hospital,Hospital Road,Manchester M27 4HA,UKC N MoE J Ladusans

Correspondence to:Dr Ladusans.

Received 26 March 1998Revised version accepted forpublication 17 June 1998

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right ventricular outflow tract obstruction andreconstruct a normal origin of the rightpulmonary artery. The operation was success-ful, thus re-establishing blood flow from themain pulmonary artery to the right lung.

This patient died aged 2 years 4 monthsfrom complications arising from severe re-stenosis of his right pulmonary artery andresulting congestive cardiac failure.

DiscussionFetal valproate syndrome is characterised bytypical facial features including a tall, narrowforehead, epicanthic folds, infraorbital groove,medial deficiency of the eyebrows, flat nasalbridge, broad nasal root, anteverted nares,shallow philtrum, long upper lip with thin ver-milion border, thick lower lip, and small down-turned mouth,2 and major anomalies are notuncommonly associated. The most frequentlyfound major malformations are neural tubedefects, congenital heart disease, oral clefts,genital abnormalities, and limb abnormalities;to date most attention has been focused onneural tube defects.

Cardiovascular anomalies have been re-ported in a significant proportion of cases offetal valproate syndrome; the incidence overallseems to be about four times that expected inthe general population. Fetal valproate syn-drome has not been associated with anyspecific heart defect or group of defects, andreports to date have documented ventricularseptal defects, patent ductus arteriosus, coarc-tation of the aorta, left hypoplastic heart,pulmonary valve stenosis, dysrhythmias, andECG abnormalities.

The pulmonary artery defects reported hereare extremely rare and the finding of two cases

of fetal valproate syndrome with such defectsimplies that a chance association is extremelyunlikely. It can be very diYcult to make thediagnosis of such defects on echocardiographyalone.9 We recommend that the possibility ofabnormal pulmonary artery origin should beborne in mind when babies with the fetalvalproate syndrome undergo cardiac assess-ment. Perhaps also a detailed fetal echocardio-gram should be oVered to women on valproatetherapy who are pregnant, as there is a definiteincreased risk of cardiac defects, includingcomplex ones as described in this report. Thismay allow earlier diagnosis and thereforepre-empt the deleterious eVect of the abnor-mality in postnatal life.

The finding of specific cardiac defects inassociation with fetal valproate syndrome alsosuggests it has defined eVects on the develop-ing embryo. Both pulmonary and aorticoutflow tracts are formed from the primitivebranchial arches and are largely derived frommigrated neural crest cells. Recent studies haveshown that ablation of the migratory neuralcrest can produce specific cardiac defects inchick embryos,10 comparable to the defectsdescribed in this report. The branchial archsyndromes, such as DiGeorge and Goldenharsyndromes, are all associated with similarcardiac defects involving the outflow tracts.Perhaps these conditions and fetal valproatesyndrome share a common mechanism of dis-ordered neural crest migration, though theymay vary in their aetiologies.11 Future researchmay give further understanding of this diseaseprocess and the way in which valproate aVectsthe fetus in other systems.

1 Dieterich E, Steveling A, Lukas A, et al. Congenital anoma-lies in children of epileptic mothers and fathers. Neuropedi-atrics 1980;11:274-83.

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3 Jager-Roman E, Deichl A, Jakob S, et al. Fetal growth, majormalformations, and minor anomalies in infants born towomen receiving valproic acid. J Pediatr 1986;108:997-1004.

4 DiLiberti JH, Farndon D, Dennis NR, et al. The fetalvalproate syndrome. Am J Med Genet 1984;19:473-81.

5 Ardinger HH, Atkin JF, Blackston D, et al. Verification of thefetal valproate syndrome phenotype. Am J Med Genet1988;29:171-85.

6 Martinez-Frias ML. Clinical manifestation of prenatalexposure to valproic acid using case reports and epidemio-logic information. Am J Med Genet 1990;37:277-82.

7 Dravet C, Julian C, Legras C, et al. Epilepsy, antiepilepticdrugs, and malformations in children of women withepilepsy: a French prospective cohort study. Neurology1992;42(suppl 5):75-82.

8 Thisted E, Ebbeson F. Malformations, withdrawal manifes-tations, and hypoglycaemia after exposure to valproate inutero. Arch Dis Child 1993;69:288-91.

9 Kim TK, Choe YH, Kim HS, et al. Anomalous origin of theright pulmonary artery from the ascending aorta: diagnosisby magnetic resonance imaging. Cardiovasc Intervent Radiol1995;18:118-21.

10 Kirby ML, Gale TF, Stewart DE, et al. Neural crest cellscontribute to normal aorticopulmonary septation. Science1983;220:1059-61.

11 Clark EB. Cardiac embryology. Its relevance to congenitalheart disease. Am J Dis Child 1986;140:41-4.

Figure 1 Cineangiogram showing left ventricular injection in case 2. The right pulmonaryartery is clearly seen arising from the ascending aorta (hemitruncus). RPA=rightpulmonary artery. AO=aorta. LV=left ventricle.

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