British Heart Journal, I973, 35) 30I-304.

Pulmonary valvular dysplasiaA cardiofacial syndrome

Leonard M. Linde, Searle W. Turner, and Robert S. SparkesFrom the Departments of Pediatrics (Cardiology) and Medicine, UCLA School of Medicine,Los Angeles, California, U.S.A.

Four patients with pulmonary valvular dysplasia are described. The primary features of this disorder includeclinical and laboratoryfindings similar to those ofpulmonary valvular stenosis but without a pulmonary ejectionclick, in association with an unusual facies, small stature, and mental retardation. The importance of therecognition of this lesion before operative intervention is stressed. Though chromosomal studies are normal,there is a possibility of aetiological genetic recessive factors. The relation of these patients to previouslydescribed cardiofacial syndromes is discussed. Recognition of their similarities may prevent the recurrent 'dis-covery' of new syndromes based on minor variations of associated anomalies.

A type of right ventricular obstruction with thick-ening and immobility of the pulmonary valve leafletshas recently been described (Koretzky et al.,I969). In contrast to other forms of pulmonary val-vular stenosis syndromes, these cases were charac-terized by absence of annular hypoplasia and thepresence of three distinct valve cusps withoutcommissural fusion. The characteristic thickening ofthe affected valve cusps prevented their excursionand resulted in obstruction to right ventricular out-flow. These features were associated with a highoperative mortality, and necessitated variations inthe usual surgical approach to this particular type ofpulmonary valve obstruction.The syndrome of pulmonary valvular dysplasia

has several distinct features: (i) a pulmonary ejec-tion murmur but no click; (2) unusual facies andphysical characteristics (Fig. I); (3) mental andgrowth retardation; (4) angiocardiographic or patho-logical evidence of thickening of the pulmonaryvalve leaflets without 'doming', consistent with lackof commissural fusion.

Case reportsThis report concerns 4 additional patients similar tothose previously described (Koretzky et al., I969).Clinical features are summarized in the Table. The car-diac findings are identical to pulmonary valvular steno-sis except for the consistent absence of an ejection click.The chest x-ray is similar to that found in pulmonaryvalvular stenosis as is the electrocardiogram, except that

Received I8 September I972.

the frontal loop rotated counterclockwise with a superior-ly placed mean QRS axis in 2 patients (Fig. 2). Similarfindings were reported by Koretzky et al. (i969). Car-diac catheterization with right ventriculography is dia-gnostic (Fig. 3) and associated congenital cardiovascularmalformations are common. In one patient (Case i) thediagnosis was confirmed at operation where the pulmon-ary valve leaflets were found to be deformed, rolled back,and thickened, but the commissures were essentiallycompletely formed and there was no appreciable fusionor stenosis.

DiscussionThe syndrome of supravalvular aortic stenosis withmental retardation and unusual facies was firstdescribed by Williams, Barratt-Boyes, and Lowe(i96i), and subsequently over I00 cases have beenreported with additional abnormalities including:infantile hypercalcaemia, narrowing of the peri-pheral systemic and pulmonary arteries, inguinalhernias, strabismus, dentition abnormalities, retinalabnormalities on angiography, and blue irides. Chro-mosomal studies performed on patients with thatsyndrome have been normal (Eberle and Beuren,I963; Joseph, Polani, and Gold, I963; de Grouchyand Emerit, I963) with one exception (Palmer, I963;Merritt et al., I963).

Hartel, Frick, and Halonen (I968) described acase of supravalvular pulmonary stenosis in a patientwith mental retardation and a peculiar facies similarto that seen in the supravalvular aortic stenosis syn-drome and suggested that their case might be avariant not previously described. Our patients had

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302 Linde, Turner, and Sparkes

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FIG. I Cases I, 3, and 2 from left to right. Note very similar facies characterized by hyper-telorism, epicanthal folds, and low set ears.

TABLE Summary of clinical and laboratoryfindings in 4 patients

Case Age Sex Percentile Mental Unusual Pulmon. Ejection Assoc. defect ElectrocardiogramNo. (yr) growth retard. facies ejection click

murmur Axis RV RAHt. Wt. hypertr. enlarge-

ment

I 5 M 3rd 3rd + + 4/6 Atrial septal defect -I000 + +2 21 M ioth ioth - + 4/6 - Ventric. septal defect; - ioo0 + +

pulm. valvularinsufficiency

3 I2 F 3rd 20th + + 3/6 - +1I200 + +4 5 F 3rd 3rd + + 4/6 Persistent ductus; + I60° +

pulm. artery stenosis

+ = Present; -= Absent. * Pulmonary arteries distal to coarctation.

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Pulmonary valvular dysplasia 303

I II III aVR aVL aVF

RV3I I V2 V3 V4 Vs Vb

FIG. 2 Electrocardiogram (Case i) showing a mean

QRS axis of 1000, right ventricular hypertrophy,

and right atrial enlargement.

facies resembling those described in the previously

mentioned reports (Fig. I) together with mental

retardation in 3 of them. The present cases therefore

may represent a variant of a cardiofacial syndrome

more common than previously expected, and possibly

due to a similar but as yet unknown cause.

One of the interesting aspects of this report is thedifficulty of differentiation of the various forms of

pulmonary valvular obstruction. The associated

craniofacial abnormaihties indicate a broad but re-

lated spectrum of facial abnormnality and pulmonaryvalve pathology and suggest a related gene locus incases described by Noonan and Ehmke (i963),Noonan (i968), Hartel et al. (1968), Koretzky et

al. (i969), Willams et al. (ie6i), and Hartel et al.

(i968). Wood (1956) mentioned the hypertelorismand round face of many patients with pulmonaryvalvular stenosis. Noonan and Ehmke (I963) and

Noonan (I968) describe a large series of patients

Angiograms Catheterization data Karyotype

Thickened Commissural Rt. Puim.pulm. valve fusion ventricle valve

+ - 87 ? Normal+ - 50 22 Normal

+ - 60 I2 Normal+ - 100 I5* Normal

FIG. 3 Lateral selective right ventricular angio-cardiogram (Case 3) in pulmonary valvular dysplasiashowing a thickenedpulmonary valve without 'doming'and post-stenotic dilatation of the pulmonary trunk.

who closely resemble those reported in the paper byKoretzky et al. (I969). Noonan's patients had hyper-telorism, short neck, low set ears, curly hair, andmental and growth retardation. In contrast to ours,her patients had micrognathia and a very high inci-dence of chest and other musculoskeletal deformi-ties. A difference of great surgical and prognosticimport is based on surgical, pathological, or angio-cardiographic proof of pulmonary valve thickeningwithout commissural fusion. In spite of reportedminor differences, it seems clear that we are dealingwith a spectrum of pulmonary valve deformities offacial and other anatomical abnormalities.Chromosomal analysis was performed on periph-

eral blood samples in each of our patients and nor-mal karyotypes were obtained. No minor structuralvariation was noted when the chromosomes wereclosely examined for each patient or on comparisonof the karyotypes from all patients.The aetiology of most congenital defects is not

known. Except for a few specific syndromes, thegenetic contribution to this group of diseases is alsopoorly defined. In a study of 56 children with pul-monary stenosis, Lamy, de Grouchy, and Schweis-guth (I957) suggested that genetic factors might bemore important in pulmonary stenosis than in othercongenital heart disorders because of the high con-sanguinity rate and familial incidence as well as thelow frequency of irregularities during pregnancy. Itis not clear in their cases how frequently the cardiacabnormality was associated with unusual facies.Campbell (I954) reviewed I25 cases of pulmonarystenosis and found an incidence of noncardiac mal-formation of I3 per cent. Though none of his

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304 Linde, Turner, and Sparkes

patients was noted to have characteristic facies, healso concluded that genetic factors might have anaetiological role in pulmonary stenosis.

Koroxenidis et al. (i966) reported a mother and4 of her 8 children with pulmonary stenosis. Of theaffected children, all had unusual facies and low setears which were not seen in the normal members ofthe family. In this family, it was thought that theheart lesions were transmitted as an autosomaldominant. Further suggestion of a genetic aetiologyin congenital heart disease comes from reports byNora and Meyer (i966) and Nora et al. (I967) inwhich a large number of families and a large numberof twins were evaluated.

Intrauterine viral infections such as rubella mayalso affect the development of the cardiovascularsystem. The heterogeneity of these genetic and en-vironmental factors can lead to some confusion be-cause different combinations may lead to the samecongenital malformation. Studies in our patientsfailed to define a specific and definite genetic aetio-logical factor. The similarity of the clinical findingsin conditions mentioned above does neverthelesssuggest the possibility of a common factor in theiraetiology. The negative family histories do notrule out the possibility of genetic recessive factorsand though dominant inheritance seems unlikely, itis possible that inheritance plays a role. The normalchromosome studies do not exclude changes, suchas partial deletion or inversion, which current tech-niques cannot detect.

CommentThe importance of preoperative recognition ofpulmonary valvular dysplasia must be stressed, be-cause simple valvulotomy will probably afford littlerelief and the operative mortality is high. If opera-tive therapy is imperative, valve replacement, re-section of a valve leaflet, or a patch graft across theannulus should be considered.The prognosis of these patients is poorer than

that of the usual pulmonary valvular stenosis, inview of associated abnormalities and the reportedhigh surgical mortality of 38 per cent (Koretzky etal., i969). The use of other operative techniques asmentioned above may reduce this surgical mortality,

but the child's prognosis for a 'functionally normal'life depends upon the degree of his noncardiovas-cular abnormalities, namely the growth and mentalretardation.

ReferencesCampbell, M. (I954). Simple pulmonary stenosis: pulmonary

valvular stenosis with a closed ventricular septum. BritishHeartJournal, I6, 273.

de Grouchy, J., and Emerit, I. (I963). Chromosome studies inpatients with supravalvular aortic stenosis. Lancet, 2, 789.

Eberle, P., and Beuren, A. J. (I963). Chromosome studies inpatients with supravalvular aortic stenosis. Lancet, 2, 438.

Hartel, G., Frick, M. H., and Halonen, P. I. (I968). Supra-valvular pulmonic stenosis, abnormal facial appearance,and mental retardation. American Heart Journal, 75, 540.

Joseph, M. C., Polani, P. E., and Gold, R. G. (I963). Chromo-some studies in patients with supravalvular aortic stenosis.Lancet, 2, 788.

Koretzky, E. D., Moller, J. H., Korns, M. E., Schwartz, C. J.,and Edwards, J. E. (I969). Congenital pulmonary stenosisresulting from dysplasia of valve. Circulation, 40, 43.

Koroxenidis, G. T., Webb, N. C., Moschos, C. B., and Lehan,P. H. (I966). Congenital heart disease, deaf-mutism andassociated somatic malformations occurring in severalmembers of one family. American Journal of Medicine, 40,I49.

Lamy, M., de Grouchy, J., and Schweisguth, 0. (I957).Genetic and nongenetic factors in the etiology of congenitalheart disease. A study of i,i88 cases. American.Journal ofHuman Genetics, 9, I7.

Merritt, A. D., Palmer, C. G., Lurie, P. R., and Petry, E. L.(I963). Supravalvular aortic stenosis: genetic and clinicalstudies (abstract). Journal of Laboratory and Clinical Medi-cine, 62, 995.

Noonan, J. A. (I968). Hypertelorism with Turner phenotype.A new syndrome with associated congenital heart disease.American Journal of Diseases of Children, II6, 373.

Noonan, J. A., and Ehmke, D. A. (I963). Associated noncar-diac malformations in children with congenital heartdisease. J'ournal of Pediatrics, 63, 468.

Nora, J. J., Gilliland, J. C., Sommerville, R. J., andMcNamara, D. G. (I967). Congenital heart disease intwins. New EnglandJournal of Medicine, 277, 568.

Nora, J. J., and Meyer, T. C. (I966). Familial nature of con-genital heart diseases. Pediatrics, 37, 329.

Palmer, C. G. (I963). Chromosome studies in patients withsupravalvular aortic stenosis. Lancet, 2, 788.

Williams, J. C. P., Barratt-Boyes, B. G., and Lowe, J. B.(I96I). Supravalvular aortic stenosis. Circulation, 24, 1311.

Wood, P. (I956). Diseases of the Heart and Circulation, 2nd ed.,p. 3I8. J. P. Lippincott, Philadelphia.

Requests for reprints to Professor L. M. Linde, Depart-ment of Pediatrics, School of Medicine, The Center forthe Health Sciences, University of California, LosAngeles, California 90024, U.S.A.

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