Bicuspid Aortic Valves in Monozygotic TwinsCindy Brown, R.D.C.S., David C. Sane, M.D., and Dalane W. Kitzman, M.D.

From the Section of Cardiology, Department of Internal Medicine, Wake Forest UniversitySchool of Medicine, Winston-Salem, North Carolina

Identical bicuspid valve anomalies were found in monozygotic twins. Screening echocardiographyshould be considered for first-degree relatives of patients with bicuspid aortic valve. (ECHOCARDIO-GRAPHY, Volume 20, February 2003)

bicuspid aortic valve, aortic stenosis, genetics, echocardiography

The recognition of bicuspid aortic valve isimportant in clinical management because pa-tients should receive prophylaxis for infectiveendocarditis and may require evaluation for as-sociated anomalies, such as coarctation of theaorta and cerebral berry aneurysms. Bicuspidaortic valve is one of the most common con-genital valvular anomalies, affecting 1% of thepopulation. An underappreciated but clinicallyimportant aspect of bicuspid aortic valve is itsfamilial clustering, which is demonstrated byour report of twins with identical bicuspid aor-tic valve anomalies.

Cases

Twin A, a 42-year-old female, was initiallyseen for benign palpitations. Physical examina-tion was normal, including blood pressure andpulses, except for a murmur of mild aortic steno-sis. Echocardiography demonstrated a normalsized left ventricle with mild concentric hyper-trophy, and ejection fraction of 67% (Fig. 1).There was a bicuspid aortic valve with commis-sures at 11 o’clock and 5 o’clock position and aprobable raphe at 1 o’clock, a Doppler peak gra-dient of 37 mmHg, mean gradient of 21 mmHg,and valve area of 1.5 cm2. Medical history wasotherwise notable for migraine headaches andmild ocular hypertension.

Twin B was also initially seen for palpita-tions. Physical examination was normal, in-cluding blood pressure and pulses, except fora murmur of mild aortic stenosis. Echocardio-graphy demonstrated a normal sized left ven-

Address for correspondence and reprint requests: DalaneW. Kitzman, M.D., Section of Cardiology, Wake ForestUniversity School of Medicine, Medical Center Boule-vard, Winston-Salem, NC 27157-1045; E-mail: dkitzman@wfubmc.edu

tricle with mild concentric hypertrophy andan ejection fraction of 55%. There was a bi-cuspid aortic valve with the commissures at11 o’clock and 5 o’clock position and a probableraphe at 1 o’clock, a Doppler peak gradient of27 mmHg, mean gradient of 14 mmHg, and cal-culated valve area of 1.8 cm2. Holter monitor re-vealed brief episodes of ectopic atrial tachycar-dia and rare episodes of ventricular bigeminy.Her medical history was notable otherwise onlyfor glaucoma, for which she was treated withtimolol maleate eye drops.

Both patients were recommended to followendocarditis prophylaxis guidelines and to in-form first degree relatives to discuss consider-ation of screening echocardiography with theirphysicians.

Discussion

This report of the occurrence of bicuspidaortic valve in twins demonstrates an un-usual example of familial clustering of congen-itally bicuspid aortic valve anomaly. Althoughfamilial clustering has been described previ-ously,1−3 there have been few reports in twins.Our patients were believed to be monozygotic(‘identical’) twins. Interestingly, the configura-tion of the aortic leaflets found in Twin A, withcommissures at 11 o’clock and 5 o’clock, and aprobable raphe at 1 o’clock, appeared identicalto that found in Twin B. Both also had relativelysimilar gradients and valve areas.

Huntington et al.1 reported that the rate ofoccurrence of bicuspid aortic valve among firstdegree relatives in 30 families was 9%. Eleven(37%) of 30 families studied had at least oneadditional member with the valvular condi-tion. In the 11 families with more than onemember with bicuspid aortic valve, the inher-itance pattern was compatible with autosomal

Vol. 20, No. 2, 2003 ECHOCARDIOGRAPHY: A Jrnl. of CV Ultrasound & Allied Tech. 183

BROWN, SANE, AND KITZMAN

Figure 1. Parasternal basal short-axis views. A. Twin A:bicuspid malformation of the view at aortic valve with mildcalcification and mildly reduced orifice area. Note the orien-tation of the bicuspid leaflets (11 o’clock to 5 o’clock). B. TwinB: although technique is slightly different, the configurationof the bicuspid valve is identical to twin A.

dominant with reduced penetrance. Based ontheir findings, Huntington et al. recommendedthat echocardiography be performed in all firstdegree relatives of persons affected with bicus-pid aortic valves. Emanual2 reported similarfindings.

Gelb et al.3 described a three generationfamily with seven members affected by bicus-pid aortic valve, patent ductus arteriosus, fifth

metacarpal hyperplasia and brachydactyly. Ourpatients did not have the skeletal abnormal-ities associated with this novel heart-handsyndrome.

The molecular defect predisposing to bicus-pid aortic valve has not been determined in hu-mans. However, it has been demonstrated thatmice lacking functional endothelial nitric ox-ide synthase (eNOS) are predisposed to devel-oping this anomaly.4 Interestingly, about 10%of eNOS null mice also develop a limb reduc-tion defect similar to that seem in patients withHolt-Oram syndrome.4 We have not performedgenetic analyses in our two patients. It is of in-terest to note that one twin has definite glau-coma and the other has elevated intraocularpressure, related disorders in which nitric oxidehas a documented role in the pathogenesis.5,6

Echocardiography is an essential tool forthe diagnosis of bicuspid aortic valve. In pa-tients with adequate echocardiographic images,echocardiography has a high sensitivity (92%)and high specificity (96%) for the diagnosis of bi-cuspid aortic valve.7 When bicuspid aortic valveis found, physicians should be aware of the rec-ommendation to screen first degree relatives.

References

1. Huntington K, Hunter AGW, Chan K-L: A prospec-tive study to assess the frequency of familial clusteringof congenital bicuspid aortic valve. J Am Coll Cardiol1997;30:1809–1812.

2. Emanuel R, Withers R, O’Brien K, et al: Congenitally bi-cuspid aortic valve: Clinicogenetic study of 41 families.Br Heart J 1978;40:1402–1407.

3. Gelb BD, Zhang J, Sommer RJ, et al: Familial patentductus arteriosus and bicuspid aortic valve with handabnormities: A novel heart-hand syndrome. Am J MedGenet 1999;87:175–179.

4. Lee TC, Zhao YD, Courtman DW, et al: Abnormal aor-tic valve development in mice lacking endothelial nitricoxide synthase. Circulation 2000;101:2345–2348.

5. Haefliger IO, Dettmann E, Liu R, et al: Potential role ofnitric oxide and endothelin in the pathogenesis of glau-coma. Surv Opthalmol 1999;43(Suppl 1):S51–S58.

6. Chiou GC: Review: Effects of nitric oxide on eye dis-eases and their treatment. J Ocul Pharmacol Ther2001;17:189–198.

7. Chan K-L, Stinson WA, Veinot JP: Reliability oftransthoracic echocardiography in the assessment ofaortic valve morphology: Pathological correlation in 178patients. Can J Cardiol 1999;15:48–52

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