American Journal of Medical Genetics 36:353-355 (1990)

Genetics of Conotruncal Malformations: Review of the Literature and Report of a Consanguineous Kindred With Various Conotruncal Malformations

Azaria J.J.T. Rein, Shaul Dollberg, and Rena Gale Department of Cardiology, Hebrew University-Hadassah Medical School (R A., J.J.T.) and Department of Pediatrics and Neonatology, Bikur Cholim Hospital (Affiliated with the Hebrew University-Hadassah Medical School) (D.S., G.R.), Jerusalem

Genetic predisposition in congenital heart disease is considered to be a component of multifactorial inheritance. Recently, mono- genic inheritance in conotruncal malforma- tions has been suggested. We describe a con- sanguineous kindred with various cono- truncal malformations, the presence of which lends support to the idea that this spectrum of malformation is monogenically inherited.

Theoretical background and experimental and clinical data are reviewed and discussed.

KEY WORDS: Congenital heart disease, monogenic inheritance, mul- tifactorial inheritance

INTRODUCTION The risk of familial recurrence of any cardiac malfor-

mation has been reported to be 1-4% [Nora and Nora 1985, 19881 and is attributed to multifactorial inheri- tance [Nora and Nora 1985,1988; Nora, 19831. Recently, conotruncal malformations have been found to carry a significantly higher risk than other cardiac defects, and a monogenic mode of inheritance has been proposed [Pierpont et al., 19881. We describe a large kindred in- cluding two sibs with truncus arteriosus communis, a first cousin once removed with transposition of the great arteries, and another second cousin with double outlet right ventricle. Theoretical, experimental, and clinical data of conotruncal malformations are reviewed and discussed.

Received for publication March 6, 1989; revision received Sep- tember 18, 1989.

Address reprint requests to Azaria J.J.T. Rein, M.D., Depart- ment of Cardiology, Hadassah University Hospital, PO Box 12000, Ein Kerem, Jerusalem, Israel 91120.

0 1990 Wiley-Liss, Inc.

CLINICAL REPORTS Patient 1 (IV-6, Fig. 1)

A 2,550 g female infant was delivered after an un- eventful pregnancy to a primiparous healthy woman married to a first cousin. Both parents came from an inbred family of Persian origin (Fig. 1). The Apgar score was 9 at 5 minutes. At age 8 weeks, the infant was transferred for hospitalization with clinical evidence of central cyanosis, congestive heart failure, and severe failure to thrive. On physical examination, the baby was tachypneic (60 respirations per minute) and cyanotic. The heart examination revealed a hyperkinetic im- pulse, a single second heart sound, and a long 316 ejec- tion type murmur. The liver was 2 cm below the costal margin. Two-dimensional echocardiography (Diasonic cv400, 5 MHz transducer) showed truncus arteriosus communis type IA with mild truncal valve regurgita- tion.

The infant underwent palliative pulmonary artery banding and was subsequently treated with digoxin and diuretics. Six months later, in another institution, she underwent complete repair, which included a patch clo- sure of the ventricular septal defect and an interposition of an aortic homograft conduit from the right ventricle to the main pulmonary artery. Fifteen months later the baby is asymptomatic and developing well.

Patient 2 (IV-7, Fig. 1) Six months after giving birth to her first daughter, the

mother was referred to us €or fetal echocardiography at 18 weeks of her second gestation. Truncus arteriosus communis type IIA was diagnosed. Interruption of preg- nancy was offered but refused by the parents.

A 2,530 female infant was delivered after 40 weeks of uneventful pregnancy with an Apgar score of 9 at 5 minutes. Two-dimensional echocardiography was per- formed at the age of 24 hours. The diagnosis of truncus arteriosus communis type IIA was confirmed. The trun- cal valve in this case was dysplastic and stenosed with an estimated peak systolic ejection gradient of 50 mm Hg. The ventricular septal defect was closed using a dacron patch and an aortic homograft interposed be-

Rein et al. 354

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Fig. 1. Family pedigree. ID: infant death.

tween the right ventricles and the pulmonary arteries. Three hours after surgery the infant died suddenly. The death was attributed to a sudden rise of pulmonic.vascu- lar resistance.

Patient 3 (11143, Fig. 1) This is a first cousin once removed of the 2 sisters

(patients 1 and 2). He was referred to us at the age of 6 weeks with congestive heart failure and cyanosis. At that time (19771, two-dimensional echocardiography was not yet available and the suspected clinical diag- nosis of S,D,D, transposition of the great arteries was confirmed by cardiac catheterization. The infant under- went palliative Blalock-Henlon atrial septectomy, and at the age of 3 years, Mustard operation was performed. Eight years later the child is asymptomatic.

Patient 4 (IV-5, Fig. 1) This child was born cyanotic with a birthweight of

2,120 g. She was diagnosed as suffering from S,D,D, double outlet right ventricle with unbalanced complete atrio-ventricular canal defect, hypoplastic left ventricle, large primum and secundum type atrial septal defects, large ventricular septal defect, and critical pulmonic valvular stenosis. She underwent a first Blalock-Taus- sig shunt in her 1st day of life. Because of increased cyanosis, she had a modified right Blalock-Taussig shunt interposed at the age of 3 years. In the subsequent months, she developed severe congestive heart failure, which was related to dilatation of the right ventricle and atrio-ventricular valve anulus with severe regurgita- tion. She underwent partial coil embolization of the right shunt but later developed severe hemolysis and fatal disseminated intravascular coagulopathy.

DISCUSSION In the reported family, 2 sibs had truncus arteriosus

communis. To our knowledge, the recurrence of this defect in two sibs has been reported in only 4 instances

[Pierpont et al., 1988; Goodyear, 1961; Brunson et al., 1988; Shapiro et al., 1981; Corone et al., 19831. The two other cases (patients 3 and 4) with S,D,D, transposition of the great arteries and S,D,D, double outlet right ven- tricle, respectively, are first degree cousins once re- moved the first and second degree cousin the second of the sibs with truncus arteriosus communis.

Recurrence of conotruncal malformations within a family with a proband with truncus arteriosus com- munis has been reported, and conotruncal (‘suscep- tibility” has been suggested. Pierpont et al. t198Sl were more specific and proposed a genetic or even monogenic inheritance mode for all conotruncal malformations, al- though multifactorial inheritance cannot be ruled out in the presence of affected parents and second and third degree relatives. The occurrence of truncus arteriosus communis in relatives of individuals with truncus arte- riosus communis has been estimated as 4.7% and even up to 9.1% in cases of “complex” (i.e., associated with other cardiac anomalies) truncus arteriosus communis [Pierpont et al., 19881. Our first 2 patients fit into this definition of a “complex” truncus arteriosus communis. The occurrence of nonconcordant lesions in relatives with truncus arteriosus communis may be as high as 13.6% according to Pierpont et al. [19881, which further lends support to a monogenic mode of inheritance (auto- soma1 recessive?) rather than multifactorial inheri- tance.

Human hearts have been divided into anatomic and developmental components for the purpose of better un- derstanding and diagnosing of cardiac defects [Van Praagh and Van Praagh, 1965,1982; Van Praagh, 19791. The segmental approach proposed by Van Praagh and Van Praagh is the theoretical basis for including truncus arteriosus communis, transposition of the great arte- ries, double outlet right ventricle, and tetralogy of Fallot within a unique group named “conotruncal malforma- tions.” In fact, these defects represent a spectrum of different malformations of the infundibulum (conus),

Genetics of Conotruncal Malformations 355

occurring at the 34th-35th days of the embriogenesis [Van Praagh and Van Praagh, 19651. The same rationale led others [Pierpont et al., 1988; Van Mierop and Kutsche, 19841 to consider interrupted aortic arch type B as a conotruncal malformation.

Experimental studies showed that by mating Kee- shond dogs with conotruncal septa1 defects, one could

Kirby ML (1987): Cardiac morphogenesis: Recent research advances. Pediatr Res 21:219-224.

Kirby ML (1988): Nodose placode provides ectomesenchyme to the developing chick heart in the absence of cardiac neural crest. Cell nssue %s 252:17-22,

Nishibataka M, Kirby ML, Van Mierop LHS (1987): Pathogenesis of persistent truncus arteriosus and dextroposed aorta in the chick embryo after neural crest ablation. Circulation 75:255-264.

obtain the whole spectrum of malformations as previ- ously quoted [Van Mierop et al., 19771. Furthermore, the same conotruncal malformations could be experimen- tally obtained in the chick and rat by giving them Bis- diamine Nimustine chloride [Takao, 19871. Thus, it seems that conotruncal malformations originate from the same primum movens, namely neural crest defect. Moreover, neural crest or “cardiac” neural crest [Kirby, 19871 ablation has been shown to be related to the patho- genesis of conotruncal malformations. [Stewart et al., 1986; Nishibataka et al., 1987; Kirby, 19881. Thus, data from the literature suggest a monogenic pattern of inheritance of at least a subgroup of conotruncal malfor- mations. Whether this mode is indeed autosomal reces- sive remains to be determined.

We suggest that a family with one member affected by a conotruncal malformation should be informed of the recurrence risk, which may be significantly higher than in any other cardiac defect.

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