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Original papers

Pediatrics

Eur J Pediatr (1992) 151 : 726-727

9 Springer-Verlag 1992

Tetralogy of Fallot in three siblings: a familial study and review of the literature G. Pacileo 1, N.N. Musewe 2, and R. Calabrb 1 1Cattedra di Cardiologia Pediatrica, Ospedale V. Monaldi, Napoli, Italy 2Department of Paediatrics, Division of Cardiology, The Hospital for Sick Children, Toronto, Ontario, Canada Received December 27, 1989 / Accepted after revision March 2, 1992

Abstract. W e r e p o r t a f a m i l y in which t h r e e o u t of f o u r siblings h a d t e t r a l o g y of F a l l o t ( T O F ) . T h e f a m i l y history s h o w e d T O F in t h e d a u g h t e r of a m a t e r n a l cousin, while no o t h e r c o n g e n i t a l h e a r t diseases w e r e d i s c o v e r e d . A l t h o u g h no t e r a t o g e n i c e n v i r o n m e n t a l a g e n t was disc o v e r e d , the a b s e n c e o f p a r e n t a l c o n s a n g u i n i t y a n d t h e p r e s e n c e of a n o t h e r a f f e c t e d r e l a t i v e suggest m u l t i f a c t o rial i n h e r i t a n c e . A u t o s o m a l recessive i n h e r i t a n c e c a n n o t b e r u l e d out.

Key words: T e t r a l o g y of F a l l o t - F a m i l i a l s t u d y - Multifactorial inheritance

Introduction M o s t e p i d e m i o l o g i c a l studies r e p o r t a h i g h e r r e c u r r e n c e risk of c a r d i a c m a l f o r m a t i o n s ( 1 % - 4 % ) in families with an a f f e c t e d m e m b e r t h a n in the g e n e r a l p o p u l a t i o n [1, 9, 10]. G e n e t i c o r e n v i r o n m e n t a l factors h a v e b e e n r a r e l y d i s c o v e r e d . D i f f e r e n t p a t t e r n s of i n h e r i t a n c e h a v e b e e n s u g g e s t e d [4, 7, 11] b u t m u l t i f a c t o r i a l i n h e r i t a n c e is m o s t f r e q u e n t l y a c c e p t e d [9, 10]. W e d e s c r i b e an u n u s u a l f a m i l y in which t h r e e siblings h a d t e t r a l o g y of F a l l o t ( T O F ) a n d discuss t h e p o s s i b l e mode of inheritance.

Family report Patient 1 He presented with cyanosis from the age of 1 month. Cardiac catheterization at 6 months showed a TOF with severe infundibular pulmonary stenosis and hypoplasic pulmonary valve. He died of hypoxia while waiting for surgical repair. Autopsy results were not available.

Patient 2 A girl, now 6 years old, was admitted to our hospital for cyanosis at rest when she was 18 months old. There was a systolic murmur of grade 2/6 intensity over the pulmonary area with no splitting $2.

Correspondence to: R. Calabr6, Via Bracco 71, 1-80100 Napoli, Italy

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[] M~o | Non-cardlac ~ngenltal anomaly 9 .... ~ 9 .......... Fig.1. Family tree: the daughter of a maternal cousin (III.10) had a tetralogy of Fallot; a maternal cousin (Ill.7) had an "intestinal malrotation" and a paternal aunt (II.7) died suddenly of an unknown cause. A, B and C represent the affected siblings Dled

Echocardiography showed a large subaortic ventricular septal defect with overriding aorta, pulmonary stenosis with hypoplasic pulmonary valve and good size pulmonary branches. At the age of 2 years surgical repair was performed. The child is now in a good haemodynamic condition.

Patient 3 A boy, now 3 years old, was admitted to our hospital aged 20 days for cyanosis and cardiac murmur. A 2/6 systolic murmur over the pulmonary area with no splitting $2 was detected. Echocardiographic findings were similar to those of patient 2 but with smallersize pulmonary branches (4 mm). At the age of 1 month a modified Blalock-Taussig shunt was performed and then at 2 years the patient underwent a radical surgical repair. The postoperative course was uneventful and there were no resulting problems. None of the above three siblings had extracardiac congenital anomalies. The facial appearance and peripheral blood chromosomes were normal. Family data showed low social class and no parental consanguinity. No diseases, X-ray tests, drugs or alcohol had been noted during pregnancies. The family tree study (Fig. 1) revealed a TOF in the daughter of a maternal cousin (III 10); unfortunately data on her maternal family could not be obtained. No other congenital heart diseases were discovered, but an extracardiac congenital malformation ("intestinal malrotation") was found in a maternal cousin (III.7). Finally a paternal aunt (11.7) died suddenly at 3 years of age of an unknown cause; there was no history which suggested cyanotic congenital heart disease. Autopsy was not performed.

Discussion T h e usual r e c u r r e n c e r a t e of T O F in a f a m i l y has previously b e e n e s t i m a t e d b e t w e e n 1% a n d 3% [1].

727 F u r t h e r m o r e a higher incidence of different lesions, particularly ventricular septal defect, pulmonary stenosis and transposition of the great arteries, in a family with a m e m b e r affected by T O F has also been reported [3, 5, 6]. Corone et al. [3] proposed that some genes m a y determine various lesions of the same heart tube, i.e. the conotruncus, as some of these malformations are consequences of conotruncal abnormalities. This hypothesis seems to be supported by the experimental work p e r f o r m e d by Van Mierop et al. [12], who obtained different types of conotruncal malformations mating Keeshond dogs with hereditary defects of conotruncal septum. The recurrence of T O F in three out of four siblings in our family is very unusual; a similar study, describing four children born with T O F in the same family, was previously described in an A m e r i c a n religious group, the Hutterite Brethren [8]. F u r t h e r m o r e F u h r m a n n reported of a family in which three siblings had T O F and two families in which two siblings had T O F [6]. Different modes of inheritance have been suggested for T O F [1, 4, 7, 16]. An autosomal dominant inheritance with reduced penetrance was proposed in 1962 by Pitt [11], who described a family in which 11 persons had T O F or one of its components and then confirmed in 1985 by Jones and Waldman [7], who reported a family in which six persons in three successive generations had some combination of pre-auricular pits (four), T O F (three), fifth finger clinodactyly (six) and seemingly characteristic fades (five). On the other hand in 1985. D e r Kaloustian et al. [4], reported a family tree containing two sisters with T O F and pulmonary atresia and suggested an autosomal recessive inheritance. Most authors have not found a Mendelian pattern of inheritance and have proposed a multifactorial inheritance hypothesis [1, 5, 7]. In our case the study of the family tree does not allow us to rule out any pattern of inheritance suggested previously. A n autosomal dominant inheritance with reduced penetrance is possible but unlikely; in this case the pathological gene m a y be present but not expressed in one parent.

A n autosomal recessive inheritance with both healthy bearer parents is more likely. If we accept this hypothesis the probability that in a family three out of four siblings could be born with T O F is (1/4) 3 i.e. 1/64. Although the high recurrence of the pathology among the siblings in our study (three/four) should favour Mendelian inheritance, the low probability of it happening, the absence of parental consanguinity and the presence of another affected relative suggest that a multifactorial inheritance hypothesis is m o r e probable.

Appendix: After

our p a p e r was accepted a new case report describing T O F in triplet siblings was published [2]. References 1. Boon AR, Farmer MB, Roberts DF (1972) A family study of Fallot's tetralogy. J Med Genet 9 : 179-188 2. Cassidy SC, Allen HD 1991) Tetralogy of Fallot in triplet siblings. Am J Cardiol 67 : 1442-1444 3. Corone P, Bonaiti C, Feingold J, Fromont S, Berthet-Bondet D (1983) Familial congenital heart disease: how are the various types related? Am J Cardiol 51:942-945 4. Der Kaloustian VM, Ratl H, Malouf J, Hatem J, Slim M, Tomeh A, Khouri J, Kutayli F (1985) Tetralogy of Fallot with pulmonary atresia in siblings. Am J Med Genet 21 : 119-122 5. Fuhrmann W (1986) Congenital heart disease in sibships ascertained by two affected siblings. Hum Genet 6 : 1-12 6. Fraser FC, Hunter AD (1975) Etiologic relations among categories of congenital heart malformations. Am J Cardiol 36: 793-796 7. Jones MC, Waldman JC (1985) An autosomal dominant syndrome of characteristic facial appearance, preauricular pits, fifth finger, clinodactyly and tetralogy of Fallot. Am J Med Genet 22 : 135-141 8. Lee RV, Buker RS Jr (1969) Congenital heart disease among the Hutterite Brethren. N Engl J Med 280:1061-1062 9. Nora JJ (1968) Multifactorial inheritance hypothesis for the etiology of congenital heart diseases: the genetics-environmental interaction. Circulation 38 : 604-617 10. Nora JJ, Nora AH (1985) Genetic epidemiology of congenital heart disease. Prog Med Genet 5:91-137 11. Pitt DB (1962) A family study of Fallot's tetrad. Aust Ann Med 11 : 179-183 12. Van Mierop HS, Patterson DF, Schnarr WR (1977) Hereditary conotruncal septal defects in Keeshond dogs: embryologic studies. Am J Cardiol 40 : 936-949

Tetralogy of Fallot in three siblings: a familial study and review of the literature.

We report a family in which three out of four siblings had tetralogy of Fallot (TOF). The family history showed TOF in the daughter of a maternal cous...
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