American Journal of Medical Genetics 37:40-41 (1990)
Familial Tetralogy of Fallot and Glaucoma Su-chiung Chen and Noreen D’Souza Department of Pediatrics, Division of Cardiology (S.-c Chen) and Genetics (N.D’S.), St. Louis University School of Medicine, St. Louis, Missouri. ~~
All 3 daughters of a mother with glaucoma had a conotruncal abnormality of the heart and glaucoma. The presence of heart and eye anomaly may be coincidental; however, both may be related to abnormal development of neural crest. The pedigree suggests autosoma1 dominant inheritance in this family.
KEY WORDS: tetralogy of Fallot, glaucoma, autosomal dominant inheritance INTRODUCTION Tetralogy of Fallot is a conotruncal abnormalilty presumably resulting from disordered mesenchymal tissue and/or neural crest migration [Clark, 19861. Multiple occurrences of tetralogy of Fallot in relatives and sibs have been reported, but it is generally thought to be multifactorial in origin with rare examples of possible monogenic inheritance [Boon et al., 1972; Miller and Smith, 19793. Extracardiac anomalies in children with tetralogy are not infrequent; however, they are mostly seen in the Goldenhar sequence [Greenwood et al., 19743, DiGeorge sequence [Greenwood et al., 1975; Greenwood, 19841, and CHARGE association [Lin et al., 19871, probably related to abnormal development of nueral crest and branchial arches. The present report illustrates glaucoma and tetralogy of Fallot type anomaly in 3 daughters of a mother with glaucoma. Their pedigree suggests autosomal dominant inheritance.
CLINICAL REPORTS Patient 1 This white girl was born prematurely to a 23-year-old gravida 2, para 1, mother after 35 weeks of gestation (Fig. 1).The product of the first pregnancy was a normal boy. Birth weight was 2,260 g, length 44 cm, and the head circumference (OFC) 31 cm. She had Apgar scores of 2 and 2 at one and 5 minutes, respectively. She had cloudy corneae and a loud systolic heart murmur. She Received for publication August 1,1989;revision received February 20, 1990. Address reprint requests to Su-chiung Chen, M.D., Cardinal Glennon Children’s Hospital, 1465 South Grand Boulevard, St. Louis. MO 63104.
0 1990 Wiley-Liss, Inc.
continued to have respiratory distress and died at age 17 hours despite vigorous anticongestive heart failure measures. Autopsy showed glaucoma and cardiac anomaly. Eye examination showed normal corneae. The anterior chamber and angle were normal except that the lens was tilted so that one end was anterior to the pupillary opening. Left eye had posterior synechiae of iris. The heart defect included atrial septal defect, ventricular septal defect, dilated pulmonary artery with absent pulmonary valve, right aortic arch, anomalous retropharyngeal left subclavian artery, and closed ducts arteriosus.
Patient 2 This girl infant was born at term to the same mother 3 years later (Fig. 1). The pregnancy was uncomplicated. Her birth weight was 3,000 g, height 47 cm. She had glaucoma thought to be due to abnormal development of trabecular meshwork which required trabeculectomy. She also had a loud heart murmur and mild cyanosis. Her ears were prominent and rotated somewhat anteriorly, but no other minor anomalies were present. Her chromosomes were normal. She had cardiac catheterization at age 3 months which confirmed the clinical diagnosis of tetralogy of Fallot and anomalous right pulmonary artery arising from ascending aorta. Her right pulmonary artery was removed from the aorta and reanastomosed to the main pulmonary artery at age 4 months. She underwent repair of her tetralogy of Fallot at age 3% years and is doing well. Patient 3 This girl was the fourth offspring of the same parents (Fig. 1). The mother was 28 years old at the time of delivery. Fetal echocardiogram was obtained because of the history of heart defects in previous sibs. The examination showed a probable tetralogy of Fallot. She was born at term, birth weight was 3,150 g, and height was 52 cm. She was also noted to have glaucoma a t birth. The diagnosis of tetralogy of Fallot was made based on clinical findings and echocardiogram. She underwent a modified Blalock-Taussig shunt at age 2 years after cardiac catheterization. Her chromosomes were normal. The mother of these 3 sisters also has congenital glaucoma (Fig. 1). However, she did not have a heart defect. The first child of these parents is a boy born 2 years before patient 1. He is healthy without glaucoma or heart defect. Family history is unremarkable. There
Familial Tetralogy and Glaucoma
I
Y
I
Fig. 1. Family pedigree. 0, Glaucoma; 0 ,Tetralogy of Fallot.
was no history of miscarriage in the mother and she denied any illness or unusual exposure during pregnancies.
DISCUSSION Congenital familial glaucoma is usually inherited in a recessive pattern; however, rare instances of dominant inheritance with goniodysgenesis have been reported [Hoskin et al., 19841. The pedigree of this present family suggests that the glaucoma is an autosomal dominant trait. Tetralogy is a common congenital heart defect with an empiric recurrence risk of 1.5 to 3.0%in sibs [Pierpont and Moller, 19861, assuming multifactorial origin. Extracardiac anomalies are common, but isolated abnormality of eyes is rare in children with tetralogy. Peters’ anomaly was reported in 2 of 3 children in a Japanese family with normal parents [Tabuchi et al., 19851, suggesting a close relationship between the development of the anterior segment of the eye and the heart anomaly. Cataract is rare [Boon et al., 19721. Colobomas are frequent in Goldenhar sequence and CHARGE association, but there are usually additional anomalies in other organ systems. All 3 sisters had mild micrognathia and
41
prominent ears resembling those of their mother. Their brother had a similar facial appearance. The association of tetralogy and glaucoma in these children could be coincidental. However, conotruncus and iridocorneal angle (trabecular meshwork) are both derived from neural crest cells [Clark, 1986; Newell, 19861; therefore, the association of eye anomaly and tetralogy could be related pathogenetically. It appears that the mother probably had a new mutant gene which was transmitted to her children in a dominant manner.
REFERENCES Boon AR, Farmer MB, Roberts DF (1972): A family study of Fallot’s tetralogy. J Med Genet 9:179-192. Clark EB (1986):Mechanisms in the pathogenesis of congenital cardiac malformations. In Pierpont ME, Moller JH (eds): “Genetics of Cardiovascular Disease.” Boston: Martinus Nijhoff, pp 3-6. Greenwood RD (1984):Cardiovascular malformations associated with extracardiac anomalies and malformation syndromes. Clin Pediatr 23:145-151. Greenwood RD, Rosenthal A, Parisi L, Fyler D, Nadas AS (1975): Extracardiac abnormalities in infants with congenital heart disease. Pediatrics 55:485-492. Greenwood RD, Rosenthal A, Sommer A, Wolff G, Craenen J (1974): Cardiovascular malformations in oculoauriculovertebral dysplasia (Goldenhar syndrome). J Pediatr 85816-818. Hoskin HD, Shaffer RN, Heatherington J (1984): Anatomical classification of the developmental glaucoma. Arch Ophthalmol 102:1331-1336. Lin AE, Chin AJ, Devine W, Park SC, Zackai E (1987):The pattern of cardiovascular malformation in the CHARGE association.Am J Dis Child 141:lOlO-1013. Miller ME, Smith DW (1979): Conotruncal malformation complex: Examples of possible monogenic inheritance. Pediatrics 63:890-893. Newell FW (1986): Anatomy and embryology. In “Ophthalmology, Principles and Concepts.” St. Louis: The C.V. Mosby Company, pp 65-66. Pierpont ME, Moller J H (1986):Congenital cardiac malformations. In “Genetics of Cardiovascular Disease.” Boston: Martinus Nijhoff, p 14. Tabuchi A, Matsuura M, Hirokawa M (1985): Three siblings with Peters’ anomaly. Ophthalmic Paediatr Genet 5205-212.
Familial Tetralogy of Fallot and Glaucoma Su-chiung Chen and Noreen D’Souza Department of Pediatrics, Division of Cardiology (S.-c Chen) and Genetics (N.D’S.), St. Louis University School of Medicine, St. Louis, Missouri. ~~
All 3 daughters of a mother with glaucoma had a conotruncal abnormality of the heart and glaucoma. The presence of heart and eye anomaly may be coincidental; however, both may be related to abnormal development of neural crest. The pedigree suggests autosoma1 dominant inheritance in this family.
KEY WORDS: tetralogy of Fallot, glaucoma, autosomal dominant inheritance INTRODUCTION Tetralogy of Fallot is a conotruncal abnormalilty presumably resulting from disordered mesenchymal tissue and/or neural crest migration [Clark, 19861. Multiple occurrences of tetralogy of Fallot in relatives and sibs have been reported, but it is generally thought to be multifactorial in origin with rare examples of possible monogenic inheritance [Boon et al., 1972; Miller and Smith, 19793. Extracardiac anomalies in children with tetralogy are not infrequent; however, they are mostly seen in the Goldenhar sequence [Greenwood et al., 19743, DiGeorge sequence [Greenwood et al., 1975; Greenwood, 19841, and CHARGE association [Lin et al., 19871, probably related to abnormal development of nueral crest and branchial arches. The present report illustrates glaucoma and tetralogy of Fallot type anomaly in 3 daughters of a mother with glaucoma. Their pedigree suggests autosomal dominant inheritance.
CLINICAL REPORTS Patient 1 This white girl was born prematurely to a 23-year-old gravida 2, para 1, mother after 35 weeks of gestation (Fig. 1).The product of the first pregnancy was a normal boy. Birth weight was 2,260 g, length 44 cm, and the head circumference (OFC) 31 cm. She had Apgar scores of 2 and 2 at one and 5 minutes, respectively. She had cloudy corneae and a loud systolic heart murmur. She Received for publication August 1,1989;revision received February 20, 1990. Address reprint requests to Su-chiung Chen, M.D., Cardinal Glennon Children’s Hospital, 1465 South Grand Boulevard, St. Louis. MO 63104.
0 1990 Wiley-Liss, Inc.
continued to have respiratory distress and died at age 17 hours despite vigorous anticongestive heart failure measures. Autopsy showed glaucoma and cardiac anomaly. Eye examination showed normal corneae. The anterior chamber and angle were normal except that the lens was tilted so that one end was anterior to the pupillary opening. Left eye had posterior synechiae of iris. The heart defect included atrial septal defect, ventricular septal defect, dilated pulmonary artery with absent pulmonary valve, right aortic arch, anomalous retropharyngeal left subclavian artery, and closed ducts arteriosus.
Patient 2 This girl infant was born at term to the same mother 3 years later (Fig. 1). The pregnancy was uncomplicated. Her birth weight was 3,000 g, height 47 cm. She had glaucoma thought to be due to abnormal development of trabecular meshwork which required trabeculectomy. She also had a loud heart murmur and mild cyanosis. Her ears were prominent and rotated somewhat anteriorly, but no other minor anomalies were present. Her chromosomes were normal. She had cardiac catheterization at age 3 months which confirmed the clinical diagnosis of tetralogy of Fallot and anomalous right pulmonary artery arising from ascending aorta. Her right pulmonary artery was removed from the aorta and reanastomosed to the main pulmonary artery at age 4 months. She underwent repair of her tetralogy of Fallot at age 3% years and is doing well. Patient 3 This girl was the fourth offspring of the same parents (Fig. 1). The mother was 28 years old at the time of delivery. Fetal echocardiogram was obtained because of the history of heart defects in previous sibs. The examination showed a probable tetralogy of Fallot. She was born at term, birth weight was 3,150 g, and height was 52 cm. She was also noted to have glaucoma a t birth. The diagnosis of tetralogy of Fallot was made based on clinical findings and echocardiogram. She underwent a modified Blalock-Taussig shunt at age 2 years after cardiac catheterization. Her chromosomes were normal. The mother of these 3 sisters also has congenital glaucoma (Fig. 1). However, she did not have a heart defect. The first child of these parents is a boy born 2 years before patient 1. He is healthy without glaucoma or heart defect. Family history is unremarkable. There
Familial Tetralogy and Glaucoma
I
Y
I
Fig. 1. Family pedigree. 0, Glaucoma; 0 ,Tetralogy of Fallot.
was no history of miscarriage in the mother and she denied any illness or unusual exposure during pregnancies.
DISCUSSION Congenital familial glaucoma is usually inherited in a recessive pattern; however, rare instances of dominant inheritance with goniodysgenesis have been reported [Hoskin et al., 19841. The pedigree of this present family suggests that the glaucoma is an autosomal dominant trait. Tetralogy is a common congenital heart defect with an empiric recurrence risk of 1.5 to 3.0%in sibs [Pierpont and Moller, 19861, assuming multifactorial origin. Extracardiac anomalies are common, but isolated abnormality of eyes is rare in children with tetralogy. Peters’ anomaly was reported in 2 of 3 children in a Japanese family with normal parents [Tabuchi et al., 19851, suggesting a close relationship between the development of the anterior segment of the eye and the heart anomaly. Cataract is rare [Boon et al., 19721. Colobomas are frequent in Goldenhar sequence and CHARGE association, but there are usually additional anomalies in other organ systems. All 3 sisters had mild micrognathia and
41
prominent ears resembling those of their mother. Their brother had a similar facial appearance. The association of tetralogy and glaucoma in these children could be coincidental. However, conotruncus and iridocorneal angle (trabecular meshwork) are both derived from neural crest cells [Clark, 1986; Newell, 19861; therefore, the association of eye anomaly and tetralogy could be related pathogenetically. It appears that the mother probably had a new mutant gene which was transmitted to her children in a dominant manner.
REFERENCES Boon AR, Farmer MB, Roberts DF (1972): A family study of Fallot’s tetralogy. J Med Genet 9:179-192. Clark EB (1986):Mechanisms in the pathogenesis of congenital cardiac malformations. In Pierpont ME, Moller JH (eds): “Genetics of Cardiovascular Disease.” Boston: Martinus Nijhoff, pp 3-6. Greenwood RD (1984):Cardiovascular malformations associated with extracardiac anomalies and malformation syndromes. Clin Pediatr 23:145-151. Greenwood RD, Rosenthal A, Parisi L, Fyler D, Nadas AS (1975): Extracardiac abnormalities in infants with congenital heart disease. Pediatrics 55:485-492. Greenwood RD, Rosenthal A, Sommer A, Wolff G, Craenen J (1974): Cardiovascular malformations in oculoauriculovertebral dysplasia (Goldenhar syndrome). J Pediatr 85816-818. Hoskin HD, Shaffer RN, Heatherington J (1984): Anatomical classification of the developmental glaucoma. Arch Ophthalmol 102:1331-1336. Lin AE, Chin AJ, Devine W, Park SC, Zackai E (1987):The pattern of cardiovascular malformation in the CHARGE association.Am J Dis Child 141:lOlO-1013. Miller ME, Smith DW (1979): Conotruncal malformation complex: Examples of possible monogenic inheritance. Pediatrics 63:890-893. Newell FW (1986): Anatomy and embryology. In “Ophthalmology, Principles and Concepts.” St. Louis: The C.V. Mosby Company, pp 65-66. Pierpont ME, Moller J H (1986):Congenital cardiac malformations. In “Genetics of Cardiovascular Disease.” Boston: Martinus Nijhoff, p 14. Tabuchi A, Matsuura M, Hirokawa M (1985): Three siblings with Peters’ anomaly. Ophthalmic Paediatr Genet 5205-212.
