- Email: [email protected]
Atrioventricular Canal Associated with Trisomy 9
selected reports Atrioventricular Canal Associated
with liisomy 9*
Brurw Manrw, M.D.; Marla Cristirw Digilio, M.D .;
Aldc Giannotti, M.D.; and Brurw Dallapiccola, M.D.
The features of a newborn with the full clinical aspect of trisomy 9 presenting with an atrioventricular canal is described. This association of anomalies has never been reported before. Interestingly, the patient also had a lef\sided obstruction which is known to be more characteristically associated with atrioventricular canal without Down's syndrome. (Chut 1989; 96:1420-21)
I
AVC=atrioventricular canal
T
he genetic anomaly most frequently associated with AVC is Down's syndrome.' In order to establish the prevalence of chromosomal anomalies in this congenital heart defect we performed a prospective cytogenetic study on a consecutive series of 172 patients with AVC. Less than half of these patients (78 = 45.3 percent) had normal karyotypes withu or without phenotypic anomalies, while 94 patients (54.6 percent) had Down's syndrome with homogenous or mosaic trisomy 21 . Two additional chromosomal anomalies were detected in this sample. One was a pericentric inversion of chromosome 1, which was segregating from a healthy father, the other was a trisomy 9, which is reported here in detail.
FIGURE 1. Facial appearance. Note the asymmetric face with small palpebral fissures, enophtalmos, bulbous nasal tip, hypoplastic and receding mandible and low-set and slanted ears.
CASE REPORT
A male infant was admitted to our hospital at 2 days of age because of multiple congenital anomalies and congestive heart failure. He was the product of a 39-week gestation of a normal 28yeaM>ld mother and a 30-yeaM>ld father. Both parents were phenotypically normal and unrelated. The patient had a normal sister. Family history was unremarkable. Pregnancy was uncomplicated and delivery was by cesarian section because of an early detachment of placenta. Birth weight was 2,600 g; length, 42 em; head circumference, 33 em (all below the third centile). Physical examination (Fig 1) revealed microbrachycephaly, frontal bossing, with a depressed medial part of frontal bone which was covered with a fine lanugo, asymmetric face, thin, poorly furnished eyebrows, small palpebral fissures, enophthalmos, bulbous nasal tip, well-designed philtrum, microstomia, with a small inverted upper lip overriding the lower, which was retracted, because of a severely hypoplastic and receding mandible. Ears were low set and mildly slanted with an incompletely overfolded scapha helix, a prominent and tortuous antehelix, hypoplastic tragus and lobe. External genitalia were severely hypoplastic and testes were not palpable. *From the Department of Pediatric Cardiology and Genetics, ''Bambino Gesu' .. Hospital, Rome, Italy. Reprint requem: Dr. Manrw, Cardiology, Bamhirw Ge.tu HoapUal, Via S. Onofrio 4, 00165 Rome, Italy
1420
Humeri and femora were rather short; hands were broad with clinodactyly of fifth fingers. There was bilateral pes cavus with retracted toes. Cardiac Assessment
A grade 2 systolic murmur was heard at the left sternal border. There was mild cyanosis, tachycardia (160/m), tachypnea (60/m), liver enlargement and poor peripheral pulses. The chest x-ray film showed cardiac enlargement with increased pulmonary blood flow and the ECG showed left axis deviation and right ventricular hypertrophy. With two-dimensional echocardiography the definitive diagnosis of complete AVC type c' was made. In addition, there was right ventricular dominance with a hypoplastic left ventricle and ascending aorta (Fig 2). The clinical condition rapidly worsened in spite of vigorous medical support, and the patient died at 3 days of age. Permission for autopsy was not granted by the parents. Cytogenetic Study
Chromosome analysis was performed on short-term lymphocyte cultures. The modal number was 47 in all 65 examined cells. Giemsa-banded cells showed that the extra chromosome was a number 9. Thus, the karyotype was 47,XY, +9 (Fig 3). The parents had normal chromosome constitutions. AV Canal Asaociated wilh Trisomy 9 (Marino et a/)
Our patient is the 12th observation of an apparent non mosaic trisomy 9 newborn. However, since only lymphocytes were examined, a mosaic trisomy 9 aneuploidy cannot be ruled out. On cUnieal examination our patient had most of the outstanding features currently found in association with this aneuploidy,3 including facial dysmorphism, genital anomalies, heart malformations and distal limb abnormalities. <-II Congenital heart defects have been reported in all patients with complete trisomy 9 .... , However, the association between AVC and trisomy 9 had not been recognized so far. In general, AVC is very common in trisomy 21 patients, but it is rare in subjects with different types of chromosomal aberrations.,_,._,. In addition, we have previously reported that the non-Down's syndrome patients with AVC have a prevalence of left-sided obstructive lesion as associated cardiac malformation. 14 This pattern is opposite the one currently found in Down's syndrome patients that rarely presented left-sided obstruction.'·'• Furthermore, in the former group of patients, which in general have normal karyotype, we demonstrated an increased frequency of minor anomalies, compared with a group of patients with different types of congenital heart defects.s.3 Interestingly, the patient reported here, had an AVC with a left-sided obstruction, which further supports the assumption that the AVC pattern found in trisomy 21 is rather peculiar. However, additional prospective studies are needed to improve current understanding of the association between AVC and chromosomal imbalances. REFERENCES
FIGURE 2. Two-dimensional echocardiogram in "four chamber"
view. Note the complete form of AVC with right ventricular (RV)
dominance and hypoplastic left ventricle (LV). RA = right atrium; LA= left atrium. DISCUSSION
Trisomy 9 is a rare and lethal aneuploidy.•-" Compared with the very low prevalence at birth, about 3 percent of chromosomally abnormal early spontaneous abortions have this imbalance. Trisomy 9 has been reported in newborns, most of which display a mosaic-aneuploidy. ""9 This likely accounts for the possibility of these conceptions to reach term of pregnancy.
5
7
10
II
15
16
11
2
7
21
0
14
JQ
FIGURE 3 . Karyotype (47,XY, +9).
'
12
18
X
1 Bharati S, Low M. The spectrum of common atrioventricular orifice (canal). Am Heart J 1973; 86:553 2 Marino B, Cipriani A, Marcelletti C, Dallapiccola B. Anomalie fenotipiche minori in pazienti con canale atrioventricolare senza S.di Down: osservazioni preliminari (Abstract). Cardiologia 1987; 12:120 3 Marino B, Guccione P. Como A, Marcelletti C, Dallapiccola B. Atrioventricular canal, normal chromosomes and phenotypic anomalies [Abstract]. Clin Res 1989; 34:99A 4 Feingold M, Atkins L . A case of trisomy 9 . J Med Genet 1973; 10:184 5 Seabright M, Gregson N, Moul S. Trisomy 9 associated with an enlarged 9qh segment in a liveborn. Hum Genet 1976; 34:323 6 Sutherland GR, Carter RF, Morris LL. Partial and complete trisomy 9: delineation of a trisomy 9 syndrome. Hum Genet 1976; 32:133 7 Mantagos S, McReynolds J, Seashore MR, Breg WR. Complete trisomy 9 in two liveborn infants. J Med Genet 1981; 18:377 8 Anneren G, Sedin G. Trisomy 9 syndrome. Acta Pediatr Scand 1981; 70:125 9 Frohlich GS. Delineation of trisomy 9 [Letter]. J Med Genet 1982;19:316 10 Delicado A, Iniguez L, Lopez Pajares I, Omenaca F. Complete trisomy 9: two additional cases. Ann Genet 1985; 28:63 11 Williams T, Zardawi I, Quaife R, Young ID. Complex cardiac malformation in a case of trisomy 9 . J Med Genet 1985; 22:230 12 Scarpa FJ, Borgaonlcar DS. A-V communis defect in trisomy E1 (17-18): report of a case. Bull Hopkins Hosp 1966; 118:395 13 Greenwood RD, Rosenthal A, Parisi L, Fyler DC, Nadas AS. Extracardiac abnormalities in infants with congenital heart disease. Pediatrics 1975; 55:485 14 De Blase L, Di Ciommo V. Ballerini L, Bevilacqua M, Marcelletti C, Marino B. Prevalence of left sided obstructive lesions in patients with atrioventricular canal without Down's syndrome. JThorac Cardiovasc Surg 1986; 3:467 CHEST I 96 I 6 I DECEMBER, 1989
1421
with liisomy 9*
Brurw Manrw, M.D.; Marla Cristirw Digilio, M.D .;
Aldc Giannotti, M.D.; and Brurw Dallapiccola, M.D.
The features of a newborn with the full clinical aspect of trisomy 9 presenting with an atrioventricular canal is described. This association of anomalies has never been reported before. Interestingly, the patient also had a lef\sided obstruction which is known to be more characteristically associated with atrioventricular canal without Down's syndrome. (Chut 1989; 96:1420-21)
I
AVC=atrioventricular canal
T
he genetic anomaly most frequently associated with AVC is Down's syndrome.' In order to establish the prevalence of chromosomal anomalies in this congenital heart defect we performed a prospective cytogenetic study on a consecutive series of 172 patients with AVC. Less than half of these patients (78 = 45.3 percent) had normal karyotypes withu or without phenotypic anomalies, while 94 patients (54.6 percent) had Down's syndrome with homogenous or mosaic trisomy 21 . Two additional chromosomal anomalies were detected in this sample. One was a pericentric inversion of chromosome 1, which was segregating from a healthy father, the other was a trisomy 9, which is reported here in detail.
FIGURE 1. Facial appearance. Note the asymmetric face with small palpebral fissures, enophtalmos, bulbous nasal tip, hypoplastic and receding mandible and low-set and slanted ears.
CASE REPORT
A male infant was admitted to our hospital at 2 days of age because of multiple congenital anomalies and congestive heart failure. He was the product of a 39-week gestation of a normal 28yeaM>ld mother and a 30-yeaM>ld father. Both parents were phenotypically normal and unrelated. The patient had a normal sister. Family history was unremarkable. Pregnancy was uncomplicated and delivery was by cesarian section because of an early detachment of placenta. Birth weight was 2,600 g; length, 42 em; head circumference, 33 em (all below the third centile). Physical examination (Fig 1) revealed microbrachycephaly, frontal bossing, with a depressed medial part of frontal bone which was covered with a fine lanugo, asymmetric face, thin, poorly furnished eyebrows, small palpebral fissures, enophthalmos, bulbous nasal tip, well-designed philtrum, microstomia, with a small inverted upper lip overriding the lower, which was retracted, because of a severely hypoplastic and receding mandible. Ears were low set and mildly slanted with an incompletely overfolded scapha helix, a prominent and tortuous antehelix, hypoplastic tragus and lobe. External genitalia were severely hypoplastic and testes were not palpable. *From the Department of Pediatric Cardiology and Genetics, ''Bambino Gesu' .. Hospital, Rome, Italy. Reprint requem: Dr. Manrw, Cardiology, Bamhirw Ge.tu HoapUal, Via S. Onofrio 4, 00165 Rome, Italy
1420
Humeri and femora were rather short; hands were broad with clinodactyly of fifth fingers. There was bilateral pes cavus with retracted toes. Cardiac Assessment
A grade 2 systolic murmur was heard at the left sternal border. There was mild cyanosis, tachycardia (160/m), tachypnea (60/m), liver enlargement and poor peripheral pulses. The chest x-ray film showed cardiac enlargement with increased pulmonary blood flow and the ECG showed left axis deviation and right ventricular hypertrophy. With two-dimensional echocardiography the definitive diagnosis of complete AVC type c' was made. In addition, there was right ventricular dominance with a hypoplastic left ventricle and ascending aorta (Fig 2). The clinical condition rapidly worsened in spite of vigorous medical support, and the patient died at 3 days of age. Permission for autopsy was not granted by the parents. Cytogenetic Study
Chromosome analysis was performed on short-term lymphocyte cultures. The modal number was 47 in all 65 examined cells. Giemsa-banded cells showed that the extra chromosome was a number 9. Thus, the karyotype was 47,XY, +9 (Fig 3). The parents had normal chromosome constitutions. AV Canal Asaociated wilh Trisomy 9 (Marino et a/)
Our patient is the 12th observation of an apparent non mosaic trisomy 9 newborn. However, since only lymphocytes were examined, a mosaic trisomy 9 aneuploidy cannot be ruled out. On cUnieal examination our patient had most of the outstanding features currently found in association with this aneuploidy,3 including facial dysmorphism, genital anomalies, heart malformations and distal limb abnormalities. <-II Congenital heart defects have been reported in all patients with complete trisomy 9 .... , However, the association between AVC and trisomy 9 had not been recognized so far. In general, AVC is very common in trisomy 21 patients, but it is rare in subjects with different types of chromosomal aberrations.,_,._,. In addition, we have previously reported that the non-Down's syndrome patients with AVC have a prevalence of left-sided obstructive lesion as associated cardiac malformation. 14 This pattern is opposite the one currently found in Down's syndrome patients that rarely presented left-sided obstruction.'·'• Furthermore, in the former group of patients, which in general have normal karyotype, we demonstrated an increased frequency of minor anomalies, compared with a group of patients with different types of congenital heart defects.s.3 Interestingly, the patient reported here, had an AVC with a left-sided obstruction, which further supports the assumption that the AVC pattern found in trisomy 21 is rather peculiar. However, additional prospective studies are needed to improve current understanding of the association between AVC and chromosomal imbalances. REFERENCES
FIGURE 2. Two-dimensional echocardiogram in "four chamber"
view. Note the complete form of AVC with right ventricular (RV)
dominance and hypoplastic left ventricle (LV). RA = right atrium; LA= left atrium. DISCUSSION
Trisomy 9 is a rare and lethal aneuploidy.•-" Compared with the very low prevalence at birth, about 3 percent of chromosomally abnormal early spontaneous abortions have this imbalance. Trisomy 9 has been reported in newborns, most of which display a mosaic-aneuploidy. ""9 This likely accounts for the possibility of these conceptions to reach term of pregnancy.
5
7
10
II
15
16
11
2
7
21
0
14
JQ
FIGURE 3 . Karyotype (47,XY, +9).
'
12
18
X
1 Bharati S, Low M. The spectrum of common atrioventricular orifice (canal). Am Heart J 1973; 86:553 2 Marino B, Cipriani A, Marcelletti C, Dallapiccola B. Anomalie fenotipiche minori in pazienti con canale atrioventricolare senza S.di Down: osservazioni preliminari (Abstract). Cardiologia 1987; 12:120 3 Marino B, Guccione P. Como A, Marcelletti C, Dallapiccola B. Atrioventricular canal, normal chromosomes and phenotypic anomalies [Abstract]. Clin Res 1989; 34:99A 4 Feingold M, Atkins L . A case of trisomy 9 . J Med Genet 1973; 10:184 5 Seabright M, Gregson N, Moul S. Trisomy 9 associated with an enlarged 9qh segment in a liveborn. Hum Genet 1976; 34:323 6 Sutherland GR, Carter RF, Morris LL. Partial and complete trisomy 9: delineation of a trisomy 9 syndrome. Hum Genet 1976; 32:133 7 Mantagos S, McReynolds J, Seashore MR, Breg WR. Complete trisomy 9 in two liveborn infants. J Med Genet 1981; 18:377 8 Anneren G, Sedin G. Trisomy 9 syndrome. Acta Pediatr Scand 1981; 70:125 9 Frohlich GS. Delineation of trisomy 9 [Letter]. J Med Genet 1982;19:316 10 Delicado A, Iniguez L, Lopez Pajares I, Omenaca F. Complete trisomy 9: two additional cases. Ann Genet 1985; 28:63 11 Williams T, Zardawi I, Quaife R, Young ID. Complex cardiac malformation in a case of trisomy 9 . J Med Genet 1985; 22:230 12 Scarpa FJ, Borgaonlcar DS. A-V communis defect in trisomy E1 (17-18): report of a case. Bull Hopkins Hosp 1966; 118:395 13 Greenwood RD, Rosenthal A, Parisi L, Fyler DC, Nadas AS. Extracardiac abnormalities in infants with congenital heart disease. Pediatrics 1975; 55:485 14 De Blase L, Di Ciommo V. Ballerini L, Bevilacqua M, Marcelletti C, Marino B. Prevalence of left sided obstructive lesions in patients with atrioventricular canal without Down's syndrome. JThorac Cardiovasc Surg 1986; 3:467 CHEST I 96 I 6 I DECEMBER, 1989
1421