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Clin. Cardiol. 12, 227-232 (1989)

The Cardiovascular Abnormalities Associated with Duplicated Segments of Chromosome 7 .I.D. TALLEY. M.D..* K . J . DOOLEY, M.D.. F.A.C.C.,? A. TUBOKU-METZGER, M . D .t G . H . BURGESS. M.D ,t

W . D. WILCOX. M.D..

F.A.C.C..1 L.

A. CLICK. R.N., M.N.,t R. D. BLACKSTON. M D.9

*Divisions of Cardiology, Department of Medicine, ?Pediatric Cardiology, $Neonatology, TGeneral Pediatrics, $Medical Genetics, Department of Pediatrics. Eniory University School of Medicine, and *the Cardiology Service of Emory University Hospital, Atlanta, Georgia, USA

Summary: Congenital heart disease is an integral part of many genetic syndromes such as the major trisomies 13, 18, and 2 1. Little information, however, is available with reference to the incidence of cardiac anomalies in the trisomy 7 syndromes. Two patients with partial trisomy 7q, one of whom had congenital heart disease, are presented. A review of the literature reveals incomplete description of the cardiovascular abnormalities in the majority of case reports of patients with this syndrome, however, when described it appears that there are no specific defects associated with trisomy 7p and 7q, but only an increased frequency of occurrence. Further clinical and postmortem data regarding details of the congenital heart defects associated with trisomy 7 is required to confimi this preliminary observation.

Key words: congenital heart disease, trisoniy 7, trisomy 18. cardiovascular abnormalities

Introduction Trisomy abnornialities of chromosome 7 were initially reported in 19721.2with the description of two patients with duplication of the long arm (4) of the chromosome. Since then duplication of the short arm (P)'-~and complete trisomy 7 have been r e p ~ r t e d . ~ - ' ~

Address for reprints:

R Dwain

Blackston, M.D. Division of Mcdical Genetics Department o f Pcdiatrics 2010 Ridgewood R d . . N . E . Atlanta, G A 3 0 3 2 2 . USA Received: October 14, 1988 Acwptcd: Ocroher 25. 1988

Cardiovascular defects have been associated with these abnormalities, however, the exact incidence has not been described. We report two additional cases and a review of the pertinent literature.

Case Report #1 A 2280-g female was born after 39 weeks of gestation to a 29-year-old female by cesarean section performed because of a frank breech presentation with failed inversion. There was no history of any maternal illness, medication or illicit drug use, stillbirths, or family history of congenital heart disease. Dysmorphic features included small facies, prominent occiput, low-set ears with overfold of the helixes, high palate, micrognathia, finger overlapping with the 5th over the 4th and the 2nd over the 3rd digits, clintdactyly, small chest, small and convex nails, and hypotrophic umbilical cord with a single umbilical artery. A grade 3/6 holosystolic murmur at the left sternal border which radiated up and across the sternum and diminished femoral pulses were noted. Chest x-ray revealed an interstitial infiltrative pattern. Right-axis deviation and right ventricular hypertrophy that were within nomial limits for age were seen on the electmcardiogram. Echocardiogram showed a coarctation of the aorta (COA) and suggested a sniall membranous ventricular septa1 defect (VSD). Chromosome analysis was initiated because trisomy I8 was suspected. The karyotype showed additional material attached to the long arm of chromosome 22 doubling the length of the long am1 (Fig. IA). This was interprctcd as unbalanced, but the origin of the additional chromosome material could not be deterniined. Parental chromosome studies were thus initiated. The mother had a reciprocal balanced translocation involving chromosomes 7 and 22 with approximately half of the distal long arm of 7 moved t o thc long am1 of 22. This resulted in a derivative chmmosome 7 which is shorter than nornial and a derivative 22

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Clin. Cardiol. Vol. 12, April 1989

(4

(B)

FIG I (A) Partial karyotype of the pnipositus (patient I ) showing additional genetic material attached to chromosome 22 (long a m Partial karyotype of the mother of patient 1 showing reciprocal,balanced translation between chromosome 7 (short a m w ) and 22 (long

about twice its normal length: 46,XX,rcpt(7;22) (q31.2;q13.3) (Fig. IB). The infant thus received from her mother a derivative 22 to which about half of the distal long arm of chromosome 7 is translocated 46,XX,22 =der (22),t(22;7)mat. The major genetic imbalance and cytogenetic diagnosis for the newborn is then partial 7 q trisomy. The father had normal chromosome studies. Cardiac catheterization showed a patent ductus artriosus (PDA) (Fig. 2A), a 31 mmHg systolic gradient across a COA (Fig. 2B), and a moderate sized membranous VSD with a net left to right shunt of 2.5 to 1 (Fig. 2C). The patient underwent ligation of the PDA, subclavian flap repair of the COA, and placement of a pulmonary artery band. The VSD was not closed. Postoperatively, the patient was maintained on digoxin, furosemide, and spironolactone. Progressive congestive heart failure developed because of hypertrophic cardiomyopathy which eventually led to the patient's death at 4 months of age. A postmortem evaluation was not obtained.

(4

Case Report #2 A 33-week gestation, 1474-g female was born ti year-old female. Polyhydramnios necessitated trimester amniocentesis to determine fetal maturity c Chromosome studies were not performed. There history of any maternal illness, medication or illic use, stillbirths, or family history of congenital disease. Dysrnorphic facial features included a broad fo with a small face in relation to the entire head, righ tal cephalhematoma, large anterior fontanel, wide-sc small beaked nose, low-set ears with a left preau skin'tag, and high-arched palate with a submuco: gingival cleft. The infant had clinodactyly, bilate gle palmar creases, and high-arched feet. A grade 2 tolic ejection murmur was detected. Electrocard was normal. Two-dimensional echocardiogram ( showed a patent foramen ovale, considered a norm

1

(B)

(C)

FIG 2 Aortogram. and left ventriculogrxn of patient I . Thc patent ductus arteriosus is seen in (A), and the coarctation of the (B). Left ventricular injection ( C ) illustrates the membranous ventricular septa1 defect (arrow). LV =left ventricle; R V =right v(

J . D. T a l k y et

d.: Cardiovascular abnormalities with trisomy 7

229

Discussion

FIG 3 Two-dimensional reversed image echocardiogram of patient 2 showing the patent foramen ovale (arrow): LA=left atrium; RA =right atnum.

ing in the newborn. Repeat echocardiogram obtained when the child was 1 1 months old was normal, including an intact atrial septum. There have been no additional cardiovascular abnormalities detected. Chromosome studies revealed extra material attached to thc short ann ofchromosome 5 : 46,XX,5p+ (Fig. 4A). Origin of the additional chromosome material was unclear, necessitating parental chromosome analysis. The father had a recipmal balanced translocation, the distal long arm of a chromosome 7 to the short arm of a chromosome 5:46,XY ,rcpt(5;7)(~15,3;q32)(Fig. 4B). The infant weived only one of the derivative chromosomes (5p+) from the lather and is thus unbalanced. Final karyotype report on the infant was 46,XX5, +der(5),t(5;7) (p15.3;q32)pat, resulting in 7q trisomy. Maternal karyotype showed nonnal female chromosome pattern.

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Chromosome abnormalities are associated with approximately 5 % of cases of congenital heart disease. l 4 Trisomy abnormalities, particularly those involving chromosomes 13, 18, and 2 1, have been associated with frequent and particular cardiovascular defects. I s Children with trisomy 13 have. approximately a 90% incidence of cardiovascular defects; the most commonly seen defects are VSD, PDA, and dextroversion. There is essentially 100% association of cardiovascular disease with trisomy 18 where VSD, PDA, and pulmonary stenosis (PS) are typically seen. Children with trisomy 21 have a 50% incidence of congenital heart disease, most commonly an atrioventricular canal (AVC) and PDA. Trisomies involving chromosomes 8, 9, and 22 have been reported to result in specific cardiac abnormalities, however, the frequency of these chromosome defects is too small to draw definitive conclusions. l 6 Cardiovascular abnormalities associated with trisomy 7 vary and may depend on the site of the extra genetic material: the short arm (p), the long arm (9). or duplication of the entire chromosome. A review of the literature of each of these categories is given in Tables 1-111. The common abnormalities associated with partial trisomy 7p are seen in Table I. Congenital heart disease was described in 33,5.7 of the 73-8 reported patients and only 1 patient is described as having a normal cardiovascular system.) In the remaining 3 patients the cardiovascular system was not described or a nonspecific diagnosis was gi~en.~.~.S Including the present report, there have been 32 patients with partial trisomy 7q described in 27 reports1,2.17-39 (Table 11). Analysis is limited by the incomplete description of the cardiovascular abnormalities in many of the case reports. In 12 patients, the cardiovascular system was not discussed.1~2~20~28-32~34~39 Nonspecific findings were

(B)

4 (A) Partial karyotype of patient 2 with additional genetic niaterial attached to chromosome 5 (long amow). ( 8 ) Partial karyotypc fathcr o f patient 2 showing reciprocal. balanced translocation between chromosome 5 (long arrow) and 7 (short amow).

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Cardiovascular abnomialities associated with partial rrisoniy 7p T.48t~t: I

Reference

B c 1’1~ul. #2 Carnevale et ul. Larson ef al. Miller et al. Moore ei d. #I Moore et cil. #2 Ohdo et ul.

TABLEI1 Cardiovascular abnormalitics associated n’Y 79

Abnormality”

Rc ferencc

Coarctation of the aorta, patent ductus arteriosus, left ventricular hypertrophy Normal NS Coniplete atrioventricular canal, right ventricular hypertrophy ND Ventricular septal defect Ventricular septal defect, pulmonary stenosis NS

Alfi et al. (17) Al Saadi and Moghadam (18) Bass et (11. (1%

“The cardiovascular abnormalities are listed as described in the individual case reports. Instances where the cardiovascular system was not discussed arc designated as ND. Nonspecific cardiovascular characteristics are designated as NS.

described in 1 1 patients. 1 8 . 2 1 . 2 3 . 2 4 . 2 6 27.30.35-38 Three children have been described with a normal cardiovascular system, one by Bass et al. ,20 Couzin et al. , 2 3 and one in the present report (patient 2 ) . In the remaining 6 patients there have k e n 8 cardiovascular defects described; VSD” (patient 1) and PDAZZ(patient 1) each occur twice and PSI9 COA (patient l ) , truncus arteriosus (TA),33and Ltnnsposition of the great arteries (LTGA)25each occurred once. There have been six reported patients with complete trisomy of chromosome 7 9 - 1 (Table 3 111). In three patients the cardiovascular system was not d i s c ~ s s e d .Another ~.~~ patient was associated with multiple cardiovascular abnormalities, however, Goldenhar syndrome was also present, obscuring the etiology of these defects.I0 The remaining two cases were n o r ~ n a l . l ~ . ~ ~ Table IV summarizes the reported cardiovascular defects associated with trisomy 7p, 7q, and complete replication of the entire chromosome. The numbers are diluted by incomplete cardiovascular description of many patients. Nonetheless, one can glean from the small numbers that cardiovascuIar abnormalities frequently accompany partial trisomy 7p and 7q. The etiology of the cardiovascular defects in the one patient with complete trisomy 7 is obscured by the association of Goldenhar syndrome. The available data, however, suggest that complete trisomy 7 has a low incidence of cardiovascular defects. When the specific cardiovascular abnormalities associated with trisomy 7p and 7q are analyzed, VSD is the most common abnomiality seen. When the frequency of these abnonnalities is compared with the incidence of these lesions in large studies of congenital heart disease in the general population,40 one sees essentially the same rate

Bass et al. #I

Abnomia

(20) (20) (21) (22)

Bass el ul. #2 Berger et (11. Berger er al. Carpentier et al. Couzin et al. # I Couzin et al. #2 Danesino er al. Dubossan er al.

(23) (23) (24) (25)

Felding and Mitelman Fryns ef ul. Grace et al. Kardon cr ml. Klasen t t al. #I Klasen er al. #2 Moric-Petmvic er al. #I Moric-Pctmvic et al. #2 Newton et ul. Novales er al. Schinzel and Tonz Schmid et al. Servillc et al. # I Servillc et al. #2

(26) (27) (28) (29) (30) (30) (31) (31) (2) (32) (33) (34) (35) (35)

Turleau et al. Vogel et al. Wahrnian el al. Winsor et al. #I Winsor er al. #2

(36) (3 7) (38) (39) (39)

(1)

Ventricular s e ~ NS Mild pulm stenosr NOmlZ

ND NS

Patcnt ductus ND NS Norm: NS Corrected trx of great ai NS NS ND ND NS ND ND ND ND ND Common t ND NS Patent ductus coarctation ( ventricular se1 NS NS NS ND ND

“As in Table I

TABLEI11 Cardiovascular abnomialitics associated plete trisomy 7 Reference

Abnoi

De Bault and Halmi #I (9) De Bault and Halmi #2 (9) Hodes et al. (10) Pflueger ct (11. Turlcau (’I al. Yunis er d . “As in Table I.

I

(1 1)

(12) (13)

A A

Multiplr Goldenhai h N0 NO

J . D . Talley e f a / . : Cardiovascular abnormalities with trisomy 7

TABLE IV

Cardiovascular abnormalities associated with duplicated segments of chromosome 7 Abnormality

ND NS Normal VSD VSD PS COA AVC

+

PS PDA LTGA TA MCA Total

7P

7q

Complcte

12 11 3 2

3

2

1

1 2 1 I 1

34

6

-~

Ahbreviutions: ND=cardiovascular system not discussed; NS =cardiovascular abnormalities not specifically diagnosed; VSD=ventricular septal defect; V S D + P S =ventricular septal defect and pulmonary stenosis; C O A =coarctation of aorta; AVC=atrioventricular canal; PS=pulmonary stenosis; PDA patent ductus arteriosus; LTGA=L-transposition of the great arteries; TA =truncus arteriosus; MCA =multiple congenital abnormal it ies.

of Occurrence. This review suggests that there are no specific cardiovasculardefects associated with partial trisomy 7p and 7q. The abnormalities seen merely reflect a distribution of defects commonly observed in congenital heart disease, but with an increased frequency of occurrence. This preliminary observation can only be confirmed with complete description of the cardiovascular system of patients with partial or complete duplication of chromosome 7. It is of interest that both our cases presented weie initially thought to be trisomy 18 because of the clinical presentation. Final studies, however, proved partial trisomy 7q in both infants, and parental studies determined the origin of the extra material. Parental studies are critical for an exact cytogenetic diagnosis in the infants and precise genetic cxmseling for future pregnancies. Additionally, evaluation of firstdegree relatives of the reciprocal translocation carriers is recommended so appropriate recurrence risks can also be given.

Acknowledgments The authors appreciate Dr. Bruce Beeber for the referral of patient 2, Dr. Jean Priest for analysis of chromosomes, Dr. Elizabeth Nugent and Ann McMillan for assistance with the echocardiograrns, the pediatric residents for their care and concern for the patients and secretarial assistance in the preparation of this manuscript.

23 I

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23 Couzin D A , Haites N. Watt JL, Johnston AW: Partial trisomy 7 (q32-> qter) syndrome in two children. J M r d Genet 23,461 (1986) 24. Danesino C , Gimelli G, Cuoco C, Ciccone MO: Triplex gene dosage effect for B-glucuronidase and possible assignment to band q22 in a partial duplication 7q. Humnn Gener 56, 371 (1981) 25. Dubosson JD, Cabml C , Crippa L, Bourgeois B: Syndrome malforrnatif avec caryotype 46,XX,7q + sans translocation parentale; duplication partiellc? Archiv fur Generik 5 I , 56 ( 1978) 26. Felding I . Mitelman F: A child with partial trisomy 7 and 20 inherited froni the mother. Heredifus 91, 91 (1979) 27. Fryns JP, de W a d e P, Van Den Berghe H: Mosaic partial trisomy 7q:46,XX/46,XX,der IX,t(7;18)(q21;q22).Ann Genet 21, 106 (1978) 28. Grace E. Sutherland GR, Stark G D , Bain AD: Partial trisomy of 7q resulting from a fami!ial translocation. Ann Genrf 16, 51 (1973) 29. Kardon NB, Pollack L, Davis J , Broeknian A, Krauss M: De novo duplication of the 7qlI->q22 region. J Med Gerier 20. 471 (1983) 30. Klasen M , Schmid M, Hansmann I , Grimm T: Partial trisomy 7q in two siblings. Ann Gener 26, 100 (1983) 31. Moric-Petrovic S , L x a Z, Krajgher A: Translocation recipq u e dans la famille de deux proposants avec une trisomie partielle du chmniosonie 7q. Ann Gmer 19, 133 (1976) 32. Novales MA, Fernandcz-Novoa C , Hevia A, San Martin V, Galera H : Partial trisoniy for the long a r m of chromosome 7. Case repnrt and review. Human Genet 62, 378 (1982)

33. Schinzel A. Tonz 0: Partial trisorny 7q and probablc monosomy of 5p in the son of a mother with a recipmc; location between Sp and 7q. Human Gener 53. 121 34. Schmid M. Wolf J , Nestler H, Kmne W: Partial trisc the long arm of chromosome 7 due to familial balance cation. Human Gener 49, 283 (1979) 35. Serville F, Broustet A, Sandler B, Bourdcau M-L, Lel Trisoniie 7q partielle. Ann Grner 18. 67 (1975) 36. Turleau C , Rossier A, de Montis G. Rouhin M, Chavi F, de Gmuchy J: Trisomie paltielk 7q. Un ou deux sync A prupns d'une nouvelle observation. Ann Gmer 19. 3; 37. Vogel W. Siebers J-W, Reinwein H: Partial trisomy Gene1 16, 277 (1973)

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38. Wahrman J , Cohen MM. Roscnniann A . Goitein R, C, Dagan J : A long unidentifiable extra chmm segment-a possible duplication of human 7q. Cyroge, Gener 20, 160 (1978) 39. Winsor EIT, Palmer CG, Ellis PM, Hunter JLP, Fe Smith MA: Meiotic analysis o f a pericentric inversion (p22q32), in the father of a child with a duplication-dl of chromosome 7. Cyrogenef Cell Genrr 20, 169 ( I ( 40. Nugent EW, PIauth WH, Jr., Edwards JE, Schlant RI liams WH: The pathology, abnormal physiology, elinica nition, and medical and surgical treatment of congenit disease. In The H r a r r . 6th ed. (Eds. Hunt JW, L o p Rackley CE, Schlant RC, Sonnenblick EH, Wallal Wenger NK). McGnw-Hill. New York (1986) 580-