PARTIAL TRISOMY 3P AND MONOSOMY 7P ASSOCIATED WITH TETRALOGY OF FALLOT AND INFANTILE SEIZURE

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1 LETTER TO THE EDITOR PARTIAL TRISOMY 3P AND MONOSOMY 7P ASSOCIATED WITH TETRALOGY OF FALLOT AND INFANTILE SEIZURE Chia-Ming Chang 1,2, Ming-Jie Yang 1,2, Chyi-Chyang Lin 3, Yueh-Chun Li 4, Pi-Lin Sung 1, Pi-Chang Lee 2,5, Lin-Chao Chen 1, Lie-Jiau Hsieh 3, Kwei-Shuai Hwang 6, Chih-Ping Chen 7,8, Kuan-Chong Chao 1,2 * 1 Department of Obstetrics and Gynecology, Cytogenetic Laboratory, Taipei Veterans General Hospital, 2 National Yang-Ming University School of Medicine, Taipei, 3 Department of Medical Genetics, China Medical University Hospital, 4 Department of Biomedical Sciences, Chung Shan Medical University, Taichung, 5 Department of Pediatrics, Taipei Veterans General Hospital, 6 Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, 7 Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, and 8 Department of Biotechnology, Asia University, Taichung, Taiwan. A 7-month-old female infant was referred because of hypothyroidism, seizure, respiratory distress syndrome, and tetralogy of Fallot (TOF) with hypoxic spell. Her father and 24-year-old mother were healthy and nonconsanguineous. There was no family history of congenital malformations. The mother denied any exposure to alcohol, teratogenic agents or infectious diseases during this pregnancy. She received regular prenatal examinations at a local clinic. The infant was born prematurely at 35 weeks of gestation. However, bradycardia, restlessness, cyanosis, gasping respiration, upgaze, and episodes of seizure developed soon after delivery. The infant s external appearance was grossly normal, and the extremities were freely movable. The body weight was less than third percentile with growth restriction. Serial studies were arranged. Echocardiography revealed an atrial septal defect, a large ventricular septal defect, right ventricular hypertrophy, and severe pulmonary stenosis that were consistent with TOF. Brain sonography revealed moderate dilatation of lateral and third ventricles, in favor of the diagnosis of benign extracerebral fluid collection. Conventional cytogenetic studies performed on the peripheral blood lymphocytes revealed an extra, undetermined material on one chromosome 7 (Figure 1). *Correspondence to: Dr Kuan-Chong Chao, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. kcchao@vghtpe.gov.tw Accepted: May 10, p24.2 3pter 3p24.2 7p22 7qter 7p der(7) 7 Figure 1. Partial G-banded karyotype shows one normal chromosomes 3, one normal chromosome 7, and one derivative chromosome 7 or der(7). The arrows indicate the breakpoints. The derivative chromosome 7 was further characterized by spectral karyotyping (SKY) using the 24-color SKY probes and showed that the additional chromosomal material on the derivative chromosome 7 originated from chromosome 3 (Figure 2). Fluorescence in situ hybridization with chromosome 3 and chromosome 7 telomeric probes showed presence of chromosome 3p attached to the derivative chromosome 7 (Figure 3) and absence of the 7p telomere (Figure 4). Based on these studies, the karyotype was 46,XX,der(7)t(3;7) (p24.2;p22), which was consistent with partial distal 7p monosomy and partial distal 3p trisomy. However, the parental karyotypes were not available. TOF is a relatively uncommon but serious defect of the heart and great vessels during embryogenesis. It consists of four defects, including pulmonary stenosis, ventricular septal defect, overriding aorta, and right 288

2 Partial Trisomy 3p and Monosomy 7p with TOF x y Figure 2. Spectral karyotyping (SKY) using 24-color SKY probes shows that the der(7) results from a translocation between chromosome 3 and chromosome 7. 3 der(7) 7 3 der(7) Figure 3. Fluorescence in situ hybridization study using 3p (green)/3q (red) telomeric probes shows that the der(7) is stained with a green signal by the 3p telomeric probe. Figure 4. Fluorescence in situ hybridization study using 7p (green)/7q (red) telomeric probes shows absence of a green signal on der(7). ventricular hypertrophy secondary to the pulmonary stenosis. These defects are the result of varying degrees of abnormality in a single developmental process i.e. the growth and fusion of the conotruncal septum. However, the actual etiology of TOF is still uncertain. TOF may be inherited as an autosomal recessive disease [1]. Numerous genetic or chromosomal aberrations are reported to be related to this disease. DiGeorge syndrome 289

3 C.M. Chang, et al Table. Reported cases with partial trisomy 3p and monosomy 7p Authors Conte Baeteman Kotzot Speleman Present et al [15] et al [14] et al [23] et al [22] case 46,XY, 46,XX, 46,XY 46,XY, 46,XX, Karyotypes der(7)t(3:7) der(7)t(3:7) dup(3)(p25), del(7)(p22.1), der(7)t(3:7) (p24.1;p22) (p24.3;p22.1) de novo de novo (p24.2;p22) Flattened face + High arched palate + Asymmetrical palatal arch + Full cheeks + + Epicantus + + Antimongoloid eye slant + + Broad, flat nasal bridge Philtrum small pit + Microstomia + Triangular-shaped mouth + Abnormally shaped ears + + Retroverted ears + + Broad neck + Muscular hypotonia + + Asymmetric skull + Prominent right frontal boss + Tetralogy of Fallot + + Seizure Renal hypoplasia + Genital hypoplasia + Cryptorchidism + Hypercholesterolemia + (22q11 microdeletion) [2] and trisomy 21 [3] are well recognized to be associated with TOF. DiGeorge syndrome leads to a variety of cardiac malformations, including TOF, interrupted aortic arch, truncus arteriosus, right aortic arch, and aberrant right subclavian artery [4]. The association of the following two genes with the pathogenesis of TOF is widely accepted. JAG1 gene that is located on chromosome 20p12 may be responsible for right-sided heart defects ranging from mild peripheral pulmonary stenosis to severe forms of TOF [5]. The cardiac homeobox gene CSX (cardiacspecific homeobox; on chromosome 5q34) is essential in cardiac development. Many other chromosomal aberrations were also reported to be associated with TOF, such as partial duplication of chromosome 1p [6], terminal deletion of chromosome 2q [7], trisomy chromosome 4 [8], terminal deletion of chromosome 7q [9], duplication of chromosome 9p [10], trisomy 14 [11], large interstitial deletion of 17p [12], and deletion of chromosome 18q [13]. Here, we describe the identification of a rare occurrence of unbalanced translocation resulting in partial trisomy 3p and partial monosomy 7p. In the present case, TOF, infantile seizure, and hypothyroidism were the major manifestations. Two similar cases were reported previously (Table). Baeteman et al showed a girl with karyotype of 46,XX,der(7) t(p24.3;p22.1) exhibiting facial dysmorphism, asymmetric skull, and a prominent right frontal boss. Electroencephalogram showed epileptic signs [14]. There was no apparent visceral abnormality. Conte et al presented a case of a 1-year-old male infant with karyotype of 46,XY,der(7)t(3;7)(p24.1;p22) who was born with clinical features including dysmorphic ears, decreased muscle tone, and seizure episodes associated with fever [15]. The authors reviewed 44 cases and summarized that the most common malformations of trisomy 3p syndrome were psychomotor and mental retardation, short neck, hypertelorism/telecanthus, and congenital heart defects. The manifestation of seizure in these three cases is noteworthy. Two genes mapping to the short arm of chromosome 3 may contribute to seizure. ITPR1 gene that is located on 3p25 26 encodes inositol 1,4,5-trisphosphate receptor. Deletion of ITPR1 leads to seizure in the animal model [16]. THRB gene that is located on 3p24.3 encodes thyroid hormone receptor β. Aberration of THRB results in 290

4 Partial Trisomy 3p and Monosomy 7p with TOF a truncated receptor and resistance to thyroid hormone and clinically manifests with hypotonia, seizure, demyelination, and bilateral ventricular enlargement of brain [17]. One gene mapping to chromosome 3p25.3 was suspected to be responsible for the congenital heart disease in the present case. CRELD1 gene that is expressed in the developing heart may confer susceptibility to atrioventricular septal defect [18]. Green et al reported that individuals with chromosome 3p25 pter deletion developed atrioventricular septal defect, low birth weight, mental retardation, microcephaly, and dysmorphism [19]. The dosage effect on phenotypes for this gene in trisomic state is still unknown. Partial deletion of the short arm of chromosome 7 is associated with recognizable phenotypes that often include craniosynostosis. Recent reports have suggested that craniosynostosis occurs only if the deletion involves 7p21 [20] or 7p13 [21], with the latter causing the Greig polysyndactyly-craniofacial anomalies syndrome, which is an autosomal dominant disorder. In the present case, the deleted terminal segment was free from the two loci mentioned above. Speleman et al described a patient with pure de novo terminal deletion of the short arm of chromosome 7(p22.1 pter), exhibiting facial dysmorphism, TOF, and genital hypoplasia [22]. Thus, the region responsible for TOF may assumedly exist within 7p22. In conclusion, duplication or deletion of a part of a single chromosome provides a unique opportunity to observe the phenotypic consequence of gain or loss of specific genetic material. Our case further adds to the evidence that partial trisomy of 3p and monosomy 7p are associated with TOF and infantile seizure. It also highlights the importance of comprehensive prenatal sonographic examinations. 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