Clinical and Cytogenetic Features of a Patient with Partial Trisomy 8Q And

Available online at www.annclinlabsci.org 332 Annals of Clinical & Laboratory Science, vol. 43, no. 3, 2013 Clinical and Cytogenetic Features of a Patient with Partial Trisomy 8q and Partial Monosomy 13q Delineated by Array Comparative Genomic Hybridization Young Bae Sohn1, Jun No Yun1, Sang-Jin Park2, Moon Sung Park3, Sung Hwan Kim3, and Jang Hoon Lee3

1Department of Medical Genetics, Ajou University School of Medicine, Suwon; 2MG MED, Inc., Seoul; and 3Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea

Abstract. Partial trisomy 8q is rare and has distinctive clinical features, including severe mental retardation, growth impairment, dysmorphic facial appearances, cleft palate, congenital heart disease, and urogenital anomalies. Partial monosomy 13q is a rare genetic disorder displaying a variety of phenotypic characteristics including mental retardation, dysmorphic facial features, and congenital anomalies. Here, we describe for the first time clinical observations and cytogenetic analysis of a patient with a concomitant occurrence of partial trisomy of 8q (8q21.3→qter) and partial monosomy 13q(13q34→qter). The patient was a female neonate with facial dysmorphia, agenesis of the corpus callosum, cleft palate, and congenital heart disease. G-band standard karyotype was 46,XX,add(13)(q34). To determine the origin of additional genomic gain in chromosome 13, array comparative genomic hybridization (CGH) was performed. Array CGH showed a 56.8 Mb sized gain on chromosome 8q and a 0.28 Mb sized loss on chromosome 13q. Therefore, the final karyotype of the patient was defined as 46,XX, der(13)t(8;13)(q21.3;q34). In conclusion, we described the clinical and cytogenetic analysis of the patient with concomitant occurrence of partial trisomy 8q and partial monosomy 13q delineated by array CGH. This report suggests that the array CGH would be a valuable diagnostic tool for identifying the origin of small additional genetic materials.

Key words: partial trisomy 8q, partial monosomy 13q, Array CGH

Introduction and 2 are characterized by severe intellectual disabilities, growth retardation, and congenital mal- Partial trisomy 8q is rare and has distinctive clinical formations of the brain, eyes, and extremities, as features, including severe mental retardation, well as of the gastrointestinal and/or genitourinary growth impairment, dysmorphic facial features systems. However, most of the patients with the (prominent forehead, down-slanting palpebral fis- Group 3 deletion have only intellectual disabilities, sures, hypertelorism, a depressed nasal bridge, low- and rarely experience growth retardation or other set malformed ears, a long philtrum, microgna- major malformations [4,6]. thia), cleft palate, congenital heart disease, and urogenital anomalies [1-3]. A concomitant occurrence of partial trisomy of 8q (8q21.3→qter) and partial monosomy of 13q Patients with 13q deletion have varied phenotypi- (13q34→qter) has not been previously described. cal features [4,5]. The 13q deletion syndrome is divided into three groups based on the location of Chromosome analysis by standard G-banding the deletion: the deletion of chromosome region karyotyping is a major diagnostic tool for patients proximal to 13q32 (group 1), distal deletion in- with congenital malformations, developmental de- cluding at least a part of 13q32 (group 2), and lays, birth defects and mental retardations [7]. distal deletion of 13q33-34 (group 3) [5]. Groups 1 However, small structural abnormalities of chromosomes, including small excessive chromosomal Address correspondence to Jang Hoon Lee; Department of Pediatrics, Ajou University School of Medicine, San 5, Wonchun-dong, segments or a marker chromosome, cannot be re- Yeongtong-gu, Suwon, 443-721, Korea; phone: +82 31 219 5165; fax: +82 31 219 4521; e mail: [email protected] solved only by conventional G-banded analysis [8].

0091-7370/13/0300-332. © 2013 by the Association of Clinical Scientists, Inc. A patient with partial trisomy 8q and partial monosomy 13q 333 Array comparative genomic hybridization (Array CGH) has been described as an additional method for identifying the origin of small genetic abnormalities [7,9-11]. Moreover, because the array CGH test does not require cell culture (as conventional chromosome analysis does), a clinician could get the test results faster.

Here, we report the clinical and cytogenetic features of a patient with concomitant partial trisomy 8q and partial monosomy 13q diagnosed by standard karyotyping and additional array CGH. This is, to the best of our knowledge, the first report of concomitant partial trisomy 8q and partial monosomy Figure 1. Abnormal morphologic feature showing crumpled ear, hypertelorism, micrognathia, 13q in a patient. and overlapping fingers and toes

Materials and Methods was suspected by trans-abdominal ultrasonography at antenatal periods. Apgar scores at one and five Clinical evaluations. The assessment of physical growth was minutes were 7 and 8 respectively. At birth, weight evaluated by Korean reference data [12]. Laboratory tests including complete blood cell count (CBC), serum AST/ALT, was 2960 g (10-25 percentile), height was 47.4 cm BUN/creatinine, blood glucose, triiodothyronine (T3), free (10-25 percentile), and head circumference was 35 thyroxine (free T4), and thyroid-stimulating hormone (TSH) cm (75-90 percentile). Abnormal morphological were performed. Brain magnetic resonance imaging (MRI) was features included crumpled ear, hypertelorism, mi- performed to investigate brain anomalies. Echocardiography was performed to evaluate cardiac morphology and function. crognathia, cleft palate, and overlapping fingers and toes (Figure 1). Laboratory tests were normal: Cytogenetic analysis. Chromosome analysis was performed on WBC 10800/µl Hb 16.3 g/dl 232 x 103/µl, AST/ cultured lymphocytes from peripheral blood by examination of ALT 25/42 U/L, BUN/creatinine 6.8/0.7 mg/dl, 20 G-banded metaphase cells. For array CGH, DNA was ex- blood glucose 74 mg/dl, T3 86 ng/dl, free T4 1.17 tracted from peripheral blood using the PureGene kit (Gentra Systems, Inc., Minneapolis, MN). Slides containing 1440 hung/dl, and TSH 4.49 uIU/ml. Neonatal tandem man BAC (Bacteral Artificial Chromosomes) clones were used mass screening tests were normal. Agenesis of the at an average resolution of 2.3 Mb for the entire genome. corpus callosum was diagnosed upon brain MRI (Figure 2). Perimembranous ventricular septal de- Results fect (VSD), secondum type atrial septal defect, and patent ductus arteriosus (PDA) were diagnosed Clinical findings.A female neonate was born at 40 with echocardiography. Abdominal sonogram re- weeks’ gestation as the first child of healthy, non- vealed no urogenital anomalies. At 37 days after consanguineous Korean parents. Her mother had birth, patch repair of VSD and ligation of PDA no history of health problems including spontane- were performed due to aggravated symptoms in- ous abortion. Fetal agenesis of the corpus callosum cluding dyspnea, oxygen dependency, and feeding 334 Annals of Clinical & Laboratory Science, vol. 43, no. 3, 2013

Figure 2. Brain MRI showing agenesis of corpus callosum (arrows). intolerance irresponsive to medical treatment. Discussion Although dyspnea and oxygen dependency were improved after heart surgery, feeding intolerance In this report, we describe for the first time, to our (uncoordination of sucking and swallowing) con- knowledge, clinical and cytogenetic findings of a tinued up to hospital discharge with orogastric tube patient with concomitant occurrence of partial tri- feeding. somy 8q and partial monosomy 13q.

Cytogenetic findings.The initial standard chromo- Full trisomy 8, or Warkany syndrome, has severe some study revealed 46,XX,add(13)(q34) karyo- effects on the developing fetus and is almost always type (Figure 3). To delineate the origin of addition- perinatally lethal. Mosaic trisomy 8 syndrome is al genomic gain in chromosome 13, array CGH less severe, and individuals with this condition are was performed. Array CGH showed a region of more likely to survive and have distinct clinical gain spanning approximately 56.8 Mb on chromo- characteristics including mental retardation, spe- some 8q and a region of loss of approximately 0.28 cific facial features (prominent forehead, deep-set Mb on chromosome 13q (Figure 4). Because the eyes, strabismus, hypertelorism with broad nasal terminal deletion size of 13q was very small, we root, micrognathia, high arched palate, cleft palate, confirmed the deletion by fluorescence in situ -hy and prominent cupped ears with thick helices), bridization (FISH) analysis with 13q34 probe joint contractures, vertebral anomalies, narrow pel- (D13S1009). The FISH analysis showed deletion vis, ureteral-renal anomalies, and other anomalies of 13q34 (Figure 5). Therefore, the final karyotype [13]. Partial trisomy 8q is less well-defined, with of the patient was 46,XX,der(13)t(8;13) relatively few patients described [3,14,15] since (q21.3;q34). The patient has both a partial trisomy Lejeune et al.[15] first reported a patient with par- 8q (8q21.3→qter) and a partial monosomy 13q tial trisomy 8q in 1972. Clinical findings of partial (13q34→qter). trisomy 8q include mental retardation, growth im- Her mother was later found to carry a balanced re- pairment, dysmorphic facial features (prominent ciprocal translocation involving chromosomes 8 forehead, downslanting palpebral fissures, hyper- and 13 that could account for the chromosomal telorism, a depressed nasal bridge, low-set mal- abnormality of the patient. Chromosome analysis formed ears, a long philtrum, micrognathia), cleft from father’s peripheral blood was 46,XY. palate, congenital heart disease, and urogenital A patient with partial trisomy 8q and partial monosomy 13q 335 anomalies. Our patient had brain malformation (agenesis of corpus callosum), a dysmorphic face (prominent forehead, hypertelorism, low-set malformed ears, micrognathia), cleft palate, and congenital heart defects that are com- patible with the clinical manifestations of partial trisomy 8q. The duplication region was 8q21.3q24.3 with an esti- mated size of 56.8 Mb (arr 88,908,177-145,788,550). The distal deletion of 13q33- Figure 3. G-band karyotype of the patient resulted 46,XX,add(13)(q34) 34 causes mental retardation, microcephaly, and genital malformations in males, but has not been associat- known to be responsible for mental retardation and ed with other major malformations [5,16]. microcephaly [16]. Our patient did not have mi- Moreover, since our patient had a very small (0.28 crocephaly, and the deletion of 13q region did not Mb) distal deletion in 13q, the various malforma- involve AHGEF7 gene. tions could be mainly the result of trisomy 8q. A 0.28 Mb (arr 113,986,985-114,266,156) deletion Despite conventional karyotyping being in com- of 13q34 identified in the patient contains 5 genes; mon use as an important diagnostic method for GRTP1 (growth hormone regulated TBC protein patients with multiple congenital anomalies and 1, RefSeq: NM_024719.2), ADPRHL1 (ADP- mental retardation, it is hard to identify a small un- ribosylhydrolase like 1, RefSeq: NM_199162.1), known origin chromosome. Array CGH is a useful DCUN1D2 (DCN1, defective in cullin ned- method for identifying unknown additional and dylation 1, domain containing 2, RefSeq: rearranged chromosomes, although the coverage NM_001014283.1), TMCO3 (transmembrane and resolution of array CGH are dependent on the and coiled-coil domain 3, RefSeq: NM_017905.4), design and density of the used array [7]. Moreover, and TFDP1 (transcription factor Dp-1, OMIM conventional karyotyping requires, at the very least, 189902, NR_026580). The roles of these five genes several days (usually more than a week in clinical in a certain disease phenotype have not been well situations) because it requires cell culture [7]. Array demonstrated. Haploinsufficiency of the AHGEF7 CGH could overcome this time lag and become a gene (OMIM 605477) (arr 110,565,783– useful diagnostic tool to rapidly identify the origin 110,756,079) located at 13q34 is of the excess chromosomal materials. Because array

Figure 4. Array CGH showing 8q duplication and 13q deletion. Arrows indicate 8q21.3q24.3 duplication (arr 8q21.3q24.3 (88908177 - 145788550) x 3) and 13q34 deletion (arr 13q34 (113986985 - 114266156) x 1). 336 Annals of Clinical & Laboratory Science, vol. 43, no. 3, 2013

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