Chromosome 1P36 Deletion Syndrome: Prenatal Diagnosis, Molecular Cytogenetic Characterization and Fetal Ultrasound Findings

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CHROMOSOME 1P36 DELETION SYNDROME: PRENATAL DIAGNOSIS, MOLECULAR CYTOGENETIC CHARACTERIZATION AND FETAL ULTRASOUND FINDINGS

Chih-Ping Chen1,2,3,4,5,6*, Ming Chen7,8,9,10, Yi-Ning Su11, Chin-Yuan Hsu1, Fuu-Jen Tsai4,12,13, Schu-Rern Chern2, Pei-Chen Wu1, Chen-Chi Lee1, Wayseen Wang2,14 Departments of 1Obstetrics and Gynecology and 2Medical Research, Mackay Memorial Hospital, 5Institute of Clinical and Community Health Nursing, 6Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, 10Department of Obstetrics and Gynecology College of Medicine, National Taiwan University, 11Department of Medical Genetics, National Taiwan University Hospital, and 14Department of Bioengineering, Tatung University, Taipei; 3Department of Biotechnology, Asia University, 4School of Chinese Medicine, College of Chinese Medicine, China Medical University, and Departments of 12Medical Research and 13Medical Genetics, China Medical University Hospital, Taichung; Departments of 7Genomic Medicine, 8Medical Research and 9Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan.

SUMMARY Objective: To present prenatal diagnosis and molecular cytogenetic characterization of de novo partial mono- somy 1p (1p36.23pter) and partial trisomy 20p (20p12.1pter) associated with ventriculomegaly, ventricu- lar septal defect and midface hypoplasia. Materials, Methods and Results: A 31-year-old, primigravid woman was referred for amniocentesis at 20 ges- tational weeks because of ventriculomegaly, ventricular septal defect, and midface hypoplasia. Amniocentesis revealed an aberrant derivative chromosome 1, or der(1). Parental karyotypes were normal. Spectral karyotyping analysis revealed that the der(1) contained a segment of chromosome 20 in the distal end of the short arm of chromosome 1. Array comparative genomic hybridization demonstrated an 8.4-Mb distal 1p deletion and a 14-Mb distal 20p duplication. The karyotype was 46,XX,der(1)t(1;20)(p36.23;p12.1)dn. Polymorphic DNA marker analysis determined the paternal origin of the aberrant chromosome. The pregnancy was subsequently ter- minated. A 462-g malformed female fetus was delivered at 22 gestational weeks with a prominent forehead, midface hypoplasia, a flat nasal bridge, low-set ears, a long philtrum, a pointed chin and micrognathia. Conclusion: Spectral karyotyping, fluorescence in situ hybridization and array comparative genomic hybridiza- tion are useful for the prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial monosomy 1p (1p36.23pter) and partial trisomy 20p (20p12.1pter) are associated with ventriculomegaly, ventricular septal defect and midface hypoplasia on prenatal ultrasound. Prenatal diagnosis of ventriculomegaly, congenital heart defects and midface hypoplasia should alert clinicians to chromosome 1p36 deletion syndrome and prompt molecular cytogenetic analysis if necessary. [Taiwan J Obstet Gynecol 2010;49(4):473–480]

Key Words: chromosome 1, chromosome 1p36 deletion syndrome, chromosome 20, monosomy 1p36, prenatal diagnosis, ultrasound

*Correspondence to: Dr Chih-Ping Chen, Department Introduction of Obstetrics and Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Prenatal diagnosis of a de novo unbalanced reciprocal Taipei, Taiwan. E-mail: [email protected] translocation involving chromosomal segments with Accepted: September 1, 2010 a subtle difference in banding results in difficulties in

Taiwan J Obstet Gynecol • December 2010 • Vol 49 • No 4 473 C.P. Chen, et al interpretation and genetic counseling, and requires ventriculomegaly, a ventricular septal defect (VSD) and molecular cytogenetic technologies such as spectral midface hypoplasia. karyotyping (SKY), fluorescence in situ hybridization (FISH), and array-based comparative genomic hybridi- zation (aCGH) to identify the nature of the aberrant Materials, Methods and Results chromosome. We previously reported the utility of SKY and FISH in the identification of a de novo aberrant A 31-year-old, primigravid woman was referred to the chromosome derived from an unbalanced reciprocal genetic counseling center for amniocentesis at 20 ges- translocation [1]. We additionally report here the pre- tational weeks because of abnormal ultrasound find- natal diagnosis and molecular cytogenetic characteri- ings of ventriculomegaly, VSD and midface hypoplasia zation of de novo partial monosomy 1p (1p36.23pter) (Figure 1). Amniocentesis revealed an aberrant deriva- and partial trisomy 20p (20p12.1pter) associated with tive chromosome 1, or der(1) (Figure 2). Chromosome

A B

C

Figure 1. Prenatal ultrasound at 20 gestational weeks reveals (A) ventriculomegaly, (B) a ventricular septal defect and (C) midface hypoplasia.

Figure 2. G-banded karyotype shows a derivative chromosome 1, or der(1). The proband’s karyotype is 46,XX,der(1)t(1;20)(p36.23;p12.1)dn. The arrows indicate the breakpoints.

474 Taiwan J Obstet Gynecol • December 2010 • Vol 49 • No 4 Chromosome 1p36 Deletion Syndrome preparations of blood lymphocytes from the parents uncultured amniocytes. Bacterial artificial chromosome revealed normal karyotypes. The derivative chromosome (BAC)-based aCGH using CMDX BAC-based aCGH was characterized by SKY using 24-color SKY probes CA2500 chips (CMDX, Irvine, CA, USA) demonstrated (Applied Spectral Imaging, Carlsbad, CA, USA). SKY partial monosomy 1p and partial trisomy 20p [arr analysis revealed that the der(1) contained a segment 1p36.33p36.23 (RP11-668E2RP11-81J7)×1, 20p of chromosome 20 in the distal end of the short arm 13p12.1 (RP11-530N10RP11-238I2)×3] (Figure 4). of chromosome 1 (Figure 3). Repeat amniocentesis Oligonucleotide-based aCGH using HumanCytoSNP- was performed at 22 gestational weeks, and 20 mL of 12vl BeadChips (Illumina, San Diego, CA, USA) further aspired amniotic fluid was applied for aCGH using demonstrated an 8.4-Mb distal 1p deletion and a 14-Mb

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6 789101112

13 14 15 16 17 18

Figure 3. Spectral karyotyping using 24-color SKY probes shows a 19 20 21 22 X Y der(1) derived from a translocation between chromosomes 1 and 20.

Chromosome 1 Chromosome 20 0 0

10 50

20

100

30

150 40

50 200

Figure 4. Bacterial artificial chromosome-based array comparative genomic hybridization shows a distal 1p 60 deletion [arr 1p36.33p36.23 (RP11-668E2RP11- 81J7)×1] and a distal 20p duplication [arr 20p13p12.1 .22.33 .567 1 1.52 3 4.5 .22.33 .567 1 1.52 3 4.5 (RP11-530N10RP11-238I2)×3].

Taiwan J Obstet Gynecol • December 2010 • Vol 49 • No 4 475 C.P. Chen, et al Known reg A Found reg B Allele freq 0.0 0.25 0.5 0.75 1.0 1

p31 p31 Known reg Found reg

B Allele freq q12 0.0 0.25 0.5 0.75 1.0 1 742,430 Detected region 1,581,470 CHR 1 2,420,510 p31 3,259,550 Start 742429 4,098,590 End 9132849 4,937,630 q12 q32 Length 8390420 5,776,670 q41 Value 1 6,615,710 7,454,750 Loss G/L 8,293,790 Conf 1706,878 9,132,830 − − 3.62 −2.74−1.37 0.001.37 2.74 3.62 1.81 0.00 1.81 Smoothed log R Smoothed log R Known reg B Found reg B Allele freq 0.0 0.25 0.5 0.75 1.0 20

p13

p12

p11

p11 Known reg Found reg q11 B Allele freq 0.0 0.25 0.5 0.75 1.0 20 q11 457,700 p13 q11 Detected region 1,867,450 p12 CHR 20 3,267,200 p11 4,666,950 q13 Start 467697 p11 6,066,700 q11 q13 End 14465220 7,466,450 q11 Length 13997523 8,866,200 q13 10,265,950 Value 3 q13 11,665,700 Gain q13 G/L 13,065,450 q13 q13 Conf 7696.879 14,485,200 −2.00 −1.00 0.00 1.00 2.00 −2.33 −1.16 0.00 1.16 2.33 Smoothed log R Smoothed log R Figure 5. Oligonucleotide-based array comparative genomic hybridization shows (A) an 8.4-Mb distal 1p deletion [arr 1p36.33p36.23 (742,429-9,132,849)×1] and (B) a 14-Mb distal 20p duplication [arr 20p13p12.1 (467,697-14,465,220)×3]. distal 20p duplication [arr 1p36.33p36.23 (742,429- Discussion 9,132,849)×1, 20p13p12.1 (467,697-14,465,220)×3] (Figure 5). The karyotype was 46,XX,der(1)t(1;20) Chromosome 1p36 deletion syndrome (OMIM 607872), (p36.23;p12.1)dn (Figure 2). Polymorphic DNA marker or monosomy 1p36 syndrome, is the most common sub- analysis determined the paternal origin of the aberrant telomeric terminal deletion syndrome, and it is associ- chromosome. The parents opted to terminate the preg- ated with multiple congenital anomalies and mental nancy. A 462-g malformed female fetus was delivered retardation [2]. Chromosome 1p36 deletion syndrome with a prominent forehead, midface hypoplasia, a flat has an estimated frequency of 1 in 5,000 live births [3] nasal bridge, low-set ears, a long philtrum, a pointed and is characterized by a typical craniofacial dysmor- chin and micrognathia (Figure 6). phism of straight eyebrows, deep-set eyes, midface

476 Taiwan J Obstet Gynecol • December 2010 • Vol 49 • No 4 Chromosome 1p36 Deletion Syndrome

A B

Figure 6. Anterior and lateral views of the craniofacial appearance of the proband. hypoplasia, a broad nasal bridge, a long philtrum, 1p36 and a karyotype of 46,XY,der(1)t(1;20)(p36;p13) a pointed chin, large anterior fontanel, microbrachy- in a fetus conceived by a carrier mother who had a previ- cephaly, epicanthal folds, low-set ears, brachydactyly, ous aneuploid child with 46,XX,der(1)t(1;20)(p36;p13) camptodactyly, short feet, developmental delay, men- and multiple anomalies. The male fetus prenatally man- tal retardation, hypotonia, seizures, structural brain ifested hydrocephalus and complex congenital heart abnormalities, congenital heart defects, eye problems, defects during prenatal ultrasound at 16 gestational hearing loss and skeletal, renal and genital abnormali- weeks, and postnatally manifested truncus arteriosus, ties [4,5]. VSD, agenesis of the corpus callosum and dilated ven- The present case prenatally manifested ventricu- tricles. The female aneuploid child had microcephaly, lomegaly, VSD, and midface hypoplasia during second- microphthalmia, optic nerve colobomas, facial dysmor- trimester ultrasound. In a study of 60 patients with phism, agenesis of the corpus callosum, hydrocephalus, chromosome 1p36 deletion syndrome, Battaglia et al tetralogy of Fallot and neonatal death. Campeau et al [5] found midface hypoplasia in 100% (60/60), brain [8] additionally reported prenatal diagnosis of mono- abnormalities in 88% (43/49) and congenital heart somy 1p36 and a karyotype of 46,XX,der(1)t(1;20) defects in 71% (34/48) of patients. In their study, the (p36.1;p12.2) by amniocentesis in a fetus conceived reported congenital heart defects included atrial sep- by a 30-year-old carrier mother because of severe fetal tal defect (28%), VSD (23%), patent ductus arteriosus ventriculomegaly on prenatal ultrasound at 21 gesta- (12%), valvular anomalies (20.5%), tetralogy of Fallot tional weeks. Parental cytogenetic analysis showed that (7.7%), coarctation of the aorta (5.1%), infundibular the mother’s karyotype was 46,XX,t(1;20)(p36.1;p12.2). stenosis of the right ventricle (2%) and Ebstein’s anomaly The phenotype of partial trisomy 20p includes a low (2%), and brain magnetic resonance imaging abnor- birth weight, occipital flattening, a round face, pro- malities included enlargement of the lateral ventricles minent cheeks, upslanting palpebral fissures, hyper- (37%), cortical atrophy (20%), enlargement of the sub- telorism, epicanthal folds, a short nose, coarse hair, arachnoid spaces (22%), diffuse brain atrophy (10%), congenital heart defects, vertebral anomalies and clin- and enlargement of the frontotemporal opercula (4%). odactyly [9]. Although some of the clinical features In chromosomal abnormalities observed in chromo- observed in our patient could be due to the effect of some 1p36 deletion syndrome, 52% of the rearran- partial trisomy 20p in addition to monosomy 1p36, gements are terminal deletions, 29% are interstitial partial trisomy 20p has been shown to be associated deletions, 12% are complex rearrangements including with no structural brain malformations [9–10]. more than one deletion or deletions with duplications, To date, at least 10 cases of prenatally detected chro- triplications, insertions and/or inversions, and only 7% mosome 1p36 deletion syndrome have been reported are derivative chromosomes derived from unbalanced [8,11–19]. Chromosome 1p36 deletion syndrome translocations [4,6]. The present case had a karyotype may prenatally manifest elevated maternal serum of 46,XX,der(1)t(1;20)(p36.23;p12.1)dn. To our knowl- α-fetoprotein levels, congenital heart defects and cere- edge, this case is the fourth reported case of monosomy bral malformations (Table). Our case additionally shows 1p36 associated with an unbalanced translocation that midface hypoplasia can be a cardinal prenatal sono- between chromosome 1p and 20p. Howard-Peebles graphic feature of chromosome 1p36 deletion syndrome. and Black [7] first reported the diagnosis of monosomy Heilstedt et al [16] reported increased maternal serum

Taiwan J Obstet Gynecol • December 2010 • Vol 49 • No 4 477 C.P. Chen, et al , growth hypospadias, hydronephrosis, Termination at 28 wk, hydrops fetalis, Termination Delivery at 37 wk, facial dysmorphism, ambiguous genitalia, PDA, ASD, Oligohydramnios; delivery at 37 wk ACC and dilated ventricles ACC retardation, plagio- microcephaly, pleural effusion,ventriculomegaly, Ebstein’s anomaly rudimentary postaxial polydactyly of diffuse edema, pulmonary segmentation defects macrocephaly, lobar macrocephaly, right optic nerveholoprosencephaly, coloboma, dilated third and lateral neonatal death ventricles, VSD, with dysmorphic features; neonatal seizures began at 9 weeks old cephaly and minor anomalies; seizures began at 13 weeks old the left hand, equinovarus deformity of the feet, neonatal death De novo De novo De novo Inheritance Outcome Maternal truncus arteriosus, VSD Termination: 46,XY,der(1)t(1;6)(p36.3;q25.2)mat Maternal Termination 46,XX,der(1)t(1;6)(p36.3;q25.2)mat Maternal ventriculomegaly, Termination, 46,XY,der(1)t(1;6)(p36.3;q22.2) 46,XY,der(1)t(1;20)(p36;p13)mat 46,XX,del(1)(p36.3) MSAFP The same mother as Case III, 3 The same mother as Case III, 3 hypertelorism and Ebstein’s anomaly of the corpus callosum at 31 wk Abnormal ultrasound: absence of cerebellar vermis, thick nuchal folds, bilateral hydronephrosis, ascites, club feet, arthrogryposis and a single umbilical artery at 23.5 wk complex congenital heart defects at 16 wk Postnatal diagnosis: polyhydramnios, hydronephrosis, cerebellar and ventricular enlargement at 24 wk Indication for prenatal genetic diagnosis Chromosomal aberration 33 Abnormal ultrasound: IUGR and anomaly 46,XY,der(1)t(1;6)(p36.3;q25.2)mat Maternal Delivered at 34 wk, IUGR, 34 Abnormal ultrasound: ventriculomegaly, 46,XY,del(1)(p36) NA Previous aneuploid child NA Previous aneuploid child NA Abnormal ultrasound: hydrocephalus and Prenatal diagnosis: 46,XY age (yr) Maternal Clinical findings of cases with prenatally detected or undetected chromosome 1p36 deletion syndrome Case III, 6 Case III, 5 Case III, 3 (1999) et al [13] (1997) Faivre et al [14] Kulharya et al [12] (1997) NA Robbins-Furman NA Elevated Cavani et al [15] (2003) Howard-Peebles & Howard-Peebles Black [7] (1994) Chen et al [11] (1997) 33 abnormal ultrasound: Elevated MSAFP, 46,XY,der(1)t(1;4)(p36.13;q33)mat Maternal Delivered with postnatal Table. Author (year)

478 Taiwan J Obstet Gynecol • December 2010 • Vol 49 • No 4 Chromosome 1p36 Deletion Syndrome wk, facial intrauterine growth restriction; intrauterine + 5 = tic coarctation, two intraventricular dysmorphic features; developmental delay at 6 months of age seizures; delayed development, enlarge- aor communications, right heart dilation, tri- cuspid valve dysgenesis at 22 wk, facial Termination Delivered unilateral with PDA, optic nerve hypoplasia, pes calcaneovalgus, at 20 wk Termination Delivery at 40 wk, dysmorphic dysmorphism dysmorphism, clinodactyly, flexiondysmorphism, clinodactyly, con- traction of lower limbs, misaligned toes, hydrocephalus, cerebellar hypoplasia, focal polymicrogyria corpus callosum, vermian hypoplasia, features, hypertonia, neonatal ment of the third and lateral ventricles, small periventricular cysts, delayed myeli- nation at 5 months of age Delivered at 34 wk, cleft palate, ASD, hypotonia; hydrocephalus and colpocephaly on MRI at 2 years old; global developmental delay at 2.5 years old VSD, PDA, dysmorphic PDA, features, VSD, ernal at 21 Termination patent ductus arteriosus; IUGR = De novo De novo De novo De novo NA Ultrasound at 27 wk revealed partial De novo atrial septal defect; PDA atrial septal = Postnatal diagnosis: 46,XX,der(1)t(1;9)(p36.3;p13)[88]/ 46,XX[12] Postnatal diagnosis: 46,XY,del(1)(p36.22) 46,XX,der(1)t(1;20)(p36.1;p12.2)mat Mat agenesis of corpus callosum; ASD = ventricular septal defect; ACC septal ventricular = VSD and midface hypoplasia at 20 wk ventriculomegaly at 21 wk IUGR at 30.3 wk feet rocker-bottom and plexus cysts, VSD, hydrocephalus at 18 wk Abnormal ultrasound: ventriculomegaly, a small choroid plexus cyst and 46,XY,del(1)(p36) nuchal edema at 21 wk defects and cerebral malformation a single umbilical artery and short femurs at Postnatal diagnosis: club foot, 17 wk; IUGR, ventriculomegaly, asymmetric ventricles and tortuous VSD, 46,XX,del(1)(p36.3) aortic arch at 31 wk -fetoprotein; VSD a -fetoprotein; 31 Abnormal ultrasound: ventriculomegaly, 46,XX,der(1)t(1;20)(p36.23;p12.1) 15 Abnormal ultrasound: hydrocephalus and Prenatal diagnosis: 46,XX 31 Abnormal ultrasound: ventriculomegaly, Prenatal diagnosis: 46,XX 30 Abnormal ultrasound: severe NA Abnormal ultrasound: congenital heart Prenatal diagnosis: 46,XY maternal serum = magnetic resonance imaging. Case 1 Case 39 Case 1 Case 2 not available; MSAFP available; not = = Present case Reddy and Yang [17] Reddy and Yang (2003) Hsieh et al [18] (2004) 29Lissauer et al [19] (2007) Abnormal ultrasound: bilateral choroid 29 46,XY,der(1)t(1;21)(p36.3;q22.1) Vialard et al [20] (2009) Campeau et al [8] (2008) NA MRI

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