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Objective To report prenatal diagnosis of 22q11.2 deletion syndrome with right aortic arch (RAA), left ductus arteriosus, cardiomegaly, and pericardial effusion in the fetus. Case report A 35-year-old woman, gravida 2, para 1, was referred to the hospital at 31 weeks of gestation because of abnormal ultrasound findings and whole-genome array comparative genomic hybridization report. G-banding chromosome analysis revealed a karyotype of 46,XX. Level II ultrasound at 22 weeks of gestation revealed RAA with the presence of the aortic arch on the right side of trachea at three vessels and trachea view, left ductus arteriosus, and mild right side pyelectasis. Cardiomegaly and pericardial effusion were also found 2 months later. Array comparative genomic hybridization detected a 2.743-Mb deletion at 22q11.2 region. Multiplex ligation-dependent amplification detected deletion in the DiGeorge syndrome critical region of chromosome 22 low copy number repeat 22-A–C. Metaphase fluorescence in situ hybridization on lymphocyte in cord blood confirmed deletion in 22q11.2 region. Conclusion Chromosome abnormalities have been found in patients with RAA. Prenatal diagnosis of RAA with or without intracardiac or extracardiac anomalies should include a diagnosis of 22q11.2 deletion syndrome.

Objective To present rapid aneuploidy diagnosis (RAD) of partial trisomy 7q (7q34→qter) and partial monosomy 10q (10q26.12→qter) by array comparative genomic hybridization (aCGH) using uncultured amniocytes. Case Report A 34-year-old, gravida 2, para 1, woman underwent amniocentesis at 20 weeks of gestation because of a previous mentally retarded child with an unbalanced reciprocal translocation inherited from the carrier father who had a karyotype of 46,XY,t(7;10) (q34;q26.12). Her first child was initially found to have a normal karyotype by routine cytogenetic analysis, but a cryptic chromosomal abnormality was subsequently diagnosed by aCGH. During this pregnancy, RAD by oligonucleotide-based aCGH using uncultured amniocytes revealed a 16.4-Mb duplication of 7q34–q36.3 and a 12.7-Mb deletion of 10q26.12–q26.3. Conventional cytogenetic analysis using cultured amniocytes revealed a karyotype of 46,XX,der(10)t(7;10)(q34;q26.12)pat. The parents elected to terminate the pregnancy. A malformed female fetus was delivered with a high prominent forehead, hypertelorism, epicanthic folds, a broad depressed nasal bridge, a prominent nose with anteverted nostrils, micrognathia, a short neck, large low-set ears, clinodactyly, small big toes, and normal female external genitalia. Conclusion aCGH is a useful tool for RAD of subtle chromosomal rearrangements in pregnancy, especially under the circumstance of a previous abnormal child with an unbalanced translocation derived from a parental subtle reciprocal translocation.

Objective To demonstrate perinatal imaging findings and to investigate the mutation in the NEK1 gene in a fetus with type II short rib-polydactyly syndrome (SRPS) (Majewski). Case Report A 34-year-old woman with a past history of fetal SRPS was referred to the hospital at 16 weeks of gestation because of sonographic diagnosis of short limbs in the fetus. Fetal ultrasound revealed short ribs, short limbs, absence of tibiae, polydactyly, syndactyly and choroid plexus cysts. At 21 weeks of gestation, polycystic kidneys were found. The pregnancy was terminated, and a fetus was delivered with facial dysmorphism, a median cleft lip, a narrow chest, micromelia, aplasia of tibiae, hypoplastic nails, syndactyly and postaxial polydactyly. The karyotype was 46,XX. Molecular analysis of fetal tissues showed a paternal-origin heterozygous splice site mutation in intron 7 (c.465-1 G>A) in the NEK1 gene, but no mutations in the genes of WDR35 , DYNC2H1 , IFT80 , EVC and EVC2 . The NEK1 mutation causes an alteration of the splice acceptor site of intron 7 (IVS7-1 G>A). No second mutation was identified. Conclusion Tibial aplasia, choroid plexus cysts and polycystic kidneys can be prominent prenatal ultrasound findings of type II SRPS. The present case provides evidence for a correlation of NEK1 mutation with type II SRPS.

Objective To present the prenatal diagnosis and molecular investigation of the parental origin and mechanism of nondisjunction underlying an 48,XXY,+18 karyotype in a fetus with congenital abnormalities, and to review the literature. Materials, Methods, and Results A 42-year-old woman was referred for amniocentesis at 18 weeks of gestation because of advanced maternal age. Prenatal ultrasound revealed bilateral choroid plexus cysts. Amniocentesis revealed a karyotype of 48,XXY,+18. The parental karyotypes were normal. Level II ultrasound revealed a flexion contracture deformity of the left wrist with absence of the thumb. The pregnancy was terminated at 22 weeks of gestation. A 332 g male fetus was delivered with clenched hands, arthrogryposis of the left wrist, aplasia of the left thumb, micrognathia, low-set ears, hypertelorism, rocker-bottom feet, and a normal penis. Quantitative fluorescent polymerase chain reaction assays using polymorphic DNA markers showed a triallelic pattern with a dosage ratio of 1:1:1 (paternal:maternal:maternal) for chromosome 18-specific markers, and a monoallelic pattern of a single maternal allele for chromosome X-specific markers. The fetus inherited two copies of two different maternal alleles on chromosome 18, and two copies of a single maternal allele on chromosome X. The molecular result, along with the karyotype of 48,XXY,+18, was consistent with the occurrence of nondisjunction of chromosome 18 in a maternal meiosis I error and nondisjunction of chromosome X in a maternal meiosis II error or less likely a postzygotic mitotic error. Conclusion The present case provides evidence that abnormal separation of chromosomes 18 and X resulting in double aneuploidy may occur in different cell divisions, and such an occurrence is related to advanced maternal age.

Objectives To present prenatal diagnosis and molecular cytogenetic characterization of de novo partial partial trisomy 21q (21q22.11→qter) associated with clinodactyly and hypoplastic midphalanx of the fifth fingers, midface hypoplasia, and an intracardiac echogenic focus on prenatal ultrasound. Materials, Methods, and Results A 34-year-old gravida 2, para 1 woman underwent amniocentesis at 20 weeks of gestation because of fetal structural abnormalities on prenatal ultrasound. A level II ultrasound at 20 weeks of gestation showed polyhydramnios, clinodactyly and hypoplastic midphalanx of the fifth fingers, midface hypoplasia, and an intracardiac echogenic focus. Amniocentesis revealed an aberrant derivative chromosome 9, or der(9). Parental karyotypes were normal. Spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) analyses revealed that the der(9) contained a segment of chromosome 21 distal to chromosome 9q, and FISH analysis additionally showed that the distal subtelomeric region of 9q was not deleted. Array comparative genomic hybridization (aCGH) demonstrated a 14.8-Mb duplication of distal 21q encompassing the Down syndrome critical region (DSCR) but no genomic imbalance in the distal euchromatic region of chromosome 9. The karyotype was 46,XX,der(9)t(9;21) (q34.3;q22.11)dn. Polymorphic DNA marker analysis revealed the maternal origin of the aberrant chromosome. The pregnancy was subsequently terminated. A malformed female fetus was delivered with a characteristic phenotype of Down syndrome. Conclusion SKY, FISH and aCGH are useful in prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial trisomy 21q encompassing the DSCR may present characteristic Down syndrome features on prenatal ultrasound.

Objective To present prenatal diagnosis of chromosome 1p32-p31 deletion syndrome with NFIA haploinsufficiency, ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and intrauterine growth restriction and to review the literature. Materials, Methods, and Results A 26-year-old, primigravid woman was referred for amniocentesis at 30 weeks of gestation because of hydrocephalus and short limbs. Prenatal ultrasound showed macrocephaly, prominent forehead, ventriculomegaly, corpus callosum hypogenesis, micrognathia, and ambiguous external genitalia. Amniocentesis was performed, and array comparative genomic hybridization using uncultured amniocytes revealed a 22.2-Mb deletion of 1p32.3-p31.1 [arr cgh 1p32.3p31.1 (55,500,291 bp–77,711,982 bp)×1] encompassing the genes of NFIA , GPR177 , and 89 additional genes. Cytogenetic analysis revealed a karyotype of 46,XX,del(1)(p31.1p32.3)dn. At 33 weeks of gestation, a dead fetus was delivered with a body weight of 1536g ( th centile); relative macrocephaly; a broad face; prominent forehead; hypertelorism; anteverted nostrils; micrognathia; low-set ears; and abnormal female external genitalia with labial fusion, labial hypertrophy, absence of vaginal opening, and clitoral hypertrophy. Polymorphic DNA marker analysis determined a paternal origin of the deletion. Conclusion Prenatal diagnosis of ventriculomegaly with an abnormal corpus callosum should alert subtle chromosome aberrations and prompt molecular cytogenetic investigation if necessary. Fetuses with chromosome 1p32-p31 deletion syndrome and haploinsufficiency of the NFIA gene may present ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and intrauterine growth restriction in the third trimester.

Objective To present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome (sSMC) derived from ring chromosome, or r(4) by spectral karyotyping (SKY), fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH). Materials, Methods, and Results A 37-year-old, primigravid woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a de novo ring-shaped sSMC in 16 of 31 amniocyte colonies. The parental karyotypes were normal. Level II ultrasound findings were unremarkable. Repeated amniocentesis revealed a karyotype of 47,XX,+mar[17]/46,XX[19]. The sSMC was characterized by SKY and FISH, which showed a chromosome 4 origin of the sSMC. aCGH demonstrated a 21.7-Mb gain in the gene dosage encompassing the region of 4p12→q13.2. The sSMC was r(4)(p12q13.2). The fetal karyotype was 47,XX,+r(4)(p12q13.2)[17]/46,XX[19]. The pregnancy was subsequently terminated. The fetus postnatally manifested hypertelorism, epicanthic folds, a prominent nose, a triangular face, low-set ears, clinodactyly of the fingers, and small big toes. Postnatal cytogenetic analyses of fetal and extraembryonic tissues revealed the karyotypes of 47,XX,+r(4)[18]/46,XX[21] in cord blood, 47,XX,+r(4)[20]/48,XX,+r(4),+r(4)[1]/46,XX[9] in umbilical cord, 47,XX,+r(4)[14]/47,XX,+dic r(4)[1]/46,XX[25] in skin, 47,XX,+r(4)[15]/46,XX[25] in amnion, and 47,XX,+r(4)[12]/47,XX,+dic r(4)[1]/46,XX[2] in placenta. Conclusion SKY, FISH, and aCGH are helpful in genetic counseling of prenatally detected sSMCs by providing the immediate and thorough information on the origin and genetic component of the sSMC.

Objective To present prenatal diagnosis and molecular cytogenetic characterization of a derivative chromosome der(18;18)(q10;q10)del(18)(q11.1q12.1)del(18)(q22.1q22.3). Materials, Methods, and Results A 32-year-old woman was referred for genetic counseling of prenatally detected isochromosome 18q [i(18q)]. She had undergone amniocentesis at 19 gestational weeks because of a trisomy 18 risk of 1/39 derived from abnormally low levels of maternal serum unconjugated estriol, inhibin A, α-fetoprotein, and total β-human chorionic gonadotropin. Amniocentesis revealed a karyotype of 46,XX,i(18)(q10). Parental karyotypes were normal. Prenatal ultrasound showed alobar holoprosencephaly. Repeated amniocentesis was requested and performed at 21 gestational weeks. Array-comparative genomic hybridization analyses revealed a 14-Mb deletion of 18p11.32-p11.21, a 37.8-Mb duplication of 18q12.1-q22.1, and a 6.9-Mb duplication of 18q22.3-q23. Metaphase fluorescence in situ hybridization study showed the absence of an 18q12.1-specific probe signal in one arm and the absence of an 18q22.2-specific probe signal in the other arm of the derivative chromosome. Quantitative fluorescent polymerase chain reaction analysis determined a paternal origin of the derivative chromosome. The cytogenetic result was 46,XX,der(18;18)(q10;q10)del(18)(q11.1q12.1)del(18)(q22.1q22.3). The fetus postnatally manifested cebocephaly. Conclusion Concomitant monosomy 18p and trisomy 18q can be associated with holoprosencephaly and abnormal maternal serum screening results. Array-comparative genomic hybridization, fluorescence in situ hybridization, and quantitative fluorescent polymerase chain reaction are useful in genetic counseling of prenatally detected isochromosomes by providing information on the origin and genetic components of the isochromosome.

Objective To present array comparative genomic hybridization (aCGH) characterization of partial monosomy 13q (13q21.32→qter) and partial trisomy 8p (8p12→pter) presenting with anencephaly and increased nuchal translucency (NT). Case Report A 34-year-old primigravid woman was referred to the hospital at 12 weeks of gestation for termination of the pregnancy because of major structural abnormalities of the fetus. Prenatal ultrasound revealed a malformed fetus with anencephaly and an increased NT thickness of 5 mm at 12 weeks of gestation. Cytogenetic analysis of the fetus revealed a derivative chromosome 13. The mother was subsequently found to carry a balanced reciprocal translocation between 8p12 and 13q21. Bacterial artificial chromosome-based aCGH using fetal DNA demonstrated partial trisomy 8p and partial monosomy 13q [arr cgh 8p23.3p12 (RP11-1150M5→RP11-1145H12)×3, 13q21.32q34 (RP11-326B4→RP11-450H16)×1]. Oligonucleotide-based aCGH showed a 36.7-Mb duplication of distal 8p and a 48.4-Mb deletion of distal 13q. The fetal karyotype was 46,XY,der(13) t(8;13)(p12;q21.32)mat. The maternal karyotype was 46,XX,t(8;13)(p12;q21.32). Conclusion The 13q deletion syndrome can be associated with neural tube defects and increased NT in the first trimester. Prenatal sonographic detection of neural tube defects should alert chromosomal abnormalities and prompt cytogenetic investigation, which may lead to the identification of an unexpected parental translocation involving chromosomal segments associated with neural tube development.

Objective To present prenatal ultrasound and perinatal magnetic resonance imaging (MRI) findings of Galloway-Mowat syndrome. Case Report A 31-year-old woman, gravida 3, para 2, was referred for genetic counseling at 29 weeks of gestation because of abnormal ultrasound findings and a previous child with Galloway-Mowat syndrome. During this pregnancy, microcephaly, intrauterine growth restriction (IUGR), and oligohydramnios were first noted at 27 weeks of gestation. Repeated ultrasounds showed microcephaly, IUGR, and oligohydramnios. MRI performed at 32 weeks of gestation showed reduced sulcation of the brain, pachygyria, poor myelination of the white matter, and cerebellar atrophy. A diagnosis of recurrent Galloway-Mowat syndrome was made. At 40 weeks of gestation, a 2,496-g female baby was delivered with microcephaly, a narrow slopping forehead, epicanthic folds, microphthalmos, a highly arched palate, a small midface, a beaked nose, thin lips, large low-set floppy ears, clenched hands, and arachnodactyly. Postnatal MRI findings were consistent with the prenatal diagnosis. Renal ultrasound showed enlarged bilateral kidneys with increased echogenicity. At the age of 2 weeks, the infant became edematous and developed nephrotic syndrome. Conclusion Microcephaly, IUGR, and oligohydramnios are significant ultrasound triad of fetal Galloway-Mowat syndrome. Prenatal ultrasound diagnosis of microcephaly, IUGR, and oligohydramnios in late second trimester or in early third trimester should alert clinicians to the possibility of Galloway-Mowat syndrome and prompt a detailed search of abnormal sulcation, cortical gyral maldevelopment, and cerebellar atrophy by fetal ultrafast MRI.

Objective To present perinatal findings, modes of ascertainments, and modes of segregation in unbalanced reciprocal translocations detected at amniocentesis. Materials and Methods Between January 1987 and July 2010, 40 cases with unbalanced reciprocal translocations were diagnosed by amniocentesis at Mackay Memorial Hospital, Taipei, Taiwan. The 40 cases originated from 29 families; 21 families with one case, 7 families with two cases, and 1 family with five cases. Results Of 40 cases, 33 (82.5%) presented fetal ultrasound abnormalities and 7 (17.5%) presented no ultrasound abnormalities. Of 40 cases, 36 (90%) had a segregation mode of adjacent-1 2:2 segregation, 3 (7.5%) had a segregation mode of 3:1 segregation with tertiary trisomy, and 1 (2.5%) had a segregation mode of 3:1 segregation with tertiary monosomy. Of 29 families, 7 (24.1%) had de novo translocations and 22 (75.9%) had inherited translocations. In seven de novo cases, the main modes of ascertainments included abnormal ultrasound findings ( n = 5) and advanced maternal age ( n = 2). In 22 inherited families, the main modes of first ascertainment included abnormal ultrasound findings ( n = 8), a previous aneuploid child ( n = 8), advanced maternal age ( n = 4), parental carrier status ( n = 1), and abnormal maternal serum screening results ( n = 1). Among 22 inherited families, 9 (40.9%) had a known parental carrier status, but 13 (59.1%) were unaware of parental carrier status at amniocentesis. Conclusion Unbalanced reciprocal translocations detected at amniocentesis are frequently associated with abnormal ultrasound findings. Prenatal diagnosis of an unbalanced translocation may incidentally detect a balanced translocation in the family. Prenatal diagnosis of fetal structural abnormalities should alert structural chromosome rearrangements and prompt cytogenetic analysis of the fetus and parents if necessary.

Objective To report five cases of major congenital malformations associated with common aneuploidies detected by rapid aneuploidy diagnosis. Case Reports The fetus in the first case presented cebocephaly, semilobar holoprosencephaly, and tetralogy of Fallot on ultrasound at 25 gestational weeks. Cordocentesis using multiplex ligation-dependent probe amplification to detect aneuploidies of chromosomes X, Y, 13, 18, and 21 in uncultured cord blood revealed three copies of all targets on chromosome 13 consistent with the diagnosis of trisomy 13. The fetus in the second case presented bilateral choroid plexus cysts, congenital diaphragmatic hernia, and club foot on ultrasound at 18 gestational weeks. Amniocentesis using array-based comparative genomic hybridization (aCGH) in uncultured amniocytes revealed a gain in the DNA dosage of chromosome 18 consistent with the diagnosis of trisomy 18. The fetus in the third case presented aortic stenosis and nuchal edema on ultrasound at 22 gestational weeks. Amniocentesis using aCGH in uncultured amniocytes revealed a result of monosomy X and Turner syndrome. The fetus in the fourth case presented nuchal cystic hygroma and ventriculomegaly on ultrasound at 17 gestational weeks. Amniocentesis using aCGH in uncultured amniocytes revealed a gain in the DNA dosage of chromosome 21 consistent with the diagnosis of trisomy 21. The fetus in the fifth case presented holoprosencephaly, omphalocele, and hydronephrosis on ultrasound at 17 gestational weeks. Amniocentesis using aCGH in uncultured amniocytes revealed a gain in the DNA dosage of chromosome 13 consistent with the diagnosis of trisomy 13. Conclusions Prenatal diagnosis of major congenital malformations should alert one to the possibility of chromosomal abnormalities. Multiplex ligation-dependent probe amplification and aCGH have the advantage of rapid aneuploidy diagnosis of common aneuploidies in cases with major congenital malformations.

Summary Objective To present prenatal diagnosis and molecular cytogenetic characterization of de novo partial monosomy 1p (1p36.23→pter) and partial trisomy 20p (20p12.1→pter) associated with ventriculomegaly, ventricular septal defect and midface hypoplasia. Materials, Methods and Results A 31-year-old, primigravid woman was referred for amniocentesis at 20 gestational 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 terminated. 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 hybridization are useful for the prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial monosomy 1p (1p36.23→pter) and partial trisomy 20p (20p12.1→pter) 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.

Summary Objective To present prenatal diagnosis and molecular cytogenetic characterization of a small supernumerary marker chromosome (sSMC) derived from chromosome 8 by multiplex ligation-dependent probe amplification (MLPA), fluorescence in situ hybridization (FISH), spectral karyotyping (SKY) and array comparative genomic hybridization (aCGH). Case Report A 42-year-old woman, gravida 6, para 3, underwent amniocentesis at 19 gestational weeks because of advanced maternal age. Amniocentesis revealed a de novo ring-shaped sSMC in all 13 colonies of the amniocytes. The karyotype was 47,XY,+mar. The MLPA showed duplications of 8p11.21-specific probes. At 24 gestational weeks, level II ultrasound revealed a left multicystic kidney in the fetus. Other internal organs were unremarkable. Repeat amniocentesis revealed a karyotype of 47,XY,+mar[25]/46,XY[2]. The sSMC was characterized by SKY and FISH, which showed a chromosome 8 origin of the sSMC. Oligonucleotide-based aCGH demonstrated a 4.4-Mb duplication of 8p11.21q11.1 [arr cgh 8p11.21q11.1 (42,637,263-47,062,180)×3]. The karyotype was 47,XY,+r(8) (p11.21q11.1)[25]/46,XY[2]. Polymorphic DNA marker analysis revealed no uniparental disomy for chromosome 8. The woman elected to continue the pregnancy and at 34 gestational weeks, a 1,820 g male baby without craniofacial dysmorphism was delivered. At the age of 1 month, the infant was apparently normal except for left multicystic kidney disease and mild ventriculomegaly. Conclusion MLPA, SKY and aCGH are helpful in genetic counseling of prenatally detected sSMCs by providing the immediate information on the origin and the genetic contents of the sSMC.

SUMMARY Objective: To present the perinatal findings and molecular genetic analysis of two siblings with Ellis-van Creveld (EvC) syndrome. Materials, Methods and Results: A 33-year-old woman, gravida 3, para 1, was referred for genetic counseling at 18 gestational weeks because of recurrent fetal skeletal dysplasia. Two years previously, she had delivered a 1,316-g dead male baby at 28 gestational weeks with a karyotype of 46,XY, postaxial polydactyly of the hands, thoracic narrowness, endocardial cushion defects, transposition of the great arteries, shortening of the long bones, malposition of the toes, and hypoplastic nails. During this pregnancy, prenatal ultrasound at 18 gestational weeks revealed shortening of the long bones (equivalent to 15 weeks), postaxial polydactyly of both hands, thoracic narrowness, and endocardial cushion defects. The pregnancy was subsequently terminated, and a 236-g female fetus was delivered with a karyotype of 46,XX, postaxial polydactyly of the hands, thoracic dysplasia, endocardial cushion defects, shortening of the long bones, and malposition of the toes and hypoplastic nails. The phenotype of each of the two siblings was consistent with EVC syndrome. Molecular analysis of the EVC and EVC2 genes revealed heterozygous mutations in the EVC2 gene. A heterozygous deletion mutation of a 26-bp deletion of c.871-2_894del26 encompassing the junction between intron 7 and exon 8 of the EVC2 gene was found in the mother and two siblings, and a heterozygous nonsense mutation of c.1195C > T, p.R399X in exon 10 of the EVC2 gene was found in the father and two siblings. Conclusion: Prenatal sonographic identification of endocardial cushion defects in association with shortening of the long bones should alert clinicians to the possibility of EvC syndrome and prompt a careful search of hexadactyly of the hands. Molecular analysis of the EVC and EVC2 genes is helpful in genetic counseling in cases with prenatally detected postaxial polydactyly, thoracic narrowness, short limbs and endocardial cushion defects. [Taiwan J Obstet Gynecol 2010;49(4):481–486]

Small supernumerary marker chromosomes (sSMCs) are small supernumerary aberrant chromosomes that are generally equal in size or smaller than a chromosome 20, and cannot be identified or characterized by conventional cytogenetic banding techniques [1–3]. sSMCs can appear in 0.044% of newborn infants and in 0.075% of prenatal cases [1,3,4]. About 70% of sSMCs are caused by a de novo event [5], about 70% of sSMCs are originated from acrocentric chromosomes [1,6], and about 70% of de novo sSMCs are associated with no phenotypic effects [4]. Prenatal diagnosis of sSMCs gives rise to difficulties in genetic counseling, and identification of the nature of the aberrant chromosome requires molecular cytogenetic technologies [4,7–10]. We present our experience of the prenatal diagnosis and molecular cytogenetic characterization of an sSMC derived from chromosome 21 using fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA). A 36-year-old woman, gravida 2, para 1, underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed an sSMC, which was C-band positive and nucleolar organizing region-stain positive. The parental karyotypes were normal. The karyotype was 47,XX,+mar (Figure 1). The sSMC hybridized with a centromere 13/21-specific α-satellite DNA probe (D13Z1/D21Z1) (cep13/21) (Cytocell, Adderbury, Oxfordshire, UK) (Figure 2). MLPA was used to determine the origin of the sSMC using a SALSA MLPA P181 centromere kit (MRC-Holland, Amsterdam, the Netherlands) (Figure 3). The results of MLPA indicated a duplication of the 21q11.2 segment containing the STCH and SAMSN1 genes. FISH determination of the duplications of the STCH and SAMSN1 genes was performed using the bacterial artificial chromosome clone probes RP11-138O15 and RP11-392H8 at 21q11.2. FISH determination of 21q21.1 involvement utilized the 21q21.1-specific bacterial artificial chromosome clone probes RP11-89M24 and RP11-109H14. FISH revealed STCH and SAMSN1 gene duplications in the fetus with sSMC(21) (Figure 4). No RP11-89M24or PRENATAL DIAGNOSIS AND MOLECULAR CYTOGENETIC CHARACTERIZATION OF A SMALL SUPERNUMERARY MARKER CHROMOSOME DERIVED FROM CHROMOSOME 21

Summary Objective To present the prenatal diagnosis and molecular cytogenetic characterization of de novo partial trisomy 7p (7p15.3→pter) and partial monosomy 13q (13q33.3→qter) associated with Dandy-Walker malformation (DWM), abnormal skull development, microcephaly and multiple congenital anomalies. Materials, Methods and Results A 42-year-old woman, gravida 6, para 1, was referred for amniocentesis at 18 weeks of gestation because of her advanced maternal age. Amniocentesis revealed an aberrant derivative chromosome 13, or der(13). The parental karyotypes were normal. Spectral karyotyping showed that the der(13) was derived from a translocation of chromosomes 7 and 13. Fluorescence in situ hybridization using subtelomeric probes revealed three signals of 7pTEL and only one signal of 13qTEL, indicating a translocation between 7p and 13q in the der(13). Array-based comparative genomic hybridization demonstrated partial trisomy 7p (7p15.3-p22.3) and partial monosomy 13q (13q33.3-q34). The karyotype was 46,XY,der(13)t(7;13)(p15.3;q33.3). Polymorphic DNA marker analysis revealed the paternal origin of the aberrant chromosome. Level II ultrasound at 24 weeks of gestation revealed microcephaly, an irregular-shaped skull, DWM, nuchal edema and transposition of the great arteries. Conclusion Spectral karyotyping, fluorescence in situ hybridization and array-based comparative genomic hybridization are useful for prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial trisomy 7p (7p15.3→pter) and partial monosomy 13q (13q33.3→qter) can be associated with DWM, microcephaly, abnormal skull development, nuchal edema and cardiovascular defects on prenatal ultrasound.

A 33-year-old woman, gravida 2, para 1, was referred to hospital for prenatal imaging evaluation of the fetal brain and limbs at 27 weeks’ gestation. The woman and her husband were healthy and non-consanguineous. Two years previously, she delivered a female baby at 26 weeks’ gestation with Joubert syndrome (JBTS), DandyWalker malformation, ventriculomegaly, cerebellar vermian hypoplasia and polydactyly of the feet. JBTS was confirmed by magnetic resonance imaging (MRI). The infant’s karyotype was 46,XX. During this pregnancy, cerebellar hypoplasia was noted at 17 weeks’ gestation, and ventriculomegaly and polydactyly were noted at 18 weeks’ gestation. Level II ultrasound examination at 27 weeks’ gestation revealed a male fetus with a femur length and an abdominal circumference equivalent to 27 weeks, polyhydramnios with an amniotic fluid index of 24.07 cm. Macrocephaly was present with an increased biparietal distance of 7.9 cm, an increased head circumference of 28.82 cm, an increased lateral ventricle posterior horn width of 2.64 cm, an increased transcerebellar distance of 3.61 cm, an increased cisterna magna length of 2.10 cm, an increased head circumference to femur length ratio of 5.66 (all > 95 th centile). Ventriculomegaly, vermian hypoplasia, postaxial polydactyly of the left hand and preaxial polydactyly of the hallux of the left foot were also present. A tentative diagnosis of recurrent JBTS was made. Fetal MRI examination at 27 weeks’ gestation revealed the “molar tooth sign”, Dandy-Walker malformation, ventriculomegaly

Here, we present the case of a female infant, the firstchild of a 32-year-old woman and a 45-year-old man,who were healthy and non-consanguineous. The familyhistory was unremarkable. The infant was delivered at37 weeks’ gestation with a birth weight of 2,834g. Shehad midface hypoplasia, cleft palate, low-set ears, andbilateral syndactyly of the hands and feet (Figures 1–3).She had a 46,XX karyotype. DNA testing for Apert syn-drome revealed a heterozygous c.755 C >G, TCG >TGGtransversion leading to a Ser252Trp (S252W) mutationin the fibroblast growth factor receptor 2 (

124 A 40-year-old, gravida 2, para 1, woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Her husband was 43 years of age. Both parents were healthy, and there was no family history of congenital malformations. Amniocentesis revealed mosaicism for a supernumerary isochromosome consisting of two entire short arms of chromosome 12 or i(12)(p10). The karyotype was 47,XX,+i(12p)[16]/ 46,XX[9] derived from 25 colonies of amniocytes, with 64% (16/25) of the amniocytes being +i(12p). The parental karyotypes were normal. Prenatal ultrasound at 19+4 weeks of gestation revealed a normal volume of amniotic fluid, macrocephaly with a biparietal diameter of 5.01 cm (21.72 weeks), hypertelorism, an abdominal circumference of 15.27 cm (20.48 weeks), a femur length of 3 cm (19.26 weeks), and a flat face with a very small nose and protruding lips (Figures 1 and 2). A diagnosis of Pallister-Killian syndrome (PKS) was made. The pregnancy was subsequently terminated, and a 399-g fetus, with macrocephaly, a large coarse face, a long philtrum, retrognathia, a Cupid’s bow mouth with thin lips, a flattened nose with a low nasal bridge, anteverted nostrils, upslanting palpebral fissures and low-set ears, was delivered (Figures 3 and 4). Postnatal ABNORMALLY FLAT FACIAL PROFILE ON TWOAND THREE-DIMENSIONAL ULTRASOUND AND ARRAY COMPARATIVE GENOMIC HYBRIDIZATION FOR THE DIAGNOSIS OF PALLISTER-KILLIAN SYNDROME

Apert syndrome (OMIM 101200) is a congenital disorder characterized by acrocephaly, craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet [1]. The reported prevalence of Apert syndrome at birth has ranged from 1 in 160,000 [2] to 1 in 64,500 births [3]. The majority of cases of Apert syndrome arise sporadically as the result of a de novo mutation in the sperm, associated with a paternal age effect; only a few cases are inherited from affected parents in an autosomal dominant pattern [4,5]. Apert syndrome is caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene (OMIM 176943) located at 10q26. Two mutations of Ser252Trp (S252W) and Pro253Arg (P253R) account for over 98% of cases of Apert syndrome [6,7]. Although cases of prenatally diagnosed Apert syndrome have been reported, many cases remain undiagnosed until delivery, or are diagnosed in late gestation when polyhydramnios and craniofacial deformities become evident. Syndromes involving craniosynostosis may be associated with abnormalities of the digits. Crouzon syndrome is associated with normal hands and feet. Jackson-Weiss syndrome is associated with normal hands, medially deviated broad great toes and cutaneous syndactyly of the second and the third toes. Apert syndrome is associated with symmetric syndactyly of the hands and feet. Pfeiffer syndrome is associated with broad abducted thumbs, broad great toes, and brachymesophalangy and partial syndactyly of the hands and feet. In cases with mild ventriculomegaly, a thorough examination of the hands in the second trimester may lead to a specific diagnosis of Apert syndrome, as in the current case. A 30-year-old, gravida 1, woman was referred to Mackay Memorial Hospital for amniocentesis at 21 weeks of gestation because of mild ventriculomegaly and clenched hands detected on prenatal ultrasound. Her husband was 32 years of age. She and her husband were both healthy and unrelated, and there was no family history of congenital malformations. Prenatal ultrasound at 18 weeks of gestation revealed a male fetus with fetal biometry equivalent to 18 weeks, a normal skull shape, mild ventriculomegaly, and clenched hands (Figures 1 and 2). Trisomy 18 was highly suspected. Amniocentesis was performed at 21 weeks of gestation. Conventional cytogenetic analysis revealed a 46,XY karyotype. Oligonucleotide-based array comparative genomic hybridization using uncultured amniocytes demonstrated no deletions or duplications. SECOND-TRIMESTER MOLECULAR PRENATAL DIAGNOSIS OF SPORADIC APERT SYNDROME FOLLOWING SONOGRAPHIC FINDINGS OF MILD VENTRICULOMEGALY AND CLENCHED HANDS MIMICKING TRISOMY 18

Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan Department of Biotechnology, Asia University, Taichung, Taiwan d School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan e Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan Department of Medical Research, Center for Medical Genetics, Changhua Christian Hospital, Changhua, Taiwan Department of Genomic Medicine, Center for Medical Genetics, Changhua Christian Hospital, Changhua, Taiwan Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan Department of Bioengineering, Tatung University, Taipei, Taiwan

A 34-year-old primigravid woman presented at 29 weeks of gestation for evaluation of fetal ascites and an intraabdominal echogenic cystic mass (Figure 1) in one twin of a twin pregnancy. The woman had not undergone any assisted reproductive technology. Aspiration of the ascites and the cystic mass revealed multiple epithelial cells and cytogenetic analysis demonstrated a 46,XX karyotype in the affected co-twin. Ultrasound following aspiration showed a distended vagina connecting to the uterine cavity and compressing the urinary bladder (Figure 2). Ultrafast magnetic resonance imaging (MRI) of the affected co-twin revealed massive ascites, a compressed urinary bladder, a distended vagina, a dilated uterus, and a dilated distal colon, consistent with a diagnosis of persistent cloaca with hydrometrocolpos and ascites (Figure 3). The unaffected co-twin (1,306 g) and affected co-twin (2,108 g) were delivered uneventfully by cesarean section at 31 weeks of gestation. Both twins had a karyotype of 46,XX. A zygosity test determined dizygosity. The affected co-twin had meconium peritonitis, urinary ascites, and a persistent cloaca. The urinary, genital, and intestinal tracts converged into a cloacal canal with a single opening at the perineum. The ascites was caused by drainage of the urine into the abdominal cavity via the vagina, the uterus and the Fallopian tubes, as well as by irritation of the peritoneum by urine and meconium. Hydrometrocolpos was caused by fluid accumulation resulting from distal vaginal obstruction through backward pressure from the cloacal canal. The hydrometrocolpos compressed the bladder causing partial bladder outlet obstruction. Dilation of the distal colon was caused by direct compression from the hydrometrocolpos and narrowing of the rectal communication. The affected infant was doing well at 1 year and 6 months of age, after corrective reconstructive surgery. A persistent cloaca results from failure or maldevelopment of the urorectal septum that divides the urogenital sinus and anorectal canal [1]. Hydrometrocolpos