Shih-Ting Lai

Prenatal diagnosis of low-level mosaicism for trisomy 13 at amniocentesis associated with a favorable outcome

OBJECTIVE We present prenatal diagnosis of low-level mosaicism for trisomy 13 at amniocentesis associated with a favorable outcome. CASE REPORT A 35-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+13[5]/46,XY[20]. Oligonucleotide array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed arr [GRCh37] (13)×3 [0.10], (X,Y)×1 compatible with trisomy 13 mosaicism. Prenatal ultrasound was unremarkable. Repeat amniocentesis was performed at 21 weeks of gestation. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes revealed a mosaic trisomy 13 level of 10% (10/100 cells). aCGH analysis on uncultured amniocytes revealed a result of arr 13q12.11q34 (20,407,323-115,092,619)×2.1 with a log2 ratio of 0.06 compatible with a 10% level of mosaicism. Polymorphic DNA marker analysis excluded uniparental disomy 13. The parental karyotypes were normal. Conventional cytogenetic analysis using cultured amniocytes at repeat amniocentesis revealed a karyotype of 46,XY in 23/23 colonies. The pregnancy was carried to 37 weeks of gestation, and a 3600-g phenotypically normal male baby was delivered. When examined at 8 months of age, the infant was doing well and was normal in psychomotor and growth development. The peripheral blood had a karyotype of 46,XY, and interphase FISH analysis on uncultured urinary cells revealed a mosaic trisomy 13 level of 4.4% (2/45 cells). CONCLUSION Low-level true mosaicism for trisomy 13 at amniocentesis without ultrasound abnormalities can be associated with a favorable fetal outcome.

Fetoplacental cytogenetic discrepancy in a pregnancy with fetal mosaic tetrasomy 12p and Pallister–Killian syndrome detected by amniocentesis

OBJECTIVE We present fetoplacental cytogenetic discrepancy in a pregnancy with prenatally detected mosaic tetrasomy 12p by amniocentesis. CASE REPORT A 34-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Cytogenetic analysis of cultured amniocytes revealed a karyotype of 47,XX,+i(12)(p10)[7]/46,XX[16]. Array comparative genomic hybridization (aCGH) analysis of the DNA extracted from cultured amniocytes revealed arr (12p)×3, (X)×2. Prenatal ultrasound findings were unremarkable. The pregnancy was subsequently terminated, and a fetus was delivered with facial dysmorphism consistent with the clinical features of Pallister-Killian syndrome (PKS). Postnatal cytogenetic analysis of the cultured cells from umbilical cord, skin, cord blood and placenta revealed 47,XX,+i(12)(p10)[6]/46,XX[34] in umbilical cord, 47,XX,+i(12)(p10)[11]/46,XX[29] in skin, 47,XX,+i(12)(p10)[3]/46,XX[47] in cord blood and 46,XX[40] in placenta. The mosaic tetrasomy 12p levels of the umbilical cord, skin, cord blood and placenta were 15%, 27.5%, 6% and 0%, respectively. aCGH analysis of the DNA extracted from uncultured cord blood and placenta revealed arr 12p13.33p11.1 (230,421-34,756,209)×3.0 in cord blood but no genomic imbalance in placenta. Polymorphic DNA marker analysis showed a maternal origin of the supernumerary isochromosome 12p in cord blood but biparental inheritance with equal fluorescent activity in placenta. CONCLUSION Pregnancy with fetal PKS and mosaic tetrasomy 12p may present fetoplacental cytogenetic discrepancy. Therefore, genetic analysis on placenta alone may fail to detect fetal mosaic tetrasomy 12p associated with PKS.

Late-onset fetal bilateral pleural effusions associated with Down syndrome

OBJECTIVE We present two cases of late-onset bilateral fetal pleural effusions associated with fetal Down syndrome. CASE REPORTS Case 1. A 33-year-old Vietnamese woman had undergone regular sonographic examinations since 23 weeks of gestation and no abnormality had been noted. However, bilateral moderate pleural effusions were found at 33 weeks of gestation, and massive pleural effusion, ascites and polyhydramnios developed at 34 weeks of gestation. Aspiration of the pleural effusion was subsequently performed. Clinical laboratory surveys of the aspiration fluid excluded toxoplasmosis and cytomegalovirus infection. Cytogenetic analysis of cultured lymphocytes derived from pleural effusion revealed a karyotype of 47,XX,+21. The parents elected to continue the pregnancy. Intrauterine fetal demise occurred at 37 weeks of gestation, and a macerated female baby was delivered. Postnatal cytogenetic analysis of the umbilical cord confirmed the prenatal diagnosis. Case 2. A 41-year-old Pakistani woman had undergone regular sonographic examinations and no abnormality had been noted. However, isolated bilateral mild pleural effusions were noted at 27 weeks of gestation. Amniocentesis revealed a karyotype of 47,XY,+21 and simultaneous array comparative genomic hybridization analysis of uncultured amniocytes confirmed the diagnosis of Down syndrome. The pregnancy was subsequently terminated. CONCLUSION Fetuses with Down syndrome may present late-onset bilateral pleural effusions. Prenatal diagnosis of late-onset bilateral pleural effusions should raise the possibility of fetal Down syndrome and cytogenetic investigation is warranted.

Prenatal diagnosis of hydrancephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II and a review of prenatal diagnosis of brain anomalies associated with thanatophoric dysplasia

OBJECTIVE We present prenatal diagnosis of hydrancephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II (TD2) and a review of prenatal diagnosis of brain anomalies associated with TD. CASE REPORT A 33-year-old woman was referred for genetic counseling at 25 weeks of gestation because of fetal ultrasound abnormalities. Prenatal ultrasound at 14 weeks of gestation revealed an increased nuchal translucency (NT) and hydrocephalus. Level II ultrasound examination at 25 weeks of gestation revealed hydrancephaly, macrocephaly, a cloverleaf skull, frontal bossing, enlarged cerebellum and cisterna magna, a narrow chest, small ribs, short straight limbs. Amniocentesis revealed a karyotype of 46,XX. FGFR3 mutation analysis using the DNA extracted from uncultured amniocytes revealed a genotype of WT/c.1948A>G (p.Lys650Glu). The result was consistent with a K650E mutation in FGFR3 and TD2. The pregnancy was subsequently terminated. CONCLUSION Fetuses with TD2 may present increased NT, early onset hydrocephalus, enlarged cerebellum and cisterna magna, and hydrancephaly on prenatal ultrasound.

Prenatal diagnosis of a familial 1q21.1-q21.2 microdeletion in a fetus with polydactyly of left foot on prenatal ultrasound

OBJECTIVE We present prenatal diagnosis of a familial 1q21.1-q21.2 microdeletion in a fetus with polydactyly of left foot on prenatal ultrasound. CASE REPORT A 30-year-old, gravida 2, para 1, woman underwent amniocentesis at 22 weeks of gestation because of fetal polydactyly of left foot and echogenic heart foci on prenatal ultrasound. She and her husband and the 2-year-old son were healthy, and there was no family history of mental disorders, skeletal abnormalities and congenital malformations. Amniocentesis revealed a karyotype of 46,XX. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed a 1.317-Mb 1q21.1-q21.2 microdeletion encompassing PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8 and GPR89B. aCGH analysis of the family members revealed that the phenotypically normal father and elder son carried the same 1q21.1-q21.2 microdeletion. The mother did not have such a deletion. The parents elected to continue the pregnancy, and a 3416-g female baby was delivered at 40 weeks of gestation with neither facial dysmorphism nor gross abnormalities except postaxial polydactyly of the left foot. CONCLUSION Fetuses with a 1q21.1-q21.2 microdeletion may present polydactyly on prenatal ultrasound, and aCGH is helpful for prenatal diagnosis under such a circumstance.

Pfeiffer syndrome with FGFR2 C342R mutation presenting extreme proptosis, craniosynostosis, hearing loss, ventriculomegaly, broad great toes and thumbs, maxillary hypoplasia, and laryngomalacia

a Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan b Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan c 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 f Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan g Department of Pediatrics, MacKay Memorial Hospital, Taipei, Taiwan h Department of Medicine, MacKay Medical College, New Taipei City, Taiwan i Department of Early Childhood Care, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan j Department of Radiology, Hsinchu MacKay Memorial Hospital, Hsinchu, Taiwan k MacKay Medicine, Nursing and Management College, Taipei, Taiwan l Department of Bioengineering, Tatung University, Taipei, Taiwan

Molecular genetic characterization of a prenatally detected 1.484-Mb Xq13.3-q21.1 duplication encompassing ATRX and a literature review of syndromic intellectual disability and congenital abnormalities in males with a duplication at Xq13.3-q21.1

OBJECTIVE We present prenatal diagnosis of dup(X)(q13.3q21.1) in a male fetus and molecular genetic analysis in three generations and a literature review of syndromic intellectual disability and congenital abnormalities in males with a duplication at Xq13.3-q21.1. CASE REPORT A 35-year-old, primigravid woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. The woman and her mother were phenotypically normal, and there was no intellectual disability in the maternal family. Cytogenetic analysis of cultured amniocytes revealed a karyotype of 46,XY. Simultaneous array comparative genomic hybridization (aCGH) analysis on uncultured amniotic fluid incidentally detected a 1.484-Mb microduplication of Xq13.3-q21.1 encompassing ATRX. Subsequent aCGH analysis on fetal blood, maternal blood and grandmothers blood revealed the same 1.484-Mb dup(X)(q13.3q21.1). Prenatal ultrasound findings were unremarkable with no growth restriction and no short stature. After genetic counseling of syndromic intellectual disability in males with ATRX duplication, the woman elected to terminate the pregnancy. The fetus postnatally manifested hypoplastic male external genitalia, clinodactyly, hypertelorism, midface hypoplasia, epicanthic folds and micrognathia. CONCLUSION Simultaneous aCGH analysis on uncultured amniotic fluid in addition to conventional cytogenetics at amniocentesis is practical and may help in detecting unknown familial inheritance of subtle X chromosome aberrations.

Prenatal diagnosis of an 8q22.2-q23.3 deletion associated with bilateral cleft lip and palate and intrauterine growth restriction on fetal ultrasound

OBJECTIVE We present prenatal diagnosis of an interstitial 8q22.2-q23.3 deletion associated with bilateral cleft lip and palate and intrauterine growth restriction (IUGR) on fetal ultrasound. CASE REPORT A 29-year-old, primigravid woman underwent elective amniocentesis at 17 weeks of gestation because of anxiety. Amniocentesis revealed a karyotype of 46, XX. However, level II ultrasound at 21 weeks of gestation revealed a fetus with IUGR and bilateral cleft lip and palate. Repeat amniocentesis was performed at 21 weeks of gestation, and array comparative genomic hybridization using uncultured amniocytes revealed a 13.5-Mb interstitial deletion of 8q22.2-q23.3 encompassing 37 Online Mendelian Inheritance of in Man (OMIM) genes including SPAG1, GRHL2, NCALD, RRM2B and ZFPM2. Polymorphic DNA marker analysis determined a paternal origin of the deletion. The pregnancy was subsequently terminated, and a malformed fetus was delivered with a depressed nose and bilateral cleft lip and palate. CONCLUSION Prenatal diagnosis of facial cleft with IUGR should raise a suspicion of subtle chromosome deletions.

Molecular genetic characterization of a prenatally detected de novo interstitial deletion of chromosome 20p (20p12-p13) encompassing JAG1 and a literature review of prenatal diagnosis of Alagille syndrome

OBJECTIVE We present prenatal diagnosis and molecular genetic characterization of a de novo interstitial deletion of chromosome 20p (20p12-p13) and a literature review of prenatal diagnosis of Alagille syndrome (ALGS). CASE REPORT A 33-year-old woman underwent amniocentesis at 17 weeks of gestation because of an abnormal result of combined first-trimester screening. Her husband was 35 years old, and there was no family history of congenital malformations. Amniocentesis revealed a karyotype of 46,XY,del(20)(p12p13), and array comparative genomic hybridization analysis on uncultured amniocytes revealed a 3.749-Mb deletion at 20p13-p12.3 and a 1.84-Mb deletion at 20p12.2 encompassing the gene of JAG1. The parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. The fetus postnatally manifested characteristic facial features of ALGS. Postnatal molecular cytogenetic analysis of fetal tissues confirmed the prenatal diagnosis. Polymorphic DNA marker analysis revealed a paternal origin of the deletion. CONCLUSION A de novo interstitial 20p deletion can be caused by a paternal effect. Pregnancy with a fetus affected with ALGS may be associated with an abnormal result of combined first-trimester screening and manifest no detectable ultrasound abnormalities.

Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 11

OBJECTIVE We present prenatal diagnosis and molecular cytogenetic characterization of a small supernumerary marker chromosome (sSMC) derived from chromosome 11. CASE REPORT A 37-year-old, gravida 3, para 2, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+mar[18]/46,XX[4]. The parental karyotypes were normal. Level II ultrasound findings were unremarkable. Array comparative genomic hybridization (aCGH) on the DNA extracted from cultured amniocytes revealed no genomic imbalance. The sSMC was characterized by spectral karyotyping (SKY) using 24-color SKY probes and fluorescence in situ hybridization (FISH) using a whole chromosome paint (wcp) probe and a CEP11 (D11Z1) probe. The result was 47,XX,+mar.ish(11)(SKY+, wcp11+, D11Z1+)[16]/46,XX[4], indicating that the sSMC was derived from chromosome 11. A healthy female baby was delivered at 37 weeks of gestation with no phenotypic abnormalities. The cord blood had a karyotype of 47,XX,+mar[32]/46,XX[8]. Polymorphic DNA marker analysis of the blood excluded uniparental disomy 11. The female infant was normal in growth and psychomotor development during follow-ups at two months of age. CONCLUSION aCGH, SKY and FISH are useful in prenatal diagnosis of an sSMC derived from the centromeric region of a non-acrocentric chromosome.