Congenital radioulnar synostosis: is prenatal diagnosis possible? - A case report.

OBJECTIVES: The main objectives of this case report are to discuss prenatal ultrasound findings of congenital radioulnar synostosis and to review the literature. CASE REPORT: A patient was diagnosed with congenital radioulnar synostosis at eight months old when parents noticed limited motions in the child's left forearm. The parent denied any traumatic or family history of bony malformations. Physical examination by a pediatric orthopedics specialist and digital radiography revealed proximal radioulnar synostosis. The case report includes perinatal course, comparison between the postnatal radiography and fetal ultrasound images. CONCLUSION: Congenital radioulnar synostosis is often associated with sex chromosome abnormalities and congenital musculoskeletal disorders or syndromes affecting limbs. Isolated congenital radioulnar synostosis is hardly diagnosed before birth, in some cases even have been neglected postnatally. Knowing the developmental milestones of the forearm and specified high-risk groups might help develop a targeted screening strategy to increase the possibility of early detection and intervention.

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.

Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 21q11.2-q21.1 and a literature review.

OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome (sSMC) derived from chromosome 21q11.2-q21.1, and we review the literature of an sSMC(21) with a duplication of 21q11.2-q21.1. CASE REPORT: A 40-year-old 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. Prenatal ultrasound findings were unremarkable. aCGH analysis of cultured amniocytes revealed a 2.855-Mb duplication of 21q11.2-q21.1 encompassing the genes of LIPI, ABCC13 and NRIP1. Metaphase fluorescence in situ hybridization analysis on cultured amniocytes revealed a result of 47,XX,+mar .ish der(13/21) (D13/21Z1+) [10]. Spectral karyotyping analysis determined the origin of chromosome 21 in the sSMC. A female fetus was delivered with no phenotypic features of Down syndrome and no structural abnormalities. We discuss the genotype-phenotype correlation of LIPI, ABCC13 and NRIP1, and review the literature of an sSMC(21) associated with dup(21)(q11.2q21.1). CONCLUSION: aCGH is useful for identification of the nature and genetic component of a prenatally detected sSMC.

Molecular genetic characterization of a prenatally detected de novo interstitial deletion of chromosome 2q (2q31.1-q32.1) encompassing HOXD13, ZNF385B and ZNF804A associated with syndactyly and increased first-trimester nuchal translucency.

OBJECTIVE: We present prenatal diagnosis and molecular genetic characterization of a de novo interstitial deletion of 2q (2q31.1-q32.1) and discuss the genotype-phenotype correlation. CASE REPORT: A 34-year-old, primigravid woman was referred to the hospital at 20 weeks of gestation for genetic counseling because of a prenatally detected de novo interstitial deletion of chromosome 2q (2q31.1-q32.1). She underwent amniocentesis at 17 weeks of gestation because of advanced maternal age and an increased first-trimester nuchal translucency (NT) thickness of 3.6 mm. Amniocentesis revealed a karyotype of 46,XY. However, array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniotic fluid and amniocytes revealed a 13.29-Mb deletion at chromosome 2q31.3-q32.1. The parents did not have such a deletion. Prenatal ultrasound findings were unremarkable. After counseling of the genotype-phenotype correlation of such a chromosome aberration with congenital malformations, the parents elected to terminate the pregnancy. The fetus postnataly manifested hypertelorism and syndactyly of the second and third toes of bilateral feet. Cytogenetic analysis of the umbilical cord revealed a karyotype of 46,XY,del(2)(q31q32). aCGH analysis on the DNA extracted from the cord blood confirmed a 13.35-Mb deletion of 2q31.1-q32.1 encompassing HOXD13, ZNF385B, ITGA4, CERKL, PDE1A, FRZB and ZNF804A. Polymorphic DNA marker analysis revealed a paternal origin of the deletion. CONCLUSION: Fetuses with an interstitial deletion of 2q31.1-q32.1 may be associated with increased first-trimester NT. Haploinsufficiency of HOXD13 is associated with syndactyly. Genomic microarray is useful in detecting subtle chromosomal abnormalities in fetuses with increased NT and normal karyotype.

Prenatal diagnosis and molecular cytogenetic characterization of concomitant familial small supernumerary marker chromosome derived from chromosome 4q (4q11.1-q13.2) and 5q13.2 microdeletion with no apparent phenotypic abnormality.

OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of concomitant familial small supernumerary marker chromosome 4 [sSMC(4)] derived from 4q11.1-q12 and q13.2, and 5q13.2 microdeletion with no apparent phenotypic abnormality. MATERIALS AND METHODS: A 32-year-old woman underwent amniocentesis at 21 weeks of gestation because of absent nasal bone on fetal ultrasound. Amniocentesis revealed a karyotype of 47,XX,+mar[13]/46,XX[3]. Array comparative genomic hybridization analysis on the cultured amniocytes revealed a 2.752-Mb duplication at 4q11-q12, a 1.949-Mb duplication at 4q13.2, and a 1.65-Mb deletion at 5q13.2. The woman underwent repeat amniocentesis at 24 weeks of gestation for molecular cytogenetic characterization. The phenotypically normal parents and their elder son underwent genetic analysis. RESULTS: At repeat amniocentesis, interphase fluorescence in situ hybridization analysis on uncultured amniocytes revealed 79.25% (84/106) mosaicism for the sSMC(4), and metaphase fluorescence in situ hybridization analysis on cultured amniocytes revealed that all 20 cells examined (100%) had the sSMC(4). Polymorphic DNA marker analysis on uncultured amniocytes excluded uniparental disomy 4. The father had a karyotype of 47,XY,+mar[2]/46,XY[38], and interphase fluorescence in situ hybridization revealed 2.91% (3/103) mosaicism for the sSMC(4) in his peripheral blood. The mother carried the 5q13.2 microdeletion. The elder son had a karyotype of 47,XY,+mar[27]/ 46,XY[13] with duplications of 4q11-q12 and 4q13.2. A 3105 g female baby was delivered at term with no apparent phenotypic abnormality. CONCLUSION: Prenatal diagnosis of concomitant sSMC and microdeletion should raise a suspicion of familial inheritance.

Detection of mosaic 15q11.1-q11.2 deletion encompassing NBEAP1 and POTEB in a fetus with diffuse lymphangiomatosis.

OBJECTIVE: We present cytogenetic and molecular cytogenetic diagnoses of mosaic deletion of chromosome 15q11.1-q11.2 in a fetus with diffuse lymphangiomatosis. CASE REPORT: A 33-year-old woman underwent amniocentesis at 22 weeks of gestation because of fetal diffuse lymphangiomatosis involving left-side chest, abdominal cavity, thigh and vulva, and intrauterine growth restriction. Amniocentesis revealed a karyotype of 46,XX,del(15) (q11.1q11.2)[9]/46,XX[26]. The mother had a karyotype of 46,XX. The father had a karyotype of 46,XY. The parents elected to terminate the pregnancy. A 610-g female fetus was delivered at 23 weeks of gestation with large cystic lymphangioma over the left abdomen, thigh, and vulva. The umbilical cord had a karyotype of 46,XX,del(15)(q11.1q11.2)[24]/ 46,XX[16]. The placental tissue had a karyotype of 46,XX,del(15)(q11.1q11.2)[23]/ 46,XX[17]. Array comparative genomic hybridization analysis of the umbilical cord and placenta revealed a 2.42-Mb deletion of 15q11.1-q11.2 encompassing the genes of NBEAP1 and POTEB. CONCLUSION: Deletion of 15q11.1-q11.2 encompassing NBEAP1 and POTEB may be associated with diffuse lymphangiomatosis.

Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 2.

OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome (sSMC) derived from chromosome 2. CASE REPORT: A 42-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+mar[10]/46,XY[12]. The parental karyotypes were normal. Array comparative genomic hybridization analysis of the DNA extracted from cultured amniocytes revealed no genomic imbalance. Spectral karyotyping analysis failed to identify the sSMC. Metaphase fluorescence in situ hybridization analysis using the satellite probes CEP1/5/19, CEP2, CEP3, CEP4, CEP6, CEP7, CEP8, CEP9, CEP10, CEP12, CEP13/21, CEP14/22, CEP15, CEP16, and CEP20 revealed a result of 47,XY,+mar .ish der(2)(D2Z+)[10]. The sSMC was derived from the α satellite of chromosome 2. Polymorphic DNA marker analysis using the markers specific for chromosome 2 on the DNAs extracted from cultured amniocytes and parental bloods excluded uniparental disomy 2. At 39 weeks of gestation, a healthy 3394-g male baby was delivered with no phenotypic abnormality. The cord blood had a karyotype of 47,XY,+mar[21]/46,XY[19]. CONCLUSION: Array comparative genomic hybridization and spectral karyotyping may fail to detect an sSMC derived from α satellite, which needs satellite probes for confirmation.

Prenatal diagnosis and molecular cytogenetic characterization of low-level mosaic trisomy 12 at amniocentesis associated with a favorable pregnancy outcome.

OBJECTIVE: We present prenatal diagnosis of low-level mosaic trisomy 12. CASE REPORT: A 40-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age, which revealed a karyotype of 47,XX,+12[5]/46,XX[24] consistent with 17.2% (5/29) mosaicism for trisomy 12. Repeat amniocentesis performed at 21 weeks of gestation revealed a karyotype of 47,XX,+12[4]/46,XX[6] consistent with 40% (4/10) mosaicism for trisomy 12. Interphase fluorescence in situ hybridization (FISH) on 112 uncultured amniocytes detected 23 cells with trisomy 12 consistent with 20.5% (23/112) mosaicism for trisomy 12. Polymorphic DNA marker analysis excluded uniparental disomy 12. Array comparative genomic hybridization (aCGH) on uncultured amniocytes revealed a result of arr 12p13.33q24.33 (230,451-133,773,499) × 2.2, 17p12 (14,191,925-15,442,037) × 1.0 consistent with 10-20% mosaic trisomy 12. The father carried the 17p12 microdeletion. The fetal ultrasound findings were unremarkable. A 3958-g female fetus was delivered at 37 weeks of gestation with no phenotypic abnormality. The cord blood had a karyotype of 46,XX. Postnatal interphase FISH on urinary cells revealed 7.14% (7/98) mosaicism for trisomy 12. CONCLUSION: Low-level mosaic trisomy 12 at amniocentesis can be associated with a favorable pregnancy outcome. Interphase FISH and aCGH on uncultured amniocytes are useful for confirmation of low-level mosaic trisomy 12 at amniocentesis.

Molecular cytogenetic characterization of Jacobsen syndrome (11q23.3-q25 deletion) in a fetus associated with double outlet right ventricle, hypoplastic left heart syndrome and ductus venosus agenesis on prenatal ultrasound.

OBJECTIVE: We present molecular cytogenetic characterization of Jacobsen syndrome (11q23.3-q25 deletion) in a fetus associated with double outlet right ventricle (DORV), hypoplastic left heart syndrome (HLHS), and ductus venosus (DV) agenesis on prenatal ultrasound. CASE REPORT: A 26-year-old woman underwent prenatal ultrasound examination at 22 weeks of gestation, which revealed intrauterine growth restriction, short femurs, DORV, HLHS, DV agenesis, single umbilical artery, and curly fourth toe of the left foot. The parents elected to terminate the pregnancy, and a 500-g female fetus was delivered at 23 weeks of gestation with facial dysmorphism, bilateral camptodactyly, and hammertoes. The parental karyotypes were normal. Cytogenetic analysis of the cord blood and umbilical cord revealed a karyotype of 46,XX,del(11)(q23). Array comparative genomic hybridization analysis of the DNA extracted from the umbilical cord revealed a 14.38-Mb deletion of 11q23.3-q25 encompassing BSX, ETS1, FLI1, and ARHGAP32. Metaphase fluorescence in situ hybridization analysis using the probes RP11-209L12 (11q25) and RP11-25M7 (11q11) showed a distal 11q deletion in the aberrant chromosome 11 in 17/17 cells examined. CONCLUSION: Prenatal diagnosis of DORV, HLHS, DV agenesis associated with intrauterine growth restriction and short limbs should include a differential diagnosis of Jacobsen syndrome.

Perinatal imaging findings and molecular genetic analysis of thanatophoric dysplasia type 1 in a fetus with a c.2419T>G (p.Ter807Gly) (X807G) mutation in FGFR3.

OBJECTIVE: We present perinatal imaging findings and molecular genetic analysis of thanatophoric dysplasia type I (TD1) in a fetus. CASE REPORT: A 28-year-old woman was referred for genetic counseling at 22 weeks of gestation because of abnormal prenatal ultrasound findings. Level II ultrasound examination revealed a narrow chest, shortened and curved long limbs, protrusion of the abdomen, and macrocephaly. A tentative diagnosis of TD1 was made. After genetic counseling, the pregnancy was terminated and a malformed fetus was delivered. Postnatal radiography findings were consistent with the diagnosis of TD1, with additional findings of short ribs, platyspondyly, and horizontal acetabular roofs. Molecular genetic analysis using umbilical cord tissue revealed a heterozygous mutation of c.2419T>G (p.Ter807Gly) (X807G) in the fibroblast growth factor receptor 3 gene (FGFR3). CONCLUSION: A second-trimester fetus with a heterozygous c.2419T>G mutation in FGFR3 may present characteristic ultrasound and X-ray findings of TD1.

Familial transmission of recurrent 15q11.2 (BP1-BP2) microdeletion encompassing NIPA1, NIPA2, CYFIP1, and TUBGCP5 associated with phenotypic variability in developmental, speech, and motor delay.

OBJECTIVE: We present recurrent 15q11.2 (BP1-BP2) microdeletion encompassing NIPA1, NIPA2, CYFIP1, and TUBGCP5 in a family with phenotypic variability in developmental, speech, and motor delay. CASE REPORT: A 32-year-old woman underwent amniocentesis at 17 weeks of gestation because of an abnormal maternal serum screening result of Down syndrome risk of 1/226. Her husband was 31 years old. She and her husband were phenotypically normal, and there was no family history of mental disorders and congenital malformations. Amniocentesis revealed a karyotype of 46,XX. Prenatal ultrasound findings were unremarkable. A 2492-g female baby was delivered at 37 weeks of gestation uneventfully. During the subsequent pregnancy, the same woman at the age of 35 years underwent amniocentesis at 18 weeks of gestation because of advanced maternal age, which revealed a karyotype of 46,XY. Prenatal ultrasound findings were unremarkable. A 2780-g male baby was delivered at 37 weeks of gestation uneventfully. About 3 years after the birth of this boy, array comparative genomic hybridization of the family revealed 15q11.2 microdeletion encompassing NIPA1, NIPA2, CYFIP1, and TUBGCP5 in the two siblings, who displayed developmental, speech, and motor delay, and in their phenotypically normal father. CONCLUSION: Recurrent phenotypic abnormality in the family with normal karyotype at amniocentesis should include a differential diagnosis of familial pathogenic copy-number variations.

Recurrent 2q13 microduplication encompassing MALL, NPHP1, RGPD6, and BUB1 associated with autism spectrum disorder, intellectual disability, and liver disorder.

OBJECTIVE: We present recurrent 2q13 microduplication in a family with autism spectrum disorder (ASD), intellectual disability, and liver disorder. CASE REPORT: A 45-year-old woman and her 52-year-old husband were referred for genetic counseling because of mental and liver disorders in their two sons and their planning for prenatal diagnosis of familial disorders in the future pregnancy. She and her husband were normal and healthy, but their 21-year-old elder son had suffered from ASD, severe intellectual disability, poor motor function, liver cirrhosis, and esophageal varices, and their 19-year-old younger son had suffered from ASD, mild intellectual disability, poor balance and coordination, hepatosplenomegaly, fatty liver, and mild liver cirrhosis. The karyotypes of the parents and sons were normal. Array comparative genomic hybridization of the family revealed a 686.5-kb 2q13 microduplication encompassing MALL, NPHP1, RGPD6, and BUB1 in the elder brother, a 658.9-kb 2q13 microduplication encompassing MALL, NPHP1, RGPD6, and BUB1 in the younger brother, and an 83.83-kb 2q13 microduplication encompassing NPHP1 in the asymptomatic father. CONCLUSION: Recurrent phenotypic abnormality in the family with normal karyotype should include a differential diagnosis of pathogenic copy-number variations.

Prenatal Ultrasound Evaluation and Outcome of Pregnancy with Fetal Cystic Hygromas and Lymphangiomas.

Cystic hygroma is a type of lymphangioma, which is a vascular anomaly associated with lymphatic malformations and formed by fluid accumulation mainly located at the cervi-cofacial and axillary regions. Cystic hygroma is mostly located in the neck (75%), followed by axilla (20%), retroperitoneum and intra-abdominal organs (2%), limbs and bones (2%), and mediastinum (1%). It is often associated with chromosome aneuploidies, hydrops fetalis, and even intrauterine fetal demise. The prognostic factors of the fetal cystic hygroma or lymphan-gioma are chromosome abnormalities, hydrops fetalis, septations, or thickness of the cystic hygroma and are associated with other major malformations. Prenatal managements including ultrasound serial follow-up, magnetic resonance imaging, or even intrauterine injection of sclerosing agents are suggested. For fetus with the risk of airway obstruction at delivery, ex utero intrapartum treatment is also indicated. Detailed prenatal counseling is necessary for better neonatal outcome.

Molecular cytogenetic characterization of Xp22.32→pter deletion and Xq26.3→qter duplication in a male fetus associated with 46,Y,rec(X)dup(Xq) inv(X)(p22.3q26.3), a hypoplastic left heart, short stature, and maternal X chromosome pericentric inversion.

OBJECTIVE: We present molecular cytogenetic characterization of an Xp22.32→pter deletion and an Xq26.3→qter duplication in a male fetus with congenital malformations and maternal X chromosome pericentric inversion. MATERIALS AND METHODS: A 22-year-old woman underwent amniocentesis at 17 weeks of gestation because of an abnormal maternal serum screening result. Prenatal ultrasound revealed a hypoplastic left heart and short limbs. Amniocentesis revealed a karyotype of 46,Y,der(X) t(X;?)(p22.31;?). The pregnancy was subsequently terminated, and a malformed fetus was delivered with short stature and facial dysmorphism. Repeat amniocentesis was performed before termination of the pregnancy. Array comparative genomic hybridization was performed on uncultured amniocytes and maternal blood. Conventional cytogenetic analysis was performed on cultured amniocytes, cord blood, and blood from both parents. Fluorescence in situ hybridization was performed on cultured amniocytes. RESULTS: The maternal karyotype was 46,X,inv(X)(p22.3q26.3). The fetal karyotype was 46,Y, rec(X)dup(Xq)inv(X)(p22.3q26.3) or 46,Y, rec(X)(qter→q26.3::p22.3→qter). Array comparative genomic hybridization on uncultured amniocytes revealed a 4.56-Mb deletion of Xp22.33-p22.32 encompassing SHOX, CSF2RA, and ARSE, and a 19.22-Mb duplication of Xq26.3-q28 encompassing SOX3, FMR1, MECP2, RAB39B, and CLIC2 in the fetus. The mother did not have X chromosome imbalance. CONCLUSION: Detection of X chromosome aberration in a male fetus should give suspicion of a recombinant X chromosome derived from maternal X chromosome pericentric inversion.

Mosaic trisomy 17 at amniocentesis: Prenatal diagnosis, molecular genetic analysis, and literature review.

OBJECTIVE: We present prenatal diagnosis and molecular genetic analysis of mosaic trisomy 17 and a review of the literature of mosaic trisomy 17 at amniocentesis. MATERIALS AND METHODS: A 42-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age, which revealed a karyotype of 47,XX,+17[4]/46,XX[17]. Prenatal ultrasound findings were unremarkable. She underwent repeat amniocentesis at 20 weeks of gestation. Interphase fluorescence in situ hybridization (FISH), array comparative genomic hybridization, and quantitative fluorescent polymerase chain reaction assays were applied to uncultured amniocytes. Conventional cytogenetic analysis was applied to cultured amniocytes and cord blood. Interphase FISH was applied to uncultured urinary cells postnatally. RESULTS: At repeat amniocentesis, molecular genetic analysis of uncultured amniocytes revealed no genomic imbalance in array comparative genomic hybridization, no uniparental disomy 17 in quantitative fluorescent polymerase chain reaction, and 4.7% (5/105 cells) mosaic trisomy 17 in interphase FISH analysis. Conventional cytogenetic analysis of cultured amniocytes revealed a karyotype of 46,XX (17/17 colonies). A phenotypically normal baby was delivered at 38 weeks of gestation. The cord blood had a karyotype of 46,XX. Interphase FISH analysis of uncultured urinary cells revealed 5.6% (5/90 cells) mosaic trisomy 17. The neonate manifested normal growth and psychomotor development during follow-ups. CONCLUSION: Low-level mosaicism for trisomy 17 detected by amniocentesis without ultrasound abnormality can be associated with a favorable outcome. Molecular genetic analysis of uncultured amniocytes at repeat amniocentesis is useful for genetic counseling. A review of the literature shows a correlation between an adverse fetal outcome and a higher trisomy 17 mosaicism level at amniocentesis associated with ultrasound abnormality.