Prenatal diagnosis of a fetus with two balanced de novo chromosome rearrangements

Two apparently balanced chromosome rearrangements were identified in a 17-week fetus by analysis of cultured amniocytes. The fetal karyotype was 46,XX,t(2;16) (q33; q24), inv(7)(p15q11.23). Parental karyotypes were normal, indicating a de novo origin of both chromosome rearrangements in the fetus. The risk of phenotypic abnormality from a de novo reciprocal translocation or inversion has been estimated at approximately 7% [Warburton, 1991]. The risk of abnormality in this fetus was estimated to be a minimum of 14%, based on the additive risk of each rearrangement, equivalent to 3.5% per chromosome breakpoint. The pregnancy was terminated because of the risk of abnormality and the detection of intrauterine growth retardation by ultrasound. In the absence of additional experience, the minimum presumed risk of phenotypic abnormality for de novo, multiple or complex chromosome rearrangements identified prenatally may be estimated as the additive risk of the number of chromosome breakpoints involved. © 1996 Wiley-Liss, Inc.     

Prenatal identification of de novo marker chromosomes using micro-FISH approach

Chromosome microdissection combined with polymerase chain reaction (PCR) and reverse chromosome painting ('micro-FISH') is a powerful technique for the unequivocal identification of complex or subtle chromosomal aberrations. We have applied this technique to the prenatal diagnosis of three fetuses with de novo marker chromosomes. One small supernumerary satellited marker chromosome was shown to have originated from the fusion of the centromeric heterochromatin of one or both of chromosomes 14 and 22. The second marker was identified as i(9)(p10) while the third marker chromosome was shown to have been derived from the 1p13.1–1q21.3 region. At birth, the clinical outcome correlated well with that expected from the prenatal cytogenetic findings. Our study highlights the importance of the application of 'micro-FISH' to prenatal diagnosis.     

Prenatal diagnosis of a de novo reciprocal translocation 46,XX,t(1;18) (p22;q23)

A case is reported in which a de novo balanced translocation 46,XX,t(l;18Xp22;q23) was diagnosed prenatally.     

Prenatal diagnosis of de novo X;autosome translocations

The identification of a de novo apparently balanced structural chromosome rearrangement at prenatal diagnosis can be problematic and raises unique genetic counseling issues. Two breakpoint rearrangements such as reciprocal translocations or inversions have a 6.7% empiric risk of phenotypic abnormality. Abnormal phenotypes are thought to result from gene disruption, position effect, or deletion at one of the breakpoints. Prenatal diagnosis of de novo X;autosome translocations is rare, and presents additional unique risks due to the effects of X-inactivation and the possibility of disruption of the single active copy of an X-linked gene. We report the identification of a de novo apparently balanced t(X;6)(q26;q23) ascertained after amniocentesis for advanced maternal age. The parents were counseled regarding the risk of a de novo apparently balanced translocation, including the potential risk of an X-linked Mendelian disorder resulting from disruption of a gene at the Xq26 breakpoint. While the normal X chromosome was late replicating in all metaphases, no conclusions from this data could be drawn as the X-inactivation ratio in amniocytes might not be representative of other tissues. The possibility of future premature ovarian failure was also noted due to the position of the breakpoint at Xq26, although no specific risk could be ascribed. The parents elected to continue the pregnancy, and at 17 months of age, the proband was phenotypically and developmentally normal. Long-term follow-up will be required to assess development delay and any fertility issues. Based on review of the few cases reported to date and excluding any risk for later reproductive abnormalities, we estimated the risk of phenotypic abnormality or developmental delay in a prenatally ascertained de novo X;autosome carrier to be as high as 50%. This case illustrates the complexities in counseling for prenatally ascertained de novo X;autosome translocations and the need for additional cases to be reported.     

Prenatal detection and molecular characterization of a de novo duplication of the distal long arm of chromosome 19

A tandem duplication of the distal long arm of chromosome 19 was identified in a 10 week fetus by analysis of chorionic villi. The fetal karyotype from two primary cultures was 46,XY,dir dup(19)(q13.2q13.4). The origin of the extra material was confirmed by fluorescence in situ hybridization using a chromosome 19 whole chromosome probe. Parental chromosomes were normal, indicating a de novo origin of the extra chromosome material. This is the first case of dup(19q) detected by prenatal diagnosis. Molecular studies demonstrated that the duplication involved a maternal chromosome 19. Am. J. Med. Genet. 71:325–328, 1997. © 1997 Wiley-Liss, Inc.     

A de novo centric fission of chromosome 11 in a patient with recurrent miscarriages

We report on a de novo centric fission of chromosome 11 in a healthy female referred for chromosome analysis due to recurrent miscarriages. Both fission products were mitotically stable. This centric fission of chromosome 11 appears to have no clinical significance for this patient other than recurrent miscarriages.     

Prenatal diagnosis of a trisomy 17p derived from a de novo non-mosaic satellited marker

A trisomy 17pter→p11.2 derived from a supernumerary de novo satellited marker was identified by GTG bands and fluorescent in situ hybridisation (FISH) in amniocytes of a fetus with malformations and intrauterine growth retardation (IUGR). At 39 weeks a male infant with a phenotype similar to other postnatal cases of 'pure.' complete trisomy 17p was born. Some additional clinical features, however, make him more severely affected than previous patients.     

Prenatal evaluation of a de novo X;9 translocation

A case of X-autosome translocation was diagnosed prenatally [46,X,t(X;9)(p21.3∼ 22.1;q22]. We describe the use of fluorescence in situ hybridization (FISH) to estimate the integrity of the Duchenne muscular dystrophy (DMD) gene. X-inactivation studies were used as well to assess the probability of phenotypic abnormalities associated with functional partial disomy X and monosomy 9. Am. J. Med. Genet. 85:476–478, 1999. © 1999 Wiley-Liss, Inc.     

Prenatal diagnosis of a familial interchromosomal insertion of Y chromosome heterochromatin

An apparently unbalanced karyotype containing an abnormal chromosome 11 was identified in a 16-week female fetus by analysis of cultured amniocytes. Fluorescence in situ hybridization (FISH) with a chromosome 11 paint identified the presence of an insertion in band 11q24. Parental karyotyping documented an unbalanced karyotype with the same der(11) chromosome in the phenotypically normal father. CBG-banding and FISH identified the insertion to be Yq12 heterochromatin: 46,XY, der(11)ins(11;Y)(q24;q12q12)ish der(11) (wcp11+,DYZ1+). The same der(11) chromosome was also found in the phenotypically normal paternal grandmother, demonstrating this additional Y chromosomal material did not affect normal female sexual development or fertility. The parents elected to continue the pregnancy and a normal girl was born at term, further confirming that this rare familial variant has no clinical significance. This case illustrates the importance of family studies, appropriate banding, and FISH analyses to accurately characterize apparent chromosomal abnormalities. Am. J. Med. Genet. 73:470–473, 1997. © 1997 Wiley-Liss, Inc.     

Prenatal diagnosis of a complete mole coexisting with a dichorionic twin pregnancy: case report

A complete mole coexisting with dichorionic twins was diagnosed by the combined use of sonography and chorionic villus sampling at 10 weeks gestation. The pregnancy resulted in the death of one fetus at 31 weeks from presumed feto-maternal haemorrhage, while the other fetus survived in good condition. A summary of the available literature, combined with this report, reveals a total of seven pregnancies with twins and a coexistent complete mole. Only two out of 14 fetuses survived. Maternal complications included one case of pre-eclampsia and one persistent trophoblastic tumour. Accurate diagnosis of complete mole is possible by genetic analysis of chorionic villi obtained with standard transabdominal sampling. Twins with a coexistent complete mole will usually undergo miscarriage. However, fetal survival is possible and the maternal risks seem limited. A concomitance between gestational trophoblastic disease and the occurrence of feto-maternal haemorrhage is observed.     

Prenatal diagnosis of a de novo ring chromosome 11

Ring chromosomes are uncommon findings in prenatal diagnosis. Growth retardation is the most significant manifestation, in particular among patients with rings of larger chromosomes. A 30-year-old gravida 1, para 0 white woman was referred for genetic counseling because of maternal anxiety. Cytogenetic analysis of amniotic fluid cells at 16 weeks gestation revealed an abnormal mosaic female chromosome complement; 46,XX,r(11)(p15q25)[14]/45,XX,-11[7]. The ring 11 showed no detectable loss of chromosomal material at 450 band level. Both parents had a normal karyotype. Fluorescence in situ hybridization demonstrated intact subtelomeric regions in the ring chromosome. A targeted ultrasound evaluation at the time of consultation suggested no significant abnormalities. The parents were counseled and subsequently decided to terminate the pregnancy. The autopsy revealed an immature female fetus with abnormal craniofacial features including brachycephaly, low-set ears and hypertelorism, bicornuate uterus, and calcifications in the renal tubules. The abnormal phenotypes could be a consequence of the ring instability, submicroscopic deletion, and/or alteration of genetic material at the site of fusion.     

Centric fission, centromere-telomere fusion and isochromosome formation: a possible origin of a de novo 12p trisomy

A 5-month-old girl had a typical 12p trisomy syndrome due to a monocentric i(12p) present in a 46-chromosome complement that also included the translocation of all 12q onto the 8p telomere; i.e., her complex karyotype could be written as 46,XX,-8,-12, +der(8),t(8;12)(p23.3;cen),+i(12p). The present concurrence of a whole-arm q translocation and an i(p) for a single chromosome, along with six previous similar instances involving chromosomes 4, 5 and 9, suggests the following origin for such a special rearrangement: a centric fission in G1 initially yielding two telocentrics; at the next replication, the tel(q) translocates onto a nonhomologous telomere (centromere-telomere fusion), whereas the tel(p) becomes an i(p). This mechanism can be either meiotic or postzygotic and surmises that the translocated long arm retains a partial centromere, which subsequently is inactivated and loses its staining properties.     

Prenatal diagnosis and normal outcome of a 46,XX/46,XY chimera: a case report

The phenotypic spectrum of 46,XX/46,XY chimeric patients is variable. It ranges from normal male or female genitalia to different degrees of ambiguous genitalia. Chimerism results from the amalgamation of two different zygotes in a single embryo, whereas mosaicism results from a mitotic error in a single zygote. Several other mechanisms resulting in a chimera have been discussed in the literature. Here, we report on a new case of chimerism (46,XX/46,XY) diagnosed at 17 weeks' gestation on amniocentesis performed because of advanced maternal age. Ultrasound examination revealed normal female external genitalia, and a healthy baby girl was delivered at term. We used polymorphic markers spanning the X chromosome and several autosomes in order to identify the genetic mechanism involved. Mosaicism was excluded because of the presence of 3 alleles at 11 autosomal and 4 X chromosome loci. On autosomes, the origin of this third allele was maternal for two pericentromeric markers (located on 2p11.2 band and 8p11.2 band), paternal for six markers and paternal or maternal for the other three markers. On the X chromosome, the origin of the third allele was maternal for all four markers. Thus, two different paternal and maternal haploid sets were observed. These results are compatible with a tetragametic chimera.     

Prenatal diagnosis of a de novo non-fluorescent Y chromosome.

We report a case with non-mosaic Yq-, missing the fluorescent segment, and detected as a fetus studied for advanced maternal age. The father had a Y chromosome of average size and paternity was established wih a plausibility of 97.7% by HLA and erythrocyte antigen typing. The child had a normal male antigen typing. The child had a normal male phenotype at delivery and developmental milestones were normal through the first year of life. The Yq- showed no mitotic instability since it was retained in foreskin culture for its in vitro lifetime of 60 population doublings.     

Balanced nonacrocentric whole-arm reciprocal translocations: A de novo case and literature review

We report a new de novo case of a balanced whole-arm reciprocal translocation, detected at prenatal diagnosis for late maternal age. A review of previous cases indicates there is a risk of chromosomally abnormal liveborn offspring when a parent is a carrier of this type of translocation, particularly when the translocated region is a small chromosomal segment. Due to the limited number of cases, exact reproductive risks are not available. This is the second example of such a translocation of chromosomes 1 and 5, raising the possibility of nonrandom involvement of certain chromosomes in balanced nonacrocentric whole-arm reciprocal translocations. © 1995 Wiley-Liss, Inc.     

Prenatal diagnosis of Tetraploidy: A case report

We report on the second trimester prenatal diagnosis of an apparently nonmosaic tetraploid fetus, 92,XXYY. Indications for cytogenetic studies of the fetus included abnormal ultrasound findings and abnormal maternal serum levels of alpha-fetoprotein (AFP)/human chorionic gonadotropin (hCG)/estriol. Chromosome analysis of amniocytes documented tetraploidy, a finding confirmed by flow cytometry of several fetal tissues. Autopsy findings in the fetus are compared with those of other cases of tetraploidy. To our knowledge this is the first reported prenatal diagnosis of a tetraploid fetus. Additionally, it illustrates the value of flow cytometric analysis of products of conception in which polyploidy is suspected. © 1993 Wiley-Liss, Inc.     

A case of prenatal diagnosis of a familial satellited Yq chromosome

A case of a fetus with a satellited Yq revealed during prenatal diagnosis because of advanced maternal age is presented. This case is the 18th reported in the literature. Cytogenetic studies in the father, uncle and grandfather of the fetus revealed that the Yqs was inherited and the possible mechanisms of origin are discussed.     

Prenatal diagnosis of female pseudohermaphroditism associated with bilateral luteoma of pregnancy: case report

Female pseudohermaphroditism associated with luteoma of pregnancy (LP) is a rare condition characterized by varying degrees of masculinization of a female fetus. We describe a case, diagnosed at 13 weeks gestation. Transvaginal ultrasound at 5 weeks of gestation revealed a normal intrauterine gestational sac and an enlarged maternal right ovary. Re-examination at 13 weeks showed a fetus with male external genitalia. Cytogenetic investigation on amniotic fluid revealed a normal female karyotype 46,XX. Follow-up sonography confirmed the previous assignment of male external genitalia and a second amniocentesis was negative for the SRY gene. High levels of androgens were found in the maternal blood. A diagnosis of female pseudohermaphroditism associated with bilateral LP was made. A healthy girl was born by Caesarean section with complete masculinization of external genitalia (Prader V). Histology confirmed a bilateral LP. To the best of our knowledge this represents the first case of prenatal diagnosis of female pseudohermaphroditism associated with LP and demonstrates the feasibility of diagnosis by sonography from 13 weeks gestation. This is also the first case described of Prader V masculinization associated with LP.     

Submicroscopic deletion in 14q32.3 through a de novo tandem translocation between 14q and 21p

We describe a male child with craniofacial anomalies, postnatal onset growth retardation, microcephaly, multiple minor anomalies, hearing loss, and moderate delay of mental and statomotor development. He carries a previously undescribed tandem translocation between the long arm of chromosome 14 and the short arm of chromosome 21 that arose de novo. As proven by fluorescence in situ hybridization a microdeletion not detectable with high-resolution G-banding occured in 14q32.3, the terminal band on the long arm of chromosome 14. The resulting phenotype includes most abnormalities encountered in patients with terminal 14q32.3 deletions but in addition includes some characteristics of the ring chromosome 14 syndrome. Am. J. Med. Genet. 80:443–447, 1998. © 1998 Wiley-Liss, Inc.     

Prenatal diagnosis of a de novo Y/22 translocation.

Prenatal chromosomal analysis was performed at 17 weeks' gestation because of the previous birth of a girl with trisomy 13. A seemingly balanced de novo Y/22 translocation was diagnosed. Translocations involving the Y chromosome are rare and no similar translocation, detected pre- or postnatally, could be found in published reports. The counselling problems are discussed. The pregnancy ended at term with the birth of a phenotypically normal boy. After birth, the prenatal diagnosis was confirmed and the H-Y antigen expression was determined.