Trisomy 15 mosaicism and uniparental disomy (UPD) in a liveborn infant

We describe a liveborn infant with uniparental disomy (UPD) with trisomy 15 mosaicism. Third trimester amniocentesis yielded a 46,XX/47,XX,+15 karyotype. Symmetrical growth retardation, distinct craniofacies, congenital heart disease, severe hypotonia and minor skeletal anomalies were noted. The infant died at 6 weeks of life. Peripheral lymphocyte chromosomes were “normal” 46,XX in 100 cells. Parental lymphocyte chromosomes were normal. Skin biopsy showed 47,XX,+15 in 80% of fibroblasts and results were equivalent in fibroblasts from autopsy lung tissue. Molecular analysis revealed maternal uniparental heterodisomy for chromosome 15 in the 46,XX cell line. We describe an emerging phenotype of trisomy 15 mosaicism, confirm that more than one tissue should be studied in all cases of suspected mosaicism, and suggest that UPD be considered in all such cases. © 1996 Wiley-Liss, Inc.     

Trisomy 15 mosaic derived from trisomic conceptus: Report of a case and a review

We report on a fetus with 47,XX,+15 chromosome abnormality detected on chorionic villus sampling (CVS). The pregnancy was terminated at 15.5 weeks of gestation and chromosome analysis done on amniocytes and fetal tissues showed a karyotype 46,XX/47,XX,+15. Autopsy showed multiple abnormalities. Short-arm polymorphisms of the three number 15 chromosomes were highly informative in the delineation of parental origin and the stage of meiotic error. Using fluorescent in situ hybridization (FISH) with D15Z1 and a chromosome 15 painting probe, in addition to DA/DAPI and G-banding, we were able to show that the trisomic conceptus was derived through maternal meiosis I error. The trisomic state was then partially corrected by the loss of one of the two maternal 15s resulting in mosaicism without uniparental disomy (UPD). Striking differences in the proportion of trisomic cells in kidneys, blood, intestine, and skin, and lower proportions of trisomic cells in transformed and frozen than in fresh tissues, illustrate the continuing cell selection in this fetus in favour of the normal cell line. Trisomy 15 conceptions are usually aborted spontaneously in the first trimester of pregnancy. The longer survival of this fetus is most probably the result of a chromosome 15 loss from the trisomic zygote. To the best of our knowledge, the presence of this lethal trisomy has been reported in only five live-born infants, and in five fetuses including the present case, it was detected prenatally and the pregnancies were terminated. © 1996 Wiley-Liss, Inc.     

Clinical,cytogenetic, and molecular findings in 45,X/47,XX,+18 mosaicism: Clinical report and review of the literature

We report cytogenetic and molecular findings performed in a patient with double mosaic aneuploidy. Chromosome analysis of amniotic fluid cells from a 17‐week‐old fetus was performed because of advanced maternal age. Two karyotypes were detected: 45,X and 47,XX,+18 (50:50%). The same cell lines were determined in uncultured and cultured amniocytes of a second amniotic fluid sample, in fetal lymphocytes, and in uncultured and cultured cells of achilles tendon by conventional cytogenetics and fluorescence in situ hybridization (FISH). In the different investigated tissues, the percentage of cells with 45,X karyotype ranged from 20–99% and the percentage of cells with 47,XX,+18 ranged from 1–80%. The pregnancy was terminated at 22 + 0 weeks because of a severe cardiac malformation. Pathologic examination showed a fetus with aspects typical for manifestation of trisomy 18 and monosomy X, especially in the internal organs. The parent and cell stage of origin was determined by short tandem repeat typing and revealed a maternal meiotic division error that led to trisomy 18, as well as a somatic loss of a paternal sex chromosome. Only two other patients with the same mosaicism have been reported so far. Genetic counseling and prognosis remains challenging. © 2002 Wiley‐Liss, Inc.     

Prenatal detection of double aneuploidy trisomy 10/monosomy X in a liveborn twin with exclusively monosomy X in blood

Both double aneuploidy and trisomy 10 are rare chromosome findings. All five published cases of trisomy 10 in liveborns were found to be mosaic with an euploid cell line. In a liveborn female twin, double aneuploidy mosaicism 47,XX, + 10/45,X was detected prenatally by amniocentesis performed because of severe intrauterine growth retardation and malformations. Chromosome analysis from neonatal lymphocyte cultures revealed exclusively the 45,X cell line. Double aneuploidy mosaicism trisomy 10/monosomy X was confirmed from skin fibroblasts. The child died at the age of 7 weeks. This is the first reported case of double aneuploidy involving trisomy 10, and the first case of trisomy 10 without a normal cell line in a liveborn. Prenatal diagnosis of trisomy 10 in a liveborn has not been published so far. The case illustrates that in specific cases amniotic fluid cells may reflect the karyotype of the fetus better than blood.     

Prenatal diagnosis of the Pallister-Killian mosaic aneuploidy syndrome by CVS

Prenatal cytogenetic analysis at 11 weeks of gestation revealed an abnormal karyotype 47, XX, + mar in all metaphases obtained from a chorionic villi sample after 24 h culture. Karyotyping of amniotic fluid cells in the second trimester showed mosaicism 47, XX, + i(12p)/46,XX with 10% aneuploid cells. The pregnancy was terminated at 20 weeks of gestation on the patient's request. The aborted fetus showed typical manifestations of the Pallister-Killian mosaic aneuploidy syndrome. The identity of the supernumerary isochromosome 12p was proven by LDH isozyme electrophoresis using cultured fibro-blasts and by nonradioactive in situ hybridization using a biotinylated set of chromosome 12-specific DNA probes.     

Monozygotic twins discordant for trisomy 21 and maternal 21q inheritance: a complex series of events

We report on a monochorionic/diamniotic twin pregnancy discordant for trisomy 21. Amniocentesis (at 13(5/7) weeks) was performed following ultrasound signs of hydrops and cystic hygroma in twin 1 (T1). Prenatal karyotype showed non-mosaic trisomy 21 in T1 (47,XX,+21[7]), and low-grade mosaic trisomy 21 in twin 2 (T2) (47,XX,+21[2]/46,XX[19]). Post mortem examination of fetal skin, kidneys and lungs confirmed trisomy 21 in T1 (47,XX,+21[548]) and the placenta (47,XX,+21[200]). T2 had a normal karyotype (46,XX[648]). Analysis of microsatellite polymorphisms in multiple samples from the placenta, hand, lungs, kidneys and the umbilical cords of both twins confirmed monozygosity for all loci tested, and trisomy 21 in T1. Unexpectedly, T1 and T2 inherited different maternal alleles for markers of the most distal 4 Mbp of 21q. At least four successive events are needed to explain the genetic status of both twins and include maternal MI premature chromatids separation or maternal II meiotic nondisjunction and post-zygotic events such as, chromosome rescue, nondisjunction, an/or recombination.     

Confined placental chimerism: Prenatal and postnatal cytogenetic and molecular analysis,and pregnancy outcome

The presence of two cell lines in chorionic villi sampling (CVS) represents a significant complication in CVS analysis, interpretation, and counseling. We report on the cytogenetic and molecular analysis of a pregnancy that was conceived on clomiphen citrate. Two cell lines (46,XX and 47,XY, + 9) were discovered in CVS analysis done for maternal age; 94% of the cells in the culture were 46,XX and 6% were 47,XY, + 9 (the direct preparation was 46,XX). As neither line could have derived from the other, chimerism and not mosaicism was suspected, with the 47,XY, + 9 cells deriving from a co-twin whose demise was the result of the autosomal trisomy. At a subsequent amniocentesis, only normal female cells were observed and a normal female infant was delivered at term. Cytogenetic analysis done on the infant's peripheral blood and on a sample of an umbilical vessel showed only 46,XX cells, while amnion and a fibrotic area of the placenta contained 2 cell lines, 46,XX and 47,XY, + 9. Molecular analysis of 3 different tissues was done by the polymerase chain reaction (PCR) and Southern blotting, using Y specific primers and probes, respectively. The presence of Y specific DNA was detected in the placenta and amnion, but not in the umbilical blood vessel. These data excluded true chimerism in the fetal tissues at the level of about 1 in 10⁵ cells and have defined for the first time probable confined placental chimerism (CPC), the result most likely of a “vanishing twin.” Whenever two cell lines are found in CVS, especially in the setting of pharmacologically stimulated ovulation, the possibility of CPC should be considered. The effects of CPC on placental function and fetal outcome merit further study. © 1994 Wiley-Liss, Inc.     

Mosaicism with a normal cell line and an unbalanced structural rearrangement

Mosaicism with a normal cell line (N) and an unbalanced autosomal structural rearrangement (UASR) is rare. This report describes a case of a newborn female with a karyotype of 46,XX,der(4)t(4;15)(q35;q22)/46,XX. Molecular cytogenetic analysis confirmed the origin of the derivative chromosome 4. Here we discuss this case as well as other cases of mosaic karyotypes involving N/UASR. Am. J. Med. Genet. 82:15–19, 1999. © 1999 Wiley-Liss, Inc.     

A stitch in time

An abnormal karyotype consisting of 48 chromosomes has been found in a 16-year-old boy with severe psychomotor retardation and congenital anomalies. The two extra chromosomes: a 15q? and a small metacentric marker appear as derivatives of chromosome 15 (48,XY, +15q?, +mar(15). The healthy father has a mosaic chromosome constitution 46,XY/47,XY, +mar(15) and this additional chromosome is also present in the propositus. It is suggested that the presence of the extra chromosome in the father's germ cells may play a role in the production of the additional 15q? chromosome responsible for the clinical syndrome of the propositus.     

False negative findings at third trimester chorionic villus sampling (C.V.S.)

A discrepancy is reported between the karyotypes of chorionic cells (direct method):46,XX and of cultured amniotic fluid cells: 47,XX, + 18 in a pregnancy of 30 weeks. A stillborn girl, with external signs of trisomy 18 syndrome, was subsequently shown to have a mosaic pattern in both the lymphocytes and the placenta.     

Dilemma of trisomy 20 mosaicism detected prenatally: Is it an innocent finding?

The clinical significance of mosaicism trisomy 20 detected prenatally following amniocentesis remains uncertain, due to the rarity of liveborn cases with inconsistent clinical findings, the short postnatal follow-up, and failure in evaluating other fetal tissues for the presence of the trisomy. We report on a 15 month-old 46,XX chromosome constitution in white blood cells, while skin fibroblasts demonstrated trisomy 20 mosaicism (54%) by fluorescence in situ hybridization (FISH) analysis. Clinical examination of the baby showed only minor phenotypic signs (bilateral epicanthal folds, delayed closure of fontanel with no other gross anomalies), but demonstrated a considerable developmental delay in gross and fine motor skills along with hypotonicity. This is the second oldest described liveborn with trisomy 20 mosaicism confirmed in skin fibroblasts. This cytogenetic aberration along with her developmental delay suggests that the two findings are related and that aberration affects various fetal tissues and is not confined to extra-embryonic tissue as suggested previously. Yet, an undiagnosed condition may be the cause of the child's developmental delay. Based on this case and following a review of the literature we suggest that when mosaic trisomy 20 is identified in amniocytes, further evaluation is required. Cord blood should be analyzed preferably by FISH. During counseling the parents should be advised of an additional risk, such as developmental delay, even when fetal cord karyotype and detailed ultrasonic scan are normal. Am. J. Med. Genet. 77:72–75, 1998. © 1998 Wiley-Liss, Inc.     

Trisomy 9 syndrome: Report of a case with Crohn disease and review of the literature

We report on a 6-year-old boy with mosaic trisomy 9. The patient was born at 42 weeks of gestation to a 27-year-old G1 white woman. Birth weight was 2,820 g, length 52 cm, and Apgar scores were 4 and 6 at 1 and 5 min, respectively. The infant presented with apparently low-set ears, overfolded helices, epicanthal folds, prominent nasal bridge, high-arched palate, micrognathia, bilateral dislocated hips, left genu recurvatum, and cryptorchidism. Chromosome analysis showed an unusual karyotype: 47,XY,+inv(9qh+)/47,XY,+mar. The marker chromosome was thought to be a remnant of the inv(9qh+) chromosome. The mother's karyotype was 46,XX,inv(9qh+), while the father's was 46,XY. At age 5 months, the patient developed seizures and gastroesophageal reflux. Crohn disease was diagnosed at age 2 years, although symptoms began at age 1 year. Recurrent bouts of pneumonia have occurred since the patient's birth. Severe psychomotor retardation was also noted. Trisomy 9 syndrome was first reported in 1973. Over 30 cases have been reproted since then. Of these case reports, only 5 patients were older than 1 year. Inflammatory bowel disease has been reported in association with other chromosome abnormalities, but to our knowledge, has not been reported in trisomy 9 syndrome. © Wiley-Liss, Inc.     

Pure and complete 12p trisomy due to a maternal centric fission of chromosome 12

Pure and complete 12p trisomy are rare. Here, we report on a unique patient with trisomy 12p syndrome due to centric fission of maternal chromosome 12. Conventional cytogenetic and fluorescence in situ hybridization (FISH) techniques revealed the proposita's karyotype to be 47,XX,+fis(12)(p10)mat whereas the maternal one was 47,XX,-12,+fis(12)(p10),+fis(12) (q10). This is the first report on centric fission of chromosome 12 leading to stable telocentrics, each with a fully functional centromere. Our observation shows that the centric fission of chromosome 12 can be a new mechanism for generation of a partial centromere and trisomy 12p syndrome.     

Clinical,cytogenetic, and molecular findings in 45,X/47,XX,+18 mosaicism: clinical report and review of the literature

We report cytogenetic and molecular findings performed in a patient with double mosaic aneuploidy. Chromosome analysis of amniotic fluid cells from a 17-week-old fetus was performed because of advanced maternal age. Two karyotypes were detected: 45,X and 47,XX,+18 (50:50%). The same cell lines were determined in uncultured and cultured amniocytes of a second amniotic fluid sample, in fetal lymphocytes, and in uncultured and cultured cells of achilles tendon by conventional cytogenetics and fluorescence in situ hybridization (FISH). In the different investigated tissues, the percentage of cells with 45,X karyotype ranged from 20-99% and the percentage of cells with 47,XX,+18 ranged from 1-80%. The pregnancy was terminated at 22 + 0 weeks because of a severe cardiac malformation. Pathologic examination showed a fetus with aspects typical for manifestation of trisomy 18 and monosomy X, especially in the internal organs. The parent and cell stage of origin was determined by short tandem repeat typing and revealed a maternal meiotic division error that led to trisomy 18, as well as a somatic loss of a paternal sex chromosome. Only two other patients with the same mosaicism have been reported so far. Genetic counseling and prognosis remains challenging.     

Trisomy 7 mosaicism prenatally misdiagnosed and maternal uniparental disomy in a child with pigmentary mosaicism and Russell- Silver syndrome

Prenatal diagnosis of true mosaic trisomy 7 is rare in amniotic fluid and can be misinterpreted as pseudomosaic. The phenotype is highly variable and may be modified by a maternal uniparental disomy of chromosome 7 leading to mild Russell-Silver syndrome (RSS). We report here the third postnatal case of mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 in a boy presenting a mild RSS. Fetal karyotype performed in amniocentesis for intrauterine growth retardation was considered normal. Mosaic trisomy 7 was diagnosed after birth, on fibroblasts karyotype performed for blaschkolinear pigmentary skin anomalies and failure to thrive. Maternal uniparental disomy of chromosome 7 was observed in blood sample. Retrospectively, trisomic 7 cells were identified in one prenatal long-term flask culture revealing a prenatal diagnosis failure. This report emphasizes the difficulty of assessing fetal mosaicism and distinguishing it from pseudomosaicism in cultured amniocytes. It is important to search for uniparental disomy as an indirect clue of trisomy 7 mosaicism and a major prognosis element. Although there are only few prenatal informative cases, detection of trisomy 7 in amniocentesis appears to be associated with a relatively good outcome when maternal uniparental disomy has been ruled out.     

Mosaic trisomy 16 in a thriving infant; maternal heterodisomy for chromosome 16

Lindor NM, Jalal SM, Thibodeau SN, Bonde D, Sauser KL, Karnes PS. Mosaic trisomy 16 in a thriving infant; maternal heterodisomy for chromosome 16
Clin Genet 1993: 44: 185–189. © Munksgaard, 1993
Trisomy 16 is the most common trisomy in spontaneous abortions and is usually, if not always, lethal in the nonmosaic state. We report a liveborn infant with trisomy 16 mosaicism first diagnosed by amniocentesis at 20 weeks gestation. At birth, the infant was growth retarded and mildly dysmorphic. At age 14 months she was developmentally normal and had facial asymmetry. Her length, weight and head circumference were normal. Pure trisomy 16 was found in cells from the placenta. A normal female karyotype was found in lymphocytes from the infant. Skin fibroblasts revealed a trisomy 16 karyotype in 6 of 30 cells. Molecular analysis showed maternal uniparental heterodisomy, indicating that the trisomic conceptus arose from a nondisjunction of maternal meiosis. Fibroblasts may be the tissue of choice for detection of low-level trisomy 16 mosaicism.     

A supernumerary microchromosome in amniotic cell cultures and talipes equinovarus in a live born female

Amniocentesis for advanced maternal age resulted in the demonstration of a supernumerary microchromosome in the amniotic fluid cells. Cytogenetic analysis of peripheral blood from the female infant revealed a mosaic karyotype 46, XX/47, XX, + marker. The only anomaly noted in the infant was talipes equinovarus.     

Retrieval of aneuploidy by fish-technique in a case with 46,XX/47,XXX/47,XX,+8

Summary We report on a 46 year old female with a new chromosomal finding [46,XX/47,XXX/47,XX,+8] who was referred for ovarian failure. The clinical presentation was highly unusual and the patient does not exhibit the characteristic phenotype of trisomy 8 syndrome. Interphase cytogenetics using FISH-technique revealed discrepancies with a different population of cells when compared with its metaphase index. Therefore, it is advised that patients with mosaic karyotypes should be evaluated by analyzing metaphase as well as interphase nuclei labeled with chromosome specific molecular tags, especially in the situations where the incidence of a mosaic cell line is very low. Nevertheless, in a cost-conscious environment, we must exercise caution prior to making universal recommendations concerning the usefulness of medical devices which are increasing at a logarithmic rate.     

Partial trisomy 10 mosaicism with cutaneous manifestations: report of a case and review of the literature

A female infant with partial trisomy 10 mosaicism and hypomelanosis of Ito is presented. Features include a prominent forehead, hypertelorism, large dysplastic ears, prominent nasal root, a cleft lip and alveolar ridge, bilateral metatarsus adductus, and streaks and whorls of hypopigmented skin. The skin findings were diagnostic for hypomelanosis of Ito. A peripheral blood karyotype was normal. Fibroblasts from a junctional skin biopsy revealed mosaicism for partial trisomy of chromosome 10 [46, XX/47, XX, +del(10) (q11.2q23.2)]. The physical findings of this patient are compared to five published cases of complete trisomy 10 mosaicism and 94 cases of isolated trisomy 10p and trisomy 10q.