Prenatal diagnosis of a fetus with unbalanced translocation (4;13)(p16;q32) with overlapping features of Patau and Wolf-Hirschhorn syndromes

Wolf-Hirschhorn syndrome (WHS) and Patau syndrome are two of the most severe conditions resulting from chromosome abnormalities. WHS is caused by a deletion of 4p16, while Patau syndrome is caused by trisomy for some or all regions of chromosome 13. Though the etiologies of these syndromes differ, they share several features including pre- and postnatal growth retardation, microcephaly, cleft lip and palate, and cardiac anomalies. We present here a female fetus with deletion of 4p16 --> pter and duplication of 13q32 --> qter due to unbalanced segregation of t(4;13)(p16;q32) in the father. She displayed overlapping features of both of these syndromes on ultrasound. To the best of our knowledge, this is the first report of a fetus with both partial trisomy 13 and deletion of 4p16, the critical region for WHS.     

Characterization of a balanced complex chromosomal rearrangement carrier ascertained through a fetus with dup15q26.3 and del5p15.33: case report

Abstract

Complex chromosomal rearrangements (CCRs) are structural aberrations involving more than two chromosomes which rarely appear in individuals with normal phenotypes. These individuals report fertility problems, recurrent miscarriages, or congenital anomalies in newborn offspring as a consequence of either meiotic failure or imbalanced chromosome segregation. A CCR involving chromosomes 5, 15, and 18 was discovered in a phenotypically normal man through a fetus with congenital malformations and partial trisomy of chromosome 15 and monosomy of chromosome 5. Ultrasound examination at 20 weeks of gestation showed severe oligoamnios and hydrothorax. Prenatal cytogenetic analysis and array comparative genomic hybridization (array-CGH) revealed a female fetus with dup15q26.3 and del5p15.33. We diagnosed the CCR using three-color fluorescence in situ hybridization (three-color FISH), and a balanced CCR using array-CGH and FISH was diagnosed in the paternal karyotype. The father is a carrier of a balanced translocation 46,XY,t(5;15;18)(p15.31;q26.3;p11.2). Due to the complexity of these rearrangements the diagnosis is difficult and the reproductive outcome uncertain. Reporting such rare cases is important to enable such information to be used for genetic counseling in similar situations and help estimate the risk of miscarriage or of newborns with congenital abnormalities.     

Prenatal diagnosis of interstitially satellited 6p

OBJECTIVES: To present the prenatal diagnosis of de novo interstitially satellited 6p and a review of the literature. CASE: An amniocentesis was performed at 18 weeks' gestation because of paternal balanced translocation, t(6;14)(p22;p12). Family history of the father showed the derivative chromosomes to be transmitted through at least two generations with three members affected with partial trisomy 6p (6p22 --> 6pter). RESULTS: Cytogenetic analysis of the cultured amniocytes revealed an interstitial insertion of a nucleolar organizer region (NOR) in 6p22 and a karyotype of 46,XX, rec(6)ins(6;14)t(6;14)(6pter --> 6p22::14p12 -->14p12::6p22 --> 6qter). Level II ultrasound examinations revealed normal findings. The parents opted to terminate the pregnancy. A 650-g fetus was delivered at 23 weeks' gestation without any gross abnormalities. Cytogenetic analysis of the cord blood lymphocytes confirmed the prenatal diagnosis. CONCLUSIONS: The present case provides evidence that a de novo interstitial insertion of a NOR into a nonacrocentric chromosome can be derived from a parental balanced reciprocal translocation involving the satellite stalk region of an acrocentric chromosome. The NOR-inserted chromosome seems to be a harmless variant. However, a de novo interstitial NOR translocation can be pathogenic if there is genomic disruption at the site of translocation, which should be included in genetic counseling and perinatal investigation.     

Clinical, cytogenetic and molecular investigation in a fetus with Wolf-Hirschhorn syndrome with paternally derived 4p deletion. Case report and review of the literature

Wolf-Hirschhorn (4p-) syndrome (WHS), caused by partial deletion of the short arm of chromosome 4, has been extensively described in children and young adults. Knowledge on fetuses with WHS is still limited due to the small number of published cases. We report on a fetus with prenatally diagnosed severe intrauterine growth retardation, reduced thoracal diameter, clubfeet deformity and midface hypoplasia including slight microretrognathia indicative for fetal karyotyping. Chromosome analysis after amniocentesis revealed a de novo terminal deletion of chromosome 4p [karyotype: 46,XX,del(4) (p16)] which was confirmed by FISH. Analyses of a set of polymorphic markers mapping in 4pter->4p15.3 showed absence of paternal haplotypes. These observations corroborate the preferential paternal origin of the de novo 4p deletion in WHS patients. Furthermore, the distal breakpoint could be narrowed to band 4p16.1. At autopsy, the fetus showed typical craniofacial dysmorphic signs of WHS, severe IUGR and delayed bone age. This report suggests the possibility of recognising the particular phenotype of WHS in utero by prenatal ultrasound and emphasises the importance of karyotyping fetuses with severe IUGR, especially when the amount of amniotic fluid is normal.     

单纯性染色体18p部分三体综合征患儿的产前遗传学诊断和文献回顾

目的探讨单纯性染色体18P部分三体综合征患者的产前诊断特点。方法联合运用传统染色体核型分析和染色体微阵列(chromosome microarray analysis,CMA)基因芯片技术对家系成员行染色体核型分析和基因组拷贝数变异检测。结果胎儿羊水染色体核型结果为46,XY,der(18),父母双方染色体核型均未见异常;胎儿基因芯片检测结果为arr[hg19]18p11.31p11.21(3,521,718-15,099,116)×3,即胎儿基因组18号染色体短臂p11.31p11.21区域存在11.58 Mb的片段重复,父母双方基因芯片结果均为阴性,提示该胎儿的18号染色体结构重排为新发生的。结论在一个有不良生育史家系的胎儿中检出一个罕见新发的单纯性染色体18p部分三体变异,这是世界少见的单纯性染色体18p部分三体综合征的产前病例报道。联合运用传统染色体核型分析和C M A基因芯片技术在预防不良产史家系中胎儿出生缺陷的产前诊断中具有重要的临床应用价值。     

Wolf-Hirschhorn syndrome due to a 3:1 segregation of a maternal balanced t(4;15)(p16.3;q11) translocation

The Wolf-Hirschhorn syndrome (WHS) is characterized by severe pre- and postnatal growth retardation, specific pattern of dysmorphisms, and severe developmental delay. These clinical findings are the result of a deletion within the short arm of chromosome 4. Most cases occur de novo and are of paternal origin. Cases due to a balanced translocation are mostly of maternal origin and the deletion of distal 4p, including the WHS critical region, is often combined with a duplication of the other chromosomal segment involved in the rearrangement. Here, we report on a newborn female infant with WHS and pure tertiary monosomy due to a 3:1 segregation of a balanced maternal 4;15 translocation. In this context, importance of fluorescence in situ hybridization (FISH) with specific probes to determine the exact breakpoints in unbalanced chromosomal rearrangements with breakpoints localized around known microdeletion syndromes is emphasized.     

Prenatal diagnosis of monosomy 4p14-->pter and trisomy 11q25-->qter: clinical presentations and outcomes

We present the case of a pregnant woman with low free beta-HCG in maternal serum Down syndrome screening that led to prenatal diagnosis of a fetus with 46,XY,der(4)t(4;11)(p14; q25). This chromosomal aneuploidy resulted from unbalanced segregation of a paternal balanced translocation, t(4;11)(p14;q25). Prenatal ultrasound revealed intrauterine growth restriction, cleft lip and palate, a thick nuchal fold, a single umbilical artery, and pyelectasis. Array-based comparative genomic hybridization and short tandem repeat markers further located the exact breakpoint of translocation. The woman had her pregnancy terminated at 23 weeks of gestational age. The proband had general appearance of Wolf-Hirschhorn syndrome and some unique findings, including single umbilical artery, severe immunoglobulin deficiency, scalp defect, and underlying bony defect. Our case underscores the importance of fetal karyotyping when low maternal serum free beta-HCG is found. It also adds information on the fetal presentations of monosomy 4p14-->pter and trisomy 11q25-->qter.     

Prenatal diagnosis of partial trisomy 12q: clinical presentations and outcome

We present a pregnant woman with a fetus prenatally diagnosed as 46, XY,der(4) t(4;12) (q35.1; q21.2). This defect resulted from the unbalanced segregation of a paternal balanced translocation, t(4;12) (q35.1; q21.2). Prenatal ultrasound revealed borderline ventriculomegaly, a thick nuchal fold, pericardial effusion, arthrogryposis, a single umbilical artery, and micropenis. Fluorescence in situ hybridization (FISH) with whole chromosome painting probe and microarray-based comparative genomic hybridization analysis further confirmed chromosomal gain of terminal 12q. The woman had her pregnancy terminated at 20 weeks of gestational age. When compared with previously reported cases, the proband had characteristics common to the phenotypes of partial trisomy 12q, including an abnormal facial appearance and multiple anomalies. Additionally, this case had previously unreported phenotypes, such as arthrogryposis, a single umbilical artery, and a micropenis. Regarding the outcome of partial trisomy 12q, the fetuses carrying trisomies distal to 12q24 have a good chance of extended postnatal survival. In contrast, the cases with trisomies involving a larger amount of 12q likely die prenatally or within a few days after birth.     

Wolf-Hirschhorn (4p-) syndrome: prenatal diagnosis, molecular cytogenetic characterization and association with a 1.2-Mb microduplication at 8p22-p21.3 and a 1.1-Mb microduplication at 10p15.3 in a fetus with an apparently pure 4p deletion

ObjectiveTo present prenatal diagnosis and molecular cytogenetic characterization of Wolf-Hirschhorn syndrome (WHS) associated with microduplications at 8p and 10p in a fetus with an apparently pure 4p deletion.Case ReportA 35-year-old gravida 2, para 1 woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Her husband was 38 years of age. There was no family history of congenital malformations. Amniocentesis revealed a karyotype of 46,XY,del(4p16.1). The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) analysis revealed a 6.5-Mb deletion at 4p16.3-p16.1, a 1.2-Mb microduplication at 8p22-p21.3, and a 1.1-Mb microduplication at 10p15.3, or arr cgh 4p16.3p16.1 (0–6,531,998 bp)×1, 8p22p21.3 (18,705,388–19,940,445 bp)×3, 10p15.3 (0–1,105,065 bp)×3. Polymorphic DNA marker analysis confirmed a paternal origin of 4p deletion. Prenatal ultrasound revealed facial dysmorphism and hypospadias. The aCGH analysis of the parents revealed no genomic imbalance. Fluorescence in situ hybridization study showed an unbalanced reciprocal translocation between chromosomes 4 and 10 at bands 4p16.1 and 10p15.3. The cytogenetic result, thus, was 46,XY,der(4)t(4;10)(p16.1;p15.3),dup(8)(p21.3p22). The parents elected to terminate the pregnancy, and a 470-g malformed fetus was delivered.ConclusionThe present case provides evidence that an apparently pure 4p deletion can be associated with subtle chromosome imbalances in other chromosomes.     

Prenatal diagnosis of a fetus affected with Down syndrome and deletion 1p36 syndrome by fluorescence in situ hybridization and spectral karyotyping

OBJECTIVE: A fetus having partial trisomy of the distal part of chromosome 21q due to a de novo translocation is reported here. METHOD: A 29-year-old woman received amniocentesis at 18 weeks of gestation because of abnormal ultrasound findings including bilateral choroid plexus cysts, atrioventricular septal defects, rocker-bottom feet, and possible hydrocephalus. RESULTS: Cytogenetic analysis revealed 46,XY, add(1)(p36.3), in which an additional material of unknown origin was attached to one of the terminal short arms of chromosome 1. Parental blood studies showed normal karyotypes in both parents. Spectral karyotyping was then performed and the origin of the additional material locating at chromosome 1p was found to be from chromosome 21. Conventional fluorescence in situ hybridization analysis was also used and confirmed the spectral karyotyping findings by use of a chromosome 21 specific painting probe, a locus specific probe localized within bands 21q22.13-q22.2 and a 21q subtelomeric probe. A hidden Down syndrome caused by a de novo translocation in this fetus was therefore diagnosed and the karyotype was designated as 46,XY, der(1)t(1;21)(p36.3;q22.1).ish der(1)(WCP21+, LSI 21+, 1pTEL-, 21q TEL+) de novo. Clinical features of the 1p36 deletion syndrome are also reviewed and may contribute to some features of this fetus. Termination of pregnancy was performed at 20 weeks of gestation. CONCLUSION: To our knowledge, our case appears to be the first to have partial monosomy 1p and partial trisomy 21q caused by de novo translocation being diagnosed prenatally.     

A fetus with trisomy 9p and trisomy 10p originating from unbalanced segregation of a maternal complex chromosome rearrangement t(4;10;9)

Complex chromosome rearrangements are only rarely seen in constitutional karyotypes. A case of prenatally detected trisomy 9p with trisomy 10p originating from adjacent segregation of a maternal complex chromosome rearrangement is reported. Ultrasound examination at 18 weeks of gestation showed cleft lip palate, club feet, structural anomalies of the cerebellum and cystic kidneys. Cytogenetic analysis of amnion cells revealed a female fetus with 47,XX,+der(9). FISH analyses together with parental karyotyping demonstrated the fetal additional chromosome to originate from malsegregation of a maternal complex chromosomal rearrangement. The mother is carrier of a balanced translocation t(4;10;9) (q12; p11;q13). Postmortem examination of the fetus showed nose anomalies, cleft lip palate, low set ears, club feet, lung anomalies, cystic kidney and aplasia of the uterus. Reporting of such rare cases is important in order to enable this information to be used for genetic counselling in similar situations.     

Prenatal detection of a de novo terminal inverted duplication 4p in a fetus with the Wolf-Hirschhorn syndrome phenotype

OBJECTIVES: To present the prenatal diagnosis of a de novo terminal inversion duplication of the short arm of chromosome 4 and a review of the literature. CASE: An amniocentesis for chromosome analysis was performed at 33 weeks' gestation because ultrasound examination showed a female fetus with multiple abnormalities consisting of severe intrauterine growth retardation, microcephaly, a cleft lip and renal hypoplasia. RESULTS: Cytogenetic analysis and FISH studies of the cultured amniocytes revealed a de novo terminal inversion duplication of the short arm of chromosome 4 characterized by a duplication of 4p14-p16.1 chromosome region concomitant with a terminal deletion 4p16.1-pter. The karyotype was thus: 46,XX, inv dup del (4)(:p14-->p16.1::p16.1-->qter). The parents opted to terminate the pregnancy. Fetopathological examination showed dysmorphic features and abnormalities consistent with a Wolf-Hirschhorn syndrome (WHS) diagnosis, clinical manifestations of partial 4p trisomy being mild. CONCLUSION: Although relatively rare, inverted duplications have been reported repeatedly in an increasing number of chromosomes. Only two previous cases with de novo inv dup del (4p) and one with tandem dup 4p have been reported, all of them associated with a 4pter deletion. We report the first case diagnosed prenatally. Breakpoints are variable, resulting in different abnormal phenotype. In our case, clinical manifestations resulted in a WHS phenotype.     

Maternal uniparental isodisomy 10 and mosaicism for an additional marker chromosome derived from the paternal chromosome 10 in a fetus

We report a case of maternal isodisomy 10 combined with mosaic partial trisomy 10 (p12.31-q11.1). Chromosome examinations from a CVS sample showed a karyotype 47,XX,+mar/46,XX [corrected]. The additional marker chromosome which was present in 6/25 interphase nuclei was shown by fluorescence in situ hybridization (FISH) to have been derived from a pericentromeric segment of chromosome 10. DNA analysis was performed from umbilical cord blood from the fetus after termination of the pregnancy at 18 weeks. The results showed that the two structurally normal chromosomes 10 were both of maternal origin, whereas the marker chromosome derived from the father. Autopsy of the fetus revealed hypoplasia of heart, liver, kidneys and suprarenal glands, but, apart from a right bifid ureter, no structural organ abnormalities. This fetus represents the second reported instance of a maternal uniparental disomy (UPD) 10.     

Chromosomal abnormalities associated with a single umbilical artery.

A single umbilical artery was seen in 10 out of 117 cytogenetically abnormal pregnancies. The abnormal karyotypes found to be associated with a single umbilical artery were trisomy 18 (n = 5), monosomy X (n = 2), triploidy (n = 1), sex chromosome (47,XYY; n = 1) and translocation (46t(X,5)(q13p15);n = 1). With the exception of the translocation case, all cases with a single umbilical artery had anatomical defects which were detectable ultrasonographically. This suggests that a single umbilical artery alone is not an indication for prenatal fetal karyotyping.     

Prenatal diagnosis of jumping translocation involving chromosome 22 with ultrasonographic findings

We report on the prenatal diagnosis and ultrasonographic findings of a second-trimester fetus with jumping translocation involving chromosome 22. A 28-year-old gravida 2, partus 1, Turkish woman was referred for genetic counselling and ultrasonographic examination at 18 weeks' gestation because of a high risk of trisomy 21 in triple test. Prenatal ultrasonography showed tetralogy of Fallot with a diverticular dilatation of the pulmonary artery, flattened brow, complete absence of the right upper limb, hypospadias, oligodactyly (three digits) in left hand and in both feet, and hyperechogenic abdominal foci. Amniocentesis revealed a karyotype of 46,XY[4]/46,XY,-8,+ der(8),t(8;22)(q24.3;q11.21)[2]/45, XY,-22,-8,+ der(8)t(8;22)(q24.3;q11.21)[22]/45,XY,-22,-5,+ der(5)t(5;22)(q35.3;q11.21)[44]. A C-banding and FISH study with a specific centromeric probe (D14Z1/D22Z1) for chromosome 22 was made. In our case, partial monosomy for the regions 22q11.21-->22pter, 8q24.3-->8qter and 5q35.3-->5qter may partially explain the fetal malformations.     

Prenatal diagnosis of a fetus with partial trisomy 7p

We report a prenatal diagnosis of a fetus with partial trisomy 7p. Ultrasonography at 28 weeks of gestation of a 27-year-old multigravid woman revealed a growth-retarded fetus with agenesis of the corpus callosum, enlarged left kidney, single umbilical artery, hypertelorism, depressed nasal bridge, frontal bossing, irregular maxiller alveolar composition, club feet, flexion deformity of the upper extremities and Epstein anomaly. Fetal karyotype was 46,XX,der(9)add(9p24),16qh+. Our results indicated that the fetus had an unbalanced translocation, which resulted in duplication of the proximal segment of 7p. Maternal karyotype was (46,XX,t(7,9)(p15.3,p24),16qh+). Because fetal death occurred at 31 weeks of gestation, induction of labor was performed. An enlarged anterior fontanel and micrognathia were seen during fetal autopsy. Trisomy 7p is related to a well-known clinical picture with a dismal prognosis. Our report showed that the outcome of the affected pregnancy may also be poor. Detection of fetal chromosomal abnormality and parental translocations are essential for counseling of the parents.     

A dysmorphic newborn infant with a complex rearrangement involving chromosomes 2, 4, and 6 detected by fluorescence in situ hybridization (FISH)

A newborn female infant with multiple congenital anomalies was found to have an unusual and abnormal karyotype. Cytogenetic studies revealed an apparent balanced translocation between chromosome 4q31.3 and chromosome 6q25.1. Additional material on chromosome 2p was identified and determined to be from chromosome 6q by analysis with fluorescence in situ hybridization (FISH). The karyotype is 46,XX,der(2)t(2;6)(p23;q25.1), t(4;6)(q31.3;q25.1). Her mother has a normal female karyotype. The father was unavailable for physical examination or cytogenetic analysis.     

Prenatal diagnosis of trisomy 18p and distal 21q22.3 deletion

OBJECTIVES: To present the perinatal findings and molecular cytogenetic analysis of concomitant trisomy 18p (18p11.2-->pter) and distal 21q22.3 deletion. CASE AND METHODS: A 29-year-old woman, gravida 2 para 1, underwent amniocentesis at 17 weeks' gestation because she was a carrier of a balanced reciprocal translocation, 46,XX,t(18;21)(p11.2;q22.3). Cytogenetic analysis of the cultured amniocytes revealed a karyotype of 46,XX,der(21)t(18;21)(p11.2;q22.3). The fetus had a derivative chromosome 21 with an extra short arm of chromosome 18 attached to the terminal region of the long arm of chromosome 21. Level II sonograms did not find prominent structural anomalies. The pregnancy was terminated subsequently. At autopsy, the proband displayed a mild phenotype of hypertelorism, a small mouth, micrognathia, a narrowly arched palate, low-set ears, and clinodactyly. The brain and other organs were unremarkable. Genetic marker analysis showed a distal deletion at 21q22.3 and a breakpoint between D21S53 (present) and D21S212 (absent), centromeric to the known holoprosencephaly (HPE) minimal critical region D21S113-21qter. CONCLUSION: Genetic marker analysis helps in delineating the region of deletion in prenatally detected unbalanced cryptic translocation. Fetuses with concomitant trisomy 18p and distal 21q22.3 deletion may manifest inapparent phenotypic abnormalities in utero. Haploinsufficiency of the HPE critical region at 21q22.3 may not cause an HPE phenotype.     

Chromosomal 10Q26 trisomy resulting from paternal T(9;10)(PTER;Q26.1).

Distal 10q trisomy is a well defined but rare syndrome, and almost always the result of an unbalanced translocation. Clinical evaluation and cytogenetic molecular analyses were performed in a 6-year-old boy with developmental delay and facial dysmorphism including marked blepharophimosis. His karyotype showed an unbalanced translocation between chromosomes 9 and 10, resulting in trisomy of the distal part of the long arm of chromosome 10q26. A balanced translocation of the segment between chromosomes 9 and 10 with breakpoints at 10q26.1 and 9pter or p24.3 was found in his father, who had normal phenotype. Unlike most cases of partial 10q trisomy which have concurrent partial monosomy of one other translocated chromosome, fluorescence in situ hybridization studies revealed this case to be a pure 10q26 trisomy. The translocated 10q segments in most cases of 10q trisomy originate from the father. Imprinting effect may exist in this chromosomal syndrome; distal 10q trisomy from paternal reciprocal translocations is more compatible with life.     

Confirmation of a balanced chromosomal translocation using molecular techniques

Investigation of a couple, who had produced three babies with cri du chat syndrome, showed initially that the mother had an apparent deletion of chromosome 5. It seemed likely that she had a balanced chromosomal translocation but it proved impossible to detect the second chromosome involved using routine cytogenetic methods. Molecular techniques using quantitative hybridization dosage studies were performed and these showed that the mother had a double dose of DNA in the suspected deleted area of chromosome 5. Further studies, using in situ hybridization techniques, revealed that the missing segment of chromosome 5 had translocated onto the short arms of a C group chromosome and further analysis of prometaphase chromosomes showed the presence of a balanced translocation, 46,XY,t(5;9)(5qter----5p14.1::9p22----9pter;9 qter----9p22::5p14.1----5pter). As a result of these findings, it was possible to offer prenatal diagnosis to the patient in future pregnancies, by detecting the presence of a balanced or unbalanced translocation in the fetus using molecular and cytogenetic techniques.