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.     

Pre- and perinatal findings in partial trisomy 7q resulting from balanced parental translocations t(7;21) and t(4;7)

We report on a fetus and a newborn, both with partial trisomy 7q21-->qter due to different familial translocations, t(7;21)(q21.2;p12) and t(4;7)(q35;q21.2). Postmortem examination of the 19-week-old female fetus disclosed dysmorphic features, cleft palate, anomalies of the great vessels, intestinal malrotation and uterus bicornis. The newborn girl revealed a pattern of minor anomalies, cleft palate, cerebellar hypoplasia, and anomalies of pancreas, gall bladder and appendix. The clinical findings in three other reported fetuses with partial trisomy 7q described so far are reviewed. A duplication 7q21-->qter, as found in the propositi, has only been described in 11 patients who all had a concurrent partial monosomy. Patient 1 is particularly interesting since she is, to our knowledge, the first reported case with pure trisomy 7q21/22-->qter. We reviewed the phenotype of the previously described patients, compared it with the propositae, and summarized the clinical features of pure trisomy 7q21/22-->qter.     

Distal partial trisomy 1q: report of two cases and a review of the literature

We report on two cases with partial trisomy 1q syndrome. One case was a mid-trimester fetus with multiple malformations that was prenatally diagnosed with a de novo distal partial trisomy 1q. Prenatal ultrasound at 24th gestational week demonstrated the presence of cleft lip and palate, increased biparietal diameter and decreased abdominal circumference. Cytogenetic analysis (GTG banding) and subsequent fluorescence in situ hybridization (FISH) using whole chromosome paint 1 and multicolor banding (MCB) demonstrated an aberrant karyotype 46,XY,dup(1)(q31q43 approximately 44). The second case was a newborn male infant with multiple congenital malformations. He had a derivative chromosome 18 as a result of a maternal insertion involving chromosomes 1 and 18. Further analyses including MCB showed his karyotype as 46,XY,ins(18;1)(q22;q23q31.1 approximately 32). The present cases and a review of the literature suggest that partial trisomy of the long arm of chromosome 1 is a distinct clinical entity.     

Prenatal foetal diagnosis of partial trisomy 3q and monosomy 13p due to a maternal balanced rearrangement

The authors describe a case of a male foetus whose ultrasound at 20 weeks' gestation revealed cystic hygroma, cleft lip and ventricular septal defect. Amniotic fluid cytogenetics using GTG banding showed a 46,XY,der(13)t(3;13)(q12;p11.1) rearrangement, and fluorescence in situ hybridization (FISH) delineated the relevant breakpoints. Familial studies identified a maternal balanced translocation involving chromosomes 3 and 13. The post-mortem examination confirmed the prenatal ultrasound findings.     

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 and fetal pathology of partial trisomy 20P-monosomy 4P resulting from paternal translocation

Amniocentesis was performed in view of a paternal balanced chromosomal rearrangement t(4;20)(p16;p12), inv(18)(p11q11). The pregnancy was complicated by severe oligohydramnios. The fetal karyotype was unbalanced: 46XX, der(4), t(4;20)(p16;p12), inv(18) (p11q11)pat., thus resulting in partial trisomy 20p and monosomy 4p. In addition, the amniotic fluid alpha-fetoprotein (AFP) became increasingly elevated with gestational age. The pregnancy was terminated at 25 weeks. The fetus presented with typical facial dysmorphic features, unilateral cleft lip and palate, severe renal hypoplasia, consistent with the 4p-(Wolf-Hirschhorn) syndrome.     

Sacrococcygeal teratoma in a fetus with prenatally diagnosed partial trisomy 10q (10q24.3-->qter) and partial monosomy 17p (p13.3-->pter)

OBJECTIVE: Clinical features of the distal 10q trisomy syndrome consist of mental retardation, facial dysmorphism and renal and cardiac anomalies. The presence of a sacrococcygeal teratoma (SCT) in a fetus with distal 10q trisomy has not been reported yet. METHODS: A 33-year-old, G5, P2 woman with a singleton pregnancy was referred to our clinic at 24 weeks of gestation for further evaluation of a fetal sacral exophytic mass. Detailed fetal sonographic examination together with chromosomal analysis by amniocentesis was performed. RESULTS: The scan revealed a large SCT together with a persistent right umbilical vein, cardiomegaly, bilateral mild hydronephrosis and intrauterine growth retardation. The fetal karyotype showed distal 10q trisomy (10q24.3-->qter) distal monosomy 17 (p13-->pter). The fetus died after a preterm delivery at 28 weeks of gestation. Postnatal examination confirmed the prenatal findings and added the typical facial features of this syndrome, which consisted of prominent forehead, small nose with depressed nasal bridge, micrognathia and bow-shaped mouth. CONCLUSION: This case provides further evidence of a possible association between chromosomal aberrations in SCTs.     

Prenatal diagnosis and molecular cytogenetic analysis of partial monosomy 10q (10q25.3-->qter) and partial trisomy 18q (18q23-->qter) in a fetus associated with cystic hygroma and ambiguous genitalia

OBJECTIVES: To present the prenatal diagnosis and molecular cytogenetic analysis of a fetus with nuchal cystic hygroma and ambiguous genitalia. CASE AND METHODS: Amniocentesis was performed at 16 weeks' gestation because of the abnormal fetal sonographic finding of a large septated nuchal cystic hygroma. Genetic amniocentesis revealed a terminal deletion in the long arm of chromosome 10. The paternal karyotype was subsequently found to be 46,XY,t(10;18)(q25.3;q23). The maternal karyotype was normal. The pregnancy was terminated. A hydropic fetus was delivered with a septated nuchal cystic hygroma and ambiguous genitalia. Fluorescence in situ hybridization (FISH), microarray-based comparative genomic hybridization (CGH), and polymorphic DNA markers were used to investigate the involved chromosomal segments. RESULTS: FISH study showed absence of the 10q telomeric probe and presence of the 18q telomeric probe in the derivative chromosome 10. Microarray-based CGH analysis showed loss of distal 10q and gain of distal 18q. Polymorphic DNA marker analysis determined the breakpoints. The fetal karyotype was 46,XY,der(10)t(10;18)(q25.3;q23)pat. The chromosome aberration resulted in partial monosomy 10q (10q25.3-->qter) and partial trisomy 18q (18q23-->qter). CONCLUSIONS: The present case provides evidence that partial monosomy 10q (10q25.3-->qter) with partial trisomy 18q (18q23-->qter) can be a genetic cause of fetal cystic hygroma and ambiguous genitalia. Cytogenetic analysis for prenatally detected structural abnormalities may detect unexpected inherited chromosome aberrations.     

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.     

Complete trisomy 9 with unusual phenotypic associations: Dandy-Walker malformation,cleft lip and cleft palate,cardiovascular abnormalities

ObjectiveTrisomy 9 is a rare chromosomal abnormality usually associated with first-trimester miscarriage; few fetuses survive until the second trimester. We report two new cases of complete trisomy 9 that both present unusual phenotypic associations, and we analyze the genetic pathway involved in this chromosomal abnormality.Case reportThe first fetus investigated showed Dandy-Walker malformation, cleft lip, and cleft palate) at the second trimester scan. Cardiovascular abnormalities were characterized by a right-sided, U-shaped aortic arch associated with a ventricular septal defect (VSD). Symmetrical intrauterine growth restriction and multicystic dysplastic kidney disease were associated findings. The second fetus showed a dysmorphic face, bilateral cleft lip, hypoplastic corpus callosum, and a Dandy-Walker malformation. Postmortem examination revealed cardiovascular abnormalities such as persistent left superior vena cava draining into the coronary sinus, membranous ventricular septal defect, overriding aorta, pulmonary valve with two cusps and three sinuses, and the origin of the left subclavian artery distal to the junction of ductus arteriosus and aortic arch.ConclusionComplete trisomy 9 may result in a wide spectrum of congenital abnormalities, and the presented case series contributes further details on the phenotype of this rare aneuploidy.     

Syndromic encephalocele in a fetal case with a 1p35-pter deletion and a 14q32-qter duplication inherited from a maternal balanced translocation

Occipital encephalocele belongs to the family of neural tube defects, which occur in one among 2000 to 5000 live births. Syndromic encephaloceles include Meckel-Gruber syndrome and various chromosomal abnormalities. We report on a fetal case (13 WG) with bilateral cleft lip and palate, choanal atresia, occipital encephalocele, bilateral club feet, bilateral multicystic kidneys, enlarged bladder and urethral atresia. The fetal chromosome analysis showed a maternally inherited unbalanced translocation between the short arm of chromosome 1 and the long arm of chromosome 14, resulting in 1p35-pter deletion and 14q32-qter duplication (46,XY,der(1),t(1;14)(p35;q32)). Since the chromosomal breakpoints have not previously been implicated in syndromic encephalocele, this observation is of interest for the identification of other genes responsible for occipital encephalocele.     

An infant with trisomy 9 mosaicism presenting as a complete trisomy 9 by amniocentesis.

We present a case in which amniocentesis performed at 33 weeks' gestation because of symmetrical intrauterine growth retardation and decreased amniotic fluid volume led to the prenatal diagnosis of a fetus with a karyotype of 47,XX,+9,t(1;20)(q42;p11.2) pat, i.e., with an extra chromosome 9 and a balanced translocation between chromosomes 1 and 20. At delivery, the baby showed clinical features of trisomy 9, yet chromosome analysis of the cord blood revealed no trisomy 9 cells, a finding confirmed by neonatal blood karyotyping. The balanced translocation was present in all cells. A skin biopsy confirmed trisomy 9 mosaicism with 10 per cent trisomy 9 cells. The baby died at 6 weeks and an autopsy was obtained. Chromosome analysis of different organs demonstrated different frequencies of the mosaicism of trisomy 9. The possible underlying mechanism for the discrepancy between the karyotype results by amniocentesis and those of other tissues is discussed.     

Prenatal diagnosis of a fetus with pure partial trisomy 1q32-44 due to a familial balanced rearrangement

We diagnosed a pure partial trisomy of the long arm of chromosome 1 in a fetus with multiple malformations detected prenatally. The father was a carrier of a balanced rearrangement involving 46,XY,inv(1)(qter-->p36::q32-->qter::p36-->q32). The fetus had preaxial polydactyly, low-set ears, macrocephaly, a prominent forehead, a broad and flat nasal bridge, a small mouth, an arched palate, micrognathia and unilateral renal agenesis. The couple had previously an infant with the same phenotypic abnormalities. The aberration was initially detected on amniocentesis with GTG banding and was confirmed by fluorescence in situ hybridization (FISH). Our case and other published pure trisomy 1q32-44 cases showed similarities, which allowed the further delineation of the trisomy 1q syndrome.     

Bilateral renal agenesis and fetal ascites in association with partial trisomy 13 and partial trisomy 16 due to a 3:1 segregation of maternal reciprocal translocation t(13;16)(q12.3; p13.2).

A female fetus with bilateral renal agenesis and fetal ascites was found to have partial trisomy 13 (pter-q12.3) and partial trisomy 16 (p13.2-pter), 47,XX,+der(13)t(13;16)(q12.3; p13.2)mat. The chromosomal aberration was due to a 3:1 segregation with tertiary trisomy transmitted from a maternal reciprocal translocation 13;16. Prenatal ultrasound of a 29-year-old, gravida 2, para 0 woman at 22 gestational weeks showed fetal ascites, severe oligohydramnios and non-visualization of fetal urinary bladder and kidneys. The pregnancy was terminated. At delivery, the proband displayed dysmorphic features of hypertelorism, a prominent glabella, epicanthic fold, a stubby nose with a depressed nasal bridge, anteverted nares, thin lips, micrognathia, low-set ears, a short neck and a distended abdomen. Necropsy confirmed bilateral renal agenesis and ascites. A cytogenetic study performed on fibroblasts obtained from the proband's skin revealed an extra supernumerary chromosome. The mother was later found to have a reciprocal translocation. Fluorescence in situ hybridization for a submicroscopic deletion in chromosome 22q11 in the proband was negative. The parents had no urological anomalies. Our observation further extends the clinical spectrum associated with proximal trisomy 13q and distal trisomy 16p. We suggest prenatal cytogenetic analysis in fetuses with urological anomalies, including renal agenesis, to uncover underlying genetic disorders.     

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.     

Partial duplication of 3q and distal deletion of 10q inherited from a maternal balanced translocation.

Partial trisomy 3q syndrome is often the result of an unbalanced translocation or inversion. The duplicated segments are mostly from 3q25 to 3qter. We describe a karyotype of 46,XY,der(10)t(3;10)(q25.3;q26.1) in a 1-day-old male infant who presented with multiple congenital anomalies including synophrys, a long philtrum, thin lips with down-turned angles of the mouth, micrognathia, a high-arched and cleft palate, clenched hands, genital hypoplasia, cryptorchidism, a large ventricular septal defect, a subependymal cyst, and corpus callosum hypoplasia. The patient had cardiopulmonary distress resulting from multiple congenital anomalies. He died of heart failure at the age of 18 days. The chromosome aberration resulted from a maternal balanced translocation. The dup(3q) syndrome superficially resembles but can be distinguished from Brachmann-de Lange syndrome. Craniofacial features, cleft palate and urinary tract anomaly are more frequent in dup(3q) syndrome. Oligodactyly and phocomelia are more characteristic of Brachmann-de Lange syndrome.     

Small inherited terminal duplication of 7q with hydrocephalus,cleft palate,joint contractures,and severe hypotonia

We report a 14-month-old girl with submucous cleft palate, resolving mild hydrocephalus, severe hypotonia and joint contractures. The finding of extreme hydrocephalus, cleft palate and club feet in a fetus of the mother's previous pregnancy suggested an inherited defect. Chromosome analysis and FISH studies in the proband revealed an abnormal homolog 13 resulting in a duplication of distal chromosome 7q, 7q35-qter, and a very small associated deletion of distal chromosome 13q, 13q34-qter. The mother showed the balanced translocation. Similar clinical signs have been described with larger distal 7q duplications. Our findings suggest that 7q35-qter, and possibly the gene for sonic hedgehog (SHH) on 7q36, is the critical region for the typical facial features and the profound hypotonia observed in the 'trisomy of distal 7q' syndrome.     

Six cases of deletion 9p24 and trisomy 19q13.4 inherited from a familial balanced translocation.

The deletion 9p with trisomy 19q syndrome is a rare disorder. We report 2 adults and 4 children with deletion 9p and trisomy 19q due to familial balanced 9p;19q translocation with clinical features suggestive of monosomy 9p. The children had dysmorphic features and psychomotor retardation while the adults were self-sufficient but worked in a sheltered environment. High-resolution chromosome analysis and fluorescence in situ hybridization confirmed that the 6 cases of unbalanced translocation, der(9)t(9;19)(p24.1;q13.4) were inherited from a balanced translocation carrier, t(9;19)(p24.1;q13.4). The dysmorphic features included trigonocephaly, small nose with stunted tip, and long philtrum. Associated anomalies included wide-set nipples, extra finger flexion creases, hernia, external genitalia hypoplasia, scoliosis, and hypopigmented skin patch. We suggest that genetic counseling is necessary for those who have family members with dysmorphic features and/or major anomalies and/or psychomotor retardation.     

Rhombencephalosynapsis in a severely polymalformed fetus with non-mosaic tetrasomy 9p, in intracytoplasmic-sperm-injection pregnancy

CASE REPORT: A fetus with rhombencephalosynapsis and prenatally diagnosed tetrasomy 9p is reported. Chromosomal analysis from amniocyte culture revealed non-mosaic supernumerary chromosome identified as isochromosome 9p (9p24-->q13::q13-->p24). Ultrasound scan revealed intrauterine growth retardation, renal anomalies, cardiac anomalies, ventriculomegaly, and agenesis of cerebellar vermis with fusion of the cerebellar hemispheres. CONCLUSION: Although most cases of cerebellar vermis agenesis in tetrasomy 9p are described with cystic malformation such as Dandy-Walker anomaly, our case indicates that this chromosomal disorder should be taken into account in fetuses with the development of cystic and non-cystic malformations of cerebellar vermis and posterior fossa.     

De novo monosomy 9p24.3-pter and trisomy 17q24.3-qter characterised by microarray comparative genomic hybridisation in a fetus with an increased nuchal translucency

OBJECTIVES: Increased nuchal translucency (NT) during the first trimester of pregnancy is a useful marker to detect chromosomal abnormalities. Here, we report a prenatal case with molecular cytogenetic characterisation of an abnormal derivative chromosome 9 identified through NT. METHODS: Amniocentesis was performed because of an increased NT (4.4 mm) and showed an abnormal de novo 46,XX,add(9)(p24.3) karyotype. To characterise the origin of the small additional material on 9p, we performed a microarray comparative genomic hybridisation (microarray CGH) using a genomic DNA array providing an average of 1 Mb resolution. RESULTS: Microarray CGH showed a deletion of distal 9p and a trisomy of distal 17q. These results were confirmed by FISH analyses. Microarray CGH provided accurate information on the breakpoint regions and the size of both distal 9p deletion and distal 17q trisomy. The fetus was therefore a carrier of a de novo derivative chromosome 9 arising from a t(9;17)(p24.3;q24.3) translocation and generating a monosomy 9p24.3-pter and a trisomy 17q24.3-qter. CONCLUSION: This case illustrates that microarray CGH is a rapid, powerful and sensitive technology to identify small de novo unbalanced chromosomal abnormalities and can be applied in prenatal diagnosis.