Prenatal diagnosis and molecular cytogenetic characterisation of a small de novo interstitial duplication 16q11.2-q13

We describe the first prenatally detected case of a small de novo interstitial duplication of chromosome 16q. This chromosomal aberration is extremely rare. Amniocentesis was indicated by advanced maternal age only. Ultrasound examinations of the foetus showed no abnormalities. Conventional and molecular cytogenetic analyses on cultured amniocytes by comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH) using partial chromosome paints and a locus-specific YAC clone revealed a de novo direct duplication of the chromosomal region 16q11.2-q13 leading to a partial trisomy 16q (46,XX,dup(16)(q11.2q13)). There are only five postnatal reports of comparable duplications involving this chromosomal region. These patients presented with little or no associated dysmorphic features but with significant neurodevelopmental delay and severe behavioural problems. After genetic counselling, the parents opted for termination of pregnancy. Post-mortem examination showed slight facial dysmorphic signs, minor dysgenesis of the ovaries and an atypical outflow of the arteria thyroidea ima.     

Neuroblastoma in a dysmorphic girl with a partial duplication of 2p caused by an unbalanced translocation

A 1-year-old female child with multiple dysmorphic features including microcephaly, hypertelorism, a short philtrum, low set ears, a narrow high arched palate, micrognathia and growth retardation was found to have a de novo chromosome abnormality including a partial duplication of the short arm of chromosome 2 and a partial deletion of the long arm of chromosome 17. The clinical features of the case shared many similarities to previous reports of trisomy 2p. Three years later, ecchymotic spots appeared around the left ocular region. Further clinical and pathological examination confirmed the diagnosis of a neuroblastoma. This is the first case of an unbalanced translocation, 46, XX, der (17), t (2; 17) (p23; q25), showing the development of a neuroblastoma in addition to the dysmorphic features. We suggest that trisomy 2p including the N-myc proto-oncogene may have predisposed the patient to the development of a neuroblastoma.     

A patient with a de novo t (6;9) and an interstitial duplication of (9)(q21.2q22.1).

We report on a 4-year-old child with psychomotor retardation, general hypotonia and only mild dysmorphic features. Her chromosome constitution was 46,XX, t (6;9) (q27;q22.1), dup (9) (q21.2q22.1). This de novo interstitial duplication was confirmed using fluorescence in situ hybridisation (FISH) with band-specific probes. This is the second report of a patient with an interstitial duplication of this region of the long arm of chromosome 9. It is concluded that in a child with an abnormal phenotype and a de novo (apparently) balanced translocation, the possibility of a small duplication or deletion should be considered.     

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.     

Aneurysm of the ductus arteriosus in a neonate with 13q-deletion

Aneurysm of the ductus arteriosus is a rare abnormality for which different ways of pathogenesis are described. We report the case of a fatal thrombosis of an aneurysm of the ductus arteriosus in an infant presenting feeding difficulties and a mild dysmorphic facies. Karyotype analysis revealed a de novo chromosomal deletion 46,XY, del (13)(q12.3,q22.3). To the best of our knowledge, this is the first case of an aneurysm of the ductus arteriosus associated with a chromosomal aberration.     

Prenatal diagnosis of de novo t(2;18;14)(q33.1;q12.2;q31.2), dup(5)(q34q34), del(7)(p21.1p21.1), and del(10)(q25.3q25.3) and a review of the prenatally ascertained de novo apparently balanced complex and multiple chromosomal rearrangements

OBJECTIVES: To present the prenatal diagnosis of a de novo complex chromosomal rearrangement (CCR) associated with de novo interstitial deletions and duplication and to review the literature. CASE AND METHODS: Amniocentesis was performed at 18 weeks' gestation because of an increased risk for Down syndrome based on maternal serum alpha-fetoprotein and human chorionic gonadotrophin screening. Amniocentesis revealed a karyotype of 46,XY,t(2;18;14)(q33.1;q12.2;q31.2),dup(5)(q34q34),del(7)(p21.1p21.1), del(10)(q25.3q25.3). The parental karyotypes were normal. The pregnancy was terminated. The fetus manifested facial dysmorphism, clinodactyly of both hands, and hypoplasia of the left great toe. Spectral karyotyping (SKY), cytogenetic polymorphism, and polymorphic DNA markers were used to investigate the imbalances and the origin of the de novo aberrant chromosomes. RESULTS: SKY showed a three-way CCR. Cytogenetic polymorphism investigation of the derivative chromosome 14 of the fetus and the parental chromosomes 14 determined the maternal origin of the translocation. Polymorphic DNA marker analysis confirmed the maternal origin of the de novo interstitial deletions and duplication. No cryptic imbalance at or near the breakpoints of the CCR was detected by the molecular analysis. CONCLUSIONS: De novo apparently balanced CCRs may be associated with imbalances in other chromosomes. We suggest further investigation and re-evaluation of cryptic or subtle imbalances in all cases classified as de novo apparently balanced CCRs.     

A de novo subtelomeric monosomy 11q (11q24.2-qter) and trisomy 20q (20q13.3-qter) in a girl with findings compatible with Jacobsen syndrome: case report and review

We report on a 2-year-old dysmorphic girl with prenatal and postnatal growth deficiency, cardiopathy, left-sided hydronephrosis due to pyelourethral junction stenosis, frequent respiratory infections and psychomotor retardation, in whom a de novo unbalanced submicroscopic translocation (11q;20q) was detected by subtelomeric multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analyses. Additional fluorescence in situ hybridization studies with locus-specific BAC probes and analyses with microsatellite markers revealed that this translocation resulted in a paternal chromosome 11q terminal deletion of approximately 8.9 Mb and a subtelomeric 20q duplication of approximately 3.7 Mb. A subtelomeric 20q trisomy has only been reported in four cases so far. A subtelomeric 11q deletion has been clinically reported in 18 patients. We review the clinical phenotype of these patients. We suggest that patients with a subterminal (11q24.2/25-qter) deletion may present with features of the well-known phenotype of terminal 11q deletion or Jacobsen syndrome.     

Prenatal diagnosis of de novo distal 11q deletion associated with sonographic findings of unilateral duplex renal system, pyelectasis and orofacial clefts

In utero diagnosis of de novo distal 11q deletion associated with renal and orofacial malformations has not been previously described. We present a 35-year-old pregnant woman with prenatal sonographic findings of a unilateral duplex renal system, pyelectasis and orofacial clefts at 20 weeks' gestation. Both genetic amniocentesis and postnatal cytogenetic analysis revealed de novo 46,XX,del(11)(q23). After birth, the fetus manifested a dysmorphic phenotype correlated with del(11q) syndrome. Genetic marker analysis showed a paternally derived distal deletion of chromosome 11q and a breakpoint centromeric to D11S1341. The present case represents the earliest prenatal diagnosis of a duplex renal system, pyelectasis and an additional feature of orofacial clefts associated with distal 11q deletion. Prenatal sonographic detection of a duplex renal system, pyelectasis and orofacial clefts should warrant a careful assessment of fetal anatomy and prompt cytogenetic analysis looking for chromosomal aberrations.     

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.     

Prenatal diagnosis of trisomy for the distal two-thirds of the long arm of chromosome 14 (q21----qter)

A de novo case of 'pure' trisomy 14q21----qter is described which was detected at amniocentesis following an abnormal ultrasound scan of a 25-year-old woman. This is apparently the largest distal 14q duplication reported in a case surviving beyond the first trimester. The infant appeared to have an association of clinical abnormalities previously observed in distal 14q trisomy and proximal 14q trisomy/mosaic trisomy 14.     

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.     

Prenatal cytogenetic assessment and inv(2)(p11.2q13)

OBJECTIVES: To present a series of prenatally detected cases of recurrent pericentric inversions with euchromatic breakpoints and to review the literature to determine whether parental karyotyping is required for genetic counselling. METHODS: Cases of recurrent pericentric inversions with euchromatic breakpoints were collected from Canadian Cytogenetic Laboratories. Cases included inversions for chromosome 1(p13q21), chromosome 2(p11.2q13), chromosome 5(p13q13) and chromosome 10(p11.2q21.2). RESULTS: The incidence of de novo inv(2)(p11.2q13) was low, with one case among 91 inversions. There were no cases of de novo inv(10) (p11.2q21.2) among 17 reported and one case of de novo inv(5)(p13q13) among 21 reported. CONCLUSION: Our study, and data from the literature, suggests that most cases of inv(2)(p11.2q13) have been stably inherited, that de novo cases of inv(2) are rare and that both inherited and de novo forms are without phenotypic or developmental consequences. We suggest that parental karyotyping for cases of inv(2) is not useful in counselling as it may generate unnecessary parental anxiety over a chromosomal finding that is likely innocuous.     

A de novo deletion of chromosome 15(q15.2q21.2) in a dysmorphic, mentally retarded child with congenital scalp defect.

We report a rare chromosomal finding in a boy with a pronounced scalp defect, dysmorphic features and mental retardation. Initially, what seemed to be a normal karyotype by conventional karyotyping was determined to be a de novo deletion involving 15(q15.2q21.2) by high resolution banding. Consequently, prometaphase analysis is warranted in some cases when conventional karyotype analysis appears normal.     

Interstitial deletion of chromosome 14q in a Taiwanese infant with microcephaly.

Deletion (14)(q11.2q13.1) is a rare cytogenetic abnormality associated with severe neurological deficit, microcephaly and psychomotor retardation. We report a case of de novo interstitial deletion of chromosome (14)(q11.2q13.1) in an 8-month-old girl, who presented with marked microcephaly, a nearly closed anterior fontanelle, dysmorphic facies, severe neurological deficits, and delayed developmental milestones. Three-dimensional computed tomography of the brain showed premature closure of the coronal suture and magnetic resonance imaging of the brain showed frontal atrophy and hypoplastic corpus callosum.     

Prenatal diagnosis of a de novo unbalanced translocation (4p+) following in vitro fertilization

We report herein a de novo unbalanced chromosome translocation in a fetus resulting from in vitro fertilization technology. Prenatal diagnostic analysis of an amniotic fluid revealed a 46,XX,4p+ karyotype. The origin of the extra material on the short arm of chromosome 4 could not be identified by a variety of banding techniques. However, examination of fetal parts did reveal some dysmorphic features.     

A novel 2.3 Mb microduplication of 12q24.21q24.23 detected by genome-wide tiling-path resolution array comparative genomic hybridization in a girl with syndromic mental retardation

We report on a female patient with severe mental retardation, dysmorphic features, deafness, spasticity, and behavioural problems in whom a 2.3 Mb duplication of 12q24.21q24.23 was detected by genome-wide tiling-path resolution array-based comparative genomic hybridization. Mental retardation, microcephaly, short stature, recurrent infections, hypotonia and facial features, such as hypertelorism, epicanthal folds, and a broad nasal bridge, were also described in patients with larger duplications overlapping the 12q24.21q24.23 region. The duplicated region contains 16 genes, of which several genes, such as thyroid hormone receptor associated protein 2, replication factor C5 and nitric oxide synthase 1, are expressed in the brain and/or are involved in embryogenesis. The current case shows that microduplications might be a more frequent cause of mental retardation and human malformation than previously appreciated.     

Molecular cytogenetic characterization of a de novo unbalanced translocation leading to trisomy 17q25-->qter and monosomy 18p11.3-->pter in a girl with dysmorphic features

An 18-year-old, gravida 1 underwent percutaneous umbilical blood sampling (PUBS) because of positive triple screen, oligohydramnios and markedly short fetal bones. Chromosome analysis showed an abnormal chromosome 18 with unidentified chromatin at the end of the p-arm. Parental karyotypes were normal. FISH analyses with wcp18 showed additional material of unknown origin on the derivative chromosome 18. Further FISH analysis with subtelomeric probes showed normal signals for the long arm of chromosome 18 (18q23) while no signals were observed for the short arm (18p11.32). These findings were confirmed using a YAC probe from the short arm of 18. The infant was delivered at 30 weeks of gestation. At age 3 months, she was developmentally delayed and has multiple dysmorphic features. Further molecular cytogenetic studies including M-FISH and subtelomere probes showed that the additional material on chromosome 18 consisted of the distal 17q25-->qter region. Based on these studies the karyotype has been interpreted as 46,XX,der(18)t(17;18)(q25;p11.32). To the best of our knowledge, this is the first report of partial monosomy 18p and partial trisomy 17q in a patient with no major CNS malformations. This case shows the importance of molecular cytogenetic techniques in detailed characterization of de novo chromosome rearrangements.     

Prenatal diagnosis and molecular cytogenetic characterization of partial dup (18p)/del (18q) due to a maternal pericentric inversion 18 in a foetus with multiple anomalies

ObjectiveThe 18q terminal deletion with inverted duplication is an extremely rare abnormality, with only three confirmed cases in Europe to date. Here, we report, for the first time, a case of de novo 18q inv-dup-del in a Turkish pregnant woman.Case reportA 30-year-old pregnant woman was referred for genetic analysis at her 25th gestational week due to foetal diaphragmatic hernia and rocker bottom feet. Cytogenetic analysis of the parents revealed a karyotype of 46,XX,inv(18) (p11.3q21.3) of the mother and a normal karyotype of the father. The foetal karyotype was defined as 46,XX,rec(18)del(18q)inv(18) (p11.3q21.3)mat.ConclusionTo our knowledge, this is the first report of a prenatal diagnosis. Genetic counselling issues for this family, particularly affected individuals, include an increased likelihood of reduced fertility and a risk of recurrence of parental inversion equal to 1/2 in surviving offspring.     

Cerebro-fronto-facial syndrome: report of a further case

Cerebro-fronto-facial syndrome had only recently been described in 2001. We present a boy who has dysmorphic features similar to the case described by Der Kaloustian et al. (2001) and propose that he represents a further case of this syndrome.     

Interstitial deletion of the short arm of chromosome 2 in a mother and child, with facial dysmorphism and mild learning difficulties

We report a mother and son with an interstitial deletion of chromosome 2: del(2)(p21p22.2). Both have mildly dysmorphic facial features and learning difficulties. This phenotype contrasts with two previously described cases with a similar deletion that presented with cyclopia and alobar holoprosencephaly.