Fetal phenotype of Prader–Willi syndrome due to maternal disomy for chromosome 15

Prader–Willi syndrome (PWS) results from either paternal deletion of 15q11–q13, or maternal uniparental disomy (UPD) of chromosome 15 or imprinting center mutation. Prenatal diagnosis of PWS is currently indicated for chromosomal parental translocation involving chromosome 15 and for decreased fetal movements during the third trimester of gestation. Here we present the prenatal diagnosis of PWS during the first trimester of gestation and autopsy findings. Chorionic villus sampling (CVS) was performed for advanced maternal age at 13 weeks' gestation. CVS showed mosaicism including cells with a normal karyotype and cells with trisomy 15. Amniocentesis showed cells with a normal karyotype. Molecular analysis demonstrated that the fetus had a typical PWS abnormal methylation profile and maternal disomy for chromosome 15. Fetal ultrasound examination showed slightly enlarged lateral ventricles and hypoplasic male external genitalia without intra-uterine growth retardation. The autopsy showed a eutrophic male fetus with facial dysmorphy, hypoplasic genitalia, abnormal position of both feet and posterior hypoplasia of the corpus callosum. This report points out that in a karyotypically normal fetus with ambiguous male external genitalia and cerebral anomalies, extensive cytogenetic and molecular biology studies are strongly recommended because of risk of PWS. Copyright © 2003 John Wiley & Sons, Ltd.     

Prenatal diagnosis of primary anophthalmia with a 3q27 interstitial deletion involving SOX2

We report an interstitial deletion of chromosome 3q26-q28 in a fetus in which anophthalmia had been detected prenatally. FISH analysis, using BAC clones encompassing the SOX2 locus, showed that SOX2 gene was involved in the chromosomal breakpoint of the deletion. This case confirms that haploinsufficiency for SOX2 plays a crucial role in human eye development and emphasizes the necessity of careful chromosomal analysis, including FISH analysis of the 3q region, in case of prenatal discovery of anophthalmia. Copyright © 2004 John Wiley & Sons, Ltd.     

Double-outlet right ventricle with absent left ventricle and mitral atresia in a fetus with a deletion 22q12

Interstitial deletions of chromosomal region 22q12 are rare. We report the prenatal diagnosis of a de novo interstitial deletion 22q12. The fetus was karyotyped because of a complex cardiac anomaly. Conventional and molecular cytogenetics showed a female karyotype with a de novo pericentric inversion of one chromosome 22 associated with a deletion of the chromosomal region 22q12 leading to a partial monosomy 22q12. At autopsy, the fetus showed double-outlet right ventricle (DORV) with absent left ventricle and mitral atresia. This observation suggests that one or several genes for the early looping step of heart development may reside in chromosomal region 22q12. Further studies are needed to identify these genes, and to search microdeletions of 22q12 region in patients with DORV. Copyright © 2004 John Wiley & Sons, Ltd.     

Increased fetal nuchal fold leading to prenatal diagnosis of ring chromosome 15

We report on the prenatal diagnosis of ring chromosome 15 in a fetus with increased nuchal fold and intrauterine growth restriction (IUGR). A 27-year-old woman gravida 2, para 1 had normal maternal serum screen tests in the early second trimester of the index pregnancy. Fetal nuchal fold thickening up to 8 mm was incidentally found during the routine obstetric ultrasound scan at 20 weeks' gestation. Amniocentesis was undertaken and the fetal karyotype was found to be 46,XY,r(15) on cytogenetic study. Fluorescence in situ hybridization (FISH) using a telomeric probe of chromosome 15 demonstrated a terminal deletion on the q arm of the ring-shaped chromosome 15. This is the first report of a prenatally diagnosed case of ring chromosome 15. Moreover, nuchal fold thickness in the second trimester may have a role in its prenatal diagnosis. Copyright © 2001 John Wiley & Sons, Ltd.     

Female pseudohermaphroditism in a fetus with a deletion 9(q22.2q31.1)

Interstitial deletions of chromosomal region 9q are rarely seen. We report the first prenatal diagnosis of a de novo interstitial deletion 9q. The fetus was karyotyped for intrauterine growth retardation (IUGR). Conventional and molecular cytogenetics showed female karyotype with a de novo deletion of the chromosomal region 9(q22.2q31.1) leading to a partial monosomy 9q. At autopsy, the fetus showed growth retardation, dysmorphy, and a female pseudohermaphroditism. These results suggest that a gene(s) for genital development reside in chromosomal region 9q22.2q31.1. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal diagnosis of a homologous Robertsonian translocation involving chromosome 15

We report the prenatal diagnosis of a fetus with a de novo Robertsonian translocation: 45,XY,der(15;15)(q10;q10). Although Robertsonian translocations are common chromosomal rearrangements, those involving homologous chromosomes are infrequent. Since chromosome 15 is imprinted, uniparental disomy (UPD) is a concern when chromosomal rearrangements involving chromosome 15 are identified. In the present case, UPD studies showed normal biparental inheritance. In contrast to the fact that most homologous acrocentric rearrangements are isochromosomes, these results indicate postzygotic formation of a Robertsonian translocation between biparentally inherited chromosomes 15. Copyright © 2001 John Wiley & Sons, Ltd.     

Structural chromosomal mosaicism and prenatal diagnosis

True structural chromosomal mosaicism are rare events in prenatal cytogenetics practice and may lead to diagnostic and prognostic problems. Here is described the case of a fetus carrying an abnormal chromosome 15 made of a whole chromosome 2p translocated on its short arm in 10% of the cells, in association with a normal cell line. The fetal karyotype was 46,XX,add(15)(p10).ish t(2;15)(p10;q10)(WCP2+)[3]/46,XX[27]. Pregnancy was terminated and fetus examination revealed a growth retardation associated with a dysmorphism including dolichocephaly, hypertelorism, high forehead, low-set ears with prominent anthelix and a small nose, which were characteristic of partial trisomy 2p. Possible aetiologies for prenatal mosaicism involving a chromosomal structural abnormality are discussed. Copyright © 2004 John Wiley & Sons, Ltd.     

Monosomy 8q: Prenatal diagnosis and autopsy findings

The autopsy findings of a fetus with deletion of the long arm of chromosome 8 are described. Many of the features are similar to those of the tricho-rhino-phalangeal syndromes, types I and II, which are associated with deletions on chromosome 8q24. Other findings in this case, such as total absence of the corpus callosum and intestinal malrotation, have not been described in these syndromes. Genes involved in the development of the latter malformations may reside in adjacent regions on the long arm of chromosome 8. An elevated serum level of beta human chorionic gonadotropin (βhCG) was found during pregnancy. This aberration should be included with other chromosomal disorders which may be detected by this test.     

Del(18p) syndrome with increased nuchal translucency in prenatal diagnosis

We report a de novo translocation between chromosome 15 and 18 resulting in monosomy 18p in prenatal diagnosis. The patient was referred for amniocentesis due to increased nuchal translucency (INT) (5 mm) at 13.6 weeks of gestation. Karyotype of the fetus revealed 45,XX,der(15;18)(q10;q10) in all metaphases. The targeted fetal ultrasound at 20 weeks of gestation did not show any special physical abnormalities other than 6.4 mm of nuchal fold thickness. Molecular cytogenetic findings using CGH and FISH confirmed the del(18p) with dicentromeres from both chromosome 15 and 18. The present study shows that the INT at first trimester was the only prenatal finding for the fetus with del(18p) syndrome and that molecular cytogenetic methods are useful for detecting chromosomal aberrations precisely. Copyright © 2004 John Wiley & Sons, Ltd.     

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. Copyright © 2001 John Wiley & Sons, Ltd.     

Fetoscopic tracheal occlusion for treatment of non-isolated congenital diaphragmatic hernia

Fetoscopic endotracheal occlusion (FETO) is a prenatal treatment that may increase survival in severe congenital diaphragmatic hernia (CDH). In the USA, FETO is offered for isolated severe left-sided CDH in the context of an FDA-approved feasibility study. FETO in non-isolated cases of severe CDH is only performed with a compassionate use exemption from US regulatory bodies. Anomalies frequently associated with CDH include congenital cystic lesions of the lung and cardiac defects. We describe two cases of non-isolated severe left-sided CDH that underwent prenatal FETO, survived after birth and underwent postnatal surgical repair. The potential benefit of FETO in this setting is discussed. © 2017 John Wiley & Sons, Ltd.     

Neuropsychiatric aspects of 22q11.2 deletion syndrome: considerations in the prenatal setting

Most major neuropsychiatric outcomes of concern to families are not detectable by prenatal ultrasound. The introduction of genome-wide chromosomal microarray analysis to prenatal clinical diagnostic testing has increased the detection of pathogenic 22q11.2 deletions, which cause the most common genomic disorder. The recent addition of this and other microdeletions to non-invasive prenatal screening methods using cell-free fetal DNA has further propelled interest in outcomes. Conditions associated with 22q11.2 deletions include intellect ranging from intellectual disability to average, schizophrenia and other treatable psychiatric conditions, epilepsy, and early-onset Parkinson's disease. However, there is currently no way to predict how severe the lifetime expression will be. Available evidence suggests no major role in these neuropsychiatric outcomes for the congenital cardiac or most other structural anomalies that may be detectable on ultrasound. This article provides an outline of the lifetime neuropsychiatric phenotype of 22q11.2 deletion syndrome that will be useful to clinicians involved in prenatal diagnosis and related genetic counselling. The focus is on information that will be most relevant to two common situations: detection of a 22q11.2 deletion in a fetus or newborn, and new diagnosis of 22q11.2 deletion syndrome in a parent without a previous molecular diagnosis. © 2016 John Wiley & Sons, Ltd.     

Prenatal overgrowth and mosaic trisomy 15q25-qter including the IGF1 receptor gene

Overgrowth is rarely associated with chromosomal imbalances. Here, we report on a male foetus presenting with overgrowth and additional material on the short arm of one of the chromosome 15 in 12% of lymphocytes and 50% of amniotic cells. Parents' karyotypes were normal, indicating a de novo origin for this unbalanced rearrangement. Complementary studies using cytogenetic and FISH studies showed that this additional material resulted in a 15q25-qter trisomy and confirmed the presence of three copies of the insulin-like growth factor 1 receptor (IGF1R) gene, included in the trisomic region. Autopsy performed after termination of pregnancy revealed isolated overgrowth and absence of visceral malformations. The possible mechanisms and origins for the formation of this mosaic pure trisomy are complex. The present observation emphasises the hypothesis that the overgrowth phenotype, frequently reported in patients with trisomy including the 15q26 region, might be causally related to a dosage effect of the IGF1R gene, as well as the importance of chromosome analysis in patients with overgrowth. It also confirms that the overgrowth is of prenatal onset in those observations. Copyright © 2004 John Wiley & Sons, Ltd.     

Prenatal diagnosis of del(15)(q11q13)

A case of del(15)(q11q13) was detected in amniotic fluid cell cultures and confirmed by cordocentesis in a 27-year-old woman with a low maternal serum alpha-fetoprotein level. The fetus was shown to have a short femoral length on ultrasonography. This structural chromosome abnormality associated with the prenatal ultrasonographic findings and the morphological characteristics visualized after termination of pregnancy strongly suggest Prader-Willi syndrome.     

The value of chromosome analysis in cases of neural tube defects: A case of anencephaly associated with fetal DUP(2) (p24→pter)

A family is described in which two anencephalic fetuses were identified in two pregnancies. Autopsy revealed kidney anomalies in both fetuses. Chromosome analysis was performed only on the second fetus, which had a 46,XY,lOq+ karyotype. Parental chromosome analysis showed the maternal karyotype to be 46,XX,t(2;10) (p24;q26) thus demonstrating that the fetus was carrying a duplication 2(p24→pter). Recurrence risks for anencephaly based on the cytogenetic abnormality were much higher than those which would be quoted for isolated anencephaly. This points out the necessity for complete diagnostic studies when a fetus with a neural tube defect is identified. The literature in regard to the 2p duplication phenotype is reviewed. It is possible that the duplication of the distal segment of 2p results in a neural tube defect/kidney anomaly phenotype.     

The possibility of prenatal diagnosis by gene dosage: Confirmation of duplication 10q24→qter from Got-l activity in fetal erythrocytes

The activity of four enzymes, including GOT-1, has been investigated in the erythrocytes of a 10q→24qter trisomic fetus. Analyses have been performed on a feto-maternal blood mixture sampled by fetoscopy and on red cells obtained by cardiac puncture, following therapeutic abortion. The demonstration of a 40 percent increase of GOT-1 activity, as compared to normal fetuses of similar gestational age, suggests that gene dosage studies may be a useful confirmatory technique in prenatal diagnosis of unbalanced chromosomal aberrations. Practical application of a similar diagnostic approach is conditioned by (1) precise characterization of fetal chromosome imbalance; (2) confirmed assignment of the gene locus coding for the gene product under investigation; (3) evidence of a linear proportionality between gene dose and concentration of the gene product in patients with the same chromosome imbalance detected in the fetus; (4) knowledge of the range of normal variation at different weeks of gestation of the enzyme activity to be tested in the fetus; (5) safety of fetal sampling procedure.     

Syndromic congenital diaphragmatic hernia: Current incidence and outcome. Analysis from the congenital diaphragmatic hernia study group registry

Background

The aim of this study was to describe the incidence of Congenital Diaphragmatic Hernia, CDH, associated with known or clinically suspected syndromes, and the postnatal outcomes from a large database for CDH.

Methods

Data from the multicenter, multinational database on infants with CDH (Congenital Diaphragmatic Hernia Study Group Registry) born from 1996 to 2020 were analyzed. Patients with known or suspected syndromes were grouped and outcome data were analyzed and compared to those without syndromic features.

Results

A total of 12,553 patients were entered in the registry during the study period, and 421 had reported known syndromes, representing 3.4% of all CDH cases in the registry. A total of 50 different associated syndromes were reported. In addition to those with clinically suspected genetic conditions, a total rate of genetic syndromes with CDH was 8.2%. The overall survival to discharge for syndromic CDH was 34% and for non-syndromic CDH was 76.7%. The most common were syndromes Fryns syndrome (19.7% of all syndromes, 17% survival), trisomy 18 or Edward syndrome (17.5%, 9% survival), trisomy 21 or Down syndrome (9%, 47% survival), trisomy 13 or Patau syndrome (6.7%, 14% survival), Cornelia de Lange syndrome (6.4% of all syndromes, 22% survival) and Pallister-Killian syndrome (5.5% of all syndromes, 39.1% survival). In addition, 379 cases had reported chromosomal anomalies and 233 cases had clinically suspected syndromes, based on two more dysmorphic features or malformations in addition to CDH, but without molecular diagnosis. The syndromic CDH group had lower birth weight and gestational age at birth and increased incidence of bilateral CDH (2.9%) and rates of non-repair (53%). The length of hospital stay was longer, and larger number of patients needed O₂ at 30 days. Extracorporeal life support was used only in 15% of the cases. Those who underwent surgical repair had survival to discharge rates of 73%.

Conclusion

Syndromic CDH is rare and only 3.4% of the reported cases of CDH have a known syndrome or association, but, if including patients with two dysmorphic features malformations, in addition to CDH, altogether as many as 8.2% have a diagnosed or suspected genetic condition. These children have with lower survival rates. Given higher rates of non-repair and decreased extracorporeal life support use, along with a high early mortality, decision-making regarding goals of care clearly influences outcomes. Survival varies depending on the genetic cause. Early genetic diagnosis is important and may influence the decision-making.     

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∼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∼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. Copyright © 2007 John Wiley & Sons, Ltd.     

Evaluation of prenatal diagnosis of associated congenital heart diseases by fetal ultrasonographic examination in Europe

Ultrasound scans in the mid trimester of pregnancy are now a routine part of antenatal care in most European countries. With the assistance of Registries of Congenital Anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of congenital heart defects (CHD) by routine ultrasonographic examination of the fetus. All congenital malformations suspected prenatally and all congenital malformations, including chromosome anomalies, confirmed at birth were identified from the Congenital Malformation Registers, including 20 registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK and Ukrainia. These registries follow the same methodology. The study period was 1996–1998, 709 030 births were covered, and 8126 cases with congenital malformations were registered. If more than one cardiac malformation was present the case was coded as complex cardiac malformation. CHD were subdivided into ‘isolated’ when only a cardiac malformation was present and ‘associated’ when at least one other major extra cardiac malformation was present. The associated CHD were subdivided into chromosomal, syndromic non-chromosomal and multiple. The study comprised 761 associated CHD including 282 cases with multiple malformations, 375 cases with chromosomal anomalies and 104 cases with non-chromosomal syndromes. The proportion of prenatal diagnosis of associated CHD varied in relation to the ultrasound screening policies from 17.9% in countries without routine screening (The Netherlands and Denmark) to 46.0% in countries with only one routine fetal scan and 55.6% in countries with two or three routine fetal scans. The prenatal detection rate of chromosomal anomalies was 40.3% (151/375 cases). This rate for recognized syndromes and multiply malformed with CHD was 51.9% (54/104 cases) and 48.6% (137/282 cases), respectively; 150/229 Down syndrome (65.8%) were livebirths. Concerning the syndromic cases, the detection rate of deletion 22q11, situs anomalies and VATER association was 44.4%, 64.7% and 46.6%, respectively. In conclusion, the present study shows large regional variations in the prenatal detection rate of CHD with the highest rates in European regions with three screening scans. Prenatal diagnosis of CHD is significantly higher if associated malformations are present. Cardiac defects affecting the size of the ventricles have the highest detection rate. Mean gestational age at discovery was 20–24 weeks for the majority of associated cardiac defects. Copyright © 2001 John Wiley & Sons, Ltd.