Gestational age-related reference values for amniotic fluid organic acids.

BACKGROUND: Normative data for amniotic fluid (AF) levels of organic acids at different gestational ages are lacking. They can provide a useful framework to investigate the accuracy of prenatal diagnosis for organic acidemias. METHODS: We report on the concentration of 21 organic acids in AF obtained by gas chromatography/mass spectrometry between the 12th and 34th weeks of gestation from 92 pregnancies that were not at risk for organic acidurias. RESULTS: We infer normal reference values that can be compared with 134 pregnancies at risk for several metabolic conditions, that is, propionic acidemia, methylmalonic acidemia (methylmalonyl-CoA mutase deficiency or defects in cobalamin metabolism), 4-hydroxybutyric acidemia, glutaric acidemia and pyroglutamic acidemia. CONCLUSION: Most of the metabolites tested did not show conspicuous variations across gestational ages in normal fetuses, with ranges that were consistently similar to available reference values from pooled samples in previous reports. With rare exceptions, knowledge of pathological versus normal values for relevant metabolites leads to clear-cut differentiation of affected versus unaffected fetuses. Nevertheless, it is strongly recommended that mutational analysis and/or additional biochemical approaches complement organic acid analysis for an adequate diagnostic workup.

Prenatal diagnosis and normal outcome of a 46,XX/46,XY chimera: a case report.

The phenotypic spectrum of 46,XX/46,XY chimeric patients is variable. It ranges from normal male or female genitalia to different degrees of ambiguous genitalia. Chimerism results from the amalgamation of two different zygotes in a single embryo, whereas mosaicism results from a mitotic error in a single zygote. Several other mechanisms resulting in a chimera have been discussed in the literature. Here, we report on a new case of chimerism (46,XX/46,XY) diagnosed at 17 weeks' gestation on amniocentesis performed because of advanced maternal age. Ultrasound examination revealed normal female external genitalia, and a healthy baby girl was delivered at term. We used polymorphic markers spanning the X chromosome and several autosomes in order to identify the genetic mechanism involved. Mosaicism was excluded because of the presence of 3 alleles at 11 autosomal and 4 X chromosome loci. On autosomes, the origin of this third allele was maternal for two pericentromeric markers (located on 2p11.2 band and 8p11.2 band), paternal for six markers and paternal or maternal for the other three markers. On the X chromosome, the origin of the third allele was maternal for all four markers. Thus, two different paternal and maternal haploid sets were observed. These results are compatible with a tetragametic chimera.

Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development.

BACKGROUND: The acronym CHARGE refers to a non-random cluster of malformations including coloboma, heart malformation, choanal atresia, retardation of growth and/or development, genital anomalies, and ear anomalies. This set of multiple congenital anomalies is frequent, despite rare patients with normal intelligence, and prognosis remains poor. Recently, CHD7 gene mutations have been identified in CHARGE patients; however, the function of CHD7 during development remains unknown. METHODS: We studied a series of 10 antenatal cases in whom the diagnosis of CHARGE syndrome was suspected, considering that a careful pathological description would shed light on the CHD7 function during development. CHD7 sequence analysis and in situ hybridisation were employed. RESULTS: The diagnosis of CHARGE syndrome was confirmed in all 10 fetuses by the identification of a CHD7 heterozygous truncating mutation. Interestingly, arhinencephaly and semi-circular canal agenesis were two constant features which are not included in formal diagnostic criteria so far. In situ hybridisation analysis of the CHD7 gene during early human development emphasised the role of CHD7 in the development of the central nervous system, internal ear, and neural crest of pharyngeal arches, and more generally showed a good correlation between specific CHD7 expression pattern and the developmental anomalies observed in CHARGE syndrome. CONCLUSIONS: These results allowed us to further refine the phenotypic spectrum of developmental anomalies resulting from CHD7 dysfunction.

Prenatal diagnosis and characterization of an analphoid marker chromosome 16.

We report on a fetus with intrauterine growth retardation and multiple malformations diagnosed on ultrasound at 32 weeks. Examination of amniotic fluid cells in culture showed a 47,XY, i(16)(q10), +mar karyotype. Chromosome analysis of both parents was normal. Using spectral karyotyping, we identified the marker chromosome as a mitotically stable acentric marker chromosome derived from chromosome 16. Further studies using subtelomeric fluorescent probes confirmed the presence of an isochromosome for the long arm of chromosome 16 and showed that the acentric marker chromosome derived from the short arm of chromosome 16 leading to a trisomy for the long arm of chromosome 16. After genetic counseling, the parents decided to terminate the pregnancy. Fetal autopsy showed a male fetus with ambiguous external genitalia, cardiac malformation, megacystis and limbs anomalies as observed in other cases of trisomy for the long arm of chromosome 16. In addition, fetal brain examination showed vermian and olfactory bulb hypoplasia.

Maternal uniparental heterodisomy of chromosome 14: chromosomal mechanism and clinical follow up.

To our knowledge, 22 cases of chromosome 14 maternal uniparental disomy (UPD(14)mat) have been reported so far. The majority of cases were ascertained because of an abnormal phenotype associated with a Robertsonian translocation involving chromosome 14. We report here on a child with UPD(14)mat detected prenatally and resulting from trisomy rescue in a maternal meiosis I non-disjunction trisomic zygote. After four years of clinical follow up, in addition to intrauterine growth retardation (IUGR), only short stature and small hands and feet were observed. These clinical data as well as the ascertainment and mechanism of origin of UPD(14)mat were compared with those observed in previously reported cases. It appears that the clinical spectrum of UPD(14)mat is milder in our patient than in patients with UPD(14)mat resulting from other chromosomal mechanisms. In addition, a hypothesis based on abnormal imprinting is proposed to explain the variability of the UPD(14)mat.

Subtle familial unbalanced translocation t(8;11)(p23.2;p15.5) in two fetuses with Beckwith-Wiedemann features.

We describe a subtle translocation t(8;11)(p23.2;p15.5) ascertained after two induced abortions in the same sibship because of the discovery of fetal hydrops on ultrasound examination. Initial cytogenetic studies performed on cultured amniotic fluid cells were considered as normal in both fetuses. High resolution banding analysis and FISH studies performed on the parents' chromosomes revealed a paternal translocation t(8;11)(p23.2;p15.5). Retrospective FISH analysis of both fetuses showed that they carried the same chromosomal imbalance including a distal monosomy 8pter and a distal trisomy 11pter. The phenotypes of the fetuses were re-examined and found to be compatible with Beckwith-Wiedemann syndromes (BWS). FISH analysis using an IGF2 probe demonstrated the presence of three copies of the IGF2 gene. This study highlights the value of searching for subtle chromosome rearrangements in families with recurrent unexplained multiple malformation syndromes discovered prenatally. Also, it contributes to a better delineation of the prenatal phenotype of BWS. Finally, it sheds new light on the aetiology of non-immune hydrops fetalis.

Prenatal diagnosis of a satellited non-acrocentric chromosome derived from a maternal translocation (10;13)(p13;p12) and review of literature.

We identified a familial balanced translocation involving chromosomes 10 and 13 through the finding of a satellited 10p chromosome in a fetus. The phenotype of two unbalanced products of the translocation resulting in pure monosomy 10p13 and trisomy 10p13 is described. This familial case and two of our unreported cases are discussed in the light of other prenatal observations with satellited non-acrocentric chromosomes reported in the literature.

Prenatal detection of a 1p36 deletion in a fetus with multiple malformations and a review of the literature.

The prenatal diagnosis of a 1p36 deletion is reported. The pregnancy was ascertained at 24 weeks of gestation because of the discovery of multiple malformations at ultrasound including hypotelorism, moderate cerebral ventricular dilatation and Ebstein anomaly with secondary cardiac failure. Following cytogenetic studies and counselling, the pregnancy was terminated and a fetal autopsy performed. The phenotype of this antenatally-diagnosed case is compared with the clinical features of 44 previously reported cases with an identical deletion of the short arm of chromosome 1p36.

Prenatal diagnosis of an 8p23.1 deletion in a fetus with a diaphragmatic hernia and review of the literature.

The prenatal diagnosis of an 8p23.1 deletion is reported. The diagnosis was ascertained at 22 weeks of gestation because of the discovery of a diaphragmatic hernia at ultrasound. Following cytogenetic studies and counselling, the pregnancy was terminated. An autopsy confirmed the presence of a diaphragmatic hernia and revealed also the existence of an atrio-ventricular canal (AVC) and an atrial septal defect (ASD). The clinical features of this antenatally diagnosed case are compared with those observed in 16 previously reported cases with an identical deletion of the short arm of chromosome 8. This suggests that a deletion 8p23.1 should be considered whenever a diaphragmatic hernia and/or an AVC is detected on ultrasound.

Molecular cytogenetic analysis of patients with holoprosencephaly and structural rearrangements of 7q.

The holoprosencephaly (HPE) sequence is a malformation complex with abnormal midline cleavage of the embryonic forebrain. HPE is genetically heterogeneous with at least 6 different chromosome regions containing genes involved in the expression of the phenotype. HPE3, recently identified as the human Sonic hedgehog gene, is localized to 7q36. We have used fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) amplification in 5 cell lines from patients with HPE (3 cases), HPE and sacral agenesis (1 case), and microcephaly (1 case) to further define the structural rearrangements of the long arm of chromosome 7 in each case. All cell lines demonstrated loss of material in the critical region of HPE3 at band 7q36, which includes the Sonic hedgehog gene. We report here the analysis of these patient cell lines.

First-trimester translucency: aneuploidy, sonographic findings, and maternal age.

The positive predictive value of 1st-trimester nuchal translucency for the diagnosis of fetal aneuploidy is reported to range from 19 to 72% in retrospective series and from 2.8 to 4.8% in prospective studies. In order to analyze the biases accounting for such discrepancies, we retrospectively analyzed a consecutive series of 66 cases of translucency and studied the rate of aneuploidy as a function of sonographic findings and maternal age. The aneuploidy rate was significantly higher in the 23 cases in whom translucency involved the fetal trunk (65%) than in the 43 cases in whom translucency was confined to the nuchal area (16%). This rate was not significantly higher in septated translucencies. These trends persisted after adjustment for maternal age, but the rate of chromosomal anomalies was twice lower in younger mothers. Among the 46 cases in whom the maternal age was < 35 years, 10% of the 30 fetuses with localized nuchal translucency had an abnormal karyotype. In contrast, the rate of aneuploidy was 85% among the 7 cases with diffuse translucency for whom the maternal age was 35 years or above. These findings confirm that both maternal age and size of the translucency should be taken into account to evaluate the risks of aneuploidy.

Serum hCG assay: a method for detection of contamination of fetal blood samples.

Serum human chorionic gonadotrophin (hCG) can be assayed in specimens obtained by percutaneous fetal blood sampling to check for the absence of maternal blood or amniotic fluid contamination. In order to assess the accuracy of this approach, we measured serum hCG in 44 pure fetal blood samples obtained by intracardiac puncture. The mean fetal serum hCG concentration was 52 IU/l, and the ratio of maternal to fetal serum hCG concentration never exceeded 1.1 per cent, which represents the smallest contamination rate detectable by this method.

Holoprosencephaly and sacral agenesis in a fetus with a terminal deletion 7q36-->7qter.

We describe here a fetus with holoprosencephaly and signs of caudal deficiency sequence. Chromosome examination showed a de novo balanced reciprocal translocation (7;22) (q36;q11) with loss of the derivative chromosome 22 in 50% of the cells examined. The present report and available published data indicate that the terminal region of the long arm of chromosome 7 contains genes implicated in the development of the central nervous system and the caudal region.

Duplication of the long arm of chromosome 13 secondary to a recombination in a maternal intrachromosomal insertion (shift).

A rare chromosomal aberration consisting of a chromosomal shift was found in a woman who had prenatal diagnosis because she had previously had a malformed girl with phenotypic features compatible with the diagnosis of Patau syndrome. Chromosome analysis using G, C, and NOR banding showed a direct intrachromosomal insertion of bands 13q12 to 13q14 onto the short arm of chromosome 13 at band 13p13. We discuss this observation and compare it with other published reports of chromosomal shifts.

Inherited Xq duplication due to a zygotic translocation t(X;X)(q23;q27).

An Xq-duplication was found in a female child with multiple malformations. The family study revealed that her mother, who has a nearly normal phenotype, carries the same duplication. The karyotype of the grandmother shows the existence of a mosaicism: 46,X,del(X) (q23)/46,X,dup(X)(q27----q23). This mosaicism can be related to a translocation t(X;X)(q23;q27) during the first cell division of the zygote.

[Paracentric inversion: a study of 2 new cases]. / A propos des inversions paracentriques: étude de deux nouvelles observations.

Two new cases of paracentric inversion are reported. One involved the short arm of chromosome 1 and affected two generations and the other involved the long arm of chromosome 5 and was described in 5 generations. The relationships between paracentric inversions and reproductive problems are discussed in the light of the literature.

[Paracentric inversions in man. Apropos of 2 familial observations]. / Les inversions paracentriques chez l'homme. A propos de deux observations familiales.

Two observations of paracentric inversion in man are reported. One is located on the long arm of chromosome 1 and was observed over two generations. The other is on the long arm of chromosome 5 and was transmitted over three generations. The possible implications of paracentric inversions on the phenotype and fertility are discussed.

Deletion of band 13q21 is compatible with normal phenotype.

A deletion of band 13q21, of maternal origin, was found in a male whose wife had had two miscarriages. The proband and his mother were both phenotypically normal. Repeated studies by high resolution banding techniques failed to demonstrate a translocation of the deleted band in the two subjects. The absence of pathological consequences of the deletion is explained by the fact that this band is one of the latest replicating in the human karyotype, which may indicate, by analogy with heterochromatin, that it carries no transcriptionally active genetic material.