Population screening for aneuploidy using maternal age and ultrasound.

The coexistence of an epidemiological register and a multidisciplinary centre for prenatal diagnosis promoted us to report data collected during six years (1990-1995) in Isère county on prenatally detected chromosomal aberrations. During the whole study period prenatal diagnosis strategy towards chromosome aberrations was based solely on maternal age and ultrasound examination. Results showed a respective contribution of one-third/two-thirds for the two detection modes (maternal age/ultrasound signs). From 1990 to 1995 a significant increase in the proportion of prenatally detected autosomal aneuploidy was observed, from 52 per cent to 75 per cent (P < 0.001). This significant variation was mainly due to an increase in the proportion of prenatally detected trisomy 21 cases, and to an increase in the proportion of aberrations which were detected through first trimester ultrasound examination. The highest positive predictive values were observed for polymalformation, cardiac anomalies and cystic hygroma ultrasound signs (51 per cent, 21 per cent and 26 per cent, respectively). Our results for trisomy 21 are close to those obtained in other studies, even when prenatal strategies are different. Their interest lies in the fact that they can be considered as a reference level of prenatal diagnosis efficiency due to a strategy based on maternal age and ultrasound signs, a level which has to be taken into account when evaluating the benefits of additional serum screening policies in other studies.

Pregnancy outcome after artificial insemination or IVF with frozen semen donor: a collaborative study of the French CECOS Federation on 21,597 pregnancies.

OBJECTIVE: To assess pregnancies and conceptus after artificial insemination (AID) or IVF with frozen semen donor (IVF-D) on sufficiently large study population in order to distinguished minor variations. STUDY DESIGN: From 1987 to 1994, all pregnancies obtained after AID or IVF-D were registered prospectively in the French CECOS Federation data base. Different factors were recorded for this study: first menarche age of the recipient women, cycle length, insemination date in the conception cycle, maternal age at delivery, hormonal treatments, donor age, sperm conservation length and follow up of the pregnancy: miscarriage, tubal pregnancy, time at delivery, sex of the foetus, weight, malformation. RESULTS: 21,597 pregnancies obtained after AID and 3381 after IVF-D were registered. 2% were lost to follow up. Foetal loss rate is 18% after AID and 21.5% after IVF-D (p < 0.001). The tubal pregnancy rate is 0.9% after AID and 1.7% after IVF-D (p < 0.0001). 18,128 children were born after AID and 3313 after IVF-D. After AID, the twin pregnancy rate is 6.9% and the multiple pregnancy (> or = 3 foetus) rate is 0.7%. After IVF-D, these rates are 24.8% and 4.2% respectively (p < 0.0001). After AID the mean weight at delivery, sex ratio, premature rate, intra uterine growth retardation rate are not different from national rates published in 1995. The foetus malformation rate (including medical abortions) is 1.9% after AID and 2.7% after IVF-D (p < 0.009). After AID the trisomy 21 rate increases with the mother age but also with the donors age if the maternal age is equal. The birth defects rate is not different from those registered in Paris, Strasbourg and Marseille. The birth defects rate observed after IVF-D is not different from the rate observed after IVF with husband semen. (2.74% versus 2.99%; p = 0.16). CONCLUSION: After AID the miscarriage and tubal pregnancy rate, the children's weight, the premature rate is not different from that of the general French population. Sex ratio is normal as is the global malformation rate. The multiple pregnancy rate (x 7 for twin and by 10 for multiple pregnancies more than 3 foetus) is high, showing the influence of ovulation induction treatment. The birth chromosomal abnormalities rate is normal and correlated not only to the mother's age but also to the donor's age. This result without clear biological explanation will require further verification in a greater population. Practically speaking, these observations encourages lowering the age limit for semen donors less than 45 years. IVF-D practice instead of AID doubles the tubal pregnancy rate (0.9% versus 1.7% and increases the twin pregnancy rate by 2.5% and the multiple pregnancy (> or = 3 fetus) rate by 3. It is necessary to promote good practice for AID for which the pregnancy rate is very different from one centre to another within the centres with AID low results a too high rate of IVF-D. Finally we can say that pregnancies from IVF-D or IVF with husband semen are not significantly different. In other words pregnancy outcome is not changed after sperm cryopreservation.

Incidence of birth defects after artificial insemination with frozen donor spermatozoa: a collaborative study of the French CECOS Federation on 11,535 pregnancies.

Artificial insemination using cryogenically preserved spermatozoa has been widely used in human reproduction for several decades. No evaluation of the resulting pregnancies and conceptions has been undertaken in sufficiently large study populations for minor variations to be distinguished. This study involves 11,535 pregnancies conceived by artificial insemination using donor spermatozoa and followed from the time that pregnancy was diagnosed. The pregnancies followed a normal course with, in particular, no excessive fetal losses. While the global incidence of birth defects was similar to that of natural conception, our observations raise doubts concerning trisomy 21. The frequency of trisomy 12 was somewhat elevated when compared with French malformation registries. A recruitment bias could, in part, explain this discrepancy, but donor age cannot be excluded as an influencing factor.

[Wilms tumor and Bloom syndrome]. / Tumeur de Wilms et syndrome de Bloom.

UNLABELLED: Bloom syndrome is characterized by growth failure, skin anomalies with sun sensitivity, minor anatomic defects, excessive chromosomic fragility and usually severe immune deficiency. The chromosome fragility predisposes these children to the development of hematologic malignancies and solid tumors. CASE REPORT: Morgan, a 4-year-old boy with Bloom syndrome, developed a Wilms tumor. Chemotherapy was poorly tolerated. Two years later, the child died from an uncontrolled progressive disease. CONCLUSION: This is the fourth reported case of Wilms tumor occurring in a child with Bloom syndrome. This possibility requires repeated abdominal ultrasonography in such patients.

[Which genetic tests in infertile men?]. / Quel bilan génétique chez l'homme infertile?

Genetic investigations of idiopathic male infertilities should be systematic and should include a familial inquiry, a careful physical examination looking for one of the many genetic syndromes with male sterility and the karyotype. Moreover the search of a microdeletion in Yq AZF region should be undertaken as soon as it is possible; The licity of ICSI in genetic male infertility is discussed depending on the autosomal recessive or Yq linked genetic origin.

Cartographic study: breakpoints in 1574 families carrying human reciprocal translocations.

Reciprocal translocations (rcp) are among the most common constitutional chromosomal aberrations in man. Using a European database of 1574 families carrying autosomal rcp, a cartographic study was done on the breakpoints involved. The breakpoints are non-randomly distributed along the different chromosomes, indicating "hot spots". Breakpoints of rcp that result in descendants that are unbalanced chromosomally at birth are more frequent in a distal position on chromosomal arms, and 65% of them are localised in R-bands. Among the R-bands, bands rich in GC islands and poor in Alu repetitive sequences are more frequently the site of breakpoints, as well as bands that include a fragile site. This result suggests that the variation in degree of methylation in GC islands could be involved in chromosomal breakage and hence in chromosomal rearrangements. The heterogeneity of the human chromosomal structure has been demonstrable by metaphase banding techniques since 1970. In contrast to G-bands, R-bands are sites of high gene concentration (Korenberg et al. 1978), are relatively rich in cytosine plus guanine (GC), and in Alu repetitive DNA sequences (Korenberg and Rykowski 1988). More recently Holmquist (1992) has proposed four types of R-bands, depending on their relative richness in GC and Alu DNA sequences. R-bands rich in GC correspond almost exactly to T-bands (Dutrillaux 1977). They contain 65% of all genes while they represent only 15% of the genome (Holmquist 1992). The aim of this study is to analyse the distribution of the breakpoints along chromosomes from a European database of autosomal rcp in order to relate it to the specificity of different chromosomal regions.

Cloning of a balanced translocation breakpoint in the DiGeorge syndrome critical region and isolation of a novel potential adhesion receptor gene in its vicinity.

Deletions of the 22q11.2 have been associated with a wide range of developmental defects (notably DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome and isolated conotruncal cardiac defects) classified under the acronym CATCH 22. A DiGeorge syndrome patient bearing a balanced translocation whose breakpoint maps within the critical region has been previously described. We report the construction of a cosmid contig spanning the translocation breakpoint and the isolation of a gene mapping 10 kb telomeric to the breakpoint. This gene encodes a novel putative adhesion receptor protein, which could play a role in neural crest cells migration, a process which has been proposed to be altered in DiGeorge syndrome.

[Human familial autosomal reciprocal translocations]. / Les translocations réciproques autosomiques familiales humaines.

Reciprocal translocations are one of the most frequently observed structural chromosome abnormalities. They are defined by a segment exchange between two non-homologous chromosomes. A great number of different translocations exist since any chromosome can be involved in the translocation and the position of the breakpoint can vary. Though generally silent these translocations can be expressed in the form of reproduction failure or, more seriously, as offspring showing mental retardation/malformation syndromes. Since the risk of malformation varies from one translocation to the next, genetic counselling and prenatal diagnosis strategies should be adopted to suit the particular malformation risks of each individual translocation. This is currently not the case. Different prediction methods (for the most probable mode of unbalance at birth, the risk of unbalance at term) are presented. A computer system, called Reci-Conseil brings these different functionalities together to create a new aid for genetic counselling. The data base on which it is founded (approx 2000 families) offers interesting perspectives for genomic mapping of partial trisomies and monosomies.

Viability thresholds for partial trisomies and monosomies. A study of 1,159 viable unbalanced reciprocal translocations.

From a data base of 1,590 independent families with autosomal reciprocal translocations, 1,159 viable unbalances were studied and the lengths of their trisomy/monosomy segments measured according to the method proposed by Daniel. About 5% of cases were found not to comply with Daniel viability criteria. The thresholds of viability vary with the mode of unbalance and with the sex of the carrier. Thus, new viability criteria are proposed as a guide for genetic counseling and prenatal diagnosis.

Logistic regression model to estimate the risk of unbalanced offspring in reciprocal translocations.

The aim of this study was to estimate the risk of viable unbalanced offspring for a parental carrier of reciprocal translocation. On a large computerized database of reciprocal translocations we used logistic regression to model this risk. The status of the progeny is the outcome variable. Explanatory covariates are cytogenetic characteristics of the translocation, age and sex of the parental carrier, and potential viability of the gametes. The results obtained by the logistic model demonstrate the important role of certain variables such as the sex of the parental carrier and the R band length of the translocated segments. Within the group of lower risk (risk of viable unbalanced offspring less than 5%), 97% of the individuals are correctly classified with this model. For this group, the choice prenatal diagnosis can be best discussed by considering both the risk for viable unbalanced offspring and the risk of induced abortion following prenatal diagnosis.

Human reciprocal translocations: is the unbalanced mode at birth predictable?

Two methods of prediction for the risk of unbalance at birth were tested on a large data base of reciprocal translocation (1376 families): the pachytene diagram predictive method (PDP method) and the discriminant method (D method). These method succeeded in correctly predicting the segregation mode in 66% of the data for the PDP method and in 80% of the data for the D method. The quality of chromosome material (in particular R bands) must be taken into account for more accurate prediction. Some difficulties still exist in predicting the 3:1 tertiary segregation mode, which can frequently be incorrectly classified as the adjacent 1 mode.

Human reciprocal translocations: a new computer system for genetic counseling.

A new computer system for genetic counseling in reciprocal translocations is described. This system, namely RCPc (RCP counseling) is a knowledge base extracted from a data base called SCD (Structural Chromosome Data) which contains 1376 families carrying reciprocal translocations. RCPc gives key information for each translocation which allows an evaluation of the risk of unbalance at birth and a prediction of the characteristics of potential unbalances. This information could provide a useful basis for deciding whether a prenatal diagnosis is required and if so, the preferred sampling method i.e. amniocentesis or chorionic villus sampling (CVS).

[Prenatal diagnosis of mucoviscidosis: indication of enzyme determination and molecular biology techniques]. / Diagnostic anténatal de la mucoviscidose: indication du dosage enzymatique et des techniques de biologie moléculaire.

Prenatal diagnosis of cystic fibrosis established by study of RFLPs flanking the gene and, since 1989, by direct detection of the major mutation delta F508 is now widely used. However, there are still some indications of prenatal diagnosis by microvillar intestinal enzymes analysis. We propose a prenatal diagnosis strategy which combines both methods. This diagnosis strategy is applied to families with a 1/4 to 1/200 risk. Screening of delta F508 in the general population is discussed.

Non-Hodgkin's lymphomas with t(11;14)(q13;q32): a subset of mantle zone/intermediate lymphocytic lymphoma?

We here describe 13 patients with non-Hodgkin's lymphoma (NHL) and a translocation t(11:14)(q13:q32). They were part of a series of 163 patients with NHL and an abnormal karyotype, serially referred to our institution between January 1984 and 1990. Patients with t(11:14) seem to present several common and interesting features. Males are more frequently affected than females, and old people more than young. They present at diagnosis with advanced disease and usually show involvement of epithelium and bone marrow. With respect to histologic diagnoses, these patients are usually considered to be of low-grade malignancies. However, most of them do very poorly, have short complete remission and frequent relapses whatever the treatment. As a whole, the median survival rate is rather low. The cytologic, histologic as well as the immunologic patterns tend to be uniform: tumours are composed of small cells and display features of mantle zone/intermediate lymphocytic lymphoma. They express high IgM and low IgD levels and more commonly bear Ig lambda light chains. They also express all pan-B antigens (except CD23) as well as the CD5 antigen, but usually lack the CD10. According to these characteristics, these tumours could be placed in between lymphocytic lymphomas (which usually express CD23) and follicular lymphomas (which commonly lack IgD and CD5 and bear CD10 as well as a t(14:18).

Localization of 27 DNA markers to the region of human chromosome 22q11-pter deleted in patients with the DiGeorge syndrome and duplicated in the der22 syndrome.

DiGeorge syndrome is a human developmental field defect with the pathological features of an abnormality of embryogenesis at 4 to 6 weeks of gestation. Cytogenetic analyses of patients have revealed a number of instances of monosomy 22q11-pter in this condition. We have analyzed 52 DNA markers that map to 22q11-pter and have found 27 that are deleted in DiGeorge syndrome patients with known monosomy for part of this region and that are duplicated in patients with the der22 syndrome. The set of clones mapping to the DiGeorge region was further assigned to a proximal or a distal location within the deletion.

Translocation t(3;22)(q23;q11) in three patients with diffuse large B cell lymphoma.

In our series of 134 patients with a diagnosis of non-Hodgkin's lymphoma (NHL) and clonal chromosomal abnormalities, three were found to show an identical t(3;22)(q28;q11) translocation. All were old patients with isolated lymphadenomegaly and diffuse large noncleaved cell lymphoma. All expressed a B cell immunophenotype, and all entered a complete remission when treated with aggressive chemotherapy. This translocation could, therefore, delineate a particular subtype of diffuse large cell NHL.

Translocation t(13;17)(q12-14;p12-13) in two patients with lymphocytic lymphoma.

Cytogenetic studies were performed at the time of diagnosis on two patients with diffuse small cell lymphocytic lymphoma. Both patients had a similar simple karyotype with a t(13;17)(q12-14;p12-13). These observations confirm the nonrandom involvement of band 13q13 in chronic lymphoproliferative diseases.

Genetic aspects of artificial insemination with donor semen: the French CECOS Federation guidelines.

The genetic problems raised by assisted reproduction using donor gametes (AID) are numerous and often complex. They concern the legitimacy and the appropriate forms of genetic screening for both gamete donors and recipients; the identification of genetic indications justifying the use of this method of reproduction; and ascertainment of the state of health of the conceptus at birth. The experience and guidelines of the French CECOS Federation, which comprises 20 AID treatment centers, are described. The discussion emphasizes the need for an international exchange of view on this subject.