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Strategies for studying the genetics of autoimmune diseases have undergone a considerable evolution during the last years, especially due to molecular biology techniques and to systematic genome studies. Genetic factors account for 20 to 40% of the risk, and environmental elements play a major role. The major histocompatibility complex comprising HLA genes remains the immunogenetic system most studied and most closely associated with various autoimmune diseases. These associations are mainly observed with HLA class II genes polymorphisms; the precise knowledge of their structure has allowed to define HLA sequence polymorphisms which are themselves risk markers: specific combinations of HLA-DQA and DQB alleles in insulin-dependent diabetes mellitus or a given DR, DQ haplotype for multiple sclerosis. No strong association with HLA-DP has been demonstrated. In all cases the genes involved have a normal structure and the disease is secondary to the combination of a given set of genes with environmental factors. The present knowledge of insulin-dependent diabetes mellitus and multiple sclerosis genetics is rather advanced. Other genes of the HLA region might also be involved in the genetic susceptibility. Results about other immunogenetic systems (T cell receptor genes or heavy chain immunoglobulin genes) are still contradictory but no major gene for autoimmune susceptibility seems to exist in these regions; however autoimmune diseases are under polygenic control; susceptibility genes shared between different diseases often occurring within the same families (Graves' disease and insulin-dependent diabetes mellitus) and genes specific for a given disease (insulin gene region in diabetes) both exist. The present rapid progress in this area is due to the use of highly polymorphic markers randomly distributed across the genome (microsatellites being most informative) and that of animal models: the list of "candidate genes or regions" potentially involved in the genetics of autoimmune diseases is enlarging; the development of coordinated epidemiological studies of molecular genetics along with the sharing of biological resources between different teams allow to build up powerful informative studies which will confirm or refute those "candidates". However, once the list of genes involved is established their mechanism of action will still take time to elucidate.

Registration of congenital malformations began in 1979 in the French department of Bas-Rhin. The results of the first 10 years of functioning of this register are presented after description of the objectives and methodology used. 131,760 consecutive births were analysed: 2.66% of infants presented with malformations. The most frequent malformations consisted of congenital heart defects (11.6%). The increase in incidence of congenital malformations was not the result of an absolute increase in malformations but to improvement of prenatal and postnatal diagnosis allowed by the technical progress in this field. In utero diagnosis of congenital malformations, especially of multiple malformations, was more and more often performed.

Our registry of congenital anomalies allows us to study systematically pregnancies which ended in the birth of a malformed child. Over 8 years 105,374 births were registered. A control was selected for each malformed baby. Numerous factors are studied. One of them is oligohydramnios. During the study period 199 children carriers of at least one congenital major malformation were born after a pregnancy complicated by oligohydramnios; which represent an incidence of 1.88%. Overall 2,787 malformed children were born during the study period, 7.14% of them were born after oligohydramnios (controls 1.6%, p less than 0.001). The malformations which were more often associated with oligohydramnios involved the urinary system (15.9%), the digestive system (10.2%), the genital system (5.9%) and the limbs (5.7%). A chromosomal aberrations was present in 11 infants (5.5%). Most of the isolated malformations were not associated with oligohydramnios, whereas the pregnancies which ended with the birth of a malformed baby were often complicated by oligohydramnios. Therefore when a fetal malformation is discovered during pregnancy the obstetrician should not be satisfied with the discovery of one anomaly associated with oligohydramnios. He (she) has to look carefully for other associated fetal malformations. The weight, the length and the head circumference at birth of the children born after oligohydramnios were less than those of the controls (p less than 0.001). The length of gestation was shorter (p less than 0.01). The weight of the placenta was smaller. In this study the only maternal factors which favoured the occurrence of oligohydramnios were diabetes and epilepsy.

Serum levels of zinc, copper, manganese, magnesium, folates and vitamin B12 and A, were titrated in the early stage of pregnancy in women who delivered children presenting malformations. These levels were compared with those of control patients who delivered normal children. There were 65 malformations. The most frequent were cardiac, musculo-skeletal, urogenital and chromosomal malformations. Only 2 cases of spina bifida were studied. The oligo-elements and vitamin levels are not different in both groups of women: those who carry malformed fetuses and those carrying normal fetuses. These results are compared with those from the literature.

Four years ago a class was started with 8 children from 7 to 11 years of age with Down's syndrome. The classroom is in a state school. The children lived at home. They were with the other children of the school for several classes and for lunch. Like other children they learned reading, writing and arithmetic. Psychomotricity was emphasized. The children's I.Q. and behavior were studied before entering the class. After 24 to 30 months every child was able to read and write. Their I.Q.'s were retested after 4 years and the results were far better than previously. The children gained confidence and began to cope very well at school and outside school.

A father and his daughter has the same features: short stature, the distal phalanges, the wrists, the elbows, the feet and the knees were flexed. All other joints had abnormal range of motion. Kypho-scoliosis was present in the father only. Father's family was normal. Upon X-rays examination no abnormalities could be seen. This syndrome is inherited as autosomal dominant.

A pedigree of branchio-oto-renal dysplasia (BOR syndrome) is reported. BOR syndrome is an autosomal dominant disorder in which affected individuals may have branchial fistulas or cysts, preauricular pits, structural defects of the outer, middle an inner ear with hearing loss, and renal anomalies which may range from mild hypoplasia to complete absence. As shown in our pedigree, all carriers of the gene may not present with all features of the syndrome. In all individuals presenting with preauricular pits and branchial clefts, both otologic and renal investigations should be performed. Genetic counselling of family members is indicated.

In order to verify the hypothesis that during pregnancy in a woman without peculiar history, signs could be discovered when the fetus is malformed we have reviewed the files of 175 women who had a malformed child and of 300 controls. All of these women had at least one clinical examination and one ultrasonographic examination during pregnancy. Two clinical symptoms were more often discovered in the mother of the malformed fetus (p less than 0.001): decrease of fetal movements and small for date fetus. The placenta is never abnormal in the mother with normal fetus. Placenta is abnormal in 31% of the mother with malformed fetus but the abnormalities are not specific. Ultrasonographic examinations allowed more often the discovery of a malformation when hydramnios (p less than 0.001) or fetal hypotrophy (p less than 0.01) or an anomaly of the morphology of the fetus is discovered. Accuracy of prenatal diagnostic is considered for the different categories of congenital malformations.

A case-control study of neural tube defects (NTD) was undertaken from 1979 to 1986 in the department of Bas-Rhin in Northeastern France. For 105,374 consecutive births the incidence of spina bifida was 0.62 in 1,000, the incidence of anencephaly was 0.33 in 1,000 and that of encephalocele was 0.14 in 1,000. Sex ratios were respectively 1.06, 0.64 and 0.75. Among the numerous etiological factors which were studied we observed a seasonal factor (more conceptions in April, less in September). Birth weight and length were lower in children with spina bifida than in controls. Metrorrhagia was more frequent during pregnancies with anencephaly as was oligoamnios in pregnancies with encephalocele. Routine US prenatal diagnosis, which was performed in 90% of the pregnant women, allowed diagnoses in 88% of the fetuses with anencephaly but only in 53% of the fetuses with spina bifida and in 64% of the fetuses with encephalocele. For these last two anomalies diagnosis could often be performed because a malformation was associated with a NTD.