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About half the cases of infertility have their origin in the male partner. Infertility due to males has several possible aetiologies. In about 30% of cases, genetic disorders are suspected of being the main cause. They could interfere with the development of the male gonads, the urogenital tract or the hypothalamo-hypophyseal axes. Such disorders could also stop germ cell generation and maturation or lead to the production of non-functional spermatozoa. Genetic disorders of chromosomal origin could give rise to abnormal karyotypes or germinal mosic figure. They could involve gene abnormalities affecting numerous genes localized on several chromosomes, in particular the Y chromosome. The physiopathologic identification of male infertility is interesting because of the risk of the genetic factors involved being transmitted to the offspring. The subject is of importance, specially because of the increasing use of intracytoplasmic sperm injections. Couples should therefore be precisely counselled to enable them to make a well-informed choice among various solutions, e.g. ART, with or without sperm donation, or adoption.

Diffuse leiomyomatosis (DL) with Alport syndrome (AS) has been shown to be associated with contiguous gene deletions of the COL4A5 and COL4A6 genes, with the COL4A6 breakpoint of the deletions invariably located in the large intron 2 of the gene. We describe four YAC clones covering the locus and a refined restriction map of the entire COL4A6 gene. These resources have allowed us to make a precise estimate of the size of COL4A6 introns 2 and 3, as well as the size of the gene itself. We also describe five novel deletions which, in conjunction with previous reports, allow the definition of a 90-kb critical region in which to search for a gene or other entity involved in the pathogenesis of DL.

Purpose Myelodysplastic syndrome with chromosomal translocation t(5;12)(q31-33;p12-13) and eosinophilia is a new entity recently described. Nine cases have been described in adults. We report the first pediatric case with a long follow-up (7 years). Patients and methods An 8-year-old girl presented with hyperleukocytosis, eosinophilia, and no clinical symptoms. Bone marrow investigations revealed myeloid hyperplasia and clonal chromosomal translocation t(5;12)(q31;p12-13). No treatment was prescribed, but 4 years later the white blood cell count reached 144 X 10(9)/L with immature myeloid cells and splenic enlargement. Hydroxyurea chemotherapy led to a hematopoietic remission. The patient is now 16 years old and well, >7 years after the initial diagnosis. Results The association: myelodysplastic syndrome, eosinophilia and translocation t(5;12)(q31-33;p12-13), seems to be a specific hematologic disorder. Study of cases previously reported in the literature shows the most important characteristics of this disease. However, there are still a number of questions about the disease itself (especially its treatment) and the significance of the chromosomal abnormalities. Conclusion This case seems to be the first report of the disease in a child and has had the longest follow-up. Other data should be collected to improve our knowledge of this hematopoietic disorder.

Retinitis pigmentosa (RP) represents a group of clinically heterogeneous retinal degenerations in which all modes of inheritance have been described. We have previously found two different clinical profiles in X linked RP as a function of age and mode of onset. The first clinical form has very early onset with severe myopia. The second form starts later with night blindness with mild myopia or none. At least two genes have been identified in X linked forms, namely RP2 (linked to DXS7, DXS255, and DXS14) and RP3 (linked to DXS84 and OTC) on the short arm of the X chromosome. In order to contribute to phenotype-genotype correlations in X linked RP, we tested the hypothesis that the two clinical profiles could be accounted for by the two different gene loci. The present study provides evidence for linkage of the clinical form with early myopia as the onset symptom with the RP2 gene (pairwise linkage to DXS255: Z = 3.13 at theta = 0), while the clinical form with later night blindness as the onset symptom is linked to the RP3 gene (pairwise linkage to OTC: Z = 4.16 at theta = 0).

In patients with androgen insensitivity syndrome (AIS), RFLP study of the androgen receptor gene made it possible to analyze whether deletions or mutations could be responsible for abnormalities in androgen responsiveness. We studied RFLPs of DNA from 25 46,XY patients with partial AIS (PAIS), defined as a concentration of androgen receptor in genital-skin fibroblasts less than 340 fmol/mg DNA, and DNA from 27 46,XY patients with complete AIS (CAIS) with no detectable androgen receptor site. DNA samples were digested with BamHI, EcoRI, HindIII and TaqI restriction enzymes and hybridized with three cDNA probes covering the three domains of the androgen receptor. When we had the maternal and an unaffected brother's DNA, we analyzed the two androgen receptor gene polymorphisms described, the HindIII and the exon 1 CAG repeat polymorphisms, in order to distinguish the two maternal X chromosomes, and to detect carriers of AIS. We did not find any large deletion among the 52 patients. We observed a heterozygous mother in 3 of 14 families studied with the HindIII polymorphism, and in 12 of 25 families using the exon 1 CAG repeat polymorphism. This study suggests that in AIS, abnormalities in androgen receptor response could be related to point mutations or microdeletions rather than to gross structural alterations of the androgen receptor gene. Furthermore, unless the point mutation has been described, exon 1 and HindIII polymorphism studies would enable the identification of carriers in 50% of families, and the prenatal diagnosis of AIS.

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report here the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 11 families affected by various forms of hypophosphatasia. Nineteen distinct mutations were found, 7 of which were previously reported. Eleven of the 12 new mutations were missense mutations (Y11C, A34V, R54H, R135H, N194D, G203V, E218G, D277Y, F310G, A382S, V406A), the last one (998-1GT) was a mutation affecting acceptor splice site.

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report here the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 11 families affected by various forms of hypophosphatasia. Nineteen distinct mutations were found, 7 of which were previously reported. Eleven of the 12 new mutations were missense mutations (Y11C, A34V, R54H, R135H, N194D, G203V, E218G, D277Y, F310G, A382S, V406A), the last one (998-1G>T) was a mutation affecting acceptor splice site.

Une inversion pericentrique du chromosome 2 a ete decelee dans 4 familles non apparentees. Les points de cassures sont identiques en 2p11 et 2q13. Les accidents de la reproduction constates chez ces couples sont analyses. La pathologie du chromosome 2 interessant cette zone particuliere est discutee.

Epidemiological studies have suggested that non-specific X-linked mental retardation (XLMR) might be at least as frequent as the fragile X syndrome. The identification of all mutations causing XLMR would thus appear of prime importance. In the absence of other clinical signs the problem of genetic heterogeneity is acute. This can be partly overcome by the analysis of large families. We have been able to perform linkage analysis in 3 such families. The condition in family 1 was described as clinically resembling the fra (X) syndrome by Proops et al [1983]: the kindred includes 7 affected males in 3 sibships. Family 2 from Denmark has affected males in 4 generations; however, several affected relatives in this extended pedigree are deceased. Family 3 from France counts 6 affected males in two sibships. The families were analysed with about 25 X-linked markers. Linkage with markers in Xp22.2-p22.3 was found in family 1: z(theta) = 2.62 at theta = 0.06 for DXS85 (probe 782). Suggestion of linkage was found in family 2 with both the Duchenne muscular dystrophy region (DXS164 in Xp21.2) and with DXS1 (Xq11-q12). In family 3, DXS159 (Xq12-q13) gave a lod score of 2.53 at theta = 0; results were compatible with localisation of the putative XLMR locus in this family proximal to DXYS1 (Xq21). These data suggest that at least two non-specific XLMR loci could exist, one in Xp22 and the other in the q12-q13 region.

The syndrome of ectrodactyly, ectodermal dysplasia and cleft lip-palate is described in a boy aged 3; although inherited in most cases as an autosomal dominant trait, it seems here to be sporadic. An atopic dermatitis clinically evident and particularly resistant to treatment is present, but IgE level is not raised. Ophthalmologic changes are prominent. Systematic intravenous pyelogram showed urinary tract strictures.

We report a case of congenital malaria due to a chloroquine-resistant strain of Plasmodium falciparum acquired in Mali. Ours is the first report of chloroquine-resistant congenital malaria in this part of Africa. We recall the various pathophysiologic, diagnostic and therapeutic features of this disease that should be considered in every neonate born to a mother who may have malaria. Although such cases are infrequent, we also discuss the very serious problems, mainly therapeutic, that they raise in several countries where they are endemic (South-East Asia and Africa particularly).

The limitation of amniocentesis is emphasised by a mother with trisomy 21 who had a baby with a normal karyotype but with malformations. The question is posed whether half the infants of women with trisomy 21 are normal and half have a trisomy. With more observations it may become apparent that there are an excess of children without the trisomy.

An experience of three centers of genetic counselling (West France). The authors attempts to explain why in 9 cases the pregnancy was not terminated.

The authors report the results of anmiocenteses carried out early in 57 cases, in order to detect hereditary disorders in high risk pregnancies. They emphasize the necessity of prior genetic consultation and obstetric examination. Among the 57 cases, 53 had the examination carried out in order to seek a chromosome anomaly. The techniques of removal and culture are described. One pregnancy was interrupted, the foetus had a chromosome abnormality. The psychological aspect and the necessity of close cooperation between gynecologists and geneticians are discussed.

After a brief review of the dysgenetic abnormalities which may affect the ear, branchial arches and pouches and the kidneys, the authors summarise those syndromes associating abnormalities of the ear and kidney on the one hand, and secondly abnormalities of the ear and facial and cervical fistulae. However, they are specifically interested in the branchio-oto-renal syndrome, reporting 5 cases. The syndrome combines deafness (middle ear and inner ear), pre-auricular and cervical fistulae and renal abnormalities. They attempt to summarise the syndrome by combining these 5 cases with the 15 published previously (4 initial cases of Melnick in 1974, 4 cases of Fitch in 1976, 7 of Fraser in 1978). The genetically transmissible nature of the syndrome would appear to be beyond doubt. The branchio-oto-renal syndrome was described for the first time in 1974 by Melnick, Bixter and Silk, who reported its existence in a father and three of his children, with an association of a malformation of the middle ear (block of the stapes), of the inner ear (cochlear hypoplasia), bilateral pre-auricular fistulae, bilateral cervical fistulae and renal hypoplasia with or without displasia. In 1974, Fitch and Srolowitz reported 4 new cases, and Fraser, Ling, Ologe and Nogrady a further 7 in 1978. The 5 cases published here bring the total known number to 20.

After defining the clinical, roentgenological and anatomic features of the various kinds of hemophilia-related joint disease (acute hemarthrosis, subacute arthritis, and chronic joint disease), we present a study of outcomes in fifty-one hemophiliac children aged 0 to 15 years and followed-up from January 1968 through December 1987 at the Angers Regional University Hospital. Four hundred and sixty-four cases of hemarthrosis were seen. Risk factors for hemarthrosis were severe hemophilia and age between 5 and 15 years, and the joints most often involved were the ankles, knees, and elbows. Sequelae of hemarthrosis were extremely prevalent in this study population: 100% of patients with severe hemophilia and 90% of patients with a factor activity of 3% or less exhibited chronic joint disease by the age of fifteen, with varying degrees of functional impairment. Because a first episode of hemarthrosis is often followed by recurrences in the same joint, we underline the need for prevention and careful treatment of acute episodes, which are the only means for decreasing articular sequelae.

A case of pregnancy in a patient with trisomy 21 with birth of a hypotrophic infant, with a normal caryotype but multiple malformations. This case illustrates the limitations on antenatal diagnosis by amniocentesis. Study of the literature confirms the unfavourable foetal prognosis as a result of the risk of transmission of the chromosomal abnormality and, secondly, the prevalence of incest.

The amniotic alpha 1-foetoprotein of the 17th week of pregnancies with amenorrhea was tested by electroimmunodiffusion and radioimmunology. The results show a very good correlation between both methods. We can see from this study the possibility for any laboratory to test alpha 1-foetoprotein in amniotic fluid of patients with high risk pregnancies, as the beginning of pregnancy when amniotic punction is necessary without using radioimmunology.

A pericentric inversion of chromosome 2 has been detected in 4 unrelated families. The break points are identical in band 2p11 and band 2q13. Reproductive history of these couples is analyzed. The pathology of these particular regions of chromosome 2 is discussed.