Twelve novel mutations in the tissue-nonspecific alkaline phosphatase gene (ALPL) in patients with various forms of hypophosphatasia.

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.

Molecular analysis of 53 fragile X families with the probe StB12.3.

Fifty-three pedigrees with the fragile X syndrome have been studied for amplification of the CGG repeat sequence adjacent to the CpG island in the FMR1 gene. Probe StB12.3 allowed direct detection of affected males, carrier females, normal transmitting males, as well as prenatal diagnosis. Comparison of our molecular data with our previous linkage data from 38 families indicates the effectiveness of direct DNA analysis. A total of 325 individuals were studied and no new mutation was found. All daughters of males with a premutation had a premutation. When the mother had a full mutation no children had a premutation. In premutated mothers, the size of the premutation seems to be a determining factor for the transition to the full mutation. All affected males had a full mutation or mosaicism and only 42% of the females with a full mutation were mentally impaired. Analysis of large families over 3 generations illustrated clearly the Sherman paradox. Furthermore, the analysis of these families is in reasonable agreement with the multiallelic model of Morton and Macpherson [Proc Natl Acad Sci USA 89:4215-4217, 1992]. Mosaic cases in the offspring of the mothers with a full mutation suggest a maternal germinal mosaicism. Then an abnormal methylation and a somatic heterogeneity established in very early steps of embryogenesis could explain these cases.

[Genetic male infertility and medically assisted reproduction]. / Infertilité masculine d'origine génétique et assistance médicale à la procréation.

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.

[Amniotic alpha 1-foetoprotein of the 17th week of pregnancies with amenorrhea (author's transl)]. / Alpha 1-foetoprotéine dans le liquide amniotique à la 17e semaine d'aménorrhée gravidique. Comparaison des résultats obtenus par électroimmunodiffusion et radioimmunologie.

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.

[Rudiger (E. E. C.) syndrome: report of a case associated with atopic dermatitis (author's transl)]. / Le syndrome de rudiger (syndrome E. E. C.) a propos d'un cas associé à un eczéma atopique.

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.

[Branchio-oto-renal malformation syndrome (author's transl)]. / Le syndrome malformatif branchio-oto-rénal. A propos de 5 observations.

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.

[Prenatal diagnosis of genetic diseases. Results of 57 early amniocenteses]. / Diagnostic prénatal des affections génétiques Bilan de 57 amniocentèses précoces

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.

[Pericentric inversion of chromosome 2 (p11 q13) in unrelated families (author's transl)]. / Inversion péricentrique inv (2) (p11 q13) dans des familles non apparentées

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.

[Malaria and pregnancy. Report of a case of congenital Plasmodium falciparum malaria]. / Paludisme et grossesse. A propos d'une observation de paludisme congénital à Plasmodium falciparum.

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).

[Hemophilic arthropathies. Apropos of 51 cases]. / Arthropathies hémophiliques. A propos de cinquante et un cas.

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.

[The fertility of trisomy 21 sufferers. One case (author's transl)]. / Fécondité des sujets trisomiques 21. Une observation.

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.

[Amniocentesis in a woman with trisomy 21 and a fetus with normal karyotype but with abnormalities]. / Amniocentèse chez une trisomique 21 avec foetus à caryotype normal mais porteur de malformations.

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.

Phenotype-genotype correlations in X linked retinitis pigmentosa.

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).

Myelodysplastic syndrome with t(5;12)(q31;p12-p13) and eosinophilia: a pediatric case with review of literature.

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.

[What course should be adopted after the discovery of a gonosome anomaly in the fetal karyotype?]. / Quelle conduite adopter après la découverte d'une anomalie gonosomique du caryotype foetal?

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

Prenatal diagnosis of pyloric atresia-junctional epidermolysis bullosa syndrome in a fetus not known to be at risk.

Junctional epidermolysis bullosa with pyloric atresia (PA-JEB) is a highly lethal, inherited, autosomal recessive disease. Thus far, prenatal diagnosis of this syndrome was only realized on pregnancies at risk for recurrence. We report the case of a 26-year-old woman, first cousin to her husband, who had undergone amniocentesis for polyhydramnios. The karyotype was normal but the amniotic fluid contained acetylcholinesterase. A targeted scan at 25 weeks' gestation did not find spina bifida, but polyhydramnios with a dilated stomach, and several other anomalies: echogenic particles in the amniotic fluid, a thin skin which closely adhered to the nasal bones, narrow nostrils, abnormal ears, fisted hands, malposition of both first toes, and kidney malformation. Despite no previous case in the family, it was thought that sonographic findings were suggestive of the PA-JEB syndrome. A fetal skin biopsy was carried out at 28 weeks' gestation. The ultrastructural examination of fetal skin displayed JEB. Genetic analysis detected a homozygous mutation in the gene encoding integrin alpha 6. Termination of pregnancy was carried out at 29 weeks' gestation. These results illustrate that in the case of a fetus not known to be at risk, diagnosis of PA-JEB can be achieved by ultrasound findings leading to fetal skin biopsy and ultrastructural examination of blistered epidermis. Some new sonographic signs should raise the possibility of significant cutaneous desquamation and blister formation in a fetus, especially when there is positive amniotic acetylcholinesterase coupled with elevated alpha-fetoprotein or suspected pyloric atresia.

The gene for spondyloepiphyseal dysplasia (SEDL) maps to Xp22 between DXS16 and DXS92.

Previous linkage studies in X-linked spondyloepiphyseal dysplasia (SEDL) placed the gene in the region Xp22.2-p22.1 by linkage to DXS41. Here we have extended our earlier studies by analyzing 15 families with 13 markers from the Xp22 region. Pairwise linkage analysis revealed significant linkage of the SEDL to 8 markers from the Xp22.2-Xp22.1 region. Maximum lod scores were obtained with DXS207, tau max = 9.16 at theta max = 0.021 with confidence limits of 0.00-0.09, and DXS197, tau max = 7.98 at theta max = 0.00 with confidence limits of 0.00-0.06. The study of one recombinant in family 4 indicated that DXS 41 is more likely proximal to DXS92 than distal. Multipoint linkage results and analysis of recombination events indicated that the mutation responsible for SEDL is located in Xp22 between DXS 16 and DXS 92.

Novel COL4A5/COL4A6 deletions and further characterization of the diffuse leiomyomatosis-Alport syndrome (DL-AS) locus define the DL critical region.

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.