[Urology]. / Urologie.

Two important expanded studies about the early detection of prostate cancer were made and give contradictory results. The American study didn't demonstrate any benefit on rate of survival, whereas the European one demonstrated 20% lower mortality, however with a non-negligible morbidity, and indubitable necessity of additional treatment. The PCA3 genetic test, praticed on urine after rectal touch, will allow in the future improving selection of patients with a pathological PSA for whom the first series of biopsies are negative, and where the question of further biopsies is still opened. The active observation of some prostate cancers (latent cancer) is a valuable therapeutic option, which, when done in an adequate manner, does not question the long term vital prognostic. The vitamines E and C as well the Selenium have no effect in preventing prostate cancer.

Maternal serum levels of placental proteins after in vitro fertilisation and their implications for prenatal screening.

OBJECTIVES: To determine whether the serum levels of pregnancy-associated plasma protein A (PAPP-A), pregnancy-specific beta(1)-glycoprotein (SP1), placental lactogen (hPL) and human chorionic gonadotrophin (hCG) are different in pregnancies obtained after in vitro fertilisation (IVF) and embryo transfer (ET) in comparison to spontaneous pregnancies. Assessment of the need to establish normal medians for biochemical trisomy screening in IVF pregnancies. METHODS: The population comprised 96 IVF-ET pregnancies, of which 79 came from fresh gonadotrophin-stimulated cycles and 17 from embryo transfers without gonadotrophin stimulation (natural cycle IVF, frozen embryo transfers), and 156 spontaneous pregnancies. A single blood sample was obtained between 7 + 0 and 16 + 3 weeks. PAPP-A, SP1, hPL and hCG were quantified and the levels compared between gonadotrophin-stimulated IVF, steroid-only- or non-stimulated IVF, and controls with respect to gestational age using non-parametric statistical analysis. RESULTS: PAPP-A and hPL levels were reduced after stimulated IVF in early gestation (before 10 pregnancy weeks); SP1 followed the same trend without reaching statistical significance. hCG tended to be increased after IVF treatment including non-gonadotrophin-stimulation cycles, and also beyond 10 pregnancy weeks. CONCLUSION: Reduced PAPP-A with increased hCG yields an increased risk in screening for foetal trisomy 21. We confirm recently published observations but do not recommend the establishment of normal medians for IVF pregnancies since the extent of the deviations is varying according to the different stimulation protocols and dosages of gonadotrophins used.

Further delineation of the facial 13q14 deletion syndrome in 13 retinoblastoma patients.

Thirteen years ago, Motegi and colleagues (J Med Genet 1987;24:696-697) summarized the specific facial phenotype of six Japanese retinoblastoma patients with interstitial 13q14 deletions. Among a series of 228 propositi with retinoblastoma referred to the Lausanne Retinoblastoma Clinic for treatment and genetic counseling between 1986 and 1997, 13 (5.7%) were diagnosed with a cytogenetic de-novo 13q14 deletion. We confirm the presence of the reported facial phenotype in our population of Caucasian patients and describe additional clinical traits, thus extending the facial phenotype associated with the 13q14 deletion. Del(13q14) comprises, among others, cranial anomalies, frontal bossing, deeply grooved and long philtrum, depressed and broad nasal bridge, bulbous tip of the nose, thick lower lip, thin upper lip, broad cheeks, and large ears and lobules. Recognition of this particular facial appearance was instrumental in the genetic diagnosis of 13q deletions and in the presymptomatic diagnosis of retinoblastoma in a significant number of our cases. Identification of this phenotype in a retinoblastoma patient allows for efficient diagnosis of recurrence in his progeny and/or sibship, while its ignorance will compromise genetic counseling due to the possible difficulties in detecting large deletions by standard molecular mutation analysis. Recognition of this syndrome in newborns without known familial risk for retinoblastoma is even more important as it is a clear warning sign that indicates immediate ophthalmic examination.

Registration of congenital anomalies in Switzerland by EUROCAT.

Since 1988 the epidemiological surveillance of congenital anomalies (malformations, chromosomal aberrations, metabolic diseases, hereditary diseases, neurosensorial defects, etc.) is carried out by the Swiss registry of EUROCAT (European Registry of Congenital Anomalies and Twins). Several Swiss cantons collaborate through their own local registry, transmitting data to the central registry in Lausanne. We present the main objectives and methods of registration and give the global prevalence rates for the main malformations for 1996 and the period 1993-1996.

[Trisomy 21 and its prenatal detection in the Canton of Vaud (1980-1996)]. / La trisomie 21 et son dépistage prénatal dans le canton de Vaud (1980-1996).

We present a genetic and epidemiological study of trisomy 21 (T21) in the Canton of Vaud, the area covered by our local registry of congenital anomalies which has participated in EUROCAT Switzerland since 1988. During the period 1980-1996, we found 240 new T21 cases, all cytogenetically proven, out of 115,064 consecutive live births. Our purpose was to study trends and impact of biochemical screening and prenatal diagnosis of T21. We considered two different periods: 1980-1989 (before biochemical screening) and 1990-1996 (with screening) during which the mean maternal ages were respectively 28.4 years (10.6% > or = 35) and 29.2 years (12.9% > or = 35). The total prevalence of T21 was 2.08 per 1000; 5.4% of the cases were stillbirths, 49.6% were induced abortions and 45% livebirths. Prenatal cytogenetic diagnosis of trisomy 21 was performed in 52.1% of cases. Among women aged 35 or over the prenatal detection rates are superposable in the two periods. However, for younger women this rate has been much higher since the introduction of biochemical screening, i.e. 9.8% before and 51.8% after the introduction of triple test. In conclusion, the increase in prenatal diagnosis tests performed because of abnormal maternal serum marker levels has increased the global prenatal detection rate from 36.6% to 63.3% in our population, and the prevalence of Down syndrome has thus slightly decreased among livebirths.

[Turner syndrome]. / Le syndrome de Turner.

This article is based on the study of 52 cases of Turner's syndrome, born between 1980 and 1996 and recorded in the Registry of Congenital Anomalies in the Canton of Vaud. In most cases the cytogenetic analysis was based on maternal multiple-marker screening, sonography findings or maternal age. The most common chromosome abnormality is complete monosomy X. The rare cases of mosaic and the one case of isochromosome mainly involve livebirths. Morphological analysis of foetuses revealed hygroma colli (84%) and hydrops (63%), frequently associated with major cardiac malformations. The livebirths present growth retardation, pterygium colli and facial dysmorphic features, but rarely complex malformations. In the light of our data, the probability of survival to birth is 0.8% and the prevalence in all clinical pregnancies is 1.1%.

Frequency and impact of autosomal dominant polycystic kidney disease in the Seychelles (Indian Ocean).

BACKGROUND: As little such data is available in African populations, we investigated the prevalence of ADPKD and the impact of the disease in the Seychelles islands, where approximately 65% of the population is of African descent and 30% of Caucasian or mixed descent. METHODS: Prevalent cases were identified over a 3-year period by requesting all the doctors in the country (most of them are employed within a national health system) to refer all presumed or confirmed cases and by systematically examining the family members of all confirmed cases. The diagnosis was based on standard criteria including ultrasonographic findings and family history. RESULTS: Forty-two cases were identified in this population of 74,331 inhabitants, a total prevalence (per 100,000 total population) of 57 (95% CI, 41-76). All but one of the cases were of Caucasian descent so that the prevalence rates of the disease in the populations of Black and Caucasian descents were respectively 2 (0-11) and 184 (132-249). The prevalence rates of the gene(s) carriers were estimated to be 75 (45-117) in the total population respectively 6 (0-33) and 236 (140-372) in the Black and Caucasian populations. Haplotype analysis in 58 cases from three families showed a common DNA fragment in all affected individuals. Cases had significantly higher blood pressure compared to the general population and 21% had serum creatinine higher than 120 mumol/l. Among the established pedigrees, mean age of death between 1960 and 1995 (haemodialysis was introduced in 1992) was younger in subjects with than those without ADPKD (50.5 vs 67.7 years; P < 0.001). CONCLUSIONS: In the Seychelles, ADPKD clusters in the Caucasian population (possibly a founder effect), is rare in individuals of black descent, and is associated with substantial clinical and survival impact.

Kerato-epithelin mutations in four 5q31-linked corneal dystrophies.

Granular dystrophy Groenouw type I (CDGG1), Reis-Bücklers (CDRB), lattice type I (CDL1) and Avellino (ACD) are four 5q31-linked human autosomal dominant corneal dystrophies. Clinically, they show progressive opacification of the cornea leading to severe visual handicap. The nature of the deposits remains unknown in spite of amyloid aetiology ascribed to the last two. We generated a YAC contig of the linked region and, following cDNA selection, recovered the beta ig-h3 gene. In six affected families we identified missense mutations. All detected mutations occurred at the CpG dinucleotide of two arginine codons: R555W in one CDGG1, R555Q in one CDRB, R124C in two CDL1 and R124H in two ACD families. This suggests, as the last two diseases are characterized by amyloid deposits, that R124 mutated kerato-epithelin (the product of beta ig-h3) forms amyloidogenic intermediates that precipitate in the cornea. Our data establish a common molecular origin for the 5q31-linked corneal dystrophies.

Prognostic factors associated with loss of heterozygosity at the RB1 locus in retinoblastoma.

The nature of the tumorigenic mutation was analyzed in 30 retinoblastoma (Rb) tumors (16 non-hereditary and 14 hereditary) and categorized into loss of heterozygosity (LOH) or retention of heterozygosity (non-LOH) at the RB1 locus. These genotypic characteristics were compared with the clinicopathological phenotype for possible correlation. The overall frequency of LOH was roughly 55%, in both hereditary and non-hereditary Rb. The presence of LOH was preferentially associated with differentiated tumors and absence of choroidal invasion. LOH was found in 82% of females versus 33% of males. Finally, LOH-initiated tumors were associated with a significantly younger age at diagnosis in hereditary Rb. In conclusion, the preferential association of LOH with absence of choroidal invasion, tumoral differentiation, and younger age at diagnosis may establish LOH as a prognostic marker in Rb patients.

A new case of Pfeiffer syndrome with mutation in FGFR2.

We report on a sporadic case of Pfeiffer syndrome in a male newborn with complex craniosynostosis, broad thumbs and great toes and early demise. SSCP and direct sequencing revealed a missense mutation at position 1037 of the exon B (or IIIc) of the FGFR2 gene (codon 342) resulting in a cysteine to serine modification (TGC-TCC). Genotype-phenotype correlations between the FGFRs mutations and the different craniosynostotic syndromes are discussed.

[Genetic counseling in oncology]. / Le conseil génétique en oncologie.

Some aspects of genetic counselling in cases with familial cancers is illustrated by use of 4 typical observations. By exact diagnosis and extended genealogic analysis the risk of consanguineous relatives may be estimated, if inheritance and genetic peculiarities of the particular disease are known. Predictive and presymptomatic testing should only be undertaken after thorough counselling. It should anyway be restricted to cases where preventive or curative measures are available.

[Retinoblastoma: clinical and molecular diagnostic aspects]. / Le rétinoblastome: aspects cliniques et diagnostic moléculaire.

Retinoblastoma, a tumor of the immature retina concerns babies and young infants in particular. They make up for 14% of malignomas in the first years of life. There are two types of retinoblastoma: In the first two alleles of the gene Rb1 must be inactivated sequentially in the same retinoblast cell until this may escape control. In this case the retinoblastoma is always unilateral and unifocal. This is explained by the lower frequency of two mutations in one retinoblast. The other type, however, is inherited: One allele Rb1 is inactivated in all cells of the organism by mutation. The probability that a second mutation arrives in different retinoblasts is thus high. In this case bilateral multifocal tumors develop. Characterization of the Rb1 gene has permitted identification or at least determination of a haplotype in persons at risk. This knowledge is decisive for early recognition of babies at risk and for genetic counselling.

[Familial hyperekplexia: startle disease. Clinical, electrophysiological and genetic study of a family]. / Hyperekplexie familiale: la "maladie du sursaut". Etude clinique, électrophysiologique et génétique d'une famille.

The major form of familial hyperekplexia, a rare autosomal dominant disorder, is characterized by an abnormal startle reaction elicited by auditory and somatosensory stimuli, with transitory stiffness during the neontam period, followed later by falling attacks accompanied by momentary generalized muscular stiffness. Affected neonates occasionally have fatal hypertonia. The minor form is characterized only by an inconstant excessive startle response. We encountered a family in which three females presented with a partial or complete major form of the disease. All our patients were hyperreflexic, insecure gait was present in two subjects, without concomitant spontaneous nocturnal myoclonus. The pathophysiological basis of the hyperekplexia remains unclear. The abnormal startle reflex, probably related to the lack of inhibition by higher centers, is relayed in the caudal brainstem (ponto-medullary reticular formation), where bulbospinal motor efferents originate. Moreover, nonspecific changes such as large somatosensory evoked potentials and long-loop reflexes ("C-responses") may indicate increased cortical neuronal excitability. Polygraphic studies in these patients were normal. The locus of the major form of the disorder is located on chromosome 5q33-q35. Sequence analysis of the alpha 1 subunit of the inhibitory glycine receptor (GLRA1) revealed a mutation at the same codon 271 in several families (G1192A and G1192T). We analyzed this gene and found a G1192A mutation changing an ARG to a LEU codon in all three presented patients. Sporadic cases may represent new mutations or lack of penetrance in some family members. Only one of our three patients needed clonazepam. The diagnosis of this disorder rules out epilepsy, or psychogenic pathological startle reaction. Electrophysiological criteria are useful, however perinatal hypertonia or a tonic generalized spasm accompanied with falls following an abnormal startle reaction and genetic studies remain the diagnostic milestones of familial hyperekplexia.

Sex mutation ratio in retinoblastoma and retinoma: relevance to genetic counseling.

PURPOSE AND METHOD: The parental origin of initial somatic and germline mutations (M1) in the retinoblastoma gene (RB1) was explored in 36 retinoblastoma (Rb) and 5 retinoma patients, of which 16 were presumably non-hereditary and 25 were hereditary. By this approach the male:female mutation ratio was determined by the gender quotient of mutation origin. RESULTS: The male to female mutation ratio in hereditary Rb was 19:2, which is consistent with a significant bias towards paternal origin of germline mutation. This ratio was of 5:2 in non-hereditary Rb which is not significant. DISCUSSION: Together with the published data, these results support a preferential paternal mutagenesis in hereditary Rb, but appear to reject paternal genomic imprinting at the RB1 locus as previously proposed in non-hereditary Rb. Genetic counseling in sporadic Rb may be substantially improved by the identification of the parental origin of initial mutation.