Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation.

BACKGROUND: Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling. METHODS: The Mattis Dementia Rating Scale (MDRS) was administered in a double blind fashion to 74 men aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score

Detection of genomic imbalances by array based comparative genomic hybridisation in fetuses with multiple malformations.

BACKGROUND: Malformations are a major cause of morbidity and mortality in full term infants and genomic imbalances are a significant component of their aetiology. However, the causes of defects in many patients with multiple congenital malformations remain unexplained despite thorough clinical examination and laboratory investigations. METHODS: We used a commercially available array based comparative genomic hybridisation method (array CGH), able to screen all subtelomeric regions, main microdeletion syndromes, and 201 other regions covering the genome, to detect submicroscopic chromosomal imbalances in 49 fetuses with three or more significant anomalies and normal karyotype. RESULTS: Array CGH identified eight genomic rearrangements (16.3%), all confirmed by quantitative multiplex PCR of short fluorescent fragments. Subtelomeric and interstitial deletions, submicroscopic duplications, and a complex genomic imbalance were identified. In four de novo cases (15qtel deletion, 16q23.1-q23.3 deletion, 22q11.2 deletion, and mosaicism for a rearranged chromosome 18), the genomic imbalance identified clearly underlay the pathological phenotype. In one case, the relationship between the genotype and phenotype was unclear, since a subtelomeric 6q deletion was detected in a mother and her two fetuses bearing multiple malformations. In three cases, a subtelomeric 10q duplication, probably a genomic polymorphism, was identified. CONCLUSIONS: The detection of 5/49 causative chromosomal imbalances (or 4/49 if the 6qtel deletion is not considered as causative) suggests wide genome screening when standard chromosome analysis is normal and confirms that array CGH will have a major impact on pre and postnatal diagnosis as well as providing information for more accurate genetic counselling.

Sonographic findings in Beckwith-Wiedemann syndrome related to H19 hypermethylation.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with congenital malformations and tumour predisposition. BWS results from variable mutations or epigenetic modifications of imprinted genes in the 11p15 chromosomal region. We present a fetus with mild general overgrowth and bilateral enlarged echogenic kidneys with loss of the corticomedullary differentiation in which prenatal diagnosis of BWS was suspected. The rest of the fetal anatomy and the amniotic fluid volume appeared normal. After termination of the pregnancy, molecular analysis confirmed the diagnosis of BWS by showing an isolated hypermethylation of the H19 gene.

Prenatal diagnosis of sacrococcygeal teratoma with constitutional partial monosomy 7q/trisomy 2p.

We report the prenatal diagnosis of a fetus with sacrococcygeal teratoma and facial dysmorphism attributed to a constitutional terminal deletion of chromosome 7q and partial trisomy of chromosome 2p likely resulting from a de novo balanced translocation. The cytogenetic abnormality was diagnosed prenatally after sonographic detection of teratoma and confirmed on peripheral blood cells at birth. The newborn died of post-operative complications at seven days of age. FISH analysis demonstrated haploinsufficiency of HLXB9, a gene identified in the triad of a presacral mass (teratoma or anterior meningocele), sacral agenesis, and anorectal malformation, which constitutes the Currarino syndrome. Despite the absence of other features of the triad, the teratoma observed in the fetus we describe might represent a partial form of Currarino syndrome.

Prenatal diagnosis of a cleidocranial dysplasia-like phenotype associated with a de novo balanced t(2q;6q)(q36;q16) translocation.

Cleidocranial dysplasia (CCD) is a congenital disorder of bone development characterized by persistently open or delayed closure of cranial sutures and wormian bones, hypoplastic and/or aplastic clavicles, wide pubic symphysis, dental anomalies and short stature. The condition is inherited as an autosomal-dominant trait and the human CBFA1 gene has been identified as the CCD gene. We describe a prenatal form of the skeletal disorder that included clavicular hypoplasia, absence of ossification of the cranial parietal bones and very poor ossification of the frontal and pubic bones. Growth restriction affecting only the long bones was also noted. The fetal karyotype revealed an apparently de novo balanced t(2q;6q)(q36;q16) translocation. This particular form of skeletal disorder associated with the absence of family history and an apparently de novo balanced translocation led the parents to opt for termination of the pregnancy.

Prenatal diagnosis of a small supernumerary, XIST-negative, mosaic ring X chromosome identified by fluorescence in situ hybridization in an abnormal male fetus.

Marker or ring X [r(X)] chromosomes of varying size are often found in patients with Turner syndrome. Patients with very small r(X) chromosomes that did not include the X-inactivation locus (XIST) have been described with a more severe phenotype. Small r(X) chromosomes are rare in males and there are only five previous reports of such cases. We report the identification of a small supernumerary X chromosome in an abnormal male fetus. Cytogenetic analysis from chorionic villus sampling was performed because of fetal nuchal translucency thickness and it showed mosaicism 46,XY/47,XY,+r(X)/48,XY,+r(X),+r(X). Fluorescence in situ hybridizations (FISH) showed the marker to be of X-chromosome origin and not to contain the XIST locus. Additional specific probes showed that the r(X) included a euchromatic region in proximal Xq. At 20 weeks gestation, a second ultrasound examination revealed cerebral abnormalities. After genetic counselling, the pregnancy was terminated. The fetus we describe is the first male with a mosaic XIST-negative r(X) chromosome identified at prenatal diagnosis. The phenotype we observed was probably the result of functional disomy of the genes in the r(X) chromosome, secondary to loss of the XIST locus.

French multi-centric study of 2000 amniotic fluid interphase FISH analyses from high-risk pregnancies and review of the literature.

This prospective and multi-centric study confirms the accuracy and the limitations of interphase FISH and shows that any cytogenetics laboratory can perform this technique. With regard to the technical approach, we think that slides must be examined by two investigators, because the scoring may be subjective. The main problem with the AneuVysion kit concerns the alpha satellite probes, and especially the chromosome 18 probe, which is sometimes very difficult to interpret because of the high variability of the size of the spots, and this may lead to false negative and uninformative cases. The best solution would be to replace these probes by locus-specific probes. Concerning clinical management, we offer interphase FISH only in very high-risk pregnancies or/and at late gestational age because of the cost of the test. We think that an aberrant FISH result can be used for a clinical decision when it is associated with a corresponding abnormal ultrasound scan. In other cases, most of the time, we prefer to wait for the standard karyotype.

Amniocentesis and amnioinfusion during pregnancy. Report of four complicated cases.

We report two foetal complications after amnioinfusion with dye injection for evaluation of severe oligohydramnios in pregnancy. In the first case, an underskin colouring was to disappear within a few days. In the second case, an irreversible skin after-effect with muscular atrophy and lesion of the underskin tissues developed progressively, although the trained practitioner did not notice any particular resistance during the injection of the dye and the ultrasonographer did not point out that the foetus had been stuck by the needle. Both later reported cases concern two life threatening maternal complications due to amniocentesis for foetal karyotyping indicated by maternal age, a septic shock occurred 24h after entering the amniotic cavity, leading to a long stay in intensive care units. In one of those cases, the patient recovered from a cardiac arrest. We come to the conclusion that the essential continuous ultrasonographic monitoring cannot avoid all complications, some of which may lead to severe adverse foetal effects and others may need an intensive medical care for the mother, mainly after iatrogenic chorioamnionitis. Experience of the perinatologist remains an important factor to limit the complications without avoiding them completely. The indications must be carefully evaluated, the information given to the patients must be clear and in the future, intraamniotic injections of dyes will have to be avoided and replaced by non-invasive tests for diagnosis of preterm premature rupture of membranes, such as diamine-oxidase, foetal fibronectin or PROM-tests. The rules of a good practice will have to be defined and widely spread.

[The genetics of labio-palatal clefts]. / Génétique des fentes labio-palatines.

Labial and/or palatine clefts are an interest in example of the interaction between genetic and environmental factors. The OFC1 gene, localized on 6p24.3 would play a primary role in the development of labial and/or palatine clefts while the OFC2 (2p13), OFC3 (19p13.2) and RARA (17q21.1) would play a role in modifying genetic susceptibility. Different environmental, nutritional and toxic factors (alcohol, tobacco, drugs...) could also directly contribute one-third of these oral clefts. Identification of subjects at risk of having a child with labial and/or palatine cleft on the basis of both phenotypic and genotypic factors would be most helpful in recognizing environmental factors triggering their development, a first step towards prevention.

Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia.

Hypophosphatasia is an inherited disorder characterised by defective bone mineralisation and deficiency of serum and tissue liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. We report the characterisation of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 13 European families affected by perinatal, infantile or childhood hypophosphatasia. Eighteen distinct mutations were found, only three of which had been reported previously in North American and Japanese populations. Most of the 15 new mutations were missense mutations, but we also found two mutations affecting donor splice sites and a nonsense mutation. A missense mutation in the last codon of the putative signal peptide probably affects the final maturation of the protein. Despite extensive sequencing of the gene and its promotor region, only one mutation was identified in two cases, one of which was compatible with a possible dominant effect of certain mutations and the putative role of polymorphisms of the TNSALP gene. In 12 of the 13 tested families, genetic diagnosis was possible by characterisation of the mutations or by use of polymorphisms as genetic markers. Hypophosphatasia diagnosis was assigned in two families where clinical, laboratory and radiographic data were unclear and prenatal diagnosis was performed in one case. The results also show that severe hypophosphatasia is due to a very large spectrum of mutations in European populations with no prevalent mutation and that genetic diagnosis of the disease must be performed by extensive analysis of the gene.

Persisting spongy myocardium. A case indicating the difficulty of antenatal diagnosis.

Persisting spongy myocardium (also known as noncompaction of the ventricular myocardium) is a rare and special form of cardiomyopathy. The few cases reported in the literature were detected postnatally and involved a high rate of cardiovascular complications. This anomaly of endomyocardial morphogenesis, which occurs during the embryonic phase at the stage of cardiac partitioning, is characterised by an excessive number of prominent trabeculae and by intertrabecular recesses within the myocardial wall. Antenatal detection is difficult in the absence of an associated malformation, which is the general situation. We report a case of antenatal cardiomyopathy which led to therapeutic abortion. The diagnosis of persisting spongy myocardium was made during fetopathologic examination.

Characterization of two add(4qter) chromosomes by comparative genomic hybridization.

We describe the combined use of comparative genomic hybridization (CGH) and fluorecence in situ hybridization (FISH) to identify the origin of de novo unbalanced translocations in a fetus with abnormalities on ultrasound examination and in a newborn with multiple congenital abnormalities. RHG banding of amniocytes and lymphocytes respectively showed a unbalanced karyotype: 46,XX,add(4)(q34), with normal parental karyotypes in both cases. CGH revealed a gain of material from distal 15q (q23qter) in the fetus and a gain of distal 7q (q31qter) in the newborn. CGH results were confirmed using FISH with painting probes in both cases. These cases demonstrate the efficiency of CGH in identifying the chromosomal origin of extramaterial in unbalanced de novo translocations.

Prenatal diagnosis of ring chromosome 14 after intracytoplasmic sperm injection.

OBJECTIVE: To collect extensively abnormal cytogenetic results in pregnancies obtained after intracytoplasmic sperm injection (ICSI). DESIGN: Case report. SETTING: University Hospital of Nantes, France. PATIENT(S): A couple with 5 years of primary infertility and severe male factor undergoing ICSI procedure. INTERVENTION(S): Ultrasound-guided transvaginal follicular aspiration, amniocentesis, and medical abortion. MAIN OUTCOME MEASURE(S): Serum levels of E2, beta-hCG, and fetal chromosomal karyotype. RESULT(S): Ultrasonic observation at 12 weeks revealed an 8-mm thick cystic hygroma in the nuchal area. Because the karyotypic analysis was [46,XX,r(14)/45,XX,-14], medical abortion was performed at 14 weeks, after the patients gave their informed consent. CONCLUSION(S): According to the prevalence of this unusual chromosomal abnormality in humans, such abnormal cytogenetic results have to be collected extensively to assess the feasibility of using ICSI procedure.

Nosology of fetal hypokinesia sequence based on CNS abnormalities: is there an Aase-Smith syndrome?

Aase-Smith syndrome (ASS) is usually defined as a dominantly inherited combination of arthrogryposis, Dandy-Walker malformation and cleft palate. We describe a sporadic case of foetal akinesia with abnormal fossa posterior, fitting the diagnosis of ASS, and discuss the nosology of this entity among syndromes with distal arthrogryposis. ASS shows a "hybrid" phenotype: adults with mild ASS could be classified as distal arthrogryposis, whereas severely affected newborns overlap with the Marden-Walker phenotype, which is recessively inherited. The specificity of the disorder comes from the coexistence of both forms in the same pedigree, so that ASS appears impossible to diagnose with certitude in sporadic cases. We suggest that the severe expression of ASS is only the extreme but aspecific expression of a dominantly inherited form of distal arthrogryposis. Implications for genetic counselling in distal arthrogryposis are outlined.

[Congenital coronary-cardiac fistula. Diagnosis by color Doppler echocardiography in an infant]. / Fistule coronaro-cardiaque congénitale: diagnostic par échocardiographie doppler couleur chez le nourrisson.

The authors report the case of a 2 month old child in whom a coronary artery fistulae was diagnosed by colour Doppler echocardiography. Routine two-dimensional echocardiography showed a very dilated right coronary artery. Turbulent flow was detected in this vessel by pulsed Doppler echocardiography. Colour Doppler showed the fistulous connection to the inferior wall of the right ventricle. Until recently, this condition could only be diagnosed by selective angiography and coronary arteriography. Although there have been few reports in the literature, colour Doppler echocardiography would seem to be a significant advance in non-invasive diagnosis of abnormal connections of the coronary arteries. It allows the differential diagnosis of coronary aneurysm, ectopic coronary arteries and sinus of Valsalva aneurysms to be excluded. The patients can be followed up by colour Doppler echocardiography and anatomic information can be obtained to guide surgery, notably the site of drainage of the fistula. Coronary artery fistulae presenting clinically with a continuous murmer atypically situated for a patent ductus arteriosus are difficult to detect by conventional echocardiography and usually required cardiac catheterisation and angiography. Color Doppler echocardiography is a valuable non invasive diagnostic tool for this condition. The others report the case of a coronary artery cardiac fistula in a neonate diagnosed by color Doppler echocardiography.

[Development of the mortality in premature infants from 32 weeks gestation and below in Fort-de-France]. / Evolution de la mortalité des prématurés de 32 semaines et moins d'âge gestationnel à Fort-de-France.

The mortality rate of prematures of gestational age less than or equal to 32 weeks during hospitalization in the neonatal intensive care unit of the University Hospital in Fort-de-France (Martinique, French Caribbeans) decreased from 69% in 1980 to 32% in 1987-1988 and to 20% in 1989. The mortality of small for gestational age children during the cumulated years 1987-1988-1989 was twice that of babies with normal birth weight. The various factors responsible for these facts were reviewed: caesarean section rates increased from 15% in 1980 to 42% in 1989, percentage of children submitted to assisted ventilation increased from 35% in 1980 to 78% in 1989 and mortality rate related to hyaline membrane disease decreased from 100% in 1980 to 33% in 1989. The comparison with a survey performed in 1985 in the Paris area showed no significant difference with the mortality rate of premature infants of gestational age greater than or equal to 27 weeks born in the University Hospital in Fort-de-France. Therefore an important effort remains necessary concerning mostly children under 27 weeks of gestational age.

[The limy bile syndrome in newborn infants. Apropos of a case]. / Le syndrome de la bile calcique chez le nourrisson. A propos d'un cas.

This is a report of a limy bile syndrome in a little girl aged 21 months, whose gall-bladder is spontaneously visible on the abdominal X Ray, with a biliary stone inside. The limy bile syndrome is very rare in infancy and childhood and is found more exceptionally in new-born. Only 12 cases were found out in medical literature among children aged from 3 to 15. The pathogenesis of the disease is unknown, but its diagnosis is very easy. The treatment is surgical and consists in cholecystectomy with per-operative cholangiography although drainage of the biliary mould can happen.

[Acute rheumatic fever in Martinique. Epidemiological, clinical and biological study]. / Le rhumatisme articulaire aigu en Martinique. Etude épidémiologique, clinique et biologique.

An epidemiological and clinical survey of rheumatic fever was carried out in Martinique. The clinical manifestations, portal of entry and socio-economic facilitating factors appeared to be the same as those observed in metropolitan France when the disease occurred with a similar frequency. The prevalence and severity of rheumatic fever in Martinique are still high (in 1982, 49 new cases in a population of 300,000, including 12 with severe carditis), but they tend to diminish as the eradication campaign goes on. The reasons for the persistence of the disease and the problems encountered in the eradication campaign are discussed in the light of epidemiological data collected during the last 3 years.