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Microdeletion 15q24 is an emerging syndrome recently described, mainly due to increased use of array-CGH. Clinical features associate mild to moderate developmental delay, typical facial characteristics (high forehead and frontal hairline, broad eyebrows, downslanting palpebral features, long philtrum), hands (particularly proximal implanted thumbs) and genital anomalies (micropenis, hypospadias). We report here on four de novo cases having 2.5-6.1 Mb deletions involving 15q24: one 15q23q24.2 (Patient 1) and three 15q24.1q24.2 deletions (Patients 2-4). We correlate phenotype to genotype according to molecular boundaries of these deletions. Since bilateral iris coloboma and severe ano-rectal malformation were only present in Patient 1, we could link these anomalies to haploinsufficiency of 15q23 genes. Neither hypospadias nor micropenis were present in Patient 3 bearing the smallest deletion, therefore we could define 500 kb 15q24.1 region linked to these anomalies.

Duplications in Xq28 involving MECP2 have been described in patients with severe mental retardation, infantile hypotonia, progressive spasticity, and recurrent infections. However, it is not yet clear to what extent these and accompanying symptoms may vary. In addition, the frequency of Xq28 duplications including MECP2 has yet to be determined in patients with unexplained X-linked mental retardation and (fe)males with severe encephalopathy. In this study, we used multiplex ligation-dependent probe amplification to screen Xq28 including MECP2 for deletions and duplications in these patient cohorts. In the group of 283 patients with X-linked mental retardation, we identified three Xq28 duplications including MECP2, which suggests that approximately 1% of unexplained X-linked mental retardation may be caused by MECP2 duplications. In addition, we found three additional MECP2 duplications in 134 male patients with mental retardation and severe, mostly progressive, neurological symptoms, indicating that the mutation frequency could be as high as 2% in this group of patients. In 329 female patients, no Xq28 duplications were detected. In total, we assessed 13 male patients with a MECP2 duplication from six unrelated families. Moderate to severe mental retardation and childhood hypotonia was noted in all patients. The majority of the patients also presented with absent speech, seizures, and progressive spasticity as well as ataxia or an ataxic gait and cerebral atrophy, two previously unreported symptoms. We propose to implement DNA copy number testing for MECP2 in the current diagnostic testing in all males with moderate to severe mental retardation accompanied by (progressive) neurological symptoms.

Neural tube defects (NTDs) are severe congenital malformations due to failure of neural tube formation in early pregnancy. The proof that folic acid prevents NTDs raises the question of whether other parts of homocysteine (Hcy) metabolism may affect rates of NTDs. This French case-control study covered: 77 women aged 17-42 years sampled prior to elective abortion for a severe NTDs (cases) and 61 women aged 20-43 years with a normal pregnancy. Plasma and erythrocyte folate, plasma B6, B12 and Hcy were tested as five polymorphisms MTHFR 677 C --> T, MTHFR 1298 A --> C, MTR 2756 A --> G, MTTR 66 A --> G and TCN2 776 C --> G. Cases had significantly lower erythrocyte folate, plasma folate, B12 and B6 concentrations than the controls, and higher Hcy concentration. The odds ratio was 2.15 (95% CI: 1.00-4.59) for women with the MTRR 66 A --> G allele and it was decreased for mothers carrying the MTHFR 1298 A --> C allele. In multivariate analysis, only the erythrocyte folate concentration (P = 0.005) and plasma B6 concentration (P = 0.020) were predictors. Red cell folate is the main determinant of NTDs in France. Folic acid supplement or flour fortification would prevent most cases. Increased consumption of vitamins B12 and B6 could contribute to the prevention of NTDs. Genetic polymorphisms played only a small role. Until folic acid fortification becomes mandatory, all women of reproductive age should consume folic acid in a multivitamin that also contains B12 and B6., ((c) 2008 Wiley-Liss, Inc.)

Objective: This study reports 18 years of experience in prenatal diagnosis (PD) of cystic fibrosis (CF) in a region where CF is frequent and the uptake of PD is common (Brittany, western France)., Method: All PDs made over the period 1989-2006 in women living in Brittany were collected., Results: We recorded 268 PDs made in 1 in 4 risk couples, plus 22 PDs directly made following the sonographic finding of echogenic bowel. Most of the 268 PDs were done in couples already having CF child(ren) (n = 195, 72.8%). Close to one-fifth followed cascade screening (n = 49, 18.3%), which identified 26 new 1 in 4 risk couples among the relatives of CF patients or of carriers identified through newborn screening (NBS). The remaining PDs were mainly made in couples whose 1 in 4 risk was evidenced following the diagnosis of echogenic bowel in a previous pregnancy (n = 22, 8.2%). Although patients' life expectancy has considerably improved, in our population the great majority of couples chose pregnancy termination when PD indicated that the foetus had CF (95.9%)., Conclusion: This study describes the distribution of PDs according to the context in which the 1 in 4 risk was discovered and highlights the real decisions of couples as regards pregnancy termination after a positive PD., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Mitochondrial DNA (mtDNA) mutations have been implicated in non-syndromic hearing loss either as primary or as predisposing factors. As only a part of the mitochondrial genome is usually explored in deafness, its prevalence is probably under-estimated. Among 1350 families with non-syndromic sensorineural hearing loss collected through a French collaborative network, we selected 29 large families with a clear maternal lineage and screened them for known mtDNA mutations in 12S rRNA, tRNASer(UCN) and tRNALeu(UUR) genes. When no mutation could be identified, a whole mitochondrial genome screening was performed, using a microarray resequencing chip: the MitoChip version 2.0 developed by Affymetrix Inc. Known mtDNA mutations was found in nine of the 29 families, which are described in the article: five with A1555G, two with the T7511C, one with 7472insC and one with A3243G mutation. In the remaining 20 families, the resequencing Mitochip detected 258 mitochondrial homoplasmic variants and 107 potentially heteroplasmic variants. Controls were made by direct sequencing on selected fragments and showed a high sensibility of the MitoChip but a low specificity, especially for heteroplasmic variations. An original analysis on the basis of species conservation, frequency and phylogenetic investigation was performed to select the more probably pathogenic variants. The entire genome analysis allowed us to identify five additional families with a putatively pathogenic mitochondrial variant: T669C, C1537T, G8078A, G12236A and G15077A. These results indicate that the new MitoChip platform is a rapid and valuable tool for identification of new mtDNA mutations in deafness.

Background: The French has been insufficiently characterized so far for mitochondrial DNA (mtDNA) diversity., Aims: The study aimed to enhance the information available for the French mtDNA pool and to explore the potential microgeographical differentiation of two French regions selected for their linguistic and historical idiosyncrasies., Subjects and Methods: A total of 868 samples from 12 different locations in France were collected. They were sequenced for the hypervariable segment I (HVS-I) and typed for haplogroup defining markers from the coding region either by restriction fragment length polymorphism (RFLP) or by a new protocol based on the 5' nuclease allelic discrimination. The mtDNA gene pools of French Basques and Bretons were compared in terms of frequency and composition with relevant neighbouring populations., Results: The French Basques' mtDNA pool shares some common features with that of the Spanish Basques, such as the high frequency of haplogroup H. However, the French Basques exhibit a number of distinct features, most notably expressed in the prevalence of haplogroups linked with the Neolithic diffusion in Europe. In Brittany, Finistère shows closer affinities with Britain and Scandinavia than the two other departments of Brittany., Conclusion: The mtDNA haplogroup composition of the French does not differ significantly from the surrounding European genetic landscape. At a finer grain, microgeographical differentiation can be revealed, as shown for the French Basque country and for Brittany.

Sensorineural hearing loss is the most frequent sensory deficit of childhood and is of genetic origin in up to 75% of cases. It has been shown that mutations of the SLC26A4 (PDS) gene were involved in syndromic deafness characterized by congenital sensorineural hearing impairment and goitre (Pendred's syndrome), as well as in congenital isolated deafness (DFNB4). While the prevalence of SLC26A4 mutations in Pendred's syndrome is clearly established, it remains to be studied in large cohorts of patients with nonsyndromic deafness and detailed clinical informations. In this report, 109 patients from 100 unrelated families, aged from 1 to 32 years (median age: 10 years), with nonsyndromic deafness and enlarged vestibular aqueduct, were genotyped for SLC26A4 using DHPLC molecular screening and sequencing. In all, 91 allelic variants were observed in 100 unrelated families, of which 19 have never been reported. The prevalence of SLC26A4 mutations was 40% (40/100), with biallelic mutation in 24% (24/100), while six families were homozygous. All patients included in this series had documented deafness, associated with EVA and without any evidence of syndromic disease. Among patients with SLC26A4 biallelic mutations, deafness was more severe, fluctuated more than in patients with no mutation. In conclusion, the incidence of SLC26A4 mutations is high in patients with isolated deafness and enlarged vestibular aqueduct and could represent up to 4% of nonsyndromic hearing impairment. SLC26A4 could be the second most frequent gene implicated in nonsyndromic deafness after GJB2, in this Caucasian population.

Objectives: To analyze the clinical features of hearing impairment and to search for correlations with the genotype in patients with DFNB1., Design: Case series., Setting: Collaborative study in referral centers, institutional practice. Patients A total of 256 hearing-impaired patients selected on the basis of the presence of biallelic mutations in GJB2 or the association of 1 GJB2 mutation with the GJB6 deletion (GJB6-D13S1830)del., Main Outcome Measures: The prevalence of GJB2 mutations and the GJB6 deletion and audiometric phenotypes related to the most frequent genotypes., Results: Twenty-nine different GJB2 mutations were identified. Allelic frequency of 35delG was 69%, and the other common mutations, 313del14, E47X, Q57X, and L90P, accounted for 2.6% to 2.9% of the variants. Concerning GJB6, (GJB6-D13S1830)del accounted for 5% of all mutated alleles and was observed in 25 of 93 compound heterozygous patients. Three novel GJB2 mutations, 355del9, V95M, and 573delCA, were identified. Hearing impairment was frequently less severe in compound heterozygotes 35delG/L90P and 35delG/N206S than in 35delG homozygotes. Moderate or mild hearing impairment was more frequent in patients with 1 or 2 noninactivating mutations than in patients with 2 inactivating mutations. Of 93 patients, hearing loss was stable in 73, progressive in 21, and fluctuant in 2. Progressive hearing loss was more frequent in patients with 1 or 2 noninactivating mutations than in those with 2 inactivating mutations. In 49 families, hearing loss was compared between siblings with similar genotypes, and variability in terms of severity was found in 18 families (37%)., Conclusion: Genotype may affect deafness severity, but environmental and other genetic factors may also modulate the severity and evolution of GJB2-GJB6 deafness.

Recent investigations identified a large deletion of the GJB6 gene in trans to a mutation of GJB2 in deaf patients. We looked for GJB2 mutations and GJB6 deletions in 255 French patients presenting with a phenotype compatible with DFNB1. 32% of the patients had biallelic GJB2 mutations and 6% were a heterozygous for a GJB2 mutation and a GJB6 deletion. Biallelic GJB2 mutations and combined GJB2/GJB6 anomalies were more frequent in profoundly deaf children. Based on these results, we are now assessing GJB6 deletion status in cases of prelingual hearing loss., (Copyright 2004 Wiley-Liss, Inc.)

Mutations in GJB2 are the most common cause of congenital nonsyndromic hearing loss. The controversial allele variant M34T has been hypothesized to cause autosomal dominant or recessive nonsyndromic hearing impairment and some in vitro data has been consistent with this hypothesis. In this report, we present the clinical and genotypic study of 11 families (seven familial forms of nonsyndromic sensorineural hearing loss (NSSNHL) and four sporadic cases) in which the M34T GJB2 variant has been identified. The M34T mutation did not segregate with the deafness in six of the seven familial forms of NSSNH. Eight persons with normal audiogram presented a heterozygous M34T variation and five normal hearing individuals were composite heterozygous for M34T and another GJB2 mutation. Four normal hearing individuals with a documented audiogram were M34T/35delG and one was M34T/(GJB6-D13S1830)del. Screening a French control population of 116 subjects we have found an M34T allele frequency of 1.72%. This percentage was not significatively different from the prevalence of the M34T allele in the deaf population, which was 2.12%. All these data suggest that the M34T variant is not clinically significant in human and is a frequent polymorphism in France.

Hoyeraal-Hreidarsson syndrome represents a severe variant of dyskeratosis congenita (Zinsser-Cole-Engman syndrome). This X-linked recessive, progressive, multisystemic disorder reported so far in 12 pedigrees is characterised by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, mental retardation, progressive combined immune deficiency and aplastic anaemia. Mutations in the DKC1gene on Xq28 have been identified in the X-linked form of dyskeratosis congenita and in some Hoyeraal-Hreidarsson syndrome patients. We report on two sibs and two other unrelated patients with the striking clinical features of Hoyeraal-Hreidarsson syndrome. Noticeably, all four had early digestive problems, with chronic, bloody diarrhoea and feeding problems causing one of the most difficult problems in the supportive treatment of this uniformly lethal condition. Pathological changes in the proliferative compartment of the digestive mucosa included alterations of the glandular architecture and focal rarefaction of the glands. This aspect seems consistent with altered telomerase function associated with a dyskerin mutation which may decrease the proliferative capacity of digestive epithelial cells. A missense mutation 146 C-->T (Thr49Met) in the DKC1gene was found in two unrelated patients, whereas mutation screening was negative for one single case. The absence of mutations of the DKC1gene in patients with Hoyeraal-Hreidarsson syndrome emphasises the probable implication of one or more other loci.

Otopalatodigital syndrome type 2 is an X-linked disorder with minimal expression in carrier females and comprises typical facial anomalies and a generalized bone dysplasia with osteodysplastic changes, brachydactyly, and impaired survival. Recently several other severe malformations were reported in the condition. Melnick-Needles syndrome is an X-linked dominant disorder. Affected males are usually sporadic cases. The exceptional males born to symptomatic women present with a lethal disorder comprising generalized osteodysplasia, deficiency of the first ray, and facial anomalies strikingly similar to those of otopalatodigital syndrome type 2. We report here on three boys with classical, severe, and lethal otopalatodigital type 2 syndrome, and three boys with severe (lethal) Melnick-Needles syndrome, born to affected mothers. We suggest that otopalatodigital type 1 and 2, Melnick-Needles syndrome and frontometaphyseal dysplasia, sharing many clinical manifestations and a similar mode of inheritance, are variants of the same condition: fronto-otopalatodigital osteodysplasia. The relationships to similar syndromes (i.e., Saint-Martin-Gardner-Morrisson syndrome, serpentine fibula syndrome, atelosteogenesis type 3, boomerang dysplasia, and Yunis-Varon syndrome) are discussed.

The difficulties in the diagnosis of Pallister-Killian syndrome are illustrated in this study of nineteen fetuses and children. Diagnosis based on clinical appearance alone is often difficult due to the broad spectrum of clinical anomalies not specific to this syndrome. Due to mosaicism, it is altogether necessary to examine several tissues for the presence of tetrasomy 12p, including circulating lymphocytes in which mosaicism can be as low as 1-3%, amniocytes, chorionic cells and skin fibro-blasts in which mosaicism ranges from 6-100%. When highly suspected on ultrasound examination, the diagnosis recommends prenatal cytogenetic studies because survivors are severely mentally retarded. All the cases are sporadic with only a single preliminary report of recurrence. The cytogenetic diagnosis is therefore helpful in order to reassure family members in regard to genetic counseling.

The medical files of 532 patients who underwent medically induced abortion over a 10-year period (1982-1991) in the French department of Ille-et-Vilaine were studied in order to evaluate the indications and outcomes. Among the patients, 358 resided in the department (67%). Comparatively with the number of births during the 10-year period, there was a relative increase in the number of medically induced abortions from 3.5/1000 to 5.5/1000. This parameter was taken into consideration for the interpretation of a parallel decrease in the perinatal mortality during the same period, from 5.9/1000 to 5.1/1000. There was a maternal indication in 91 cases which correspond to the former category of therapeutic induced abortions. There was a clear increase in 1991 corresponding to abortions induced because of extremely premature rupture of the membranes which were formerly allowed to continue to dead births. Foetal indications were frequent: 441 cases (83%). Exogenous causes were lower (15.6%), particularly due to the disappearance of indications resulting from maternal irradiation. For indications related to infection, the vaccination against rubella and improved prenatal diagnosis resulted in the disappearance of rubella as an indication during the last three years of the study and a clear decrease in the number of toxoplasmosis indications. There were few indications due to maternal infection by human immunodeficiency virus (4 cases). Chromosomal abnormalities were the main cause of medically induced abortion among the foetal indications (27.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Megalocornea (corneal diameter > or = 13 mm) is associated with mental and neurological impairment, and minor anomalies in Neuhäuser syndrome (megalocornea-mental retardation syndrome). Here we report 4 new cases of megalocornea and mental retardation. Those unrelated patients have a consistent pattern of anomalies with possible recessive inheritance which clearly differs from that of the original patients of Neuhäuser et al. [1975]. We discuss the heterogeneity of the syndromes with megalocornea and mental retardation. Based on these cases and on a review of the literature, we suggest a provisional clinically oriented classification in 5 subtypes: (1) a recessive form type Neuhäuser (with iris hypoplasia and minor anomalies), (2) a recessive form type Frank-Temtamy (with camptodactyly, scoliosis and growth retardation), (3) a recessive type 3, including our 4 personal cases (with normal irides, severe hypotonia, relative or absolute macrocephaly and minor anomalies), (4) a possible Frydman type (with normal irides, megalencephaly and obesity), and (5) provisionally unclassifiable cases.

We performed mutation analysis and RFLP haplotype analysis of chromosomes associated with classical phenylketonuria (PKU) in contemporary French families. We also did genealogical reconstructions for seven obligate carriers in five contemporary French-Canadian families living in eastern Quebec, who carry the M1V mutation causing PKU. The M1V mutation, heretofore considered to be associated exclusively with French-Canadians, was found on 4 of 152 independent French chromosomes. The French and Quebec M1V mutations all occurred on RFLP haplotype 2. The contemporary mutant French chromosomes clustered in southern Brittany (Finistère Sud). Genealogical reconstructions of the Quebec families identified 53 shared ancestors and a center of diffusion in the Perche region in 17th century France. The two clusters in France, one historical and the other contemporary, are not incompatible, if one assumes the possibilities that settlers returned from Nouvelle France or moved from Perche to southern Brittany. The M1V mutation is serving as a useful marker for historical demography.

Rett syndrome (RS) was diagnosed in a girl with a t(X;22) (p11.22;p11). This translocation was also present in her unaffected mother and her sister affected by a neurological disorder compatible with a "forme fruste" of RS. Different etiological mechanisms are considered: gene disruption, X inactivation disturbance, metabolic interference. Whatever this may be, the localization of a RS related gene to the short arm of chromosome X is likely.

The authors report 3 cases of infants presenting with cerebral lesions related to violent head shaking. They emphasize the diagnostic difficulties when the classical signs of the battered child (marks of blows, fractures) are lacking. The traumatism is rarely recognized: only the negativity of the usual medical causes of subdural hematoma, meningeal or retinal hemorrhage and a peculiar familial history lead to the possible diagnosis of shaken baby syndrome. The value of skull CT-scan is major, showing intracranial lesions which could not be found before. Because of the observed lesions, evolution is often severe.

Among clinical manifestations of the battered child syndrome, ophthalmic manifestations play a prominent role in the recognition of this syndrome. From personal cases, the authors describe different ocular findings, specially intraocular hemorrhages with the important risk of sequelae. They show the role of the ophthalmologist among several situations. As the ophthalmologist may be the first to examine these traumatized infants his prompt recognition is important to take all necessary steps.

We have seen two cases of diprosopy associated with anencephaly in Brittany between 1975 and 1984. Diprosopy is a partial or total duplication of the face. It consists of the phenomenon of late division in the embryo of the cephalic portion of the neural plate between the 16th and the 18th days. This gives rise to an incomplete type of monozygotic twinning or a conjoint twin. There are several different forms of the organs that are duplicated. We have seen a case of diprosopos distomos dirhinos diophthalmos and a case of disprosopos distomos dirhinos triophthalmos. These two cases were associated with anencephaly, the second also having a spina bifida and a diaphragmatic hernia. One can explain the incidence of anencephalies in cases of diprosopies by the desturbance created by the latter on the embryological events that succeed it. The delay in nerve formation makes it impossible for the neural tube to close completely, and this is why sometimes the anencephaly is associated with spina bifida. In more general terms one can postulate that all conjoint twins that are, of course, monozygotic and monochorial can interfere with early enbryological development and increase the risks of failure of the neural tube to close.

Brittany is celtic, like Ireland and Wales where the incidence of neural tube defects is raised. We searched the hospital files in Brittany for all live and still births, and terminations of pregnancy after prenatal diagnosis for the years 1975-1984. 225 cases of spina bifida and 210 cases of anencephaly were identified; giving an incidence of 0.60 per 1000 births for spina bifida and 0.56 per 1000 births for anencephaly. No seasonality was found for both malformations. Analysis of the sex ratio for anencephaly indicated significantly higher proportion of females to males. Maternal age in the affected group was similar to the normal population. Casual heterogeneity among neural tube defects patients was presumed because 14% of our cases had other congenital anomalies.

Authors examined 80 pairs of parents with affected children with spina-bifida. They compared the incidence of spina-bifida occulta in parents and in 211 controls. The conclusion is: there is no increased incidence of spina-bifida occulta in parents of spina-bifida.

To define more precisely, in molecular terms, the region involved in Beckwith-Wiedemann syndrome (BWS), we have studied patients with BWS and a constitutional duplication of 11p15 using eight 11p15 markers. In the first case with a de novo duplication and extra material on 11p, the region spanning pter to CALCA, excluded, was duplicated. In the second case, the rearrangement was characterized using somatic cell hybrids established with lymphocytes from the father who carried a balanced translocation t(11;18)(p15.4;p11.1). The breakpoint lay exactly in the same region. It could thus be inferred that the two sons, who were the first cases reported of BWS with dup11p15 and adrenocortical carcinoma (ADCC), carried a duplication similar to that observed in the first case. Together with evidence for specific somatic chromosomal events leading to loss of 11p15 alleles in familial cases of ADCC, it can be hypothesized that a gene involved in predisposition to ADCC maps to region 11p15.5.

We used 5 polymorphic probes strongly linked to the gene of cystic fibrosis (CF) to perform the genotypical study of 48 families with at least one child presenting with the disease. The last Km19 and XV2c probes showed a very important linkage imbalance with the CF gene (allele 2 = 6.6 kb of Km19/Pstl, chi 2 = 56; allele 1 = 2.1 kb of XV2c/Taql, chi 2 = 21). These two markers define a B haplotype which confers a relative risk of 55 to be gene carrier. From these data, the predictive value for an individual presenting with this haplotype to be heterozygous was computed to be 1/5. Presently, the risk of 1/20 for a randomized subject to be gene-carrier should be reexamined after study of this genotype. These results are very important practically, as they modify the classical data of genetic counselling concerning cystic fibrosis for the couples with a risk higher than 1/4.

Prenatal diagnosis of cystic fibrosis is today possible by chemical study of amniotic fluid during the 18th week of pregnancy. We have, among 90 families seen for genetic counseling between 1972 and 1985, estimated the risk of recurrence; it was of 0.25 in 55 cases; between 0.05 and 0.16 in 30 cases, greater than 0.01 in 16 cases. Before suggesting a prenatal diagnosis, it is necessary to take as basis the risk of abortion and the reliability of the method. The first risk is well known, less 0.005, in these young women; reliability can be estimated: almost 0.01 of false wrong negative, and this number is probably overvalued if all technical conditions are perfect. In front of these risks, it seems possible to propose a prenatal diagnosis from a risk of 0.01, the families being informed of all risks. We think so to hearten some families and to make possible for them to live quietly these pregnancies, probably non undertaken without our help.

An association between trisomy 11p15 and Beckwith-Wiedemann syndrome is described in two brothers. The first presented at birth with gigantism and macroglossia, umbilical hernia and abdominal distention, hypoglycemia and atresia of the pulmonary artery, leading to the diagnosis of Beckwith-Wiedemann syndrome. Facial dysmorphism also included: a hypoplastic midface, hypertelorism, and a short nose with a flattened bridge. The karyotype showed a trisomy 11p15 with a monosomy 18p11, due to a t(11;18)(p154;p111)pat. His brother, born a year later, showed the same signs. The association between trisomy 11p15 and Beckwith-Wiedemann syndrome is in certain cases well established.

We report a clinical analysis of 327 cases of Spina Bifida and 102 cases of Anencephaly in Brittany. Maternal age, parity, birth weight are not different from random population. Male rate is 0.40 for Anencephaly and 0.50 for Spina Bifida. The study of pregnancies shows an increased frequency of hydramnios during anencephaly pregnancies (0.34) and high rate of abnormalities during the pregnancy of Spina Bifida (0.34) or Anencephaly (0.86). Four mothers of Spina Bifida were taking valproic acid. Thirty children (0.07) had other malformations.

A diencephalic astrocytoma was diagnosed by ultrasonography in a 5 months old girl with nystagmus and emaciation. A 27 months follow-up with ultrasonography, computed tomography and magnetic resonance imaging, showed an initial improvement after irradiation and afterwards the development of complications with ventricular dilatation and parenchymal calcifications.

The case of a 4 years old boy, hospitalized for an unexplained coma, is reported. He is the first child of a non-consanguin couple. The psychomotor development of this child was considered as normal up to the age of 18 months; then, a delay in language development, behaviour disorders with an important instability interrupted by episodes of somnolence, were observed. This child was treated for psychotic disorders. At the age of 3 and half, he had two episodes of seizures associated with fever. He was hospitalized for a 24 hours coma (4 years old). An hepatomegaly and a dry, brittle hair were then observed. Hyperammonemia was made obvious by a protein tolerance test. The diagnosis of argininosuccinate lyase (ASAL) deficiency was based on the increased levels of ASA in plasma and urine. The deficiency was proved by a fibroblast culture. With protein restriction, hepatomegaly disappeared, hair became normal, the behaviour disorders and the delay in language development was improved. However, some school difficulties persist. This case shows that an hereditary metabolic syndrome can be revealed by psychotic like symptoms in childhood.

The article brings to light the very first case of trisomy 20p resulting from a maternal pericentric inversion in a 2 1/2-year old boy. The study outlines the characteristic clinical features of the syndrome, i.e. round face, upslanting palpebral fissures, microretrognathia, normal growth, slight psycho-motor retardation and congenital heart defects. The association of the der(20) inv(20) (p112q133) mat and brachymesophalangy of index ("Mohr-Wriedt" type of brachydactyly) enables the authors to suggest that chromosome 20 may be held responsible for this particular malformation.

We report here the first case of a mosaic Down's syndrome in which both clones are trisomic for chromosome 21, one of them (90%) by a Robertsonian translocation (15;21) appearing de novo, and the other (10%) by an additional chromosome 21. Three hypotheses can explain the appearance of such a mosaic: that of a chimera formed by the fusion of two trisomy 21 zygotes, one of which had a Robertsonian translocation, the other an additional trisomy 21 zygote; that of a fusion between a chromosome 15 and a chromosome 21 in one of the early segmentation blastomeres of a trisomy 21 zygote; the more probable hypothesis of the occurrence of a fission at the break-attachment point of a Robertsonian translocation (15;21) in one of the cells arising from the early postzygotic divisions of a zygote which was a trisomy 21 by Robertsonian translocation (15;21).

Truncus arteriosus is an uncommon heart malformation; it is not reported that recurrence is high; nevertheless authors report three families with two or more cases; in the third there is a very high consanguinity (two uncle-niece marriages). The authors compare the situation with hypoplastic left heart and think that some cases of truncus arteriosus would have an autosomal recessive inheritance. That is an another argument for suggesting an echocardiographic survey of the pregnancies in these families.

The authors have studied the different situations that prompt a request for genetic counseling if different members of the same family suffer from cancer. Six possibilities are considered: the cancer concerned is a genetic disease per se (e.g. retinoblastoma, thyroid cancer with amyloid stroma); the genetic disease is often complicated with cancer (e.g. intestinal polyposis); the genetic disease is occasionally complicated with cancer (e.g. neurofibromatosis); cancer is part and parcel of the genetic disease (e.g. chromosomal abnormalities); in addition, there are two special situations: "cancer-prone families" and families who request genetic counseling after one single case (e.g. cancer of leukaemia in a child).

Two further cases of congenital diaphragmatic hernia with delayed presentation are reported: a 6-month-old male presented a posterolateral diaphragmatic hernia with small bowel in left hemithorax masquerading as pleural effusion; an 11-year-old boy with Down's syndrome presented a retrocostoxyphoid hernia revealed by vague faintness. The authors emphasize the deceptive clinical aspect, the different means for diagnosis, the risk of wrong diagnosis and pleural drain, the usual good outcome of these late-onset diaphragmatic herniation.

We have studied neural tube malformations in twins in order to research into the role of genetic and environmental factors. 12 pairs of twins in which one child had a neural tube defect were studied in Brittany, which is a Celtic country. We found no evidential agreement about the role each factor played. On the other hand there was an excess of twins in the siblings of those with neural tube defects, especially in the siblings of the mothers. There were more dizygotic twin mothers. Analysing the literature has made it possible for us to find a level of agreement of 7.5% for monozygotic twins and 4.6% for dizygotic twins. This last figure corresponds to the recurrence rate found after one case. The aetiological theories are reviewed. Among factors bringing about neural tube defects would seem to be the microenvironment of the uterus and the delay between ovulation and fertilization and implantation of the fertilized egg. Nutrition of the embryo and possible vitamin deficiencies could explain this inter-action between the mother and the fetus. If there is a genetic factor, it is more likely to be maternal than fetal.