Biomedical subjects

A L Delezoide

Publications and source records attributed to A L Delezoide.

At least 37 records · Page 2Linked to original sources

PubMed1999

A new lethal syndrome of exomphalos, short limbs, and macrogonadism.

We report a new lethal multiple congenital abnormality (MCA) syndrome of exomphalos, short limbs, nuchal web, macrogonadism, and facial dysmorphism in seven fetuses (six males and one female) belonging to three unrelated families. X rays showed enlarged and irregular metaphyses with a heterogeneous pattern of mineralisation of the long bones. Pathological examination showed adrenal cytomegaly, hyperplasia of Leydig cells, ovarian stroma cells, and Langherans cells, and renal microcysts. We suggest that this condition is a new autosomal recessive MCA syndrome different from Beckwith-Wiedemann syndrome, especially as no infracytogenetic deletion or uniparental disomy of chromosome 11 was found.

Abnormalities, Multiple↗

PubMed1998

Expression of the RET proto-oncogene in human embryos.

The patterns of RET proto-oncogene expression in mouse, rat, and chicken and the anomalies observed in targeted RET mutants suggest that RET plays a major role in development of mouse enteric nervous system and in kidney organogenesis. Here, we report on in situ hybridization studies describing the pattern of RET proto-oncogene expression during early development of human embryos between 23 and 42 days. We show that the RET gene is expressed in the developing kidney (nephric duct, mesonephric tubules, and ureteric bud), the presumptive enteric neuroblasts of the developing enteric nervous system, cranial ganglia (VII+VIII, IX, and X) and in the presumptive motor neurons of the spinal cord. Yet, despite the high level of RET gene expression in the kidney and in the motor neurons of the developing central nervous system in human embryos, only rare cases with renal agenesis have been reported in Hirschsprung disease patients, and no clinical evidence of spinal cord involvement has been shown in patients carrying RET germline mutations (i.e., multiple endocrine neoplasia syndromes and Hirschsprung disease).

Central Nervous System↗

PubMed1998

Clinical homogeneity of the Stüve-Wiedemann syndrome and overlap with the Schwartz-Jampel syndrome type 2.

The Stüve-Wiedemann syndrome (SWS) is a rare disorder characterized by respiratory distress, hyperthermic episodes, and early lethality and radiologically by bowing of the long bones with internal cortical thickening and large metaphyses. We report findings in 8 new patients suggesting that this syndrome is clinically homogeneous. All patients had feeding and swallowing difficulties, respiratory insufficiency, abnormal appearance, muscle hypotonia, and postnatal short stature. Recurrent episodes of unexplained fever occurred in all and were the cause of death in 6 of 8 cases. Parental consanguinity and sib recurrence suggest autosomal recessive inheritance. The clinical, radiological, and histological similarities between our patients with SWS and those with the recently delineated "neonatal" Schwartz-Jampel syndrome (SJS type 2) lead us to suggest that SWS and SJS type 2 may be a single entity.

Abnormalities, Multiple↗

PubMed1998

Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia.

Thanatophoric dysplasia (TD) is a lethal skeletal disorder caused by recurrent mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene. The mitogenic response of fetal TD I chondrocytes in primary cultures upon stimulation by either FGF 2 or FGF 9 did not significantly differ from controls. Although the levels of FGFR 3 mRNAs in cultured TD chondrocytes were similar to controls, an abundant immunoreactive material was observed at the perinuclear level using an anti-FGFR 3 antibody in TD cells. Transduction signaling via the mitogen-activated protein kinase pathway was assessed by measuring extracellular signal-regulated kinase activity (ERK 1 and ERK 2). Early ERKs activation following FGF 9 supplementation was observed in TD chondrocytes (2 min) as compared with controls (5 min) but no signal was detected in the absence of ligand. By contrast ligand-independent activation of the STAT signaling pathway was demonstrated in cultured TD cells and confirmed by immunodetection of Stat 1 in the nuclei of hypertrophic TD chondrocytes. Moreover, the presence of an increased number of apoptotic chondrocytes in TD fetuses was associated with a higher expression of Bax and the simultaneous decrease of Bcl-2 levels. Taken together, these results indicate that FGFR 3 mutations in TD I fetuses do not hamper chondrocyte proliferation but rather alter their differentiation by triggering premature apoptosis through activation of the STAT signaling pathway.

Apoptosis↗

PubMed1998

Expression of genes (CAPN3, SGCA, SGCB, and TTN) involved in progressive muscular dystrophies during early human development.

The developmental expression pattern of four human genes, three of which are involved in progressive muscular dystrophies, was investigated. The rationale for these experiments is that these patterns might provide useful information on the pathophysiology underlying these myopathies. Despite the presence of overlapping clinical signs, the spatiotemporal expression profiles of the corresponding genes differed widely. Transcripts of alpha-sarcoglycan (SGCA) were visible as soon as myotomes were formed, and constitute, together with titin transcripts, precocious muscular system landmarks. beta-sarcoglycan (SGCB) was initially transcribed in a ubiquitous manner, and, toward the second part of the embryonic period, became specific to striated muscle, heart, and the central nervous system. Whereas titin (TTN) transcription and translation seem to be coupled, for the sarcoglycans, translation seemed restricted to skeletal muscle. Calpain3 (CAPN3) RNA was found in only skeletal muscles during the fetal period. It was, however, present earlier in the whole heart, where it selectively disappeared. Finally, evidence for differentially spliced calpain3 variants in smooth muscles was also seen. The expression profiles of these genes is suggestive of their having a role during myogenesis, knowledge of which could be pertinent to the understanding of the pathophysiology of the associated diseases.

Adult↗

PubMed1998

Insulin-like 4 (INSL4) gene expression in human embryonic and trophoblastic tissues.

Polypeptide growth factors play an important role in the regulation of human embryonic development. Insulin-like 4 gene (INSL4) is a member of the insulin family, which includes insulin, IGF-I, IGF-II, relaxin, and INSL3. Using RT-PCR, we previously found abundant INSL4 mRNA in the human placenta. In this study, we examined the chronology and spatial expression of this gene in sections of human placenta and conceptus by means of in situ hybridization. Expression of the IGF-II gene was studied as a positive control. INSL4 distribution was tissue- and cell-specific. Indeed, INSL4 mRNA was most abundant in syncytiotrophoblast cells. In fetal tissues, INSL4 mRNA was identified in the perichondrium of all four limbs, vertebrae, and ribs. Moreover, INSL4 mRNA was abundant in interbone ligaments. These findings indicate that the INSL4 gene may play an important role in trophoblast development and regulation of bone formation. IGF-II mRNA, in agreement with the literature, are mainly located in the mesodermal core in the villous trophoblast and in most embryonic tissues.

Gene Expression Regulation, Developmental↗

PubMed1998

MR imaging of fetal cerebral anomalies.

BACKGROUND: Prenatal diagnosis of fetal brain anomalies relies mainly upon ultrasonography. However, even in the most experienced hands, the technique has limitations for some difficult diagnoses. MRI is an excellent imaging modality for the paediatric and adult brain. OBJECTIVE: To assess the value of prenatal MRI when a cerebral anomaly was detected by US and where the prognosis depended on the identification of other anomalies undetectable by US, or where fetuses were at risk for a CNS lesion even when the US was normal. MATERIALS AND METHODS: Four hundred prenatal MRI examinations were performed since 1988, and confirmed by postnatal follow-up or pathological examination. Two-thirds of the examinations were performed after 25 weeks of gestation, one-third between 21 and 26 weeks. Fetal immobilisation was obtained by maternal premedication with flunitrazepam, administered orally 1 h before the examination. The examinations were performed on 1.5 T scanners using one or two surface coils. RESULTS: Prenatal MRI allowed the diagnosis of serious unsuspected lesions such as neuronal migration disorders, ischaemic and haemorrhagic lesions and the abnormalities observed in tuberous sclerosis. It helped to characterise ventricular dilatation and anomalies of the corpus callosum and of the posterior fossa. CONCLUSIONS: MRI is a valuable complementary tool when prenatal US is incomplete, doubtful or limited. Prenatal MRI is particularly useful for the detection of ischaemic and haemorrhagic lesions, neuronal migration disorders and tuberous sclerosis lesions. Detection of these associated anomalies worsens the fetal prognosis, has medico-legal implications and modifies obstetric management. Normal prenatal MRI does not exclude an anomaly.

Agenesis of Corpus Callosum↗

PubMed1998

Presentation of six cases of Stüve-Wiedemann syndrome.

Stüve-Wiedemann syndrome (SWS) is a rare disorder characterized by bowing of the long bones, camptodactyly, respiratory distress, hyperthermic episodes and early lethality. We report six additional cases of SWS, suggesting that this syndrome is homogeneous. All patients had feeding and swallowing difficulties, respiratory insufficiency, dysmorphic features and radiolucent metaphyses with abnormal trabecular pattern. Recurrent episodes of unexplained fever was the cause of death in almost all cases. Parental consanguinity and recurrence in sibs is highly suggestive of autosomal recessive inheritance.

Abnormalities, Multiple↗

PubMed1998

Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification.

Mutations in FGFR 1-3 genes account for various human craniosynostosis syndromes, while dwarfism syndromes have been ascribed exclusively to FGFR 3 mutations. However, the exact role of FGFR 1-3 genes in human skeletal development is not understood. Here we describe the expression pattern of FGFR 1-3 genes during human embryonic and fetal endochondral and membranous ossification. In the limb bud, FGFR 1 and FGFR 2 are initially expressed in the mesenchyme and in epidermal cells, respectively, but FGFR 3 is undetectable. At later stages, FGFR 2 appears as the first marker of prechondrogenic condensations. In the growing long bones, FGFR 1 and FGFR 2 transcripts are restricted to the perichondrium and periosteum, while FGFR 3 is mainly expressed in mature chondrocytes of the cartilage growth plate. Marked FGFR 2 expression is also observed in the periarticular cartilage. Finally, membranous ossification of the skull vault is characterized by co-expression of the FGFR 1-3 genes in preosteoblasts and osteoblasts. In summary, the simultaneous expression of FGFR 1-3 genes in cranial sutures might explain their involvement in craniosynostosis syndromes, whereas the specific expression of FGFR 3 in chondrocytes does correlate with the involvement of FGFR 3 mutations in inherited defective growth of human long bones.

Bone and Bones↗

PubMed1998

The distribution of SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord and muscular atrophy. SMA is caused by alterations to the survival of motor neuron (SMN) gene, the function of which has hitherto been unclear. Here, we present immunoblot analyses showing that normal SMN protein expression undergoes a marked decay in the postnatal period compared with fetal development. Morphological and immunohistochemical analyses of the SMN protein in human fetal tissues showed a general distribution in the cytoplasm, except in muscle cells, where SMN protein was immunolocalized to large cytoplasmic dot-like structures and was tightly associated with membrane-free heavy sedimenting complexes. These cytoplasmic structures were similar in size to gem. The SMN protein was markedly deficient in tissues derived from type I SMA fetuses, including skeletal muscles and, as previously shown, spinal cord. While our data do not help decide whether SMA results from impaired SMN expression in spinal cord, skeletal muscle or both, they suggest a requirement for SMN protein during embryo-fetal development.

Animals↗

PubMed1998

Lung growth and maturation after tracheal occlusion in diaphragmatic hernia.

Tracheal occlusion (TO) was performed at 120 d of gestation by noninvasive endoscopic technique using a releasable latex balloon, in fetal lambs with diaphragmatic hernia (DH) established at 85 d. The lungs were studied at 139 d in five fetuses with DH + TO, five fetuses with DH only, and six control fetuses. Fluid retention consecutive to TO allowed fetal lungs to grow. Histological pulmonary structure was more mature in DH + TO than in DH alone. The growth-inducing effect of TO was however incomplete, with an increased protein/DNA ratio. Tissue phospholipids were increased, but this was not reflected in the surfactant compartment. The major surfactant component, disaturated phosphatidylcholine, was reduced to 58% of its control value in DH, and further reduced to 17.5% of its control value in DH + TO. The proportion of surfactant protein B immunoreactive cells, assumed to represent the proportion of type II cells, was increased in DH (27% of all parenchymal cells), and reduced in DH + TO (7.8%) as compared with control fetuses (15%). In conclusion, although noninvasive tracheal occlusion in utero is feasible and may partly compensate the adverse effects of DH on lung organogenesis, it reduces the number of type II cells and induces a dramatic surfactant deficit. Using this technique in human fetuses requires careful consideration until further evaluation of lung functional characteristics has been achieved in this experimental model.

Animals↗

PubMed1997

Undersulfation of cartilage proteoglycans ex vivo and increased contribution of amino acid sulfur to sulfation in vitro in McAlister dysplasia/atelosteogenesis type 2.

Mutations in the diastrophic dysplasia sulfate transporter gene cause a family of chondrodysplasias including, in order of increasing severity, diastrophic dysplasia, atelosteogenesis type 2 and achondrogenesis type 1B. McAlister dysplasia is a lethal chondrodysplasia considered on the basis of minor radiographic features to be a disorder different from atelosteogenesis type 2. Here, we demonstrate that McAlister dysplasia arises from mutations in the diastrophic dysplasia sulfate transporter gene and that this disorder essentially coincides on molecular and biochemical grounds with atelosteogenesis type 2. The fetus affected by McAlister dysplasia we have studied is a compound heterozygote for mutations leading to R279W and N425D substitutions in the diastrophic dysplasia sulfate transporter. Proteoglycan sulfation was studied in epiphyseal cartilage and in chondrocyte cultures of the patient by high performance liquid chromatography of chondrotinase digested proteoglycans; a high amount of non-sulfated disaccharide was observed as a consequence of the alteration of the transporter function caused by the mutations. However, sulfated disaccharides were detectable even if in low amounts, both in cultured cells and tissue. Functional impairment of the sulfate transporter was demonstrated in vitro by reduced incorporation of [35S]sulfate relative to [3H]glucosamine in proteoglycans synthesized by chondrocytes and by sulfate-uptake assays in fibroblasts. Parallel in vitro studies in a patient with achondrogenesis 1B indicated that the severity of the clinical phenotype seems to be correlated to the residual activity of the sulfate transporter. The capacity of fibroblasts to use cysteine as an alternative source of sulfate was evaluated by double-labeling experiments. Relative incorporation of [35S]cysteine-derived sulfate in the glycosaminoglycan chains was increased in the patient's cells, indicating that, in vitro, the catabolism of sulfur-containing amino acids can partially compensate for intracellular sulfate deficiency. Residual sulfation observed in proteoglycans extracted from cartilage suggests that this mechanism may be operating also in vivo.

Anion Transport Proteins↗

PubMed1997

Familial Blomstrand chondrodysplasia with advanced skeletal maturation: further delineation.

We report on two sibs with a rare lethal chondrodysplasia born to a non-consanguineous couple. The hallmarks of this affection, also called Blomstrand chondrodysplasia, are short limbs, polyhydramnios, hydrops fetalis, facial anomalies, increased bone density, and a remarkable advance in skeletal maturation. We describe the radiologic and pathologic manifestations in these two cases. This recurrence affecting a male and a female fetus, born to the same couple, suggests autosomal recessive inheritance.

Adult↗

PubMed1997

Screening of the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects.

We report the analysis of the distribution of the C677T mutation on the methylenetetrahydrofolate reductase (MTHFR) gene in prenatally diagnosed neural tube defects (NTD) cases and controls. In contrast to previous reports, we found the same distribution in fetuses with NTD and controls, which suggests that the MTHFR C677T mutation cannot be regarded as a genetic risk factor for NTD.

Anencephaly↗

PubMed1997

Abnormal FGFR 3 expression in cartilage of thanatophoric dysplasia fetuses.

Thanatophoric dysplasia (TD), the commonest lethal skeletal dysplasia in humans, is accounted for by recurrent mutations in the fibroblast growth factor receptor 3 gene (FGFR 3), causing its constitutive activation in vitro. Taking advantage of medical abortion of 18 TD fetuses, cartilage sections were studied for FGFR 3 gene expression by in situ hybridization and immunohistochemistry. Specific antibodies revealed high amounts of FGFR 3 in cartilage of TD fetuses with no increased level of the corresponding mRNA. The specific signal was mainly detected in the nucleus of proliferative and hypertrophic chondrocytes. Based on this observation and the abnormal expression of collagen type X in hypertrophic TD chondrocytes, we suggest that constitutive activation of the receptor through formation of a stable dimer increases its stability and promotes its translocation into the nucleus, where it might interfere with terminal chondrocyte differentiation.

Cartilage↗

PubMed1997

Tracheal obstruction in experimental diaphragmatic hernia: an endoscopic approach in the fetal lamb.

Congenital diaphragmatic hernia (CDH) is associated with a neonatal mortality of up to 50 per cent resulting from pulmonary hypoplasia. Experimental ligation of the trachea increases pulmonary growth in fetuses with experimental diaphragmatic hernia (EDH). To provide a potentially reversible tracheal occlusion (TO) using a minimally invasive procedure, we designed the endoscopic placement of a latex tracheal balloon in fetal lambs with EDH. Following surgical creation of a left EDH at 85 days' gestation, endoscopic occlusion of the fetal trachea was performed at 120 days. The fetuses were retrieved at 139 days. The procedure was successful in 5/11 attempts, resulting in liveborns in which the balloon occluded the trachea completely with expanded lungs and reduction of the herniated viscera into the abdomen. These cases were compared with five cases of EDH without TO and six controls. In the TO group, the lung weight was significantly greater but the radial alveolar count, DNA content, and protein content were similar to normal controls. All lung growth parameters were greater in the TO than in the EDH group. Occlusion of the trachea using an endoscopic technique could provide a useful alternative to open fetal surgery in fetuses with CDH.

Airway Obstruction↗

PubMed1997

[Detection of chromosome anomalies using in situ hybridization on fetal tissue sections].

The use of in situ hybridization to detect and characterize chromosome anomalies on cytogenetic preparations is now largely applied in clinical laboratories. Its use in embryofetopathology on formalin-fixed and paraffin-embedded tissues, when an aneuploid condition is suspected but a routine chromosomal analysis is not possible was assessed in the present study. Control values of hybridization signals obtained after different enzymatic digestion protocols have been established on normal fetal tissues. Tissue conservation and fetal age as well as other parameters have also been analysed. A successful hybridization has been achieved in most cases. Failure of hybridization was observed in specimens associated with extensive tissular lysis. In conclusion, the application of in situ hybridization on fetal tissues is very useful to detect chromosome anomalies in embryofetopathology.

Aneuploidy↗

PubMed1996

Undersulfation of proteoglycans synthesized by chondrocytes from a patient with achondrogenesis type 1B homozygous for an L483P substitution in the diastrophic dysplasia sulfate transporter.

Achondrogenesis type 1B is an autosomal recessive, lethal chondrodysplasia caused by mutations in the gene encoding a sulfate/chloride antiporter of the cell membrane (Superti-Furga, A., Hästbacka, J., Wilcox, W. R., Cohn, D. H., van der Harten, J. J., Rossi, A., Blau, N., Rimoin, D. L., Steinmann, B., Lander, E. S., and Gitzelmann, R.(1996) Nat. Genet. 12, 100-102). To ascertain the consequences of the sulfate transport defect on proteoglycan synthesis, we studied the structure and sulfation of proteoglycans in cartilage tissue and in fibroblast and chondrocyte cultures from a fetus with achondrogenesis 1B. Proteoglycans extracted from epiphyseal cartilage and separated on agarose gels migrated more slowly than controls and stained poorly with alcian blue. The patient's cultured cells showed reduced incorporation of [35S]sulfate relative to [3H]glucosamine, impaired uptake of sulfate, and higher resistance to chromate toxicity compared to control cells. Epiphyseal chondrocytes cultured in alginate beads synthesized proteoglycans of normal molecular size as judged by gel filtration chromatography, but undersulfated as judged by ion exchange chromatography and by the amount of nonsulfated disaccharide. High performance liquid chromatography analysis of chondroitinase-digested proteoglycans showed that sulfated disaccharides were present, although in reduced amounts, indicating that at least in vitro, other sources of sulfate can partially compensate for sulfate deficiency. A t1475c transition causing a L483P substitution in the eleventh transmembrane domain of the sulfate/chloride antiporter was present on both alleles in the patient who was the product of a consanguineous marriage. The results indicate that the defect of sulfate transport is expressed in both chondrocytes and fibroblasts and results in the synthesis of proteoglycans bearing glycosaminoglycan chains which are poorly sulfated but of normal length.

Achondroplasia↗