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Biomedical subjects

S Lyonnet

Publications and source records attributed to S Lyonnet.

At least 127 records · Page 7Linked to original sources
PubMed1996

Exclusion of allelism of Noonan syndrome and neurofibromatosis-type 1 in a large family with Noonan syndrome-neurofibromatosis association.

A large four-generation family with Noonan syndrome (NS) and neurofibromatosis-type 1 (NF1) was studied for clinical association between the two diseases and for linkage analysis with polymorphic DNA markers of the NF1 region in 17q11.2. Nonrandom segregation between NS and NF1 phenotypes was observed. Neurofibromatosis was tightly linked to NF1 markers, whereas Noonan syndrome was found not be allelic to NF1. These results suggest that two mutations at two independent but closely linked loci are the cause of neurofibromatosis-Noonan syndrome (NF-NS) association in this family.

Alleles↗
PubMed1996

[Advances in genetics: what benefits children?].

The advent of genetic therapy has raised great hopes, but it is clear that for children and their parents, the primary benefit from recent progress is in the possibility of positive diagnosis and presymptomatic diagnosis allowing more adapted management. For the family, genetic counselling allows well informed family planning and birth of healthy children. For the child to be born, continuing progress in genotypic diagnosis often leads to very delicate questions during the antenatal period, especially since certain diagnoses are still difficult and prognosis less than sure. The wide range of tools in molecular genetics may provide the answer in many situations. The rapid development of genetic tools in developed countries should now raise the question of their use in developing countries. This point might have a particular impact in research on genetic factors and sensibility to frequent infectious diseases such as tuberculosis or malaria. In this case, the aim is not diagnosis but the discovery of genes regulating susceptibility which could lead to pharmaceutical developments. This is undoubtedly a long term objective, but should not be overlooked.

Age Factors↗
PubMed1996

[Isolated neonatal dysfunction of brainstem].

BACKGROUND: Brainstem dysfunction in newborns (BDN) is an association of symptoms originally described in the Pierre-Robin sequence. BDN is thought to result from a deficiency of the sucking and swallowing embryonic organization. POPULATION AND METHODS: Between 1983 to 1993, 48 infants without cleft palate were referred for suck and swallow abnormalities. They were considered to have BDN because they presented three of the four following criteria: neonatal suck and swallow difficulties; pharyngeo-oesophageal uncoordination with abnormal oesophageal manometria; upper airway obstruction, either clinically obvious or detected on laryngoscopy; vagal overactivity, either clinically obvious or detected during Holter recording with ocular compression. RESULTS: Among these 48 infants, 30 were affected with polymalformative syndrome often involving embryonic fields derived from the neural crest. Three infants had a conotruncal cardiac malformation and 15 had no associated malformation. These latter 15 infants presented with facial dysmorphic features including reciding chin, glossoptosis. U-shape palate and a vertical tongue. From birth or the first weeks of life, they had suck and swallow difficulties with various functional symptoms: slow baby bottle intake, cough or velo-pharyngeal incoordination, upper airway obstruction or apparent life threatening events (ALTE). Diagnosis was confirmed by both clinical observation and three simple investigations namely: laryngoscopy, oesophageal manometria and Holter recording with ocular compression. Ten children were nasogastric tube or gastrostomy fed, one had a tracheostomy and one had a nightly O2 supplementation. While the overall functional prognosis was good whatever the initial symptoms, 50% of these children had mental retardation, mostly moderate. CONCLUSION: Examination of short-term follow-up in these children has stressed that BDN requires a specific management of both nutritional and respiratory troubles. Finally, BDN should lead to the active search of an underlying polymalformative syndrome and to an accurate neurologic evaluation.

Abnormalities, Multiple↗
PubMed1996

[Pregnancy and the child of a mother with phenylketonuria].

Pregnant women with hyperphenylalaninemia are at high risk of spontaneous abortion and of giving birth to infants with congenital malformations, microcephaly and mental defect. Among mothers whose phenylalaninemia is greater than 1200 mumol/L (20 mg/100 mL), 95% have at least one child with mental retardation. A low phenylalanine diet with a good control of phenylalaninemia, started before conception, reduces this risk, better results being obtained when plasma phenylalanine levels are maintained below 360 mumol/L (6 mg/100 mL) as compared with levels maintained between 360 to 600 mumol/L (6-10 mg/100 mL). Thus, systematic contraception and planned pregnancies must be recommended in all hyperphenylalanemic young women. This implies early information of phenylketonuric teenage girls and their parents. In addition, efforts must be made to join and inform all women having had hyperphenylalaninemia at birth, whether they received a dietary treatment or not. It is also important that general practitioners, pediatricians and obstetricians be aware of the high recurrence risk in hyperphenylalanemic women who gave birth to a microcephalic or malformed infant.

Female↗
PubMed1996

Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome).

Hirschsprung disease (HSCR) and Waardenburg sundrome (WS) are congenital malformations regarded as neurocristopathies since both disorders involve neural crest-derived cells. The WS-HSCR association (Shah-Waardenburg syndrome) is a rare autosomal recessive condition that occasionally has been ascribed to mutations of the endothelin-receptor B (EDNRB) gene. WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants. Since mouse mutants for the EDNRB ligand, endothelin-3 (EDN3), displayed a similar phenotype, the EDN3 gene was regarded as an alternative candidate gene in WS-HSCR. Here, we report a homozygous substitution/deletion mutation of the EDN3 gene in a WS-HSCR patient. EDN3 thus becomes the third known gene (after RET and EDNRB) predisposing to HSCR, supporting the view that the endothelin-signaling pathways play a major role in the development of neural crests.

Amino Acid Sequence↗
PubMed1996

Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease.

Hirschsprung disease (HSCR, aganglionic megacolon) is a common congenital malformation leading to bowel obstruction, with an incidence of 1/5,000 live births. It is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract. As enteric neurons are derived from the vagal neural crest, HSCR is regarded as a neurocristopathy. On the basis of a skewed sex-ratio (M/F = 4/1) and a risk to relatives much higher than the incidence in the general population, HSCR has long been regarded as a sex-modified multifactorial disorder. Accordingly, segregation analysis suggested an incompletely penetrant dominant inheritance in HSCR families with aganglionosis extending beyond the sigmoid colon. We and others have mapped a dominant gene for HSCR to chromosome 10q11.2 and have ascribed the disease to mutations in the RET proto-oncogene. However, the lack of genotype-phenotype correlation, the low penetrance and the sex-dependent effect of RET mutations supported the existence of one or more modifier gene(s) in familial HSCR. In addition, thus far, RET mutations only accounted for 50% and 15-20% of familial and sporadic HSCR patients, respectively. RET encodes a tyrosine kinase receptor whose ligand was unknown. Recently, the Glial cell line-derived neurotrophic factor (GDNF) has been identified to be a ligand for RET. Moreover, Gdnf-/- knockout mutant mice display congenital intestinal aganglionosis and renal agenesis, a phenotype very similar to the Ret-/- mouse. These data prompted us to hypothesize that mutations of the gene encoding GDNF could either cause or modulate the HSCR phenotype in some cases.

Drosophila Proteins↗
PubMed1996

Waardenburg-Hirschsprung disease in two sisters: a possible clue to the genetics of this association?

A Tunisian infant of consanguineous parents had pigmentary disorders, congenital deafness and long-segment Hirschsprung disease. Her elder sister had the same disorders but with short-segment aganglionosis. Their father, mother and two brothers are healthy without history of deafness, constipation or pigmentary disorder. We confirm that this Waardenburg-Hirschsprung association seems to be a distinct clinical entity with a possible autosomal recessive mode of inheritance. Linkage analyses performed in this family support the view that neither the RET locus (candidate for familial dominant Hirschsprung disease) nor the HuP2 locus (candidate for Waardenburg syndrome type I) are involved in the disease phenotype. We suggest that Waardenburg-Hirschsprung complex is a distinct genetic entity and at least one additional locus altering cranial neural crest cell development is responsible for pleiotropic features observed in this association.

Hirschsprung Disease↗
PubMed1996

Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease.

Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Two susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene. Hitherto however, homozygosity for EDNRB mutations accounted for the HSCR-Waardenburg syndrome (WS) association. Here, we report heterozygous EDNRB missense mutations (G57S, R319W and P383L) in isolated HSCR. These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features. In addition, the present data give further support to the role of the endothelin-signalling pathway in the development of neural crest-derived enteric neurons.

Female↗
PubMed1996

Increased paternal age in CHARGE association.

The acronym CHARGE refers to a non-random clustering of congenital malformations whose cause remains unknown. Here, we report on a series of 41 patients and find a significant increase in mean paternal age of birth of CHARGE patients (33.7 +/- 8 years) compared with the control population (30.8 +/- 5 years). In contrast, maternal age was not statistically different in patients and controls. These data suggest the possible role of a dominant mutation or, less likely, a subtle chromosomal abnormality in CHARGE association.

Abnormalities, Multiple↗
PubMed1996

Refined mapping of a gene for split hand-split foot malformation (SHFM3) on chromosome 10q25.

Split hand-split foot malformation (SHFM) is a genetically heterogeneous limb developmental defect characterised by the absence of digital rays and syndactyly of the remaining digits. Three disease loci have recently been mapped to chromosomes 7q21 (SHFM1), Xq26 (SHFM2), and 10q25 respectively (SHFM3). We report the mapping of SHFM3 to chromosome 10q25 in two large SHFM families of French ancestry (Zmax for the combined families = 6.62 at theta = 0 for marker AFM249wc5 at locus D10S222). Two recombinant events reduced the critical region to a 9 cM interval (D10S1709-D10S1663) encompassing several candidate genes including a paired box gene PAX2 (Zmax = 5.35 at theta = 0). The fibroblast growth factor 8 (FGF 8), the retinol binding protein (RBP4), the zinc finger protein (ZNF32), and the homeobox genes HMX2 and HOX11 are also good candidates by both their position and their function.

Chromosome Mapping↗
PubMed1996

C618R mutation in exon 10 of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease.

The cosegregation of multiple endocrine neoplasia (MEN) type 2A with Hirschsprung's disease (HSCR), two diseases associated with mutation of the RET proto-oncogene, is infrequent. A 30-yr-old man was referred for screening of MEN 2A. Surgery for HSCR was performed at 4 yr of age. Basal and pentagastrin-stimulated calcitonin levels were abnormal. Histological examination of the thyroid confirmed bilateral medullary thyroid carcinoma. Screening of family members revealed six subjects with medullary thyroid carcinoma or abnormal pentagastrin-stimulated calcitonin test; one had an unilateral pheochromocytoma and two were affected with HSCR. DNA sequence analysis showed a heterozygote C618R mutation in exon 10 of the RET proto-oncogene in the proband and his mother, as well as in second-degree relatives with MEN 2A phenotype or HSCR. In this study, we report on a novel kindred with MEN 2A and HSCR phenotype associated with a point mutation (C618R) in one of the cysteine codons at the extracellular domain of the RET proto-oncogene.

Adult↗
PubMed1996

A translocation at 12q2 refines the interval containing the Holt-Oram syndrome 1 gene.

A gene for Holt-Oram syndrome (HOS) has been previously mapped to chromosome 12q2 and designated HOS1. We have identified a HOS patient with a de novo chromosomal rearrangement involving 12q. Detailed cytogenetic analysis of this case reveals three breaks on 12q, and two of these are within the HOS1 interval. By using a combination of chromosome painting and FISH with YACs and cosmids, it has been possible to map these breakpoints within the critical HOS1 interval and thus provide a focus for HOS gene-identification efforts.

Arm↗
PubMed1996

[Genetics of Hirschsprung disease].

Hirschsprung's disease (HD) is one of the commonest gastrointestinal malformations, as it affects one child out of 5,000 births. It classically induces severe neonatal intestinal obstruction requiring surgical treatment which currently ensures a favourable prognosis for most of the affected children. Although the great majority of cases are sporadic, the existence of familial forms (10% of cases) has allowed localization and then identification of an autosomal dominant gene on chromosome 10, the RET proto-oncogene, responsible for 50% of familial forms and 15% of sporadic cases. A second gene has been recently localized on chromosome 13, the endothelium beta receptor (EDNRB) gene. Two homozygous mutations of the EDNRB gene have been identified in two consanguineous families, in which HD is associated with Waardenburg's syndrome (WS). Other heterozygous mutations have been identified in patients presenting with isolated HD and an 5% of cases of HD can be considered to present mutations of this gene. Finally, the authors have recently identified a mutation of the endothelium gene 3 (EDN3), one of the EDNRB ligands in a patient presenting with a combination of HD and WS. This mutation, present at the homozygous state in this patient, is predictive of complete absence of EDN3 protein: this is therefore the third known gene responsible for HD.

Drosophila Proteins↗
PubMed1996

[Genetics of Hirschsprung disease].

Hirschsprung disease (HD) is one of the commonest gastro-intestinal malformations, as it affects one child out of 5,000 births. It classically induces severe neonatal intestinal obstruction requiring surgical treatment which currently ensures a favourable prognosis for most of the affected children. Although the great majority of cases are sporadic, the existence of familial forms (10% of cases) has allowed the localization and then the identification of an autosomal dominant gene on chromosome 10, the RET proto-oncogene, responsible for 50% of familial forms and 15% of sporadic cases. A second gene has been recently localized on chromosome 13, the endothelin beta receptor (EDNRB) gene. Two homozygous mutations have been identified in two consanguineous families, in which HD is associated with Waardenburg syndrome (WS). Other heterozygous mutations have been identified in patients presenting with isolated HD and 5% of cases can be considered to present mutations of this gene. Finally the authors have recently identified a mutation of the endothelin 3 gene (EDN3), one of EDNRB ligands in a patient presenting a combination of HD and WS. This mutation, present at the homozygous state in this patient, is predictive of complete absence of EDN3 protein: this is therefore the third known gene responsible for HD.

Endothelin-3↗
PubMed1995

Sternal cleft: case report and review of a series of nine patients.

Cleft sternum is a rare malformation due to partial or total failure of sternal fusion at an early stage of embryonic development. Sternal clefts can be classified as superior, inferior, or complete. Here we report on a 2-year-old boy with inferior sternal cleft and complex cardiac malformation. We review a series of 9 children with sternal clefts, referred to us over a 10-year period. Hypothetical mechanisms for this developmental anomaly are discussed.

Abnormalities, Multiple↗
PubMed1995

Craniosynostosis and kidney malformation in a case of Hennekam syndrome.

Hennekam syndrome is a rare autosomal recessive syndrome which was described for the first time in 1989. Here, we present a girl with intestinal lymphangiectasia, severe lymphedema of limbs, seizures, mild mental retardation, and facial anomalies consistent with the diagnosis of Hennekam syndrome. In addition, she had an ectopic kidney and craniosynostosis of the coronal suture, 2 manifestations not previously reported in this syndrome. While the molecular basis of Hennekam syndrome remains, as yet, unknown, this report illustrates its variable clinical expression.

Craniosynostoses↗