Biomedical subjects
Publications and source records attributed to M Le Merrer.
We report on a "new" syndrome in 2 unrelated children with some manifestations of Kniest dysplasia and with spine abnormalities suggestive of dyssegmental dysplasia. Glaucoma with important ocular impairment was associated with severe dwarfism. No mutation of the COL2A1 gene was detected. The inheritance of this new type of skeletal dysplasia in unknown.
From a series of 1,408 patients with craniosynostosis hospitalized between 1976 and 1994, 561 probands with non-syndromal isolated sagittal synostosis were analyzed. The prevalence of sagittal synostosis was estimated in the order of 1 in 5,000 children. Family information was obtained from 373 probands distributed among 366 families. The male:female ratio was 3.5:1. There was no maternal or paternal age effect. In 22 of the 366 pedigrees, a high degree of familial aggregation was observed, giving a 6% figure of familial cases. Segregation analysis of 253 families indicates that sagittal synostosis is transmitted as a dominant disorder with 38% penetrance and 72% of sporadic cases. The frequency of twinning was 4.8% with only 1 concordance for sagittal synostosis in a monozygotic twin pair. The possibility of a mechanical pathogenesis in sporadic cases is discussed.
UNLABELLED: The Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder characterized by dysmorphic facial features with abnormal limbs and genitalia. Two forms have been recognized based on clinical course and severity: the classical SLO (type I) and the lethal acrodysgenital syndrome (type II). Type I SLO has been recently ascribed to a defect in cholesterol synthesis. Taking advantage of a series of seven patients including five type I and two type II SLO, we describe micrognathia, severe microcephaly, major ante and post natal growth retardation and feeding difficulties as consistent features in the disease. In addition, we give support to the presence of abnormal cholesterol levels in the lethal acrodysgenital syndrome but find no correlation between plasma sterol levels and the clinical severity of the disease. CONCLUSION: The identification of the same biochemical defect in both types of Smith-Lemli-Opitz Syndrome suggests that despite major discrepancies in clinical course and severity, type I and type II SLo are probably allelic disorders.
Saethre-Chotzen syndrome is an autosomal dominant acrocephalosyndactyly syndrome whose gene has been assigned to chromosome 7p. Cytogenetic and linkage analyses have enabled the interval encompassing the disease gene to be delimited to a short region of chromosome 7p15.3-p21.2. Based on the genetic analysis of three unreported families, we confirm the location of the disease gene(s) in the interval defined by loci D7S664 and D7S493 (Zmax = 4.78 at [symbol: see text] = 0 at the D7S488 locus) but fail to decide whether one or more disease-causing genes map in this genetic interval.
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Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. In the most common subtype (TD1), femurs are curved, while in TD2, straight femurs are associated with cloverleaf skull. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene were identified in both subtypes. While TD2 was accounted for by a single recurrent mutation in the tyrosine kinase 2 domain, TD1 resulted from either stop codon mutations or missense mutations in the extracellular domain of the gene. Here, we report the identification of FGFR3 mutations in 25/26 TD cases. Two novel missense mutations (Y373C and G370C) were detected in 8/26 and 1/26 TD1 cases respectively. Both mutations created cysteine residues in the juxta extramembrane domain of the receptor. Sixteen cases carried the previously reported R248C (9/26 cases), S249C (2/26 cases) or stop codon FGFR3 mutations (5/26 cases). Our results suggest that TD1 is a genetically homogeneous condition and give additional support to the view that newly created cysteine residues in the extracellular domain of the protein play a key role in the severity of the disease.
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.
The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (Gly380Arg) in the gene encoding fibroblast growth factor receptor 3 (FGFR-3) has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dysplasia (TD; types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity: 100% of patients examined exhibited mutations in the transmembrane domain of FGFR-3. Although most cases of hypochondroplasia were accounted for by a recurrent missense substitution (Asn540Lys) in the first tyrosine kinase domain of FGFR-3, a significant proportion (40%) of the patients in the present study did not possess this Asn540Lys mutation. Furthermore, in three families with hypochondroplasia, the genetic defect was not linked to the FGFR-3 locus, thus supporting the clinical heterogeneity of this disease. In TD, a recurrent mutation located in the second tyrosine kinase domain of FGFR-3 has been detected in all TDII patients. By contrast, seven distinct mutations in three different protein domains were identified in 25 out of 26 TDI patients in this study. This suggests that TD, like achondroplasia, is a genetically homogeneous skeletal disorder.
Hypochondroplasia (HCH) is an autosomal dominant condition characterised by short stature, micromelia, and lumbar lordosis. In a series of 29 HCH probands (13 sporadic cases, 16 familial cases), we tested their DNA for the N540K recurrent mutation previously described in the proximal tyrosine kinase domain of the FGFR3 gene on chromosome 4p16.3, and we detected this mutation in 21/29 HCH patients. Interestingly, three familial cases were clearly unlinked to chromosome 4p16.3. Reviewing the clinical and radiological manifestations of the disease a posteriori, we observed that the N540K mutation was associated with relative macrocrania with a high and large forehead and short hands. By contrast, in the three pedigrees inconsistent with linkage to chromosome 4p16.3, the clinical phenotype was milder, macrocephaly and shortening of the long bones was less obvious, the hands were normal, and no metaphyseal flaring was noted. This study supports the view that HCH is a clinically and genetically heterogeneous condition.
Achondroplasia (ACH), the most common cause of chondrodysplasia in man (1 in 15,000 live births), is an autosomal dominant condition of unknown origin characterized by short-limbed dwarfism and macrocephaly. Recently, a gene for ACH has been mapped to chromosome 4p16.3. The genetic interval encompassing the disease gene contains a member of the fibroblast growth factor receptor (FGFR) family which is expressed in articular chondrocytes (FGFR3). We report here recurrent missense mutations, in a CpG doublet of the transmembrane domain of the FGFR3 protein (G380R) in 17 sporadic cases and 6 unrelated familial forms of ACH and show that the mutant genotype segregates with the disease in these families. Thus, it appears that recurrent mutations of a single amino acid in the transmembrane domain of the FGFR3 protein account for all cases (23/23) of achondroplasia in our series.
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From a series of 1265 individuals with different craniosynostoses hospitalized between 1976 and 1993, 260 probands with nonsyndromic unilateral (181) or bilateral (79) coronal synostosis were analysed. The prevalence of craniosynostoses was estimated as 1 in 2100 children. In the group of coronal synostosis, family history was obtained on 192 probands in 180 pedigrees. The male:female ratio was 1:2. The average paternal age was 32.7 +/- 6.4 years, which is significantly higher than normal. In 26 of the 180 pedigrees, a high degree of familial aggregation was observed, giving a 14.4% figure of familial cases. The bicoronal synostoses were significantly more often familial than the unicoronal synostoses. Segregation analysis of these families leads to the conclusion that coronal synostosis is transmitted as a dominant disorder with 0.60 penetrance and 61% of sporadic cases.
Spondyloepiphyseal dysplasia tarda (SEDL) is an X-linked recessive disorder characterized in affected males by short stature resulting from a growth defect of the vertebral bodies. We have extended our earlier studies by analyzing 15 families with newly identified microsatellite DNA markers; analysis of recombination events with these markers indicates that the gene responsible for SEDL is located in Xp22 between DXS 16 and DXS 987 on an interval spanning approximately 2 Mb.
Crouzon craniofacial dysostosis (CFD) is an autosomal dominant form of craniosynostosis characterized by an abnormal skull shape, with hypertelorism, prominent eyes and midfacial retrusion. Recently, a gene for CFD has been mapped to chromosome 10q25-q26 and mutations in exon B of the fibroblast growth factor receptor 2 (FGFR2) gene have been identified. Here, we report the mapping of a CFD gene to chromosome 10q by close linkage to probe AFMa197wb1 at locus D10 S1483 in six unrelated families of French ancestry (Zmax = 4.69 at theta = 0) and provide additional evidence of genetic homogeneity of this condition. In addition, we report a novel mutation in exon B of the FGFR2 gene (Cys 342 Trp) in familial CFD and describe recurrent mutations at codon 342 as a particularly frequent event in CFD. Since mutations in the extracellular domain of the FGFR2 gene are observed in a few clinically distinct craniosynostosis syndromes (CFD, Jackson-Weiss, Apert and Pfeiffer), the present study gives support to the variable clinical expression of FGFR2 mutations in humans.
UNLABELLED: The term congenital dyserythropoietic anaemia (CDA) designates a group of rare but well defined erythrocytic disorders. Type I is defined by macrocytosis and megaloblastic changes of the bone marrow cells. Two unrelated children with CDA are described with associated defects: absence of nails and short or absent phalanges, polysyndactyly of the fourth metacarpal. One of them had also areas of depigmentation. CONCLUSION: The association of congenital dyserythropoietic anaemia with morphological defects of hands and feet is suggested to constitute a new syndrome caused by a single morphogenetic gene.
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