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Biomedical subjects

M Le Merrer

Publications and source records attributed to M Le Merrer.

At least 55 records · Page 3Linked to original sources
PubMed1999

Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia.

Members of the CCN (for CTGF, cyr61/cef10, nov) gene family encode cysteine-rich secreted proteins with roles in cell growth and differentiation. Cell-specific and tissue-specific differences in the expression and function of different CCN family members suggest they have non-redundant roles. Using a positional-candidate approach, we found that mutations in the CCN family member WISP3 are associated with the autosomal recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD; MIM 208230). PPD is an autosomal recessive disorder that may be initially misdiagnosed as juvenile rheumatoid arthritis. Its population incidence has been estimated at 1 per million in the United Kingdom, but it is likely to be higher in the Middle East and Gulf States. Affected individuals are asymptomatic in early childhood. Signs and symptoms of disease typically develop between three and eight years of age. Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations have not been reported in PPD. Cartilage appears to be the primary affected tissue, and in one patient, a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones. We have identified nine different WISP3 mutations in unrelated, affected individuals, indicating that the gene is essential for normal post-natal skeletal growth and cartilage homeostasis.

Adolescent↗
PubMed1999

Mutations within or upstream of the basic helix-loop-helix domain of the TWIST gene are specific to Saethre-Chotzen syndrome.

Saethre-Chotzen syndrome (ACS III) is an autosomal dominant craniosynostosis syndrome recently ascribed to mutations in the TWIST gene, a basic helix-loop-helix (b-HLH) transcription factor regulating head mesenchyme cell development during cranial neural tube formation in mouse. Studying a series of 22 unrelated ACS III patients, we have found TWIST mutations in 16/22 cases. Interestingly, these mutations consistently involved the b-HLH domain of the protein. Indeed, mutant genotypes included frameshift deletions/insertions, nonsense and missense mutations, either truncating or disrupting the b-HLH motif of the protein. This observation gives additional support to the view that most ACS III cases result from loss-of-function mutations at the TWIST locus. The P250R recurrent FGFR 3 mutation was found in 2/22 cases presenting mild clinical manifestations of the disease but 4/22 cases failed to harbour TWIST or FGFR 3 mutations. Clinical re-examination of patients carrying TWIST mutations failed to reveal correlations between the mutant genotype and severity of the phenotype. Finally, since no TWIST mutations were detected in 40 cases of isolated coronal craniosynostosis, the present study suggests that TWIST mutations are specific to Saethre-Chotzen syndrome.

Acrocephalosyndactylia↗
PubMed1999

COL9A3: A third locus for multiple epiphyseal dysplasia.

Multiple epiphyseal dysplasia (MED), an autosomal dominant osteochondrodysplasia, is a clinically and genetically heterogeneous disorder characterized by mild short stature and early-onset osteoarthritis. The phenotypic spectrum includes the mild Ribbing type, the more severe Fairbank type, and some unclassified forms. Linkage studies have identified two loci for MED. One of these, EDM1, is on chromosome 19, in a region that contains the cartilage oligomeric matrix protein (COMP) gene. Mutations have been identified in this gene in patients with the Ribbing type, the Fairbank type, and unclassified forms of MED. The second locus, EDM2, maps to chromosome 1, in a region spanning COL9A2. Recently, a splice-site mutation was found in COL9A2, causing skipping of exon 3 in one family with MED. Because of the exclusion of the EDM1 and EDM2 loci in some families, the existence of a third locus has been postulated. We report here one family with MED, evaluated clinically and radiologically and tested for linkage with candidate genes, including COMP, COL9A1, COL9A2, and COL9A3. No linkage was found with COMP, COL9A1, or COL9A2, but an inheritance pattern consistent with linkage was observed with COL9A3. Mutation analysis of COL9A3 identified an A-->T transversion in the acceptor splice site of intron 2 in affected family members. The mutation led to skipping of exon 3 and an in-frame deletion of 12 amino acid residues in the COL3 domain of the alpha3(IX) chain and thus appeared to be similar to that reported for COL9A2. This is the first disease-causing mutation identified in COL9A3. Our results also show that COL9A3, located on chromosome 20, is a third locus for MED.

Adolescent↗
PubMed1999

SHOX gene mutations and deletions in dyschondrosteosis or Leri-Weill syndrome.

Dyschondrosteosis is an autosomal dominant form of mesomelic dysplasia that is often combined with a deformity of the forearms called Madelung deformity. Based on the observation of X-Y translocations (p22,q12) in patients with dyschondrosteosis, the authors tested the pseudoautosomal region in eight affected families and showed linkage of the dyschondrosteosis gene to a microsatellite DNA marker at the DXYS233 locus (Zmax = 6.26 at theta = 0). Since the short stature homeobox-containing gene (SHOX) involved in idiopathic growth retardation and possibly Turner syndrome maps to this region, SHOX was regarded as a strong candidate gene for dyschondrosteosis. This article reports the detection of large-scale SHOX deletions in seven of the eight families and a nonsense mutation of SHOX in the remaining family affected with dyschondrosteosis. Additional evidence suggests that Langer mesomelic dwarfism results from homozygous mutations at the genetic locus responsible for dyschondrosteosis.

Bone Diseases↗
PubMed1999

IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies.

We report three boys with adrenal hypoplasia congenita (AHC) and additional findings that represent a new syndrome, IMAGe: Intrauterine growth retardation, Metaphyseal dysplasia, AHC, and Genital anomalies. Each presented shortly after birth with growth retardation and severe adrenal insufficiency. Each of the three patients had mild dysmorphic features, bilateral cryptorchidism, a small penis, and hypogonadotropic hypogonadism. Skeletal surveys revealed metaphyseal dysplasia in all three and epiphyseal dysplasia in two. The patients had documented or suspected hypercalciuria and/or hypercalcemia, resulting in nephrocalcinosis in one and in prenatal liver and spleen calcifications in another. AHC presents most often either as an isolated abnormality, caused by mutations in the DAX1 gene, or as part of an Xp21 contiguous gene syndrome, caused by a deletion of the Duchenne muscular dystrophy, glycerol kinase, and DAX1 genes. All three patients with the IMAGe association had normal creatine kinase levels and no evidence of glycerol kinase deficiency. Sequence analysis of DNA from these patients revealed no mutation in the DAX1- or steroidogenic factor-1-coding sequences, nor was a deletion of DAX1 detected. Identification of the molecular basis of the IMAGe association will give new insight into the pathogenesis of this syndromic relationship involving bone, adrenal cortical, and pituitary development.

Adrenal Insufficiency↗
PubMed1999

A novel parathyroid hormone (PTH)/PTH-related peptide receptor mutation in Jansen's metaphyseal chondrodysplasia.

Two heterozygous PTH/PTH-related peptide (PTHrP) receptor missense mutations were previously identified in patients with Jansen's metaphyseal chondrodysplasia (JMC), a rare form of short limb dwarfism associated with hypercalcemia and normal or undetectable levels of PTH and PTHrP. Both mutations, H223R and T410P, resulted in constitutive activation of the cAMP signaling pathway and provided a plausible explanation for the abnormalities in skeletal development and mineral ion homeostasis. In the present study we analyzed genomic DNA from four additional sporadic cases with JMC to search for novel activating mutations in the PTH/PTHrP receptor, to determine the frequency of the two previously identified missense mutations, H223R and T410P, and to determine whether different mutations present with different severity of the disease. The H223R mutation was identified in three novel JMC patients and is, therefore, to date the most frequent cause of JMC. In the fourth patient, a novel heterozygous missense mutation was found that changes isoleucine 458 in the receptor's seventh membrane-spanning region to arginine (I458R). In COS-7 cells expressing the human PTH/PTHrP receptor with the I458R mutation, basal cAMP accumulation was approximately 8 times higher than that in cells expressing the wild-type receptor despite impaired surface expression of the mutant receptor. Furthermore, the I458R mutant showed higher responsiveness to PTH than the wild-type receptor in its ability to activate both downstream effectors, adenylyl cyclase and phospholipase C. Like the H223R and the T410P mutants, the I458R mutant had no detectable effect on basal inositol phosphate accumulation. Overall, the patient with the I458R mutation exhibited clinical and biochemical abnormalities similar to those in patients with the previously identified H223R and T410P mutations.

Animals↗
PubMed1999

Clinical variability in patients with Apert's syndrome.

OBJECT: Apert's syndrome is characterized by faciocraniosynostosis and severe bony and cutaneous syndactyly of all four limbs. The molecular basis for this syndrome appears remarkably specific: two adjacent amino acid substitutions (either S252W or P253R) occurring in the linking region between the second and third immunoglobulin domains of the fibroblast growth factor receptor (FGFR)2 gene. The goal of this study was to examine the phenotype/genotype correlations in patients with Apert's syndrome. METHODS: In the present study, 36 patients with Apert's syndrome were screened for genetic mutations. Mutations were detected in all cases. In one of the patients there was a rare mutation consisting of a double-base pair substitution in the same codon (S252F). A phenotypical survey of our cases was performed and showed the clinical variability of this syndrome. In two patients there was no clinical or radiological evidence of craniosynostosis. In two other patients with atypical forms of syndactyly and cranial abnormalities, the detection of a specific mutation was helpful in making the diagnosis. CONCLUSIONS: The P253R mutation appears to be associated with the more severe forms, with regard to the forms of syndactyly and to mental outcome. The fact that mutations found in patients with Apert' s syndrome are usually confined to a specific region of the FGFR2 exon IIIa may be useful in making the diagnosis and allowing genetic counseling in difficult cases.

Acrocephalosyndactylia↗
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↗
PubMed1999

Sex related expressivity of the phenotype in coronal craniosynostosis caused by the recurrent P250R FGFR3 mutation.

A recurrent point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that converts proline 250 into arginine is commonly associated with coronal craniosynostosis and has allowed definition of a new syndrome on a molecular basis. Sixty-two patients with sporadic or familial forms of coronal craniosynostosis were investigated for the P250R FGFR3 mutation. It was identified in 20 probands originating from 27 unrelated families (74%), while only 6/35 sporadic cases (17%) harboured the mutation. In both familial and sporadic cases, females were significantly more severely affected than males. Hence, while 68% of females carrying the P250R mutation showed brachycephaly, only 35% of males had the same phenotype. In the most severe forms of the disease, the association of bicoronal craniosynostosis with hypertelorism and marked bulging of the temporal fossae were common hallmarks that might be helpful for clinical diagnosis. Taken together, these results indicate that the P250R FGFR3 mutation is mostly familial and is associated with a more severe phenotype in females than in males. The sex related severity of the condition points to the possible implication of modifier genes in this syndrome.

Craniosynostoses↗
PubMed1998

Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia.

We report the absence of functional parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptors (PTH/PTHrP receptor) in Blomstrand chondrodysplasia, a genetic disorder characterized by advanced endochondral bone maturation. Analysis of PTH/PTHrP receptor genomic DNA from a patient with Blomstrand chondrodysplasia demonstrated that the patient was heterozygous for a point mutation (G--> A substitution at nucleotide 1176) inherited from the mother. Analysis of PTH/PTHrP receptor cDNA demonstrated that: (a) this point mutation caused the deletion of the first 11 amino acids of exon M5 (encoding the fifth transmembrane domain of the receptor), resulting from the use of a novel splice site created by the base substitution; (b) the mutant receptor was well expressed in COS-7 cells, but did not bind PTH or PTHrP, and failed to induce detectable stimulation of either cAMP or inositol phosphate production in response to these ligands; and (c) the paternal allele was not expressed. Thus, only the abnormal and nonfunctional PTH/PTHrP receptors encoded by the maternal allele were expressed by chondrocytes from this patient. In view of the known role played by the PTH/PTHrP receptor in bone and cartilage development, these results strongly support the conclusion that the absence of functional PTH/ PTHrP receptors is responsible for the skeletal abnormalities seen in Blomstrand chondrodysplasia, abnormalities that are the mirror image of those observed in Jansen's chondrodysplasia. These findings emphasize the importance of signaling through this receptor in human fetal skeletal development.

Base Sequence↗
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

Segregation analysis in nonsyndromic holoprosencephaly.

Holoprosencephaly (HPE) is a developmental defect due to a failure of cleavage of the forebrain. The brain malformations are usually associated with facial anomalies. From a series of 258 HPE records involving at least one affected child, 97 cases in 79 families with nonsyndromic and nonchromosomal HPE were selected. The male:female ratio was 0.87. A high degree of familial aggregation was observed in 23/79 families (29%). A segregation analysis performed in the 79 nuclear families led to the conclusion that the transmission of nonsyndromic HPE is compatible with an autosomal dominant mode of inheritance. Under this hypothesis, the penetrance was estimated as 82% for major types (alobar, semilobar, lobar) and 88% when major and minor types (atypical) were included. The proportion of sporadic cases was estimated to be 68%. This genetic model allows a prediction of the recurrence risk after an isolated case of 13% for major types and 14% when minor types are included.

Diseases in Twins↗
PubMed1998

Novel recurrent nonsense mutation causing neurofibromatosis type 1 (NF1) in a family segregating both NF1 and Noonan syndrome.

Neurofibromatosis type 1 (NF1), a genetic disorder with neuroectodermal involvement, demonstrates phenotypic overlap in some patients with Noonan syndrome (NS), ultimately resulting in the so-called neurofibromatosis-Noonan syndrome (NF-NS). A strong association of the two phenotypic traits was recently illustrated by a four-generation family, although NF1 and NS were eventually demonstrated to segregate independently on the basis of polymorphic DNA markers [Bahuau et al., 1996: Am J Med Genet 66:347-355]. Identification of the causal NF1 mutation seemed a prerequisite to further dissecting this singular familial association. Using the protein truncation assay, a nonsense mutation (C2446T-->R816X) of the neurofibromin gene was evidenced. This mutation occurred on a CpG dinucleotide within exon 16 and 5' to the GAP domain-specifying region of the gene. R816X creates a recognition site for endonuclease HphI, absent in 2 individuals with NS only. Screening 184 unrelated NF1 patients, three novel occurrences of the mutation were found in individuals diagnosed with classical NF1. Based on the assumption of genotype-phenotype correlation in these individuals, clinical and molecular analyses of this four-generation family demonstrated that the NF-NS phenotype was additive, being the result of both classical NF1 and NS. This particular observation also suggests the presence of an NS locus on 17q, which might be of interest for further linkage studies.

DNA Mutational Analysis↗
PubMed1998

Syndromal and nonsyndromal primary trigonocephaly: analysis of a series of 237 patients.

From a series of 1,713 patients with craniosynostosis hospitalized between 1976 and 1996, 237 propositi with metopic synostosis were analyzed. The prevalence of metopic synostosis was estimated in the order of 1 in 15,000 children. Family information was obtained from 184 propositi from 179 families. The male-to-female ratio was 3.3:1. There was no maternal or paternal age effect. A family history was obtained in 10 of the 179 families, giving a 5.6% figure of familial cases. The frequency of twinning was 7.8% with two concordances for metopic synostosis in two monozygotic twin pairs. The male-to-female ratio, the twinning frequency, and the proportion of familial cases in trigonocephaly are very similar to those observed in scaphocephaly, which also involves the longitudinal sutural system. Fetal exposure to valproic acid was noticed in eight cases. The series was divided into two groups: nonsyndromal trigonocephaly (n = 184) and trigonocephaly associated with other malformations (n = 53). The second group included 13 cases of well-delineated syndromes and 40 cases of trigonocephaly associated with one or more malformations, but without any known syndrome, that could be undelineated syndromes. These groups differed significantly in their mental prognosis.

Birth Weight↗
PubMed1998

Metaphyseal anadysplasia type II: a new regressive metaphyseal dysplasia.

We report on six unrelated children, three boys and three girls, with a metaphyseal dysplasia of early onset and spontaneous regressing evolution. During the first months of life the children present with enlargement of costochondral junctions and knobby wrists. On radiographs the metaphyseal changes of the knees are specific with fine irregularities. The femoral necks are blurred but not hypoplastic. The stature is not affected and there are no metabolic abnormalities. The radiographic findings regress during growth and the abnormalities disappear after the age of ten years. These metaphyseal changes and their mode of inheritance are different from previous cases described as anadysplasia. We propose therefore to delineate this syndrome as a new type of regressive metaphyseal dysplasia and to name it anadysplasia type II.

Cartilage↗
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↗