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Pierre Maroteaux - One of the best experts on this subject based on the ideXlab platform.
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common mutations in the fibroblast growth factor receptor 3 fgfr 3 gene account for achondroplasia Hypochondroplasia and thanatophoric dwarfism
Clinical Pediatric Endocrinology, 1997Co-Authors: Jacky Bonaventure, F Rousseau, Arnold Munnich, Laurence Legeaimallet, Le M Merrer, Pierre MaroteauxAbstract:The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene, has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and Hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported, exhibited mutations in the transmembrane receptor domain. Although most of Hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three Hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this disease. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor has been detected in 100% of TD II cases, while 7 distinct mutations in three different protein domains were identified in 25 out of 26 TD I patients, suggesting that TD, like achondroplasia is a genetically homogenous skeletal disorder.
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Clinical and genetic heterogeneity of Hypochondroplasia.
Journal of medical genetics, 1996Co-Authors: François Rousseau, Pierre Maroteaux, Arnold Munnich, Jacky Bonaventure, Laurence Legeai-mallet, H. Schmidt, Jean Weissenbach, M. Le MerrerAbstract: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.
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Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, Hypochondroplasia, and thanatophoric dwarfism.
American journal of medical genetics, 1996Co-Authors: Jacky Bonaventure, M. Le Merrer, F Rousseau, Arnold Munnich, Laurence Legeai-mallet, Pierre MaroteauxAbstract:The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and Hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most Hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three Hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases, our series seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder.
Gary A. Bellus - One of the best experts on this subject based on the ideXlab platform.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or Hypochondroplasia.
American journal of medical genetics. Part A, 2003Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had Hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and Hypochondroplasia to a N540K mutation in the same gene. The patient with Hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or Hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or Hypochondroplasia.
American Journal of Medical Genetics Part A, 2002Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had Hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and Hypochondroplasia to a N540K mutation in the same gene. The patient with Hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or Hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development. © 2002 Wiley-Liss, Inc.
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FGFR3 Mutations K650N and K650Q Cause Hypochondroplasia
Genetics in Medicine, 2000Co-Authors: Gary A. Bellus, Clair A. Francomano, A T Garber, C R Bryke, C A Weaver, P W Speiser, Melanie K. Webster, D A Donoohue, Elaine SpectorAbstract:More than 50% of individuals with Hypochondroplasia are heterozygous for mutations at a single FGFR3 nucleotide that result in N540K substitutions. Although genetic heterogeneity has been demonstrated in several families, it is likely that FGFR3 mutations other than N540K also cause Hypochondroplasia. We have screened more than 65 individuals with suspected clinical diagnoses of Hypochondroplasia (but who do not have N540K mutations) for mutations in FGFR3 exon 15 that disrupt a Bbs-l restriction site. We report here the discovery of 3 novel mutations (G1950T:K650N, G1950C: K650N & A1948C: K650Q) occurring in 5 individuals with clinical features of Hypochondroplasia. The phenotype of these individuals tends to be milder than that of individuals with N540K mutations. Total height deficit was less [K650N/Q = -2.09 SD +/- 0.67 (n=5), N540K. = -3.25 SD +/- 1.09 (n=36): P
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fgfr3 mutations k650n and k650q cause Hypochondroplasia
Genetics in Medicine, 2000Co-Authors: Gary A. Bellus, Clair A. Francomano, A T Garber, C R Bryke, C A Weaver, P W Speiser, Melanie K. Webster, D A Donoohue, Elaine SpectorAbstract:More than 50% of individuals with Hypochondroplasia are heterozygous for mutations at a single FGFR3 nucleotide that result in N540K substitutions. Although genetic heterogeneity has been demonstrated in several families, it is likely that FGFR3 mutations other than N540K also cause Hypochondroplasia. We have screened more than 65 individuals with suspected clinical diagnoses of Hypochondroplasia (but who do not have N540K mutations) for mutations in FGFR3 exon 15 that disrupt a Bbs-l restriction site. We report here the discovery of 3 novel mutations (G1950T:K650N, G1950C: K650N & A1948C: K650Q) occurring in 5 individuals with clinical features of Hypochondroplasia. The phenotype of these individuals tends to be milder than that of individuals with N540K mutations. Total height deficit was less [K650N/Q = -2.09 SD +/- 0.67 (n=5), N540K. = -3.25 SD +/- 1.09 (n=36): P <0.05] and shortening of the metacarpals and proximal digits was less pronounced. In addition, other radiographic features such as narrowing of the lumbar interpedicular distance and overgrowth of the fibula tended to be milder. Mutations in the K650 codon of FGFR3 that cause thanatophoric dysplasia type II (K650E) and SADDAN syndrome (K650M) result in ligand independent constitutive activation of FGFR3 tyrosine kinase. The K650N and K650Q mutations activate FGFR3 tyrosine kinase to similar extents however the degree of activation is more than 10 fold less than that of the K540E and K650M mutations. These results highlight the importance of the K650 codon in FGFR3 function.
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confirmatory linkage of Hypochondroplasia to chromosome arm 4p
American Journal of Medical Genetics, 1995Co-Authors: Jacqueline T Hecht, Gary A. Bellus, C. Herrera, Giselle A. Greenhaw, Clair A. Francomano, Susan H BlantonAbstract:Hypochondroplasia is an inherited chondrodystrophy that is characterized by disproportionate short stature. A recent linkage study by LeMerrer et al. suggested that Hypochondroplasia and achondroplasia are allelic conditions. Three groups have now mapped the achondroplasia locus to the telomeric region of chromosome 4. Recently, two mutations in fibroblast growth factor receptor 3 (FGFR3) at nucleotide 1138, in the transmembrane domain, were identified in 169 of 170 unrelated individuals with achondroplasia. Here, we report the results of a linkage study in 4 multigenerational families with Hypochondroplasia and mutational analysis of nucleotide 1138 in one individual from each of these families, two nonfamilial Hypochondroplasia individuals and sequencing of the transmembrane domain of the FGFR3 in three affected unrelated individuals. 13 refs., 1 tab.
Andrew R. Zinn - One of the best experts on this subject based on the ideXlab platform.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or Hypochondroplasia.
American journal of medical genetics. Part A, 2003Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had Hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and Hypochondroplasia to a N540K mutation in the same gene. The patient with Hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or Hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or Hypochondroplasia.
American Journal of Medical Genetics Part A, 2002Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had Hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and Hypochondroplasia to a N540K mutation in the same gene. The patient with Hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or Hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development. © 2002 Wiley-Liss, Inc.
Giedre Grigelioniene - One of the best experts on this subject based on the ideXlab platform.
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Asn540Lys mutation in fibroblast growth factor receptor 3 and phenotype in Hypochondroplasia.
Acta paediatrica (Oslo Norway : 1992), 2007Co-Authors: Giedre Grigelioniene, Ole Eklöf, E. Laurencikas, B. Ollars, Niels Thomas Hertel, Jan P. Dumanski, Lars HagenäsAbstract:Hypochondroplasia is characterized by a disproportionate short stature with rhizomelic shortening of the limbs. Amino acid substitutions Asn540Lys, Asn540Thr and Ile538Val in the fibroblast growth factor receptor 3 (FGFR3) are considered to cause Hypochondroplasia. In this study we examined the FGFR3 gene for the previously described Hypochondroplasia mutations and the phenotype of 23 probands with clinically and radiologically diagnosed Hypochondroplasia. For the phenotype comparison, the patients were divided into two groups: Group 1: Hypochondroplasia with Asn540Lys substitution; Group 2: Hypochondroplasia with no mutations identified so far. A three-generation family negative for the known Hypochondroplasia mutations was examined with polymorphic markers flanking the FGFR1, FGFR2 and FGFR3 genes. Nine (39%) of 23 probands were found to be heterozygous for the Asn540Lys substitution. The individuals positive for the Asn540Lys substitution were significantly more disproportionate than the individuals without this mutation. In this respect, a genotype-phenotype correlation was found in our patients. However, some individuals belonging to the group without mutations identified so far showed similarly abnormal proportions. Genotyping/haplotyping in the three-generation family with Hypochondroplasia showed that FGFR1, FGFR2 and FGFR3 genes were not linked to the Hypochondroplasia phenotype in this family, thus further confirming the genetic heterogeneity of Hypochondroplasia. CONCLUSION: Individuals with Hypochondroplasia heterozygous for the Asn540Lys substitution are significantly more disproportionate than individuals without this mutation. Our study further confirms the clinical and genetic heterogeneity of Hypochondroplasia.
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Genetics of Achondroplasia and Hypochondroplasia
The Skeleton, 2004Co-Authors: Giedre GrigelionieneAbstract:Achondroplasia and Hypochondroplasia are relatively common skeletal dysplasias characterized by disproportionate short stature, rhizomelic shortening of the limbs, and increased head circumference. Short stature and body disproportion are usually severe and uniform in achondroplasia, whereas phenotype in Hypochondroplasia varies from severe achondroplasia-like forms to mild shortness and body disproportion. Mild forms of Hypochondroplasia are on clinical grounds difficult to differentiate from idiopathic short stature or normal height at the shorter end of the height spectrum.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or Hypochondroplasia.
American journal of medical genetics. Part A, 2003Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had Hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and Hypochondroplasia to a N540K mutation in the same gene. The patient with Hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or Hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or Hypochondroplasia.
American Journal of Medical Genetics Part A, 2002Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had Hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and Hypochondroplasia to a N540K mutation in the same gene. The patient with Hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or Hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development. © 2002 Wiley-Liss, Inc.
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a novel missense mutation ile538val in the fibroblast growth factor receptor 3 in Hypochondroplasia
Human Mutation, 1998Co-Authors: Giedre Grigelioniene, Ole Eklöf, Lars Hagenäs, Luitgard Neumeyer, P E Haereid, M AnvretAbstract:Hypochondroplasia and achondroplasia are skeletal dysplasias, characterised by autosomal dominant inheritance and disproportionate short stature, which occurs mainly due to growth failure of the extremities. Both dysplasias have been mapped to fibroblast growth factor receptor 3 (FGFR3) gene. For Hypochondroplasia, two point mutations, both responsible for the Asn540Lys substitution in the region coding the tyrosine kinase domain have been reported. Here we report an A to G transition at position 1651, predicting an Ile538Val substitution in the FGFR3, in Hypochondroplasia. The substitution is found in a swedish family with three affected members. The criteria for Hypochondroplasia were disproportionate short stature and radiological evidence of shortened long bones and decrease or absence of normal increase in interpedicular distances of the lumbar column. The mutation was detected by direct sequencing and restriction enzyme Tai I digestion. The base change was not found in the FGFR3 genes of unaffected members of the family nor in seventy-five unrelated unaffected individuals, suggesting that it was not a polymorphism. The Ile538Val substitution is a conservative amino acid change (a hydrophobic amino acid incorporated for another hydrophobic amino acid). Nevertheless, it is located in the stretch of nine amino acids, which is highly conserved among all the human fibroblast growth factor receptors. Considering the location of this substitution and the segregation with the phenotype in this family, we propose that it is a causative mutation of Hypochondroplasia. It is difficult to establish whether the Ile538Val substitution is rare in Hypochondroplasia patients or whether the individuals, who have a moderate degree of short stature, rarely seek medical help for the short stature and consequently are rarely diagnosed as affected by Hypochondroplasia. Hum Mutat 11:333, 1998. © 1998 Wiley-Liss, Inc.
Jacky Bonaventure - One of the best experts on this subject based on the ideXlab platform.
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common mutations in the fibroblast growth factor receptor 3 fgfr 3 gene account for achondroplasia Hypochondroplasia and thanatophoric dwarfism
Clinical Pediatric Endocrinology, 1997Co-Authors: Jacky Bonaventure, F Rousseau, Arnold Munnich, Laurence Legeaimallet, Le M Merrer, Pierre MaroteauxAbstract:The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene, has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and Hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported, exhibited mutations in the transmembrane receptor domain. Although most of Hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three Hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this disease. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor has been detected in 100% of TD II cases, while 7 distinct mutations in three different protein domains were identified in 25 out of 26 TD I patients, suggesting that TD, like achondroplasia is a genetically homogenous skeletal disorder.
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Clinical and genetic heterogeneity of Hypochondroplasia.
Journal of medical genetics, 1996Co-Authors: François Rousseau, Pierre Maroteaux, Arnold Munnich, Jacky Bonaventure, Laurence Legeai-mallet, H. Schmidt, Jean Weissenbach, M. Le MerrerAbstract: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.
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Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, Hypochondroplasia, and thanatophoric dwarfism.
American journal of medical genetics, 1996Co-Authors: Jacky Bonaventure, M. Le Merrer, F Rousseau, Arnold Munnich, Laurence Legeai-mallet, Pierre MaroteauxAbstract:The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and Hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most Hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three Hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases, our series seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder.
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Common mutations in the gene encoding fibroblast growth factor receptor 3 account for achondroplasia, Hypochondroplasia and thanatophoric dysplasia.
Acta paediatrica (Oslo Norway : 1992). Supplement, 1996Co-Authors: Jacky Bonaventure, M. Le Merrer, F Rousseau, Laurence Legeai-mallet, A Munnich, P MaroteauxAbstract: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.