Clinical and genetic investigation of hypochondroplasia and dyschondrosteosis

University dissertation from Stockholm : Karolinska Institutet, Department of Women's and Children's Health

Abstract: Linear body growth is a multifactorial trait influenced by many environmental and intrinsic factors. Among the intrinsic determinants of body height, genetic and endocrine factors are considered to be the most important. Children with short stature are usually referred to paediatric endocrinology clinics and a significant proportion of these suffer from skeletal dysplasias. Hypochondroplasia and dyschondrosteosis (Léri-Weill syndrome) are characterised by disproportionate short stature. The phenotype in hypochondroplasia is mainly characterised by rhizomelic (proximal) shortening of the limbs, whereas dyschondrosteosis confers mesomelic short stature (shortening of the middle segment). An aberration of the forearm, called Madelung deformity, is a frequent feature of dyschondrosteosis. In both hypochondroplasia and dyschondrosteosis, the phenotype varies from moderate to severe short stature and body disproportion and it is usually mild in early childhood, which causes diagnostic difficulties. In these cases, molecular genetic analysis is an important diagnostic tool. Point mutations in the FGFR3 (fibroblast growth factor receptor 3) gene, causing the Asn54OLys substitution, have been described in 40-70% of hypochondroplasia cases. Haploinsufficiency of the SHOX (short stature homeobox-containing) gene due to deletions or point mutations has been found in dyschondrosteosis and in some cases of idiopathic short stature. In this study, the frequency of the Asn540Lys mutation was determined in 30 Swedish probands with clinically and radiologically confirmed hypochondroplasia. Nine unrelated individuals were found to be heterozygous for the Asn54OLys mutation, whereas one proband in a familial case with hypochondroplasia was found to have a novel mutation IIe538Val. Overall, FGFR3 mutations were found in only 33% of hypochondroplasia probands. In a single three-generation hypochondroplasia family, we excluded involvement of FGFR3, which supports the genetic heterogeneity in hypochondroplasia. The hypochondroplasia individuals without the Asn540Lys mutation were less disproportionate, suggesting that these cases might have a phenotype resembling idiopathic short stature or mild dyschondrosteosis. Considering the above-mentioned findings and clinical overlap between hypochondroplasia and dyschondrosteosis, we analysed 18 probands with hypochondroplasia (negative for the known FGFR3 mutations) and 32 probands with dyschondrosteosis, for mutations in the SHOX gene. In dyschondrosteosis group, 16 unrelated families (50%) had SHOX gene deletions, whereas 9 probands (28%) carried point mutations/minute deletions in the SHOX gene. In total 78% of the probands with dyschondrosteosis had mutations in the SHOX gene and seven mutations were previously not described. All novel mutations segregated with the dyschondrosteosis phenotype in familial cases and were not found in 90 unrelated, unaffected individuals, suggesting that these mutations are pathogenic. No SHOX mutations were found in hypochondroplasia individuals lacking known FGFR3 gene mutations, which suggests that SHOX gene defects are not involved in the pathogenesis of hypochondroplasia. Considering a high percentage of SHOX gene mutations in dyschondrosteosis and difficulties in differential diagnosis between hypochondroplasia and dyschondrosteosis, especially in children, molecular analysis of SHOX gene could be an important diagnostic tool. Seven sporadic cases with isolated Madelung deformity were also examined and no SHOX gene mutations that could be considered pathogenic were identified. Thus, it is less likely that mutations in the SHOX gene are involved in the development of isolated Madelung deformity.

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