SHOX point mutations and deletions in Leri-Weill dyschondrosteosis

SHOX (Short HOmeoboX containing gene) (OMIM 312865) is the single gene found in the “short stature critical region”, a 170 kb DNA segment of the pseudoautosomal (PAR1) region identified through genotype/phenotype correlations in X/Y abnormalities.1 The finding of a mutation generating a premature stop codon in exon 5 of SHOX , cosegregating with idiopathic short stature (ISS), provided evidence for the involvement of this gene in growth retardation, including the short stature of Turner syndrome.1 At the heterozygous level, large deletions or point mutations of the SHOX gene have been found in families affected by Leri-Weill dyschondrosteosis (LWD, OMIM 127300), a dominantly inherited skeletal dysplasia with disproportionate short stature owing to mesomelic shortening of the forearm and lower leg and Madelung deformity of the arm.2,3 In addition, the biallelic inactivation of the SHOX gene was shown in fetuses with Langer-type mesomelic dysplasia (OMIM 249700),2,3 a recessive form of dwarfism which was confirmed as the homozygous counterpart of LWD, as previously proposed on a clinical genetic basis.4 Some authors reported mutations in all the LWD cases studied,3,5 whereas others found SHOX mutations in about 60% of the cases.6,7 The same proportion of SHOX gene mutations are reported in the present study based on the analysis of a large group of Italian LWD families. Patients and families were recruited, after informed consent, in the context of a collaborative study in several Italian paediatric endocrinology centres. Height and sitting height were measured to nearest 0.1 cm using a Harpenden anthropometer and measurements were converted into centiles, according to the Tanner tables. All subjects were submitted to x ray examination including the forearms and lower legs. Inclusion criteria for the study were: (1) normal karyotype, with lack of demonstrable sex chromosome abnormality using …