Severe SHOX gene haploinsufficiency in a girl with a novel mutation (M1T) involving the first codon of coding region.

Our aim is to report on one additional novel and peculiar mutation of SHOX gene in a Calabrian girl with Leri-Weill dyschondrosteosis (LWD) that is not included to now in the updated SHOX allelic variant database. The proband was referred to our Unit of Pediatric Endocrinology at the age of 6.9 years, due to disproportionate short stature and Madelung deformity. Her height (H) deficiency was -3.6 DS and sitting H (SH) / H ratio was distinctly supranormal (0.56). Birth weight and length had been -2.0 and -2.8 SDS, respectively. None of the parents exhibited either short stature or dysmorphic features or body disproportions or Madelung deformity. This clinical picture as a whole suggested diagnosis of LWD. This diagnosis was supported by the results of SHOX gene analysis, which revealed a novel thiamine to cytosine transition at codon 1 in exon 2, that resulted in a novel missense mutation (M1T) with methionine (M) to be replaced by threonine (T). To conclude, in this patient with LWD we have detected a novel de novo SHOX mutation, which is peculiar in that it involves the first methionine of the first coding exon and therefore it may have a deleterious functional impact on the protein biosynthesis, with a consequent severe haploinsufficiency. This can account for the early onset and severe impairment of growth and the poor height prognosis observed in this case.