SHOX deficiency in children with growth impairment: evaluation of known and new auxological and radiological indicators.

Background: The phenotypic features of SHOX deficiency (SHOX-D) are highly variable and can be very mild, especially in young children. The aim of this retrospective study was to evaluate auxological and radiological indicators that could be predictive of SHOX-D in children.

Methods: Molecular analysis of the SHOX gene was performed in 296 subjects with growth impairment or skeletal disproportion, without alternative diagnosis.

Duplications upstream and downstream of SHOX identified as novel causes of Leri-Weill dyschondrosteosis or idiopathic short stature.

Leri-Weill dyschondrosteosis is a pseudoautosomal dominantly-inherited skeletal dysplasia ascribed to haploinsufficiency of the SHOX gene caused by deletions, point mutations, or partial duplications of the gene, or to heterozygous deletions upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory DNA elements that show enhancer activity. Recently, two SHOX conserved non-coding element duplications, one upstream and one downstream, were reported in patients referred with idiopathic short stature. To further evaluate the role of these duplications in SHOX-related disorders, we describe seven patients (five with Leri-Weill dyschondrosteosis and two with short stature) all of whom have duplications of part of the upstream or downstream conserved non-coding element regions, identified by multiplex ligation-dependent probe amplification.

Germline mosaicism in achondroplasia detected in sperm DNA of the father of three affected sibs.

We describe a sib recurrence for achondroplasia with parents of average stature. The three sibs shared the paternal allele and all carried the same causal mutation in the fibroblast growth factor receptor 3 gene (FGFR3): G > A nt1138 (Gly380Arg). We were able to identify this mutation on sperm DNA confirming paternal germinal mosaicism.

FGFR3 mutation in thanatophoric dysplasia type 1 with bilateral cystic renal dysplasia: coincidence or a new association?

Thanatophoric dysplasia (TD) is a lethal dwarfism condition due to missense mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Examination of TD patients reveals mainly the involvement of the skeletal system and the brain, but also renal and cardiovascular anomalies have been described. We report the prenatal detection of TD type 1 (TD1) associated with bilateral cystic renal dysplasia (CRD) Potter's type II, in which the molecular analysis reveals the typical Arg248Cys substitution in the FGFR3 gene.