title: Phenotypic characterization of patients with deletions in the 3'-flanking SHOX region.
abstract: Context. Leri-Weill dyschondrosteosis is a clinically variable skeletal dysplasia, caused by SHOX deletion or mutations, or a deletion of enhancer sequences in the 3'-flanking region. Recently, a 47.5 kb recurrent PAR1 deletion downstream of SHOX was reported, but its frequency and clinical importance are still unknown. Objective. This study aims to compare the clinical features of different sizes of deletions in the 3'-flanking SHOX region in order to determine the relevance of the regulatory sequences in this region. Design. We collected DNA from 28 families with deletions in the 3'-PAR1 region. Clinical data were available from 23 index patients and 21 relatives. Results. In 9 families (20 individuals) a large deletion ( ∼ 200-900 kb) was found and in 19 families (35 individuals) a small deletion was demonstrated, equal to the recently described 47.5 kb PAR1 deletion. Median height SDS, sitting height/height ratio SDS and the presence of Madelung deformity in patients with the 47.5 kb deletion were not significantly different from patients with larger deletions. The index patients had a median height SDS which was slightly lower than in their affected family members (p = 0.08). No significant differences were observed between male and female patients. Conclusions. The phenotype of patients with deletions in the 3'-PAR1 region is remarkably variable. Height, sitting height/height ratio and the presence of Madelung deformity were not significantly different between patients with the 47.5 kb recurrent PAR1 deletion and those with larger deletions, suggesting that this enhancer plays an important role in SHOX expression.
authors: CHCG-Department of Clinical Genetics, Leiden University Medical Center , Leiden , The Netherlands.
authors: Sarina G
authors: SG
authors: Kant
authors: Sander J
authors: SJ
authors: Broekman
authors: Caroline C
authors: CC
authors: de Wit
authors: Marloes
authors: M
authors: Bos
authors: Sitha A
authors: SA
authors: Scheltinga
authors: Egbert
authors: E
authors: Bakker
authors: Wilma
authors: W
authors: Oostdijk
authors: Hetty J
authors: HJ
authors: van der Kamp
authors: Erik W
authors: EW
authors: van Zwet
authors: Annemieke H
authors: AH
authors: van der Hout
authors: Jan M
authors: JM
authors: Wit
authors: Monique
authors: M
authors: Losekoot
keywords: Disproportion; Downstream deletion; Madelung; Phenotype; SHOX; Short stature
references: J Med Genet. 2009 Dec;46(12):834-9
references: 19578035
references: Eur J Hum Genet. 2010 May;18(5):527-32
references: 19997128
references: Nat Genet. 1998 May;19(1):70-3
references: 9590293
references: Horm Res Paediatr. 2011;76(3):178-85
references: 21912078
references: Am J Hum Genet. 2005 Oct;77(4):533-44
references: 16175500
references: J Clin Endocrinol Metab. 2011 Feb;96(2):E356-9
references: 21068148
references: Am J Hum Genet. 2006 Jan;78(1):167-70
references: 16385461
references: Eur J Hum Genet. 2012 Jan;20(1):125-7
references: 22071895
references: Arch Dis Child. 2005 Aug;90(8):807-12
references: 15863466
references: Horm Res Paediatr. 2011 Feb;75(2):81-9
references: 21325865
references: Nat Genet. 1998 May;19(1):67-9
references: 9590292
references: J Med Genet. 2007 May;44(5):306-13
references: 17182655
references: PLoS One. 2011;6(6):e21498
references: 21731768
references: Hum Mol Genet. 2007 Jan 15;16(2):210-22
references: 17200153
references: J Clin Endocrinol Metab. 2004 Sep;89(9):4403-8
references: 15356038
references: Horm Res Paediatr. 2012;77(4):250-60
references: 22572840
references: J Clin Endocrinol Metab. 2012 Jul;97(7):E1257-65
references: 22518848
references: J Med Genet. 2012 Jul;49(7):442-50
references: 22791839