Brachymesomelic dysplasia with Peters anomaly of the eye results from disruptions of the X chromosome near the SHOX and SOX3 genes

Abstract

We report on a mother and son affected with an unusual skeletal dysplasia and anterior segment eye abnormalities. Their skeletal phenotype overlaps with the SHOX-related skeletal dysplasias and is intermediate between Leri-Weill dyschondrosteosis (LWD) and Langer Mesomelic dysplasia (LMD). The mother has bilateral Peters anomaly of the eye and was reported as having a new syndrome; the son had severe bilateral sclerocornea. Chromosome analysis showed that the mother has a pericentric inversion of the X chromosome [46,X,inv(X)(p22.3q27)] and the son, a resultant recombinant X chromosome [46,Y,rec(X)dup(Xq)inv(X)(p22.3q27)]. The observed skeletal and ophthalmologic abnormalities in both patients were similar in severity. The additional features of developmental delay, growth retardation, agenesis of the corpus callosum, cryptorchidism and hypoplastic scrotum in the son are consistent with Xq28 duplication. Analysis of the son's recombinant X chromosome showed that the Xp22.33 breakpoint lies 30-68 kb 5' of the SHOX gene. This finding suggests that the skeletal dysplasia in both mother and son is allelic with LWD and LMD and results from a novel misexpression of SHOX. Analysis of the Xq27.1 breakpoint localized it to a 90 kb interval 3' of the SOX3 gene, supporting a novel role of SOX3 misexpression in the development of Peters anomaly of the eye.

Enhancer elements upstream of the SHOX gene are active in the developing limb

“…However, this limb phenotype possibly differs from the one observed for deletions of the SHOX coding region or of the SHOX downstream region, as the regulatory region upstream of SHOX may control slightly different expression domains in the limb bud. Indeed, the skeletal anomalies seen in the patient described by Bleyl et al, 16 in whom the SHOX upstream region is translocated away and therefore separated from the SHOX gene, overlap with but are more severe and partly distinct from those seen in LWD. The patient's distal limbs are notably short and radiographs showed a shortened bowed radius and a short thickened ulna, consistent with the symptoms typically seen in LWD.…”

“…In the index patient, a pericentric inversion of the X chromosome led to the disruption of the upstream region of SHOX. 16 The telomeric part of the X chromosome distal to SHOX was translocated to a different chromosomal context, resulting in the loss of all three upstream enhancers (CNE-2, CNE-3 and CNE-5), whereas the coding region of the SHOX gene was preserved (Figure 3). The skeletal dysplasia was suggested to result from a misexpression of SHOX due to the loss of unknown putative regulatory elements.…”

“…The additional eye symptoms of the patient were explained as being due to the second break point of the pericentric inversion, which affected the SOX3 gene. 16 As in situ hybridization revealed that SHOX is also expressed in the developing eye and cornea ( Figure 2C) and therefore could also be considered to cause the eye phenotype, we decided to reassess this hypothesis and analyze the SHOX upstream CNEs for potential enhancer function in the developing cornea. We carried out an in ovo enhancer assay in the developing cornea (HH25-26) using the same reporter constructs that we previously used in limb bud experiments ( Figure 2 and Table 1).…”

Identification of the first PAR1 deletion encompassing upstream SHOX enhancers in a family with idiopathic short stature

“…14 The mother presented a pericentric inversion of X chromosome (46, X, inv(X; p22.3q27)) and the son presented a recombinant X chromosome (46,Y, rec(X)dup(Xq)inv(X)p22.3q27) with a telomeric deletion 5¢ of SHOX. Both mother and son presented with severe short stature, mesomelic shortening and multiple bone malformations, an Figure 1 Schematic representation of the genomic location and approximate extensions of the observed upstream SHOX deletion.…”

“…The deletion detected in a patient with brachymesomelic dysplasia with Peters anomaly of the eye is also shown. 14 The extension limits were determined according to the reported array and PCR data. Black solid lines indicate deleted sequences, white lines indicate the presence of two copies while hashed lines indicate non-informative areas.…”