Complex deletion/duplication rearrangement involving the X chromosome in a male with novel phenotype combining elements of Langer mesomelic dysplasia and severe rhizomelic shortening. R. Mendoza-Londono1, L. Dupuis1, P. Babyn2, D. J. Stavropoulos3 1) Division of Clinical & Metabolic Genetics and; 2) Department of Diagnostic Imaging and; 3) Department of Pediatric Laboratory Medicine; The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Langer-type mesomelic dysplasia (MIM 249700) is a recessive skeletal dysplasia that results from haploinsufficiency for SHOX, located in the pseudoautosomal region of chromosomes X and Y. It is characterized by severe mesomelic shortening and micrognathia. Radiologic findings include: mesomelia with short and broad ulna and radii, marked shortening of the tibia and rudimentary fibula. The rest of the skeletal elements are usually not involved. We present the radiologic and cytogenetic findings in a four month old boy who was identified during the prenatal period to have rhizomelic shortening. On assessment at 4 months of age he had mildly dysmorphic features given by a broad nasal bridge, micrognathia and plagiocephaly. His extremities were significantly short. His radiographs showed asymmetric marked bilateral shortening of the femurs with a triangular shape. The tibias and fibulas were poorly modeled and had moderate shortening. The humerii, radius, ulna and radii were markedly short and bowed. Both hands had ulnar deviation. X-rays of the parents demonstrated bilateral Madelung deformities in the mother. Cytogenetic analysis revealed a male karyotype with an unbalanced X chromosome harboring a terminal deletion with breakpoint at Xp22.33. The deleted region is replaced by an additional copy of chromosome region Xq28 to Xqter [46,Y,der(X)(qter->q28::p22.33->qter).ish der(X)(pter-,qter++)]. Array CGH with an oligoarray platform confirmed the terminal deletion/duplication. The deletion involves 62 oligonucleotide probes (0.749 Mb) and results in the loss of the SHOX gene on the X chromosome. The terminal duplication involves 136 oligonucleotide probes (5.898 Mb) and results in the gain of one copy of approximately 108 genes. Molecular testing for SHOX mutations in the other allele is underway Our patient presents with a novel phenotype including features of Langer mesomelic dysplasia as well as atypical findings including severe rhizomelic shortening. His phenotype is likely the result of haploinsufficiency and excess dosage for genes located in the area of the deletion/duplication. Further delineation of his rearrangement is underway to allow the identification of genes that may be critical for the development of the limbs proximal segment.