Campomelic dysplasia
Campomelic dysplasia (CMPD; MIM 114290) is an autosomal dominant skeletal dysplasia characterized by shortening and angular bowing of the long bones, hypoplastic scapulae, 11 pairs of ribs, lack of mineralization of thoracic pedicles, cervical spine and pelvic malformations, clubfeet and Pierre Robin sequence. Tracheobronchomalacia causes respiratory problems that often lead to death during the neonatal period. Acampomelic campomelic dysplasia (ACMPD) is a variant of campomelic dysplasia that lacks the angular deformities of the long bones. Sex reversal or gradations of genital defects occur in about 65% to 75% of individuals with a 46, XY karyotype. CMPD and ACMPD are caused by mutations in SOX9. The SOX proteins are a group of transcription factors that are characterized by the presence of a DNA-binding motif known as the high mobility group (HMG) domain. Members of this group play a diverse role during embryonic development and several are associated with human disease. The majority of the SOX9 mutations (about 90% to 95%) consist of missense, non-sense and splice site mutations, and small exonic deletions or insertions. Some cases of CMPD or ACMPD are caused by chromosome 17 rearrangements remote from SOX9. Breakpoints associated with CMPD or ACMPD have been detected up to 1Mb 5’ or 3’ from the gene. The implication is that remote rearrangements involving chromosome 17 affect cis-acting elements involved in regulation of SOX9. In general, the more remote the chromosome 17 rearrangement is from the SOX9 gene, the less severe the phenotype. The rearrangements and large deletions constitute about 5% to 10% of the mutations.
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