Chassaing et al. (2005) reported a 4-generation family segregating an apparent X-linked dominant chondrodysplasia, in which 4 males and 6 females were affected. Features seen in the affected males included intrauterine growth retardation and hydrocephaly, macrocephaly, frontal bossing, ... Chassaing et al. (2005) reported a 4-generation family segregating an apparent X-linked dominant chondrodysplasia, in which 4 males and 6 females were affected. Features seen in the affected males included intrauterine growth retardation and hydrocephaly, macrocephaly, frontal bossing, microphthalmia, small low-set ears, and short flat nose. Radiography revealed macrocephaly with poor mineralization of the skull, severe platyspondyly, thin ribs, with only 11 rib pairs in 2 of the male patients, hypoplasia of the iliac wings, poor ossification of the pubis, distinctive metaphyseal cupped metacarpals, metatarsals, and phalanges, and hypoplastic calcaneus. Microscopic examination of the bones in 3 male patients showed similar anomalies, including severe flattening of the anlage of vertebral bodies, which were poorly delimited and under-ossified, whereas the intervertebral disks were thick with abnormal craniocaudal orientation of the fibroblasts. Resting cartilage showed sparse matrix and increased density of chondrocytes, which were irregular in size and shape and often had a fibroblastic appearance. The chondrocyte columns of the growth plate were small and rather irregular, with large cores of mineralized cartilage persisting among the primarily osseous trabeculae. Endochondral, diaphyseal, and endomembranous ossification of the cranium led to thickening of the trabecular bone, resulting in a severely reduced bone marrow cavity, especially in the diaphysis of the long bones. Identification of skeletal abnormalities and hydrocephalus during the pregnancy of 3 male fetuses led to termination of pregnancy; the fourth affected male died at 6 days of life. Affected females showed a milder phenotype, involving short stature with rhizomelic shortening of the limbs, sometimes associated with body asymmetry and mild mental retardation.
By exon sequencing, Simon et al. (2010) identified a variant in exon 29 of the HDAC6 gene, 281 bp after the translation termination codon (c.*281A>T; 300272.0001) that completely segregated with the chondrodysplasia phenotype in the family described by ... By exon sequencing, Simon et al. (2010) identified a variant in exon 29 of the HDAC6 gene, 281 bp after the translation termination codon (c.*281A>T; 300272.0001) that completely segregated with the chondrodysplasia phenotype in the family described by Chassaing et al. (2005). The variant was located in the sequence corresponding to the seed sequence of miR433 (611711). Transduction experiments with an HDAC6 3-prime untranslated region (UTR)-bearing transgene showed that the mutation abrogated the posttranscriptional regulation normally exerted by this microRNA. The authors concluded that the HDAC6 3-prime UTR variant suppressed miR433-mediated posttranscriptional regulation, causing overexpression of HDAC6 and resulting in this form of X-linked chondrodysplasia. - Exclusion Studies In an affected member of a 4-generation family segregating X-linked dominant chondrodysplasia, Chassaing et al. (2005) analyzed the L1CAM (308840) and EBP (300205) genes, but identified no mutations.