Diastrophic dysplasia

The diastrophic dysplasia family of disorders include a spectrum of recessive chondrodysplasias that comprise severe forms, achondrogenesis type 1B  and atelosteogenesis type 2, an intermediate form, diastrophic dysplasia (DTD), and a milder form, the recessively inherited multiple epiphyseal dysplasia.

Diastrophic dysplasia (DTD) is a severe, though usually nonlethal form of skeletal dysplasia with marked short stature, bilateral clubfoot, cleft palate, characteristic hand deformities, changes of the ear pinnae, progressive kyphoscoliosis of the spine, and joint stiffness. The fingers are short, and the thumb is both proximally placed and deviated to the radial side (the so-called “hitchhiker thumb”). DTD is a progressive condition, degenerative arthritis of the hip is common in young adults and the spine may develop excessive lumbar lordosis, thoracolumbar kyphosis and scoliosis.

The common origin of the DTD chondrodysplasias are mutations in the SLC26A2 (also known as DTDST) gene on chromosome 5, which encodes an ubiquitously expressed sulfate transporter of the cell membrane. Functional impairment of the transporter cause reduced intracellular sulfate uptake leading to undersulfation of proteoglycans of articular and growth plate cartilage.

Transgenic mice harboring an A386V substitution, previously detected at the homozygous state in a patient with a non-lethal form of DTD, were generated by homologous recombination in embryonic stem cells. Homozygous mutant mice were characterized by growth retardation, skeletal dysplasia and joint contractures, thereby recapitulating essential aspects of the DTD phenotype in man. This animal model is used in SYBIL to elucidate the molecular basis of reduced long bone growth in DTD and to develop potential pharmacological therapies of the disorder.