A Case of Platyspondylic Lethal Skeletal Dysplasia Torrance Type

Platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T), is one of the phenotypes of type II collagenopathy and is characteristic of severe bone growth disorder. This phenotype may limit the growth and expansion of the lungs, which is known to cause death from respiratory failure during or shortly after birth, but in few less severe cases, patients have been reported to have survived to adulthood. We have experienced a case of PLSD-T in a preterm infant who was delivered via cesarean section at the gestational age of 29 weeks 3 days, with a birth weight of 1.15 kg. Physical examination of the infant revealed characteristic findings of short arms and legs, small thorax, distended abdomen, and cleft palate. On the basis of the subsequent genetic testing, the patient had a heterozygous mutation in the encoded c-propeptide region of collagen, type II, alpha 1 (COL2A1), c.4335G>A (p.Trp1445*) in exon 52. This is the first case of PLSD-T diagnosed in Korea, and we hereby report the case.

Endoplasmic reticulum stress-mediated apoptosis contributes to a skeletal dysplasia resembling platyspondylic lethal skeletal dysplasia, Torrance type, in a novel Col2a1 mutant mouse line.

In humans, mutations in the COL2A1 gene encoding the α1(II) chain of type II collagen, create many clinical phenotypes collectively termed type II collagenopathies. However, the mechanisms generating this diversity remain to be determined. Here we identified a novel Col2a1 mutant mouse line by screening a large-scale N-ethyl-N-nitrosourea mutant mouse library. This mutant possessed a p.Tyr1391Ser missense mutation in the C-propeptide coding region, and this mutation was located in positions corresponding to the human COL2A1 mutation responsible for platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T). As expected, p.Tyr1391Ser homozygotes exhibited lethal skeletal dysplasias resembling PLSD-T, including extremely short limbs and severe dysplasia of the spine and pelvis. The secretion of the mutant proteins into the extracellular space was disrupted, accompanied by an abnormally expanded endoplasmic reticulum (ER) and the up-regulation of ER stress-related genes in chondrocytes. Chondrocyte apoptosis was severely induced in the growth plate of the homozygotes. These findings strongly suggest that ER stress-mediated apoptosis caused by the accumulated mutant proteins in ER contributes to skeletal dysplasia in Co12a1 mutant mice and PLSD-T patients.