Cole-Carpenter syndrome (CCS) is commonly classified as a rare Osteogenesis Imperfecta disorder. This was following the description of two unrelated patients with very similar phenotypes who were subsequently shown to have a heterozygous missense mutation in P4HB. Here, we report a 3-year old female patient who was diagnosed with a severe form of OI. Exome sequencing identified the same missense mutation in P4HB as reported in the original cohort, thus reinforcing a recurrent missense mutation in P4HB as the underlying aetiology of Cole-Carpenter syndrome.
We discuss this patient with particular emphasis on the phenotype and similarities with the previously reported patients with CCS. The clinical phenotype appears consistent in patients reported so far but interestingly, there also appears to be a definitive phenotypic clue (crumpling metadiaphyseal fractures of the long tubular bones with metaphyseal sclerosis which are findings that are uncommon in OI) to the underlying genotype (P4HB variant).
P4HB (Prolyl 4-hydroxylase, beta subunit) encodes for PDI (Protein Disulfide isomerase) and in cells, in its tetrameric form, catalyses formation of 4-hydroxyproline in collagen. The recurrent variant in P4HB, c.1178A>G, p.Tyr393Cys, sits in the C-terminal reactive centre and is said to interfere with disulphide isomerase function of the C-terminal reactive centre.
P4HB catalyses the hydroxylation of proline residues within the X-Pro-Gly repeats in the procollagen helical domain. Initial experiments on patient fibroblasts showed no major difference in extracellular collagen type I deposition as judged by immunofluorescence. While there was a minor trend towards an increase in extracellular collagen type I compared to control, this was not statistically significant. Given the inter-dependence of ECM components in assembly of a functional matrix, our data suggest that it is the organisation and assembly of the functional ECM that is perturbed rather than the secretion of collagen type I per se. This will require further functional analysis of whole ECM, which is ongoing.
We discuss the genetic heterogeneity of Cole-Carpenter syndrome as originally described and the underlying mechanism of P4HB in collagen production and how this recurrent variant causes a rare form of osteogenesis imperfecta.
Disclosure: The authors declared no competing interests.