Cole-Carpenter syndrome in a patient from Thailand

Cole-Carpenter syndrome (CCS), commonly classified as a rare type of osteogenesis imperfecta, is a disorder with severe bone fragility, craniosynostosis, and distinct facial features. Recently, the heterozygous missense mutation, c.1178A>G, p.Tyr393Cys, in exon 9 of P4HB which encodes protein disulfide isomerase, has been found in three Caucasian patients with CCS. Ethnic background is known to affect clinical manifestations, especially facial features of dysmorphic syndromes. Here, we describe the first Asian CCS patient possessing the recurrent mutation in P4HB. Although she had several common features of CCS including bulging forehead, ocular proptosis, midface hypoplasia, long bone deformity, popcorn epiphyses, vertebral fractures, and scoliosis, she did not have hydrocephalus, wormian bones, and dentinogenesis imperfecta, commonly seen in Caucasian patients. Interestingly, she is the only one without macrocephaly. Radiologically, metadiaphyseal fractures of the long bones with metaphyseal sclerosis were found, substantiating that they provide a definitive radiological feature of CCS. In addition, we showed for the first time a three-dimensional facial scan of a patient with CCS. She had been given intravenous bisphosphonate since the age of 9 months and had responded well. Our study presents the clinical features of the first Asian patient, supports metaphyseal scleroses and fractures as radiological clues, strengthens early bisphosphonate administration, and confirms the etiologic role of the c.1178A>G variant in P4HB across populations.