A recessive form of craniodiaphyseal dysplasia caused by a homozygous missense variant in SP7/Osterix

Craniodiaphyseal dysplasia (CDD) is an ultra-rare and severe sclerosing bone dysplasia, usually presenting in early childhood with progressive sclerosis of the cranial and facial bones. Heterozygous variants in the SOST gene have been reported in two unrelated CDD patients. We now report on two subjects from a large consanguineous family with mild phenotypic features of CDD. Physical examination revealed facial dysmorphism, short stature and a lean body habitus. Radiographs showed severe hyperostosis of the calvarium, skull base and mandibula, broadened claviculae and ribs, scoliosis, and diaphyseal expansion of the long bones. One of the two subjects had a history of recurrent fractures. Serum analysis in the proband revealed very high levels of bone formation (P1NP, osteocalcin) and resorption markers (CTX-1, TRAcP 5b), suggesting a high bone turnover. Exome sequencing led to the identification of a homozygous missense variant (c.913T>C, p.(Tyr305His)) in SP7, encoding the Osterix transcription factor. The variant is located in the first zinc-finger domain, a highly conserved region responsible for DNA-binding. Luciferase reporter assays were performed to investigate the DNA-binding capacity of mutant Osterix to AT-rich sequences, as these motifs mediate the transcription of genes in osteoblasts. This analysis showed a 90 % loss in binding capacity of mutant Osterix. Based on our data, we hypothesize that our variant may have neomorphic effects resulting in the SP7-related autosomal recessive CDD phenotype. Further studies are required to dissect the precise mechanisms on how bi-allelic variants in SP7 can cause a sclerosing bone dysplasia.