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The SP7 gene encodes a zinc finger transcription factor (Osterix), which is a member of the Sp subfamily of sequence-specific DNA-binding proteins, playing an important role in osteoblast differentiation and maturation. SP7 pathogenic variants have been described in association with different allelic disorders. Monoallelic or biallelic SP7 variants cause Osteogenesis imperfecta type XII (OI12), a very rare condition characterized by recurrent fractures, skeletal deformities, undertubulation of long bones, hearing loss, no dentinogenesis imperfecta, and white sclerae. Monoallelic or biallelic SP7 variants may also cause sclerotic skeletal dysplasias (SSD), partially overlapping with Juvenile Paget's disease and craniodiaphyseal dysplasia, characterized by skull hyperostosis, long bones sclerosis, large ribs and clavicles, and possible recurrent fractures. Here, we report the long-term follow-up of an 85-year-old woman presenting with a complex bone disorder including features of either OI12 (bone fragility with multiple fractures, severe deformities and short stature) or SSD (striking skull hyperostosis with optic atrophy, very large ribs and clavicles and long bones sclerosis). Exome sequencing showed previously undescribed biallelic loss of function variants in the SP7 gene: NM_001173467.2(SP7): c.359_362del, p.(Asp120Valfs*11); NM_001173467.2(SP7): c.1163_1174delinsT, p.(Pro388Leufs*33). RT-qPCR confirmed a severely reduced SP7 transcription compared to controls. Our report provides new insights into the clinical and molecular features and long-term outcome of SP7 -related bone disorders (SP7 -BD), suggesting a continuum phenotypic spectrum characterized by bone fragility, undertubulation of long bones, scoliosis, and very heterogeneous bone mineral density ranging from osteoporosis to osteosclerosis. • Monoallelic or biallelic SP7 variants cause Osteogenesis imperfecta type XII (OI12). • SP7 variants may also cause sclerotic skeletal dysplasias (SSD). • We report the long-term follow-up of a patient with features of either OI12 or SSD. • She carried previously unreported biallelic variants in SP7 affecting transcription. • Our report provides new insights into SP7 related bone disorders. [ABSTRACT FROM AUTHOR]

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. • A consanguineous family with craniodiaphyseal dysplasia • A homozygous missense variant (c.913T>C, p.(Tyr305His)) in SP7 , encoding the Osterix transcription factor • A 90 percent loss in binding capacity of mutant Osterix to AT-rich sequences was shown [ABSTRACT FROM AUTHOR]