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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]

Craniodiaphysial dysplasia is an extremely rare genetic disorder characterized by a severe form of bone dysplasia and a distinctive facial dysmorphisms, as a result of a massive generalized hyperostosis and sclerosis, primarily involving the facial bones and the skull. We present a 10-years-old girl referred to an otolaryngology consultation with complaints of progressive hearing loss. The clinical aspects, pathogenesis and management of this disease are also review in this paper. Furthermore, we describe the first case of craniodiaphysial dysplasia rehabilitated with Bone-Anchored Hearing Aid, despite the concerns inherent to the involvement of the skull bone that characterizes the disease. [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]

We describe a rare syndrome characterized by severe craniofacial hyperostosis, sclerosis, obliteration of paranasal sinuses and foramina of skull base, in a 10-year-old female child who presented with abnormal facial features and recurrent dacryocystitis due to narrowing of nasolacrimal duct.

Sclerosing bone dysplasias are a group of rare, monogenic disorders characterized by increased bone density resulting from the disturbance in the fragile equilibrium between bone formation and resorption. Over the last decade, major contributions have been made toward better understanding of the pathogenesis of these conditions. These studies provided us with important insights into the bone biology and yielded the identification of numerous drug targets for the prevention and treatment of osteoporosis. Here, we review this heterogeneous group of disorders focusing on their utility in the development of novel osteoporosis therapies. [ABSTRACT FROM AUTHOR]

We report the magnetic resonance (MR) imaging findings in a 4-year-old girl with characteristic radiographic and computed tomography (CT) features of craniodiaphyseal dysplasia. MR imaging exquisitely depicted cranial nerve compression, small foramen magnum, hydrocephalus, and other intracranial complications of this syndrome. A syrinx of the cervical spinal cord was demonstrated. We suggest that MR imaging become a routine component of the evaluation of these patients. [ABSTRACT FROM AUTHOR]

A Negro girl has been followed from age 1 1/2 to 6 years for a severe musculoskeletal disorder with many of the clinical and roentgenological characteristics of Camurati-Engelmann disease. Atypical features, however, have included a geographic pattern of sclerosis of the long bones, a markedly increased density of the neural arches of the vertebral column, and a sharply demarcated sclerosis in the calvaria. The findings in the long bones and spine have become somewhat less pronounced over a five-year period, but the sclerosis of the skull has increased in both extent and thickness. Initially thought to have Camurati-Engelmann disease, the patient now is considered, on the basis of skeletal changes during this time, to have a diagnosis of craniodiaphyseal dysplasia. [ABSTRACT FROM AUTHOR]

The results of histologic, microradiographic and electron microscopic investigations carried out on two bone biopsies pertaining to a case of craniodiaphyseal dysplasia are reported. They show that the affected skeletal segments are chiefly characterized by enhancement of bone volume, and defective calcification of the bone matrix. Moreover, interstitial calcification of skeletal muscle has been found. [ABSTRACT FROM AUTHOR]