Insights into Natural History, Phenotypic, and Molecular Spectrum in a Large Cohort of Osteosclerotic Disorders

Osteosclerotic bone diseases include more than 30 rare diseases characterized by excessive bone formation. The aim of this study is to compare the molecular pathogenesis and prognostic features of 12 different osteosclerotic diseases. Thirty-four patients from 23 families were included, 25 of whom were followed for a period of one to 22 years. Exome sequencing was performed in 20 families. Primary hypertrophic osteoarthropathy (PHOAR1/2) was found in 12 patients, followed by juvenile Paget's disease (JPD)-5 in five, craniometaphyseal dysplasia (CMD) and Camurati-Engelmann disease (CED) in four, Ghosal hematodiaphyseal dysplasia (GHDD) in three patients, sclerosteosis-1 in two patients, and ultra-rare diseases including trichothiodystrophy-1, prenatal Caffey disease, melorheosteosis, and Lenz-Majewski hyperostotic dwarfism in one patient each. Patients with CMD and sclerosteosis-1 had severe cranial sclerosis leading to facial dysmorphism. CMD was characterized by metaphyseal widening, radiolucency, and diaphyseal sclerosis of the long bones in early childhood and later developed Erlenmeyer flask deformity sparing the vertebrae and pelvis, whereas sclerosteosis-1 manifested as generalized sclerosis. CED and GHDD share bone pain, difficulty in walking, and diaphyseal sclerosis, with some patients also having bone marrow involvement. Interestingly, patients with CED and JPD-5 showed osteopenia in early childhood, followed by the development of osteosclerosis in late childhood. Clinical and radiologic findings improved over time in PHOAR1 patients, whereas they progressed in JPD-5 and trichothiodystrophy-1 patients. Intra- and interfamilial clinical differences were observed in CMD, CED, JPD-5, and GHDD. The knowledge gained about the natural history of osteosclerotic diseases will make an important contribution to their diagnosis and management.