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

Abstract

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.

Keywords: ANKH; HPGD; SOST; TBXAS1; TNFRSF11B; Osteosclerotic disorders.

Fig. 1

Four patients with craniometaphyseal dysplasia: P1 at the age of 18 months (a, c, d, f), 12 (b) and 8 years (e, g). P2 at the age of 8.5 and 22 years (h, i). P3 at the age of 5.5 (h, j, l) and 16 years (k). Facial palsy and typical facial features including long face, broad nasal bridge, hypertelorism, midface hypoplasia, and prognathism were revealed on photographs (a, b, h, i). P4 had mild dysmorphic face at the age of 44 years (m). Cranial radiographs of P1 (f) and P4 (n) reveal diffusely sclerotic calvarium with obliteration of sinuses. Radiographs of long bones show widening and radiolucency of metaphyses and diaphyseal sclerosis of long bones during early childhood (c, d, j). Note diaphyseal sclerosis has resolved over time (k). No sclerosis on pelvis, hand, and vertebrae graphies (e, g, l). P5 and P6 with sclerosteosis-1, at the age of 37 (o–r) and 45 years (s–u), respectively. Long, flat face, broad forehead, prognathism, and macrocephaly (o, s), diffuse cranial sclerosis (p, t) and significant hyperostosis on the vertebrae, pelvis, and tubular bones (q, r, u)

Fig. 2

Patient 7 with Camurati–Engelmann disease at 9.5 (a, c) and 17 years (b, d, e). Note progressive diaphyseal involvement, periosteal hyperostosis, cortical thickening, and Erlermeyer flask deformity. Patient 12 at the age 3 (f–h) and her sister (P13) at 6.5 (i) and P11 at 18 years with Ghosal hematodiaphyseal dysplasia (j). Radiographs revealed diaphyseal widening and sclerosis, and cortical thickening

Fig. 3

Photographs and radiographs of patients with Juvenile Paget’s disease-5 (a–h). Radiographs of P16 at 10 and 16 months of age, respectively (a, b) revealed osteopenia, multilayered, and irregular new bone formation at the diaphysis, and diaphyseal expansion. P14 showed severe scoliosis at the age of 23 years (c), anterior curvature of the tibia (d), and diffuse and patchy osteosclerosis of the long bones at the age of 13 and 23 years (e, f). P18 at the age of 30 years (g, h). Note the joint contractures with a forward bent posture with patchy osteosclerosis and coarse trabecular pattern. Photographs and radiographs of patients with hypertrophic osteoarthropathy type 1 (i–o). P24 at 17 years of age (i–o) showed coarse facial features (i), digital clubbing (j), enlargement and pachyderma of the hands (k), swelling of the knee (i–l). P22 at the age of 13 years (m, n), and P26 at the age of 24 years (o) showed acro-osteolysis (m) cortical thickening and periosteal hyperostosis (n, o)

Fig. 4

Patients with ultra-rare osteosclerotic disorders. P31 with Trichothiodystrophy-1 (a, c) at 3.8 years of age and 9.5 years of age (b). Note sparse, brittle hair, and diaphyseal and pelvic sclerosis, irregular acetabulum. P32 at 34 months of age with melorheostosis (d–f), right elbow contracture with dripping wax-like lesions and hyperostosis on pelvis radiograph. P33 with Lenz-Majewski hyperostotic dwarfism (g–i) at 6 months of age with prominent forehead, hypertelorism, severe brachydactyly with partial syndactyly, diaphyseal sclerosis, and metaphyseal osteopenia. A fetus with perinatal Caffey disease (j, k) showing generalized osteosclerosis and loss of cortex medulla border