Overview and definition
Van Buchem disease (VBD) is a rare autosomal recessive sclerosing bone dysplasia characterized by progressive, symmetric hyperostosis of the skull, mandible, clavicles, ribs, and diaphyseal cortices of the long bones.[1][2] It belongs to the spectrum of SOST-related sclerosing bone dysplasias and represents the milder phenotype compared with sclerosteosis.[3] The underlying defect is a 52-kb noncoding deletion downstream of the SOST gene on chromosome 17q12-q21 that removes a bone-specific regulatory element, resulting in reduced—but not absent—expression of sclerostin, an osteocyte-derived inhibitor of the canonical Wnt signaling pathway.[4][5] The consequent disinhibition of osteoblastic bone formation produces lifelong accumulation of qualitatively normal but excessively dense bone.[2][3] The signature imaging pattern is marked enlargement and sclerosis of the mandible and calvarium with cortical thickening of the tubular bones. Management is symptomatic and surgical, as no disease-specific therapy is currently available.[3]
Terminology and classification
The condition was first described in 1955 and designated hyperostosis corticalis generalisata.[6] It is most commonly referred to as Van Buchem disease (VBD). Within the current GeneReviews classification, it is formally termed SOST-related endosteal hyperostosis, van Buchem type.[3] The broader disease category, SOST-related sclerosing bone dysplasia, encompasses both VBD and sclerosteosis.[3] Older literature occasionally uses "hyperostosis corticalis generalisata familiaris" or "hyperphosphatasemia tarda".[7] The term "endosteal hyperostosis" reflects the predominantly endosteal pattern of bone deposition. VBD should not be confused with hyperostosis frontalis interna, a benign incidental finding limited to the frontal bone.[8]
Epidemiology
VBD is exceedingly rare; approximately 30 affected individuals have been reported worldwide.[7] The vast majority are of Dutch ancestry, traced to a small genetic isolate in the Netherlands sharing a common ancestor approximately nine generations ago.[1] No consistent sex predilection has been established. Skeletal features typically become apparent in childhood or young adulthood, with mandibular overgrowth often first noticed around puberty.[3][6] Cranial nerve deficits—particularly facial palsy and hearing loss—may present in childhood.[9] The disease progresses throughout life, though the clinical course tends to stabilize in adulthood.[2][3]
Clinical presentation
Presentation and tempo
Affected individuals appear normal at birth.[3] The earliest clinical manifestation is commonly facial nerve palsy, which may present in childhood.[9] Mandibular overgrowth becomes apparent in young adulthood and is the most striking craniofacial feature.[3][6] The disease is progressive, with radioclinical abnormalities becoming more prominent with age, though symptom progression tends to plateau in adulthood.[2][10]
Cranial nerve involvement
- Facial nerve palsy (CN VII): The most common complication, reported in all patients in the largest cohort[2]
- Hearing loss (CN VIII): Conductive and sensorineural, with childhood onset; present in the vast majority of patients[2][3]
- Less common entrapments: Visual loss (CN II), trigeminal neuralgia or anosmia (CN V)[3][11]
Other findings
- Headaches: Related to calvarial thickening and, rarely, raised intracranial pressure[2][12]
- Increased intracranial pressure: Rare, documented in a minority of patients; sudden death from brainstem herniation has not been reported in VBD[2][3]
- Stature and digits: Normal height; no syndactyly or nail abnormalities, distinguishing VBD from sclerosteosis[3]
- Torus palatinus: Reported in families with the dominant form[13]
- Teeth: Not typically affected by the disease process, though dental malocclusion may occur secondary to mandibular overgrowth[3][7]
Laboratory findings
- Serum alkaline phosphatase is commonly elevated, particularly the bone-specific fraction[3][13]
- Bone formation markers (P1NP, osteocalcin) are significantly elevated and decline with age[2][3][14]
- Serum sclerostin is detectable but markedly reduced compared with carriers and healthy controls[2][3]
- Serum calcium, phosphorus, and parathyroid hormone are normal[3]
- No hematological abnormalities are found[13]
Radiographic findings
The radiographic appearance of VBD is regarded as characteristic among the sclerosing bone dysplasias.[13] Findings are bilateral, symmetric, and progressive with age.[10]
Location and distribution in the jaws
The mandible is the most prominently affected craniofacial bone and shows a degree of enlargement and thickening not seen in other sclerosing dysplasias such as osteopetrosis.[13] The entire mandibular body, ramus, and angle are involved, producing a markedly widened and dense mandible on panoramic radiography.[1][6] The maxilla is less conspicuously affected, though the skull base demonstrates diffuse sclerosis.[9][11]
Periphery and shape
The mandibular cortex is markedly thickened, with smooth, well-defined external contours reflecting the endosteal and periosteal apposition of normal lamellar bone.[10][13] There is no irregular periosteal reaction or cortical destruction. The overall mandibular shape is broadened and squared, with loss of normal contour proportions.[6]
Internal architecture
The internal architecture is characterized by diffuse, homogeneous sclerosis. In the mandible, the medullary space is encroached upon by endosteal cortical thickening but is not completely obliterated.[13] The trabecular pattern, where visible, is coarsened. In the calvarium, there is progressive thickening and sclerosis of both the inner and outer tables, with narrowing or obliteration of the diploic space.[9][10] The skull base is densely sclerotic.[9][11]
Effects on teeth and adjacent structures
Teeth are not typically affected by the disease process itself.[3] Dental occlusion may remain normal despite the marked mandibular enlargement.[6] However, misalignment of teeth can occur secondary to altered jaw proportions.[7] Root resorption attributable to VBD has not been described. Sclerostin expression is absent or markedly decreased in cementocytes of affected individuals, but overt hypercementosis has not been a consistent finding.[15]
Cranial foramina and neural canals
A characteristic and clinically critical finding is progressive narrowing of the cranial nerve foramina due to hyperostotic bone deposition at the skull base.[3][9] The facial nerve canals are narrowed, correlating with the high prevalence of facial palsy.[9] The internal auditory canals and other skull base foramina may also be stenotic.[3] On cross-sectional imaging, this foraminal narrowing is the key finding that explains the cranial neuropathies.[9][11]
Cortical involvement and extent beyond the jaws
- Calvarium: Diffuse thickening and sclerosis of the frontal, parietal, temporal, and occipital bones, with progressive reduction of intracranial volume in severe cases[9][10][12]
- Clavicles and ribs: Characteristically involved with cortical thickening and sclerosis[1]
- Long bones: Diaphyseal cortical thickening with encroachment on the medullary cavity; the distribution is predominantly diaphyseal, though the bone ends are also affected. Abnormal modeling of the bone ends (e.g., Erlenmeyer flask deformity) is not a feature of VBD[13]
- Hands: Increased metacarpal outer diameter, cortical thickness, and bone mineral density; mild distortion of tubular bones of the hands and feet may be seen[3][14]
Growth pattern and progression
Morphometric analysis of serial hand and skull radiographs demonstrates that cortical thickness, defective modeling, and craniofacial sclerosis all progress with age, confirming lifelong active bone metabolism.[10] Bone mineral density measured by DXA is markedly elevated, with Z-scores ranging from 5.4 to 12.3 SD above the mean at the spine and 5.2 to 12.1 SD above the mean at the hip.[3]
Other imaging findings
Medical CT
Head CT is the primary cross-sectional modality for evaluating the craniofacial complications of VBD. CT demonstrates thickened calvarium, diffusely sclerotic skull base, and enlarged mandible in affected individuals.[9] The critical contribution of CT is the detailed assessment of cranial nerve foramina: narrowed facial nerve canals, internal auditory canals, and optic canals can be precisely measured and correlated with clinical neuropathies.[9][16] In severe cases, CT demonstrates reduction of intracranial volume and narrowing of the foramen magnum, findings that guide decisions regarding decompressive surgery.[12]
MRI
MRI is useful for evaluating intracranial complications, including assessment of intracranial pressure, papilledema, and brainstem compression.[12] Sclerotic bone demonstrates low signal intensity on both T1- and T2-weighted sequences. MRI can also assess the degree of cranial nerve compression within narrowed foramina.
Bone densitometry (DXA)
DXA confirms markedly elevated bone mineral density at all measured sites and is useful for longitudinal monitoring of disease progression.[2][3]
Differential diagnosis
The differential diagnosis of VBD centers on other sclerosing bone dysplasias that produce cranial hyperostosis and mandibular enlargement. Family history, skeletal survey, and genetic testing are essential for definitive distinction.[8]
| Entity | Why it is considered | Best discriminator |
|---|---|---|
| Sclerosteosis | Autosomal recessive cranial and mandibular hyperostosis with diaphyseal sclerosis, same SOST gene locus | Syndactyly, tall stature, nail dysplasia, and undetectable serum sclerostin distinguish sclerosteosis; VBD lacks digit anomalies and has detectable low sclerostin[2][3][17] |
| Camurati-Engelmann disease (progressive diaphyseal dysplasia) | Cranial hyperostosis with diaphyseal sclerosis of long bones and cranial nerve involvement | Prominent limb pain, proximal muscle weakness, and predominantly diaphyseal long-bone involvement with loss of diploë; autosomal dominant inheritance (TGFB1)[3][8][18] |
| Worth-type endosteal hyperostosis | Endosteal hyperostosis with mandibular enlargement and cranial nerve involvement | Autosomal dominant (LRP5); torus palatinus, milder phenotype, normal height, no syndactyly[3][8] |
| Autosomal dominant osteopetrosis (Albers-Schönberg disease) | Generalized osteosclerosis with cranial thickening | "Rugger-jersey" spine, Erlenmeyer flask deformity, "bone-in-bone" appearance, fracture predisposition, and potential bone marrow failure distinguish osteopetrosis; VBD shows no modeling defects at bone ends and no fracture predisposition[13][19][20] |
| Paget disease of bone | Focal skull thickening with cortical and trabecular coarsening | Focal rather than symmetric involvement; mixed lytic-sclerotic phases, cotton-wool skull appearance, markedly elevated alkaline phosphatase, and older age at onset[21] |
The highest-risk diagnostic pitfall is failure to distinguish VBD from sclerosteosis, as both are SOST-related and share overlapping craniofacial imaging features. Careful clinical examination for syndactyly and measurement of serum sclerostin levels, combined with genetic testing for the 52-kb noncoding deletion versus SOST coding mutations, provide definitive differentiation.[2][3][17]
Histopathology
Bone biopsy in VBD reveals increased bone volume with thickened cortex and trabeculae.[3] The hallmark finding is increased osteoblastic bone formation with normal or decreased osteoclastic bone resorption.[1][3] The deposited bone is qualitatively normal lamellar bone without abnormal mineralization, distinguishing VBD from osteopetrosis, in which defective osteoclast function leads to retention of calcified cartilage and abnormal mineralization.[3] Despite the markedly increased density, the bone demonstrates increased biomechanical competence and resistance to fractures.[3]
At the molecular level, sclerostin expression is absent or markedly decreased in osteocytes and cementocytes.[15] The residual low-level sclerostin production in VBD—in contrast to the complete absence in sclerosteosis—is thought to account for the milder phenotype.[2][4] The underlying 52-kb noncoding deletion removes a SOST-specific enhancer element active in bone, reducing but not abolishing SOST transcription.[4][5]
Management and prognosis
Workup and referral
Diagnosis is established by the combination of characteristic phenotypic and radiographic findings, family history, elevated bone formation markers with low serum sclerostin, and confirmed by molecular genetic testing demonstrating the 52-kb deletion downstream of SOST.[2][3] A skeletal survey, head CT with attention to cranial nerve foramina, audiometry, and ophthalmologic evaluation should be performed at diagnosis.[3][8] Referral to a multidisciplinary team including genetics, neurosurgery, otolaryngology, and ophthalmology is appropriate.
Treatment
No disease-specific therapy is currently available.[3] Management is symptomatic and primarily surgical:
- Cranial nerve decompression: Surgical decompression of narrowed foramina may be required for progressive facial palsy, hearing loss, or visual impairment. Bone regrowth after surgery can cause symptom recurrence[3]
- Decompressive craniotomy: In rare cases of raised intracranial pressure or cognitive decline, large craniotomy and foramen magnum decompression have been performed with symptomatic relief[12]
- Mandibular recontouring: Surgical reduction of mandibular hyperostosis has been performed for aesthetic and functional indications with good results[6]
- Surgical challenges: The extremely dense bone may damage standard surgical instruments; drill bits may be too short and power tools may be insufficient[3]
Glucocorticoid therapy has been explored: in one adult with severe VBD, prednisone suppressed bone formation biochemically and arrested further bone accumulation over two years.[22] However, short courses of prednisolone in children with VBD during facial palsy exacerbations did not produce clinical improvement despite biochemical suppression of bone turnover.[3] Long-term benefits remain unstudied.
Prognosis
The clinical course tends to stabilize in adulthood, with the majority of patients reporting no progression of symptoms or new complications over time.[2][3] Life expectancy appears normal