Van Buchem disease

Van Buchem disease, also called hyperostosis corticalis generalisata, is an autosomal recessive sclerosing bone dysplasia caused by a homozygous deletion downstream of SOST that abolishes sclerostin production and leads to progressive hyperostosis of the skull, mandible, clavicles, ribs and diaphyses

The excess bone narrows cranial nerve foramina and the spinal canal, so the cardinal complications are hearing loss, facial palsy, trigeminal neuralgia, optic atrophy, raised intracranial pressure, dental crowding and spinal stenosis rather than fracture

Unlike sclerosteosis, which is caused by coding loss-of-function variants in SOST and produces tall stature with syndactyly and nail hypoplasia, Van Buchem disease leaves height and limbs largely normal and is distinguished mainly by its regulatory deletion and its milder appendicular phenotype

Terminology and classification

• The eponym honours Frans van Buchem, the Dutch physician who described the disorder in 1955 in two members of one family from the former island of Urk, and the descriptive term hyperostosis corticalis generalisata emphasises the generalised cortical thickening that defines the radiograph
• It is classified among the craniotubular hyperostoses, a group of sclerosing bone dysplasias that also includes sclerosteosis, craniodiaphyseal dysplasia, Camurati-Engelmann disease and LRP5-related high-bone-mass conditions
• ICD-10 assigns M89.8 to other specified disorders of bone and ICD-11 places the condition at LD24.1Y, while Orphanet uses ORPHA:3416 and MONDO uses MONDO:0009395 for the same entity
• Additional cross-references are OMIM 239100 for the phenotype, OMIM 144750 for LRP5, UMLS C0432272 and GARD 2833, and the two OMIM numbers must not be conflated because 239100 refers to Van Buchem disease while 144750 refers to a component gene
• The 2019 revision of the Nosology and Classification of Genetic Skeletal Disorders lists the condition among the sclerosing bone dysplasias and separates it from sclerosteosis at the level of the causal lesion rather than at the level of the clinical picture alone
• The principal entity that must not be missed is sclerosteosis, because both disorders share sclerostin deficiency and cranial nerve entrapment but differ in stature, hand malformation, severity and recurrence risk counselling

History

• Frans van Buchem described the first two patients in 1955 in a consanguineous family from Urk, and he correctly inferred that bone formation exceeded resorption, producing progressive thickening of the skeleton with age
• The Urk population remained genetically isolated for centuries as an island community, and its high consanguinity raised the local incidence of the disorder and of carrier status, which explains why a small Dutch fishing community contributed most early cases
• The gene was identified through the study of sclerosteosis, in which homozygous coding variants in SOST were found in 2001 to abolish sclerostin, a cystine-knot protein expressed by osteocytes and acting as a negative regulator of bone formation
• In 2002 Balemans and colleagues showed that Dutch patients with Van Buchem disease carry a homozygous 52-kb deletion in the SOST-MEOX1 intergenic region on chromosome 17q12-q21, establishing that the disease is caused by loss of a regulatory element rather than by a coding mutation
• Subsequent work identified a bone-specific enhancer within the deleted interval that drives SOST expression in osteocytes, which provided the mechanistic link between the deletion, absent sclerostin and unchecked Wnt signalling
• A 2025 longitudinal study of 11 genetically confirmed adults followed for a mean of 8.9 years showed that bone mineral density stabilises after puberty but cranial nerve compression continues to progress, which reframed the disease as progressive neural rather than progressive skeletal

Epidemiology

• Fewer than 30 genetically confirmed patients have been reported worldwide, and 22 of them are from the Netherlands, with 14 originating specifically from Urk, so the published epidemiology is dominated by a single founder population
• The disorder is autosomal recessive, so the recurrence risk for each pregnancy of two carrier parents is 25%, and the Urk founder effect raises carrier frequency locally far above the background rate
• Age at diagnosis in reported cases ranges from childhood to the sixth decade, and the 2017 Taiwanese index case was diagnosed at 54 years after presenting with mandibular enlargement, frontal bossing and macrocephaly that had begun around age 40
• The 2025 follow-up cohort had a median age of 47 years and a range of 20 to 60 years, and its mean follow-up of 8.9 years is the longest systematic observation of adult progression published so far
• Bone mineral density is markedly elevated, with lumbar spine Z-scores of 10.2 ± 1.3 standard deviations and femoral neck Z-scores of 8.9 ± 2.2 standard deviations, values far beyond those seen in ordinary osteoporosis or Paget disease
• In that cohort 7 of 11 patients developed permanent facial paresis, 9 had progressive hearing loss, 2 required cranial surgery for raised intracranial pressure and 3 developed osteoarthritis, so neurological and otological morbidity predominated over fracture
• Dental problems, including delayed eruption, malocclusion and impaction caused by mandibular hyperostosis, were common in the follow-up cohort and are an under-recognised source of morbidity in adult patients
• No sex predilection, no ethnic predisposition beyond the Dutch founder effect and no environmental risk factor have been identified, and the condition is not notifiable in any country, so case ascertainment depends on Orphanet and specialist centres

Pathophysiology

• The homozygous 52-kb deletion removes a distant bone-specific enhancer of SOST, so osteocytes fail to transcribe sclerostin even though the SOST coding sequence itself is intact, a classic example of a regulatory rather than a coding lesion
• Sclerostin normally binds LRP5 and LRP6 and blocks canonical Wnt-beta-catenin signalling in osteoblasts, and its absence disinhibits osteoblast differentiation and matrix mineralisation, producing bone formation that outpaces resorption
• Because the deletion is homozygous and the enhancer acts in cis, heterozygotes retain one functional SOST allele and are clinically unaffected, which is why carrier parents of an affected child are usually asymptomatic
• Hyperostosis is most marked at sites of intramembranous ossification and at biomechanically loaded diaphyses, which explains the predilection for the skull, mandible, clavicles, ribs and long-bone shafts rather than for the vertebral bodies
• Cranial nerve compression results from foraminal encroachment rather than from demyelination, so the deficits are progressive and potentially reversible if decompression is performed before axonal loss becomes irreversible
• Raised intracranial pressure arises when skull thickening reduces the cranial vault capacity and impairs venous drainage, and it may occur without papilloedema, so direct ophthalmoscopy alone is insufficient for surveillance

Clinical features

• The facial appearance is characterised by frontal bossing, a broad and thickened skull, mandibular enlargement with prognathism, a wide nasal bridge and a heavy jaw, and the changes become more conspicuous from adolescence onward
• Hearing loss is the commonest initial symptom, is usually sensorineural or mixed because the ossicular chain and internal auditory meatus are narrowed, and progresses in most patients over decades
• Facial nerve palsy may be recurrent or permanent and is often preceded by facial numbness or trigeminal neuralgia, reflecting progressive narrowing of the facial and trigeminal canals within the petrous bone
• Visual loss results from optic canal stenosis and optic atrophy, and headaches, papilloedema and vomiting indicate raised intracranial pressure that may require urgent decompression
• Skeletal manifestations include bone pain, spinal stenosis with radiculopathy or myelopathy, osteoarthritis of large joints, dental crowding and delayed eruption, while height and limb length remain normal
• There is no increased fracture risk and no haematological, hepatic or renal involvement, so the main morbidity is compressive neuropathy, hearing and vision loss, dental disease and spinal canal stenosis

Diagnosis

• Diagnosis is suggested by the combination of cranial nerve palsies, hearing loss, mandibular enlargement and generalised cortical thickening on skull radiographs or computed tomography, especially in a patient of Dutch ancestry or from a consanguineous family
• Radiographs show generalised hyperostosis with loss of the diploic space, thickened calvarium, enlarged mandible and dense diaphyses, and computed tomography delineates foraminal and spinal canal stenosis better than plain films
• Dual-energy X-ray absorptiometry shows markedly elevated bone mineral density with Z-scores typically above 8, and serum alkaline phosphatase may be elevated while calcium, phosphate and parathyroid hormone remain normal
• Molecular confirmation requires SOST sequencing to exclude coding variants and dosage analysis by MLPA or microarray to detect the 52-kb deletion, because standard sequencing alone will miss the common Dutch regulatory deletion
• The differential diagnosis includes sclerosteosis, craniodiaphyseal dysplasia, Camurati-Engelmann disease, Worth syndrome and other LRP5-related high-bone-mass disorders, osteopetrosis and Paget disease, each separated by inheritance, stature, hand findings and gene
• Baseline assessment should include audiometry, facial nerve examination, visual acuity and visual fields, fundoscopy, dental review and spinal imaging when symptoms suggest stenosis, because each of these complications can be treated before it becomes irreversible

Management

• No disease-specific pharmacotherapy is approved, and management is directed at decompressing compromised cranial nerves and the spinal canal, controlling intracranial pressure and preserving hearing, vision and dental function
• Optic canal decompression, facial nerve decompression and craniotomy with dural expansion are performed when vision, facial movement or intracranial pressure deteriorate, and early surgery before axonal loss gives better functional results
• Conductive or mixed hearing loss is managed with hearing aids and, in selected cases, cochlear implantation or ossicular reconstruction, and audiological review should be repeated at least annually because loss progresses
• Spinal stenosis with myelopathy or refractory radiculopathy is treated by laminectomy and foraminal decompression, and surgery should not be delayed until neurological deficit is fixed because bone continues to accumulate
• Dental crowding, malocclusion and impaction require orthodontic and oral surgical planning, and preventive dental care is important because mandibular hyperostosis makes extractions and implants technically difficult
• Analgesics and physical therapy address bone pain and osteoarthritis, and bisphosphonates or other antiresorptive drugs are not indicated because the disorder is one of excessive formation rather than excessive resorption
• Surveillance should include annual audiometry, visual acuity and fundoscopy, facial nerve assessment, dental review and periodic imaging of the skull base and spine, with urgent review for new headache, visual change or facial weakness
• Genetic counselling explains the 25% recurrence risk, the absence of symptoms in heterozygous carriers, the availability of prenatal diagnosis by deletion testing and the importance of testing relatives in consanguineous families
• Prognosis is dominated by the rate of cranial nerve and spinal canal compromise rather than by mortality, and the 2025 follow-up showing stable bone density but progressive neural compression supports lifelong surveillance even after skeletal growth ceases

Research and controversies

• Whether bone density truly plateaus after puberty was contested until the 2025 longitudinal study showed stable lumbar spine and femoral neck Z-scores over 8.9 years, which suggests that the skeletal component burns out while foraminal narrowing does not
• The ideal timing of prophylactic decompression is unresolved, because operating on asymptomatic foraminal narrowing exposes patients to surgical risk while waiting for symptoms may allow irreversible optic or cochlear damage
• Restoring sclerostin is conceptually attractive but difficult, because sclerostin is a secreted osteocyte product and the deletion removes its enhancer, so gene addition, enhancer replacement or cell-based delivery would all be required
• Antisclerostin antibodies and other Wnt-stimulating agents are contraindicated in principle because they would amplify the very pathway that is already disinhibited, and this inverse logic is an important safety consideration for any future trial
• Because fewer than 30 patients are known, international registries and natural-history collaboration are the only realistic route to trial-ready cohorts, and patient organisations and Orphanet are central to identifying eligible families