Van Buchem disease (hyperostosis corticalis generalisata; OMIM 239100) is an autosomal recessive sclerosing bone dysplasia caused by a homozygous ~52-kb noncoding deletion located ~35 kb downstream of the SOST gene in the SOST-MEOX1 intergenic region on chromosome 17q12-q21. The deletion arose through Alu-mediated homologous recombination and removes a bone-specific long-range cis-regulatory enhancer (ECR5) that is required for high-level SOST transcription in osteocytes. ECR5 activity is driven by the osteocyte-expressed transcription factor MEF2C. Loss of this enhancer produces a hypomorphic sclerostin state — circulating sclerostin is reduced but typically still detectable, in contrast to sclerosteosis where coding loss-of-function mutations render sclerostin undetectable. Hypomorphic sclerostin fails to antagonize LRP5/6-mediated canonical Wnt/beta-catenin signaling in osteoblasts, resulting in increased osteoblast bone formation and progressive generalized hyperostosis with predominant skull/mandibular involvement and cranial-nerve entrapment. Van Buchem disease is generally milder than sclerosteosis and lacks the syndactyly and tall stature seen in that disorder; complications typically stabilize after the third decade and life expectancy appears normal. Van Buchem disease was one of the first human disorders shown to be caused by deletion of a distant regulatory element rather than a coding mutation.
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name: Van Buchem Disease
creation_date: '2026-02-13T00:31:42Z'
updated_date: '2026-04-30T00:00:00Z'
category: Mendelian
description: >
Van Buchem disease (hyperostosis corticalis generalisata; OMIM 239100) is an
autosomal recessive sclerosing bone dysplasia caused by a homozygous ~52-kb
noncoding deletion located ~35 kb downstream of the SOST gene in the
SOST-MEOX1 intergenic region on chromosome 17q12-q21. The deletion arose
through Alu-mediated homologous recombination and removes a bone-specific
long-range cis-regulatory enhancer (ECR5) that is required for high-level
SOST transcription in osteocytes. ECR5 activity is driven by the
osteocyte-expressed transcription factor MEF2C. Loss of this enhancer
produces a hypomorphic sclerostin state — circulating sclerostin is reduced
but typically still detectable, in contrast to sclerosteosis where coding
loss-of-function mutations render sclerostin undetectable. Hypomorphic
sclerostin fails to antagonize LRP5/6-mediated canonical Wnt/beta-catenin
signaling in osteoblasts, resulting in increased osteoblast bone formation
and progressive generalized hyperostosis with predominant skull/mandibular
involvement and cranial-nerve entrapment. Van Buchem disease is generally
milder than sclerosteosis and lacks the syndactyly and tall stature seen in
that disorder; complications typically stabilize after the third decade and
life expectancy appears normal. Van Buchem disease was one of the first
human disorders shown to be caused by deletion of a distant regulatory
element rather than a coding mutation.
disease_term:
preferred_term: hyperostosis corticalis generalisata
term:
id: MONDO:0009395
label: hyperostosis corticalis generalisata
parents:
- Sclerosing Bone Dysplasias
inheritance:
- name: Autosomal Recessive
description: >
Autosomal recessive inheritance. All known patients from an extended
Dutch inbred family. The 52-kb deletion results from homologous
recombination between Alu sequences.
evidence:
- reference: PMID:11836356
reference_title: "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease."
supports: SUPPORT
snippet: "Van Buchem disease is an autosomal recessive skeletal dysplasia characterised by generalised bone overgrowth, predominantly in the skull and mandible"
explanation: "Confirms autosomal recessive inheritance of Van Buchem disease."
prevalence:
- population: Dutch founder population and published clinical cohorts
percentage: 15 of 18 known Dutch patients in 2013 cohort
notes: >-
No population-based prevalence estimate was identified for Van Buchem
disease. Published cohorts indicate that the disorder is confined to a small
Dutch founder isolate descended from a common ancestor, and the largest
modern clinical series characterized 15 of the 18 known Dutch patients at
the time. Independent molecular confirmation in 2002 identified the same
52-kb deletion in 15 affected Dutch individuals.
evidence:
- reference: PMID:9463328
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We studied 11 van Buchem patients and their highly inbred family, who live in The Netherlands in a small ethnic isolate, that had a common ancestor approximately 9 generations ago."
explanation: Documents that Van Buchem disease was identified in a small Dutch founder isolate rather than in a broad population cohort.
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We studied the demographic, clinical, biochemical, and densitometric features of 15 patients with VBD (12 adults and 3 children) and 28 related carriers of the gene mutation."
explanation: Provides the largest modern clinically characterized Van Buchem disease cohort located during this curation pass.
- reference: PMID:12116252
reference_title: "A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We refined the critical interval to the < 1-Mb region between D17S2250 and D17S2253 in 15 affected individuals, all of whom shared a common disease haplotype."
explanation: Independently confirms the Dutch founder origin and identifies a shared disease haplotype across 15 affected individuals.
pathophysiology:
- name: ECR5 Enhancer Deletion Causing SOST Downregulation
description: >
A homozygous ~52-kb deletion located approximately 35 kb downstream of the
SOST gene, in the SOST-MEOX1 intergenic region on chromosome 17q12-q21,
arose by Alu-mediated homologous recombination and removes a bone-specific
long-range cis-regulatory enhancer (ECR5) required for high-level SOST
transcription in bone. ECR5 activity is driven by the osteocyte-expressed
transcription factor MEF2C, and its loss reduces SOST expression in adult
skeleton without disrupting the SOST or MEOX1 coding sequence. BAC
transgenesis confirmed that only the wild-type SOST allele expresses high
levels of human SOST in adult bone, supporting a regulatory (position-effect
/ enhancer-loss) mechanism.
cell_types:
- preferred_term: Osteocyte
term:
id: CL:0000137
label: osteocyte
evidence:
- reference: PMID:11836356
reference_title: "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease."
supports: SUPPORT
snippet: "a 52 kb deletion in all patients from the van Buchem family. The deletion, which results from a homologous recombination between Alu sequences, starts approximately 35 kb downstream of the SOST gene"
explanation: "Identifies the 52-kb downstream deletion as the Van Buchem disease mutation."
- reference: PMID:11836356
reference_title: "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease."
supports: SUPPORT
snippet: "no evidence was found for the presence of a gene within the deleted region, we hypothesise that the presence of the deletion leads to a down regulation of the transcription of the SOST gene by a cis regulatory action or a position effect"
explanation: "Establishes that the deletion affects gene regulation rather than removing a coding gene."
- reference: PMID:12116252
reference_title: "A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population."
supports: SUPPORT
snippet: "Although the deletion itself does not appear to disrupt the coding region of any known or novel gene(s), the closest flanking genes are MEOX1 on the proximal side, and SOST on the distal side of the deletion."
explanation: "Independently localizes the 52-kb deletion to the SOST-MEOX1 intergenic region with intact flanking coding genes."
- reference: PMID:15965026
reference_title: "Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease."
supports: SUPPORT
snippet: "Only the SOST(wt) allele faithfully expressed high levels of human SOST in the adult bone and had an impact on bone metabolism, consistent with the model that the VB noncoding deletion removes a SOST-specific regulatory element"
explanation: "BAC transgenesis confirms the Van Buchem deletion removes a SOST-specific regulatory element."
- reference: PMID:15965026
reference_title: "Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease."
supports: SUPPORT
snippet: "we were able to identify a candidate enhancer element that drives human SOST expression in osteoblast-like cell lines in vitro and in the skeletal anlage of the embryonic day 14.5 (E14.5) mouse embryo"
explanation: "Identifies the ECR5 enhancer element within the deleted region that drives bone-specific SOST expression."
- reference: PMID:22886088
reference_title: "Targeted deletion of Sost distal enhancer increases bone formation and bone mass."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "the absence of the Sost-specific long-range regulatory element ECR5 causes VB disease in rodents, and that Mef2C is the main transcription factor responsible for ECR5-dependent Sost transcriptional activation in the adult skeleton"
explanation: "Mouse ECR5 knockout recapitulates Van Buchem disease and identifies MEF2C as the upstream transcription factor."
downstream:
- target: Hypomorphic Sclerostin and Loss of Wnt Antagonism
description: >
Loss of the ECR5 enhancer reduces but does not abolish SOST transcription
in osteocytes, producing a hypomorphic sclerostin state.
causal_link_type: DIRECT
- name: Hypomorphic Sclerostin and Loss of Wnt Antagonism
description: >
Reduced osteocyte SOST transcription produces low but typically detectable
circulating sclerostin in Van Buchem disease patients (mean ~8 pg/mL vs ~28
pg/mL in carriers and ~40 pg/mL in controls), in contrast to sclerosteosis
where serum sclerostin is undetectable. The residual sclerostin partially
explains the milder Van Buchem phenotype. Sclerostin normally binds the
LRP5/LRP6 Wnt co-receptors on osteoblast-lineage cells and antagonizes
canonical Wnt/beta-catenin signaling; loss of this antagonism is the
proximate molecular consequence of reduced sclerostin.
cell_types:
- preferred_term: Osteocyte
term:
id: CL:0000137
label: osteocyte
biological_processes:
- preferred_term: Negative regulation of canonical Wnt signaling pathway
term:
id: GO:0090090
label: negative regulation of canonical Wnt signaling pathway
modifier: DECREASED
evidence:
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "were lower than those of carriers (mean 28.7 pg/mL; 95% CI, 24.5-32.9 pg/mL; p < 0.001) and healthy controls (mean 40.0 pg/mL; 95% CI, 34.5-41.0 pg/mL; p < 0.)"
explanation: "Quantifies the hypomorphic-but-detectable sclerostin state in Van Buchem disease, with a clear gene-dose effect."
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The small amounts of sclerostin produced by patients with VBD may explain their milder phenotype compared to that of patients with sclerosteosis, in whom serum sclerostin is undetectable."
explanation: "Links the residual sclerostin in VBD to the milder clinical phenotype relative to sclerosteosis."
- reference: PMID:15778503
reference_title: "Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we found that sclerostin bound to LRP5 as well as LRP6 and identified the first two YWTD-EGF repeat domains of LRP5 as being responsible for the binding"
explanation: "Establishes the molecular target of sclerostin: LRP5/LRP6 Wnt co-receptors."
- reference: PMID:15778503
reference_title: "Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the high bone mass phenotype associated with the loss of sclerostin may be attributed, at least in part, to an increase in canonical Wnt signaling resulting from the reduction in sclerostin-mediated Wnt antagonism"
explanation: "Mechanistically links reduced sclerostin to increased canonical Wnt signaling and the high bone mass phenotype."
downstream:
- target: Unopposed Canonical Wnt Signaling and Excessive Bone Formation
description: >
Loss of LRP5/6 antagonism by sclerostin permits sustained canonical
Wnt/beta-catenin signaling in osteoblast-lineage cells.
causal_link_type: DIRECT
- name: Unopposed Canonical Wnt Signaling and Excessive Bone Formation
description: >
Without adequate sclerostin antagonism at LRP5/6, canonical Wnt/beta-catenin
signaling in osteoblasts is sustained, driving osteoblast differentiation
and unopposed bone formation by structurally normal bone. Histopathology in
Van Buchem disease shows increased cortical and trabecular thickness without
a mineralization defect. Bone formation markers (P1NP) are elevated in adult
patients and correlate inversely with serum sclerostin and positively with
bone mineral density. Continued Wnt ligand secretion is required to sustain
the high-bone-mass state, as shown by porcupine inhibition reducing bone
mass in Sost loss-of-function mice.
cell_types:
- preferred_term: Osteoblast
term:
id: CL:0000062
label: osteoblast
biological_processes:
- preferred_term: Canonical Wnt Signaling Pathway
term:
id: GO:0060070
label: canonical Wnt signaling pathway
modifier: INCREASED
- preferred_term: Osteoblast Differentiation
term:
id: GO:0001649
label: osteoblast differentiation
modifier: INCREASED
- preferred_term: Ossification
term:
id: GO:0001503
label: ossification
modifier: INCREASED
evidence:
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Serum procollagen type 1 amino-terminal propeptide (P1NP) levels were also significantly higher in adult patients (mean 96.0; 95% CI, 54.6-137.4 ng/mL versus mean 47.8; 95% CI, 39.4-56.2 ng/mL, p = 0.003 in carriers"
explanation: "Confirms increased osteoblast bone formation activity in Van Buchem disease via the bone formation marker P1NP."
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Serum sclerostin levels were inversely correlated with serum P1NP levels (r = -0.39, p = 0.018) and BMD values (femoral neck r = -0.69, p < 0.001; lumbar spine r = -0.78, p < 0.001)."
explanation: "Quantitatively links reduced sclerostin to increased bone formation (P1NP) and bone mineral density in vivo."
- reference: PMID:22886088
reference_title: "Targeted deletion of Sost distal enhancer increases bone formation and bone mass."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "mice lacking ECR5 or Mef2C through Col1-Cre osteoblast/osteocyte-specific ablation result in high bone mass (HBM) due to elevated bone formation rates"
explanation: "Mouse ECR5 knockout demonstrates that loss of the Van Buchem enhancer increases bone formation rates."
- reference: PMID:37612291
reference_title: "Inhibiting WNT secretion reduces high bone mass caused by Sost loss-of-function or gain-of-function mutations in Lrp5."
supports: PARTIAL
evidence_source: MODEL_ORGANISM
snippet: "We treated three different mouse models of high bone mass caused by aberrant Wnt signaling, including homozygosity for loss-of-function in Sost, which models sclerosteosis"
explanation: "Demonstrates that ongoing Wnt ligand production is required to sustain the high-bone-mass phenotype in sclerostin-deficient mice; supports the Wnt-dependence of the Van Buchem mechanism by analogy to the sclerosteosis model."
downstream:
- target: Cranial Hyperostosis
description: >
Excess osteoblast bone formation produces predominant skull and mandibular
thickening (calvarial and skull-base hyperostosis, mandibular overgrowth).
causal_link_type: DIRECT
- target: Generalized Osteosclerosis
description: >
Excess osteoblast activity also thickens long-bone cortices, ribs,
clavicles and pelvis, producing generalized cortical hyperostosis with
diaphyseal sclerosis.
causal_link_type: DIRECT
- target: Increased Bone Mineral Density
description: >
Sustained bone formation produces markedly elevated DXA bone mineral
density (Z-scores commonly +5 to +12).
causal_link_type: DIRECT
- target: Cranial Nerve Foraminal Narrowing
description: >
Excess osteoblast bone formation in the skull base progressively narrows
cranial nerve foramina (intermediate node Cranial Hyperostosis).
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Calvarial and skull-base hyperostosis (Cranial Hyperostosis phenotype) progressively narrows the cranial nerve foramina and auditory canals.
- name: Cranial Nerve Foraminal Narrowing
description: >
Progressive calvarial and skull-base hyperostosis narrows the cranial nerve
foramina and the internal/external auditory canals, mechanically compressing
cranial nerves VII (facial), VIII (vestibulocochlear), and II (optic),
producing the cranial nerve entrapment syndrome that defines the clinical
morbidity of Van Buchem disease. External auditory canal exostoses
contribute an additional conductive component to the hearing loss.
locations:
- preferred_term: Cranium
term:
id: UBERON:0003128
label: cranium
evidence:
- reference: PMID:12116252
reference_title: "A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Van Buchem disease is an autosomal recessive sclerosing bone dysplasia characterized by skeletal hyperostosis, overgrowth of the mandible, and a liability to entrapment of the seventh and eighth cranial nerves."
explanation: "Establishes cranial nerve VII and VIII entrapment as a defining clinical feature of Van Buchem disease."
- reference: PMID:11836356
reference_title: "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients"
explanation: "Documents the cranial nerve VII, II, and VIII complications attributable to skull-base hyperostosis."
downstream:
- target: Facial Nerve Palsy
description: Compression of cranial nerve VII as it traverses the narrowed facial canal causes recurrent facial palsy.
causal_link_type: DIRECT
- target: Hearing Impairment
description: Compression of cranial nerve VIII through narrowed internal auditory canals, plus external auditory canal exostoses, produces mixed conductive and sensorineural hearing loss.
causal_link_type: DIRECT
- target: Optic Atrophy
description: Optic nerve compression through narrowed optic canals causes optic atrophy and visual loss.
causal_link_type: DIRECT
- target: Increased Intracranial Pressure
description: Calvarial overgrowth restricts intracranial volume and impairs CSF outflow, occasionally causing raised intracranial pressure.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Calvarial thickening and skull-base hyperostosis reduce intracranial volume and may obstruct CSF egress.
phenotypes:
- name: Cranial Hyperostosis
description: >
Progressive calvarial and skull-base thickening with sclerosis is the most
prominent clinical feature of Van Buchem disease and the proximate cause of
cranial nerve foraminal narrowing.
phenotype_term:
preferred_term: Cranial hyperostosis
term:
id: HP:0004437
label: Cranial hyperostosis
evidence:
- reference: PMID:11836356
reference_title: "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease."
supports: SUPPORT
snippet: "generalised bone overgrowth, predominantly in the skull and mandible"
explanation: "Skull and mandible overgrowth are the predominant features."
- reference: PMID:12116252
reference_title: "A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Van Buchem disease is an autosomal recessive sclerosing bone dysplasia characterized by skeletal hyperostosis, overgrowth of the mandible"
explanation: "Independent confirmation of skeletal hyperostosis with mandibular overgrowth as the cardinal phenotype."
- name: Mandibular Hyperostosis
description: >
Progressive mandibular overgrowth produces enlarged jaw, facial distortion,
and dental/orthodontic complications. In a Dutch cohort, mandibular
enlargement was present in 10/12 (83%) adult patients.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Mandibular hyperostosis
term:
id: HP:0004472
label: Mandibular hyperostosis
evidence:
- reference: PMID:12116252
reference_title: "A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "skeletal hyperostosis, overgrowth of the mandible"
explanation: "Establishes mandibular overgrowth as a defining clinical feature."
- name: Generalized Osteosclerosis
description: >
Diffuse skeletal sclerosis extends beyond the skull and mandible to ribs,
clavicles, pelvis, and long-bone diaphyses, with cortical thickening and
medullary narrowing. Older review literature describes the skeleton as
approximately 3-4 times heavier than normal.
phenotype_term:
preferred_term: Generalized osteosclerosis
term:
id: HP:0005789
label: Generalized osteosclerosis
evidence:
- reference: PMID:11836356
reference_title: "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "generalised bone overgrowth, predominantly in the skull and mandible"
explanation: "Documents the generalized character of the bone overgrowth (predominant but not limited to skull/mandible)."
- name: Increased Bone Mineral Density
description: >
Markedly elevated bone mineral density on dual-energy X-ray absorptiometry
is universal in Van Buchem disease patients. Mean Z-scores in a Dutch
cohort were +8.7 (femoral neck) and +9.5 (lumbar spine), with no observed
fracture phenotype.
frequency: OBLIGATE
phenotype_term:
preferred_term: Increased bone mineral density
term:
id: HP:0011001
label: Increased bone mineral density
evidence:
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Bone mineral density (BMD) was markedly increased in all patients (mean Z-score 8.7 ± 2.1 and 9.5 ± 1.9 at the femoral neck and spine, respectively)"
explanation: "Quantitative DXA evidence of universal markedly increased BMD in Van Buchem disease patients."
- name: Facial Nerve Palsy
description: >
Facial palsy results from compression of cranial nerve VII as it traverses
the narrowed facial canal. In a Dutch cohort (n=15) all patients had at
least one episode of facial palsy (median age at first occurrence 2.5
years), and 6/15 underwent decompression surgery. It is one of the
earliest and most consistent presenting manifestations of Van Buchem
disease.
frequency: OBLIGATE
phenotype_term:
preferred_term: Facial palsy secondary to cranial hyperostosis
term:
id: HP:0007285
label: Facial palsy secondary to cranial hyperostosis
evidence:
- reference: PMID:11836356
reference_title: "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease."
supports: SUPPORT
snippet: "Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients"
explanation: "Facial nerve palsy is a major clinical complication in most patients."
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The most common clinical findings in patients were facial palsy (100%) and various degrees of hearing impairment (93%); raised intracranial pressure had been documented in 20%."
explanation: "100% of the 15-patient Dutch cohort had facial palsy, supporting the OBLIGATE frequency band."
phenotype_contexts:
- onset:
onset_category: CHILDHOOD
notes: Median age at first occurrence in the Dutch cohort was 2.5 years.
- name: Optic Atrophy
description: >
Progressive optic nerve compression where it traverses the narrowed optic
canal can cause optic atrophy and visual loss in severe Van Buchem disease.
Less consistent than facial palsy or hearing loss in published cohorts.
phenotype_term:
preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
evidence:
- reference: PMID:11836356
reference_title: "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease."
supports: SUPPORT
snippet: "facial nerve palsy, optic atrophy, and impaired hearing occur in most patients"
explanation: "Optic atrophy is a recognized complication from cranial nerve compression."
- name: Hearing Impairment
description: >
Childhood-onset hearing loss is near-universal in Van Buchem disease and
typically begins as conductive loss (from external auditory canal exostoses
and ossicular involvement) before progressing to a mixed/sensorineural
pattern as cranial nerve VIII becomes entrapped by progressive cranial
hyperostosis. In a Dutch cohort 14/15 (93%) had hearing impairment and
10/15 had external auditory canal exostoses.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:11836356
reference_title: "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease."
supports: PARTIAL
snippet: "impaired hearing occur in most patients"
explanation: "Hearing impairment is a major clinical complication."
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "facial palsy (100%) and various degrees of hearing impairment (93%)"
explanation: "93% hearing impairment in the 15-patient Dutch cohort supports the VERY_FREQUENT band."
phenotype_contexts:
- onset:
onset_category: CHILDHOOD
notes: Hearing impairment is typically childhood-onset and progressive.
- name: Increased Intracranial Pressure
description: >
Calvarial overgrowth restricts intracranial volume and impairs CSF outflow,
occasionally producing raised intracranial pressure. Documented in
approximately 20% of patients in the Dutch cohort, this is much less
common in Van Buchem disease than in sclerosteosis but is the most
serious complication when it occurs and may require decompressive
craniectomy or CSF diversion.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Increased intracranial pressure
term:
id: HP:0002516
label: Increased intracranial pressure
evidence:
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "raised intracranial pressure had been documented in 20%"
explanation: "Quantifies raised intracranial pressure in 20% of the Dutch Van Buchem disease cohort, supporting the OCCASIONAL frequency band."
- reference: PMID:6754874
reference_title: "Two cases of Van Buchem's disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both presented in early adult life with signs and symptoms of raised intracranial pressure and underwent partial craniectomy."
explanation: "Independent case series documenting raised intracranial pressure as a presenting feature severe enough to warrant craniectomy."
biochemical:
- name: Reduced Serum Sclerostin
presence: DECREASED
context: >
Circulating sclerostin is markedly reduced but typically still detectable
in Van Buchem disease patients. In a Dutch cohort the mean serum
sclerostin was 8.0 pg/mL (95% CI 4.9-11.0) in patients vs 28.7 pg/mL in
heterozygous carriers and ~40 pg/mL in healthy controls, demonstrating a
gene-dose effect. This contrasts with sclerosteosis, where serum
sclerostin is typically undetectable.
evidence:
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "were lower than those of carriers (mean 28.7 pg/mL; 95% CI, 24.5-32.9 pg/mL; p < 0.001) and healthy controls (mean 40.0 pg/mL; 95% CI, 34.5-41.0 pg/mL; p < 0.)"
explanation: "Direct quantitative measurement of reduced serum sclerostin with a clear gene-dose effect across patients, carriers, and controls."
- name: Increased Serum P1NP (Procollagen Type 1 N-Terminal Propeptide)
presence: INCREASED
context: >
P1NP, a marker of osteoblast bone formation activity, is significantly
elevated in adult Van Buchem disease patients (mean 96.0 ng/mL vs 47.8 in
carriers and 37.8 in controls) and inversely correlates with serum
sclerostin, providing a biochemical readout of unopposed Wnt-driven bone
formation. P1NP declines with age, paralleling the clinical stabilization
after the third decade.
evidence:
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Serum procollagen type 1 amino-terminal propeptide (P1NP) levels were also significantly higher in adult patients (mean 96.0; 95% CI, 54.6-137.4 ng/mL versus mean 47.8; 95% CI, 39.4-56.2 ng/mL, p = 0.003 in carriers"
explanation: "Quantifies the elevated bone formation marker P1NP in Van Buchem patients vs carriers."
genetic:
- name: SOST Regulatory Deletion (52-kb downstream)
association: Causative
gene_term:
preferred_term: SOST
term:
id: hgnc:13771
label: SOST
notes: >
Homozygous ~52-kb noncoding deletion located ~35 kb downstream of SOST in
the SOST-MEOX1 intergenic region on chromosome 17q12-q21. The deletion
arose by Alu-mediated homologous recombination and is 100% concordant with
Van Buchem disease in the Dutch founder population. It removes the ECR5
bone enhancer but no coding genes. Routine SOST coding-region sequencing
misses this lesion; molecular diagnosis requires targeted deletion testing
(qPCR, long-range PCR, MLPA, or targeted microarray). Sclerosteosis maps
to the same locus and involves the same gene (SOST) but through coding
loss-of-function mutations rather than regulatory deletion; Van Buchem
disease generally lacks the syndactyly and tall stature of sclerosteosis.
evidence:
- reference: PMID:11836356
reference_title: "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease."
supports: PARTIAL
snippet: "we mapped both disease genes to the same region on chromosome 17q12-q21, supporting the hypothesis that van Buchem disease and sclerosteosis are caused by mutations in the same gene"
explanation: "Van Buchem disease and sclerosteosis map to the same locus, both involving SOST."
- reference: PMID:12116252
reference_title: "A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we report here the identification of a 52-kb deletion located within the interval and encompassing D17S1789 that is 100% concordant with the disorder."
explanation: "Confirms the 52-kb deletion as 100% concordant with Van Buchem disease in the Dutch cohort."
- reference: PMID:29080811
reference_title: "Genetics of Sost/SOST in sclerosteosis and van Buchem disease animal models."
supports: SUPPORT
evidence_source: OTHER
snippet: "VBD is caused by a noncoding deletion that removes a SOST-specific regulatory element in bone."
explanation: "Recent review confirms the noncoding regulatory deletion as the canonical Van Buchem disease lesion."
- reference: PMID:11181578
reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
supports: PARTIAL
snippet: "Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients"
explanation: "Distinguishes Van Buchem from sclerosteosis by absence of hand malformations and tall stature."
treatments:
- name: Facial Nerve Decompression
description: >
Surgical decompression of the facial nerve canal for recurrent or
progressive facial palsy. Performed in 6/15 patients in the Dutch cohort.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
located_in:
preferred_term: cranium
term:
id: UBERON:0003128
label: cranium
evidence:
- reference: PMID:23074140
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "facial palsy (100%) and various degrees of hearing impairment (93%); raised intracranial pressure had been documented in 20%."
explanation: "Establishes the clinical burden that facial nerve decompression addresses; the same cohort reports decompression in a subset of patients."
- name: Cranial Decompression / Craniectomy
description: >
Partial or bilateral craniectomy for severe raised intracranial pressure
or restricted intracranial volume. Older neurosurgical case series show
feasibility with long-term survival, though late neurologic morbidity
from continued bony encroachment can occur.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
located_in:
preferred_term: cranium
term:
id: UBERON:0003128
label: cranium
evidence:
- reference: PMID:6754874
reference_title: "Two cases of Van Buchem's disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both presented in early adult life with signs and symptoms of raised intracranial pressure and underwent partial craniectomy. Following surgery normal intellectual function was maintained and both survived to old age."
explanation: "Demonstrates feasibility and long-term survival after partial craniectomy for raised intracranial pressure in Van Buchem disease."
- name: Hearing Aid
description: >
Conventional hearing aids for the conductive and mixed hearing loss
component, often as first-line audiologic intervention before progression
to advanced surgical options.
treatment_term:
preferred_term: hearing aid usage
term:
id: MAXO:0009030
label: hearing aid usage
- name: Cochlear Implantation
description: >
Cochlear implantation considered when external/internal auditory canal
obliteration or auditory nerve compromise limits the benefit of
conventional hearing aids.
treatment_term:
preferred_term: cochlear device implantation
term:
id: MAXO:0009025
label: cochlear device implantation
- name: Glucocorticoid Therapy (Experimental)
description: >
Case-level evidence (single patient) suggests prednisone may decrease bone
formation markers and prevent further BMD increase in selected patients.
This is not established standard care; broader experience in two children
showed limited clinical benefit.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: prednisone
term:
id: CHEBI:8382
label: prednisone
- name: Genetic Counseling
description: >
Genetic counseling for affected families and cascade testing in the
Dutch founder context, given autosomal recessive inheritance and a
recurrent recognizable deletion.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
Van Buchem disease (VBD) is a very rare, autosomal recessive, high-bone-mass craniotubular hyperostosis caused not by a coding mutation but by a biallelic ~52-kb noncoding deletion downstream of SOST that removes a bone enhancer and decreases expression of the osteocyte-derived Wnt antagonist sclerostin. Clinically it is characterized by progressive skull/mandibular hyperostosis and cranial-nerve entrapment (notably recurrent facial palsy and hearing loss), extremely elevated DXA Z-scores, and generally normal life expectancy with stabilization after early adulthood. Key quantitative datasets are available from a Dutch cohort (n=15 patients, n=28 carriers) including BMD, serum sclerostin, and bone turnover markers. (balemans2002identificationofa pages 1-2, loots2005genomicdeletionof pages 3-4, lierop2013vanbuchemdisease pages 1-2)
VBD is a severe sclerosing bone dysplasia/craniotubular hyperostosis with generalized cortical and endosteal bone overgrowth, most prominent in the skull and mandible, which can lead to cranial nerve entrapment (facial palsy, hearing loss, visual loss) and occasionally increased intracranial pressure. (balemans2002identificationofa pages 1-2, appelmandijkstra2026sclerosingbonedysplasias pages 1-3)
Not retrieved in the sourced full texts during this tool run: Orphanet ID, ICD-10/ICD-11 codes, and MeSH ID. (appelmandijkstra2026sclerosingbonedysplasias pages 1-3)
Evidence for VBD in this report comes from: - Aggregated cohorts/case series (e.g., Dutch cohort with 15 patients and 28 carriers) (lierop2013vanbuchemdisease pages 1-2, lierop2013vanbuchemdisease pages 2-3) - Individual case reports/series describing neurosurgical decompression and long-term outcomes (dixon1982twocasesof pages 1-3, dixon1982twocasesof pages 3-5) - Molecular genetics and functional genomics defining the causal deletion and enhancer mechanism (balemans2002identificationofa pages 1-2, loots2005genomicdeletionof pages 3-4)
Structured reference artifacts | Identifier system | ID/value | Label | Notes/synonyms | Primary citation | |---|---|---|---|---| | MONDO | MONDO:0009395 | hyperostosis corticalis generalisata | MONDO target disease in the prompt; corresponds to Van Buchem disease / hyperostosis corticalis generalisata | (staehling‐hampton2002a52kbdeletion pages 9-9, appelmandijkstra2026sclerosingbonedysplasias pages 17-18) | | OMIM | 239100 | Van Buchem disease | OMIM entry explicitly cited for Van Buchem disease; synonym in sourced texts: hyperostosis corticalis generalisata | (staehling‐hampton2002a52kbdeletion pages 9-9, loots2005genomicdeletionof pages 3-4) | | Orphanet | Not retrieved in sourced texts | Van Buchem disease | Orphanet identifier was requested but was not present in the retrieved evidence excerpts; disease described as very rare and mainly reported in the Netherlands | (appelmandijkstra2026sclerosingbonedysplasias pages 8-9, appelmandijkstra2026sclerosingbonedysplasias pages 1-3) | | ICD-10 | Not retrieved in sourced texts | Van Buchem disease | No ICD-10 code was present in the sourced texts reviewed | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3) | | ICD-11 | Not retrieved in sourced texts | Van Buchem disease | No ICD-11 code was present in the sourced texts reviewed | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3) | | MeSH | Not retrieved in sourced texts | Van Buchem disease | No MeSH identifier was present in the sourced texts reviewed | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3) | | Disease name / preferred term | Van Buchem disease | Van Buchem disease | Rare autosomal recessive sclerosing bone dysplasia caused by a biallelic 52-kb deletion downstream of SOST; often presented as milder than sclerosteosis | (balemans2002identificationofa pages 1-2, appelmandijkstra2026sclerosingbonedysplasias pages 1-3, loots2005genomicdeletionof pages 3-4) | | Historical/radiologic synonym | hyperostosis corticalis generalisata | hyperostosis corticalis generalisata | Recurrent synonym in primary and review literature; also described as hyperostosis corticalis generalisata familiaris in older reports | (balemans2002identificationofa pages 1-2, appelmandijkstra2026sclerosingbonedysplasias pages 8-9, dixon1982twocasesof pages 1-3) | | Mechanistic/nosologic synonym | SOST-related endosteal hyperostosis, van Buchem type | SOST-related endosteal hyperostosis, van Buchem type | Modern descriptive label emphasizing SOST regulatory etiology and distinction from SOST coding-loss sclerosteosis | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3) |
Table: This table summarizes the key identifiers and nomenclature for Van Buchem disease from the retrieved evidence. It includes supported MONDO and OMIM identifiers and clearly marks identifier systems not retrieved in the sourced texts.
Genetic cause (Mendelian): VBD is caused by a homozygous ~51.7–52 kb deletion located ~35 kb downstream of SOST within the SOST–MEOX1 intergenic region on 17q12–q21; the deletion contains no coding gene and is hypothesized (and functionally supported) to remove a cis-regulatory enhancer required for bone expression of SOST. (balemans2002identificationofa pages 1-2, staehling‐hampton2002a52kbdeletion pages 4-5, loots2005genomicdeletionof pages 3-4)
Mechanistic causal chain: 1) Biallelic downstream deletion removes bone enhancer(s) (including ECR5) → 2) reduced SOST transcription/sclerostin production in bone → 3) reduced inhibition of canonical Wnt signaling at osteoblast lineage cells → 4) increased bone formation and high bone mass with progressive hyperostosis → 5) cranial nerve entrapment and craniofacial complications. (loots2005genomicdeletionof pages 3-4, lierop2013vanbuchemdisease pages 1-2)
No environmental, infectious, or lifestyle risk factors were identified in the sourced texts; the disorder is primarily determined by genotype. (balemans2002identificationofa pages 1-2)
No specific genetic or environmental protective factors were identified in the retrieved VBD-focused sources.
Not established for VBD in the retrieved literature; given the single major causal CNV and consistent phenotype, gene–environment interaction evidence appears limited/absent in these sources.
A well-characterized Dutch cohort (15/18 known Dutch patients) reported: - Facial palsy: 15/15 (100%); median age at first occurrence 2.5 years; decompression surgery performed in 6/15. (lierop2013vanbuchemdisease pages 2-3) - Hearing impairment: 14/15 (93%); external auditory canal exostoses in 10/15, sometimes severe narrowing. (lierop2013vanbuchemdisease pages 2-3) - Raised intracranial pressure: documented in ~20%. (lierop2013vanbuchemdisease pages 1-2, lierop2012theroleof pages 82-85) - Very high BMD: femoral neck mean 2.16 g/cm² (Z 8.7 ±2.1) and lumbar spine mean 2.13 g/cm² (Z 9.5 ±1.9). (lierop2013vanbuchemdisease pages 2-3)
Natural history from reviews and cohort data suggests progression in childhood/young adulthood with stabilization after ~third decade and normal life expectancy. (appelmandijkstra2026sclerosingbonedysplasias pages 6-8, lierop2012theroleof pages 82-85)
The most impactful manifestations are neurologic/sensory complications (facial palsy, hearing loss, visual compromise, pain/neuralgia), which can require repeated specialist evaluations and surgical interventions. (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11)
A focused phenotype-to-HPO mapping for major features is provided in the artifact below.
| Phenotype (plain language) | Suggested HPO term(s) | Typical onset | Frequency/quant data (percentages or stats) | Progression/natural history | Key citations |
|---|---|---|---|---|---|
| Facial palsy / recurrent facial nerve compression | HP:0010628 Facial palsy; HP:0001303 Facial nerve paralysis | Usually childhood; median first episode 2.5 years in one Dutch cohort; can be present at birth | 100% (15/15) had past episodes of facial palsy in the 2013 Dutch cohort; broader comparison reported facial palsy in 89% of Van Buchem cases vs 93% in sclerosteosis | Often recurrent; may require decompression in selected cases; complications tend to stabilize after the third decade/adulthood | (lierop2013vanbuchemdisease pages 2-3, appelmandijkstra2026sclerosingbonedysplasias pages 3-6, lierop2012theroleof pages 82-85) |
| Hearing loss, often conductive first and later sensorineural | HP:0000365 Hearing impairment; HP:0000405 Conductive hearing impairment; HP:0000407 Sensorineural hearing impairment | Childhood onset | 14/15 (93%) had hearing impairment in the 2013 cohort; review notes childhood-onset conductive hearing loss with later sensorineural involvement; comparative review estimated hearing loss in 78% of Van Buchem disease vs 94% in sclerosteosis | Progressive cranial hyperostosis narrows canals/affects ossicles and cranial nerve VIII; hearing complications may stabilize in adulthood | (lierop2013vanbuchemdisease pages 2-3, appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 6-8, appelmandijkstra2026sclerosingbonedysplasias pages 3-6) |
| Cranial nerve entrapment syndrome (VII, VIII, optic and other cranial nerves) | HP:0001291 Cranial nerve palsy; HP:0000648 Optic atrophy; HP:0000516 Visual impairment; HP:0000458 Facial asymmetry | Childhood to young adulthood, depending on site | Common disease-defining feature; includes facial palsy, hearing loss, visual loss/optic neuropathy, neuralgia/anosmia; external auditory canal exostoses in 10/15 and severe canal narrowing in some patients | Progressive skull/skull-base hyperostosis causes nerve compression; disease often becomes less progressive/stabilizes in adulthood | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 6-8, lierop2013vanbuchemdisease pages 2-3, sebastian2018geneticsofsostsost pages 7-11) |
| Mandibular overgrowth and facial distortion (frontal bossing, enlarged jaw, proptosis) | HP:0000280 Coarse facial features; HP:0000347 Micrognathia/retrognathia not appropriate; suggested instead HP:0010800 Abnormal mandible morphology; HP:0002007 Frontal bossing; HP:0000520 Proptosis | Usually young adulthood for mandibular prominence; craniofacial changes accumulate over time | In adults, nearly all had facial distortion; 11/12 adults had large high forehead and 10/12 enlarged mandible in one cohort; comparative review reported cranial hyperostosis/facial distortion in 68% of Van Buchem cases | Progressive during growth/early adulthood; mandibular overgrowth most apparent in young adulthood; tends to stabilize in adulthood | (lierop2013vanbuchemdisease pages 2-3, appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 6-8, sebastian2018geneticsofsostsost pages 1-7) |
| Markedly increased bone mineral density / generalized skeletal hyperostosis | HP:0005684 Increased bone mineral density; HP:0003014 Hyperostosis; HP:0000923 Generalized osteosclerosis | Detectable in childhood, increases with age | DXA in review: spine Z-scores about +5.4 to +12.3 and hip Z-scores about +5.2 to +12.1; 2013 cohort mean femoral neck Z-score 8.7 ± 2.1 and spine Z-score 9.5 ± 1.9; skeleton described as ~3–4 times heavier than normal in older review literature | BMD rises with age and tends to plateau/stabilize in late adulthood; fracture risk not reported as increased | (appelmandijkstra2026sclerosingbonedysplasias pages 6-8, lierop2013vanbuchemdisease pages 1-2, lierop2012theroleof pages 66-73, sebastian2018geneticsofsostsost pages 1-7) |
| Increased intracranial pressure | HP:0002516 Increased intracranial pressure | Usually later childhood to adulthood; severe cases | About 20% in the Dutch cohort/review; comparative review reported 16% in Van Buchem disease vs 71% in sclerosteosis | Uncommon but serious complication of cranial hyperostosis; rare in Van Buchem disease relative to sclerosteosis; can necessitate decompressive procedures or shunting in severe cases | (lierop2013vanbuchemdisease pages 1-2, lierop2012theroleof pages 82-85, appelmandijkstra2026sclerosingbonedysplasias pages 3-6, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) |
Table: This table summarizes the core clinical phenotypes of Van Buchem disease with suggested HPO mappings, typical onset, quantitative frequency data, and natural history. It is useful for knowledge-base curation and phenotype annotation.
Canonical pathogenic lesion: biallelic ~52-kb downstream deletion (noncoding CNV). (balemans2002identificationofa pages 1-2, lierop2013vanbuchemdisease pages 2-3)
Breakpoint mechanism: endpoints within Alu repeats; likely Alu-mediated homologous recombination. (staehling‐hampton2002a52kbdeletion pages 4-5)
Variant class: germline, structural variant (deletion), noncoding regulatory. (balemans2002identificationofa pages 1-2, staehling‐hampton2002a52kbdeletion pages 4-5)
Loots et al. functionally linked the deletion to loss of a distant bone enhancer. As described in the abstract, they concluded: “Only the SOST(wt) allele faithfully expressed high levels of human SOST in the adult bone… consistent with the model that the VB noncoding deletion removes a SOST-specific regulatory element.” (Genome Research, 2005-06; DOI: 10.1101/gr.3437105) (loots2005genomicdeletionof pages 3-4)
No specific modifier genes or epigenetic mechanisms for VBD severity were identified in the retrieved sources.
Allele frequencies (e.g., gnomAD) were not reported in the sourced texts.
Genetics artifact | Gene/locus | Variant type | Canonical lesion description | Mechanism | Inheritance | Founder/population notes | Key primary references | |---|---|---|---|---|---|---| | SOST regulatory region | Structural variant; biallelic noncoding deletion | Recurrent ~52-kb homozygous deletion located ~35 kb downstream of SOST on 17q12-q21 | Removes a distal bone-specific cis-regulatory enhancer, causing reduced SOST/sclerostin expression and excess bone formation (balemans2002identificationofa pages 1-2, loots2005genomicdeletionof pages 3-4) | Autosomal recessive (balemans2002identificationofa pages 1-2, appelmandijkstra2026sclerosingbonedysplasias pages 1-3) | Classic Dutch Van Buchem families; strong clustering in the Netherlands, especially a small founder village/population (staehling‐hampton2002a52kbdeletion pages 4-5, lierop2013vanbuchemdisease pages 1-2, lierop2012theroleof pages 66-73) | Balemans et al., 2002, J Med Genet DOI: 10.1136/jmg.39.2.91; Staehling-Hampton et al., 2002, Am J Med Genet DOI: 10.1002/ajmg.10401 (balemans2002identificationofa pages 7-8, staehling‐hampton2002a52kbdeletion pages 4-5) | | SOST–MEOX1 intergenic region | Intergenic deletion breakpoint-defined CNV | Deletion lies in the SOST–MEOX1 intergenic region; endpoints are normally 51.7 kb apart and likely arose through Alu-mediated homologous recombination (staehling‐hampton2002a52kbdeletion pages 4-5) | Pathogenicity is regulatory rather than coding: neighboring SOST and MEOX1 coding regions remain intact, supporting a position effect / enhancer loss model (staehling‐hampton2002a52kbdeletion pages 4-5, staehling‐hampton2002a52kbdeletion pages 8-9) | Autosomal recessive disease requires biallelic deletion (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 3-6) | All 15/15 Dutch patients in the 2002 series were homozygous for the deletion (staehling‐hampton2002a52kbdeletion pages 4-5); 2013 Dutch cohort confirmed deletion in 15/18 known Dutch patients studied (lierop2013vanbuchemdisease pages 2-3) | Staehling-Hampton et al., 2002, Am J Med Genet DOI: 10.1002/ajmg.10401; van Lierop et al., 2013, JBMR DOI: 10.1002/jbmr.1794 (staehling‐hampton2002a52kbdeletion pages 4-5, lierop2013vanbuchemdisease pages 2-3) | | ECR5 within downstream SOST regulatory landscape | Deleted enhancer element within noncoding interval | Comparative/in vivo functional studies localized a candidate enhancer, ECR5, within the 52-kb deleted interval downstream of SOST (loots2005genomicdeletionof pages 3-4, loots2005genomicdeletionof media ef8ab351) | Loss of ECR5 abolishes normal osteoblast-lineage / bone expression control of SOST, yielding a hypomorphic sclerostin-deficiency state relative to sclerosteosis (loots2005genomicdeletionof pages 3-4) | Consistent with recessive disease due to markedly reduced but not absent sclerostin expression (staehling‐hampton2002a52kbdeletion pages 8-9, appelmandijkstra2026sclerosingbonedysplasias pages 6-8) | Explains why Van Buchem disease is usually milder than sclerosteosis and lacks typical syndactyly (loots2005genomicdeletionof pages 3-4, appelmandijkstra2026sclerosingbonedysplasias pages 3-6) | Loots et al., 2005, Genome Research DOI: 10.1101/gr.3437105 (loots2005genomicdeletionof pages 3-4, loots2005genomicdeletionof media ef8ab351) | | SOST (coding region) | No causal coding variant in classic Van Buchem disease | In classic Van Buchem disease, SOST coding mutations were not found; this distinguishes it from sclerosteosis, where pathogenic SOST loss-of-function coding variants occur (balemans2002identificationofa pages 1-2, staehling‐hampton2002a52kbdeletion pages 8-9) | Disease results from reduced transcription of normal SOST protein rather than altered protein sequence (balemans2002identificationofa pages 1-2, loots2005genomicdeletionof pages 3-4) | Recessive | Important diagnostic implication: routine single-gene sequencing of SOST may miss Van Buchem disease if deletion analysis is not performed (appelmandijkstra2026sclerosingbonedysplasias pages 3-6) | Balemans et al., 2002, J Med Genet DOI: 10.1136/jmg.39.2.91; Loots et al., 2005, Genome Research DOI: 10.1101/gr.3437105 (balemans2002identificationofa pages 1-2, loots2005genomicdeletionof pages 3-4, appelmandijkstra2026sclerosingbonedysplasias pages 3-6) | | Cytogenetic/molecular testing target | Targeted deletion analysis | Recommended lesion to test: biallelic 52-kb deletion downstream of SOST; methods reported/recommended include qPCR, long-range PCR, MLPA, or gene-targeted microarray because routine sequencing may not detect the lesion (appelmandijkstra2026sclerosingbonedysplasias pages 3-6) | Confirms molecular diagnosis and distinguishes Van Buchem disease from other high-bone-mass disorders and from SOST coding-variant sclerosteosis (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 3-6) | Recessive | Most informative in patients with compatible craniotubular hyperostosis, especially with Dutch ancestry/family history (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, lierop2013vanbuchemdisease pages 1-2) | Appelman-Dijkstra & van Lierop review citing established molecular diagnosis; primary deletion papers as basis (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 3-6, balemans2002identificationofa pages 7-8, staehling‐hampton2002a52kbdeletion pages 4-5) |
Table: This table summarizes the canonical molecular lesion in Van Buchem disease: a recessive 52-kb noncoding deletion downstream of SOST in the SOST–MEOX1 intergenic region. It highlights the enhancer-loss mechanism, founder context, and the primary studies that established the diagnosis.
VBD is a Mendelian disorder driven by a specific recessive CNV; the retrieved sources did not provide evidence for environmental, lifestyle, or infectious contributors to disease risk or severity. (balemans2002identificationofa pages 1-2, lierop2013vanbuchemdisease pages 1-2)
Suggested GO Biological Process terms (examples aligned to mechanism): - GO:0001503 ossification - GO:0045773 positive regulation of bone mineralization - GO:0030282 bone mineralization - GO:0044338 canonical Wnt signaling pathway
In the Dutch cohort: - Serum sclerostin (patients) mean 8.0 pg/mL (95% CI 4.9–11.0) vs carriers 28.7 and controls ~40.0; sclerostin inversely correlated with BMD (lumbar spine r = −0.78). (lierop2013vanbuchemdisease pages 1-2, lierop2012theroleof pages 66-73) - Bone formation marker P1NP (adult patients) mean 96.0 ng/mL, higher than carriers and controls. (lierop2013vanbuchemdisease pages 1-2)
Direct 2023–2024 VBD-specific clinical cohorts were not retrieved in this run; however, there are relevant mechanistic advances in the broader “high bone mass from increased Wnt signaling” space: - A 2023 mouse study demonstrated that chemical inhibition of porcupine (Wnt secretion) reduces both trabecular and cortical bone mass in multiple high-bone-mass models, including Sost loss-of-function (used as a sclerosteosis model), supporting that continued Wnt ligand production sustains the high-bone-mass state and providing a plausible conceptual strategy for symptomatic relief in related disorders. (Bone Research, 2023-08; DOI: 10.1038/s41413-023-00278-5) ()
Visual evidence (SOST locus and deleted enhancer interval) The following figure panels document the downstream SOST deletion interval and conserved enhancer element(s) implicated in VBD. (loots2005genomicdeletionof media ef8ab351, loots2005genomicdeletionof media 6d141620)
Primary system: skeletal system, especially craniofacial and tubular bone cortices. - Skull/calvarium/skull base: hyperostosis and sclerosis (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, dixon1982twocasesof pages 1-3) - Mandible: overgrowth (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, lierop2013vanbuchemdisease pages 2-3) - Temporal bone/external auditory canal/internal auditory canal: narrowing/exostoses contributing to hearing loss (lierop2013vanbuchemdisease pages 2-3, dixon1982twocasesof pages 1-3) - Long bone diaphyses, ribs, clavicles: cortical thickening/hyperostosis (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, dixon1982twocasesof pages 3-5)
Suggested UBERON terms (examples): - UBERON:0003129 calvaria - UBERON:0001712 mandible - UBERON:0001846 temporal bone - UBERON:0002101 femur (diaphysis emphasis)
Key dysfunctional molecule is secreted sclerostin (extracellular). Suggested GO Cellular Component: - GO:0005576 extracellular region
Epidemiology statistics in retrieved sources: - “Approximately 30” described cases (review-level statement) (lierop2012theroleof pages 77-82) - A modern reference text cites ~31 reported individuals mainly from the Netherlands/Germany (appelmandijkstra2026sclerosingbonedysplasias pages 8-9) - Dutch cohort included 15 of 18 known Dutch patients at the time. (lierop2013vanbuchemdisease pages 2-3)
Prevalence/incidence and carrier frequency specific to VBD were not retrieved from Orphanet or population datasets in the sourced texts.
Diagnosis relies on characteristic craniotubular hyperostosis with cranial-nerve entrapment symptoms, plus radiographic and densitometric confirmation of marked hyperostosis and very high BMD. (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, lierop2013vanbuchemdisease pages 2-3)
Because the causal lesion is a noncoding deletion, SOST sequencing can be negative; recommended molecular confirmation requires targeted deletion/CNV testing (e.g., qPCR, long-range PCR, MLPA, targeted microarray). (appelmandijkstra2026sclerosingbonedysplasias pages 3-6, staehling‐hampton2002a52kbdeletion pages 4-5)
No established disease-modifying therapy exists in the retrieved VBD-focused clinical literature; management is predominantly symptomatic and surgical.
Examples reported/recommended: - Hearing interventions: hearing aids, middle ear surgery, cochlear implants (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) - Facial nerve decompression: performed in 6/15 in one cohort (lierop2013vanbuchemdisease pages 2-3) - Orbital decompression, mandibular reduction, and decompressive cranial surgery/VP shunting for selected severe complications (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11)
Older neurosurgical case series demonstrate feasibility of partial/bilateral craniectomy with symptom relief and long survival, though later neurologic complications from progressive bony encroachment can occur. (dixon1982twocasesof pages 1-3, dixon1982twocasesof pages 3-5)
A case-level report described prednisone associated with a “dramatic decrease in bone formation” and no further increase in spine/hip BMD during therapy, with biochemical markers tracking dose, suggesting glucocorticoids might be explored as a medical alternative when surgery is difficult; evidence is limited and not sufficient to establish standard care. (lierop2012theroleof pages 97-100)
Because VBD is driven by increased Wnt signaling secondary to reduced sclerostin, the most conceptually aligned disease-modifying approach would be to reduce Wnt pathway output; a 2023 preclinical study showed porcupine inhibition reduced high bone mass in Sost-loss mouse models. Translation to VBD has not been established. ()
Treatment/diagnostics artifact with MAXO mappings | Domain | Test/intervention | What it shows / goal | Real-world implementation notes | Suggested MAXO term(s) | Key citations | |---|---|---|---|---|---| | Imaging | DXA (spine, hip/femoral neck) | Quantifies markedly elevated bone mineral density; supports diagnosis and follow-up | In Dutch cohort, mean femoral neck BMD 2.16 g/cm² (Z-score 8.7 ± 2.1) and spine BMD 2.13 g/cm² (Z-score 9.5 ± 1.9); review reports spine Z-scores ~+5.4 to +12.3 and hip ~+5.2 to +12.1; serial BMD may help document stabilization in adulthood, though frequent testing may have limited management impact | MAXO: measurement of bone mineral density | (lierop2013vanbuchemdisease pages 2-3, appelmandijkstra2026sclerosingbonedysplasias pages 6-8, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) | | Imaging | Plain radiographs | Demonstrate endosteal hyperostosis and altered bone contours | Typical findings include calvarial/skull-base widening and sclerosis, hyperostosis of tubular bone shafts, broad dense clavicles and ribs, sclerosis of scapulae/pelvis, narrowing of medullary cavity; useful for differential diagnosis versus osteopetrosis and other craniotubular dysplasias | MAXO: radiography | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, charoenngam2022hereditarymetabolicbone pages 11-13, dixon1982twocasesof pages 1-3, dixon1982twocasesof pages 3-5) | | Imaging | CT of skull/temporal bones | Defines skull thickness, foraminal/canal narrowing, cranial nerve entrapment, surgical anatomy | CT shows marked cranial vault and skull-base thickening, petrous bone involvement, occipital exostoses, mastoid/internal auditory canal narrowing; used when hearing loss, facial palsy, visual symptoms, or raised ICP are suspected | MAXO: computed tomography imaging | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, lierop2012theroleof pages 77-82, dixon1982twocasesof pages 1-3, sebastian2018geneticsofsostsost pages 7-11) | | Functional assessment | Audiology assessment | Detects conductive and sensorineural hearing loss and guides hearing intervention | Hearing impairment reported in 14/15 patients in one cohort; childhood-onset conductive loss may progress to sensorineural involvement; recommended for surveillance and treatment planning | MAXO: audiologic evaluation | (lierop2013vanbuchemdisease pages 2-3, appelmandijkstra2026sclerosingbonedysplasias pages 6-8, appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) | | Functional assessment | Ophthalmology assessment | Evaluates optic neuropathy, proptosis, papilledema, vision loss, signs of raised ICP | Recommended regularly because cranial hyperostosis can compromise optic canals and orbit; may trigger orbital decompression or ICP-directed procedures | MAXO: ophthalmologic examination | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) | | Functional assessment | Neurologic / cranial nerve assessment | Detects facial palsy, neuralgia, anosmia, myelopathy, and signs of intracranial hypertension | Facial palsy occurred in 100% of patients in one Dutch cohort, median first occurrence age 2.5 years; neurologic follow-up is central to timing decompression procedures | MAXO: neurologic examination | (lierop2013vanbuchemdisease pages 2-3, appelmandijkstra2026sclerosingbonedysplasias pages 6-8, appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) | | Labs | Bone turnover markers (P1NP, alkaline phosphatase, osteocalcin, CTX) | Reflect increased bone formation and age-related change in turnover | Adult patients had mean P1NP 96.0 ng/mL vs 47.8 in carriers and 37.8 in controls; CTX may be increased in childhood then decline toward low-normal adulthood; routine Ca/P/PTH often not consistently abnormal | MAXO: laboratory test; MAXO: measurement of bone turnover biomarker | (lierop2013vanbuchemdisease pages 1-2, appelmandijkstra2026sclerosingbonedysplasias pages 6-8, charoenngam2022hereditarymetabolicbone pages 11-13) | | Labs | Serum sclerostin | Mechanistic biomarker showing reduced but usually detectable sclerostin | Mean serum sclerostin ~8.0 pg/mL in patients vs 28.7 in carriers and ~40.0 in controls; lower than normal but typically detectable, unlike sclerosteosis where it may be undetectable | MAXO: measurement of circulating biomarker | (lierop2013vanbuchemdisease pages 1-2, appelmandijkstra2026sclerosingbonedysplasias pages 6-8, lierop2012theroleof pages 66-73) | | Genetics | Targeted deletion testing for the 52-kb downstream SOST lesion (qPCR, long-range PCR, MLPA, targeted microarray) | Confirms diagnosis by identifying the canonical biallelic pathogenic noncoding deletion in the SOST–MEOX1 intergenic region at 17q12-q21 | Important because routine single-gene SOST sequencing may miss the pathogenic regulatory deletion; deletion testing is specifically recommended when phenotype suggests Van Buchem disease | MAXO: genetic testing; MAXO: copy number variation analysis | (appelmandijkstra2026sclerosingbonedysplasias pages 3-6, appelmandijkstra2026sclerosingbonedysplasias pages 1-3, balemans2002identificationofa pages 1-2, staehling‐hampton2002a52kbdeletion pages 4-5) | | Genetics | Sequence analysis of SOST coding region | Mainly differential diagnosis with sclerosteosis rather than primary test for classic Van Buchem disease | Van Buchem disease usually lacks SOST coding mutations; negative sequencing does not exclude disease because the canonical lesion is noncoding | MAXO: sequence analysis | (balemans2002identificationofa pages 1-2, loots2005genomicdeletionof pages 3-4, appelmandijkstra2026sclerosingbonedysplasias pages 3-6) | | Surgery | Facial nerve decompression | Relieves recurrent or progressive facial nerve entrapment/palsy | Performed in 6/15 patients in one cohort; used for clinically significant recurrent palsy or nerve compression; literature suggests pediatric cases may also require decompression | MAXO: nerve decompression surgery | (lierop2013vanbuchemdisease pages 2-3, appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) | | Supportive / surgical | Hearing aids, middle ear surgery, cochlear implantation | Improves functional hearing in conductive or mixed hearing loss | Review recommends hearing aids or middle ear surgery; cochlear implant considered when canal obliteration or auditory nerve damage limits conventional options | MAXO: hearing aid provision; MAXO: cochlear implantation; MAXO: otologic surgery | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) | | Surgery | Orbital decompression | Relieves proptosis and optic/orbital compression | Considered for severe orbital crowding or visual compromise due to cranial hyperostosis | MAXO: orbital decompression surgery | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) | | Surgery | Mandibular reduction / corrective craniofacial surgery | Addresses mandibular overgrowth and facial distortion; may improve function/cosmesis | Mandibular enlargement is common in adulthood; one cohort noted corrective mandibular surgery in 1 patient; technically challenging because bone is very thick and dense | MAXO: mandibular reduction surgery; MAXO: craniofacial reconstructive surgery | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, lierop2013vanbuchemdisease pages 2-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) | | Surgery | Craniectomy / cranial decompression | Treats raised intracranial pressure and restricted intracranial volume | Used in severe cases; older case reports describe partial/bilateral craniectomies with recovery from early symptoms and long survival, though later neurologic morbidity can still occur; review notes ICP is less common in Van Buchem disease than in sclerosteosis | MAXO: craniectomy; MAXO: cranial decompression surgery | (dixon1982twocasesof pages 1-3, dixon1982twocasesof pages 3-5, appelmandijkstra2026sclerosingbonedysplasias pages 1-3, lierop2012theroleof pages 82-85) | | Surgery | Ventriculoperitoneal shunt | CSF diversion for raised intracranial pressure / hydrocephalus-like presentation | Recommended when ICP increases and decompression alone is not sufficient or appropriate; especially relevant in severe cranial involvement | MAXO: ventriculoperitoneal shunt placement | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) | | Supportive | Dental / orthodontic care | Manages facial skeletal changes and occlusal/oral complications | Included in multidisciplinary surveillance because mandibular overgrowth and craniofacial remodeling can affect dentofacial function even when teeth are often relatively spared | MAXO: dental management; MAXO: orthodontic treatment | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11, appelmandijkstra2026sclerosingbonedysplasias pages 6-8) | | Medical (experimental/limited evidence) | Glucocorticoids (prednisone) | Attempt to suppress excessive bone turnover and slow further BMD increase | Evidence limited to case-level experience: prednisone decreased formation/resorption markers and prevented further spine/hip BMD increase in one patient, but broader review notes little clinical benefit in two children and repeat surgeries may still be needed; not established standard therapy | MAXO: glucocorticoid therapy | (lierop2012theroleof pages 97-100, appelmandijkstra2026sclerosingbonedysplasias pages 9-11) | | Care model | Multidisciplinary surveillance | Early detection of hearing, visual, dental, cranial nerve, and ICP complications | Suggested follow-up includes periodic DXA/biochemistry, audiology, ophthalmology, neurology, dental assessment, and genetic counseling; recommendations are expert-opinion based because formal clinical guidelines are lacking | MAXO: clinical surveillance; MAXO: genetic counseling | (appelmandijkstra2026sclerosingbonedysplasias pages 1-3, appelmandijkstra2026sclerosingbonedysplasias pages 9-11, appelmandijkstra2026sclerosingbonedysplasias pages 8-9) |
Table: This table summarizes the main diagnostic evaluations and current management approaches for Van Buchem disease, emphasizing what each test or intervention is used for in practice. It is useful for translating the literature into a structured clinical workflow, including targeted genetic testing and symptom-directed surgical care.
Primary prevention is genetic (carrier detection and reproductive counseling) rather than environmental. - Genetic counseling and cascade testing in families from high-risk founder contexts are the most relevant prevention strategies, given autosomal recessive inheritance and a recurrent deletion. (appelmandijkstra2026sclerosingbonedysplasias pages 3-6, lierop2013vanbuchemdisease pages 2-3)
No newborn screening or population screening programs were identified in retrieved sources.
No naturally occurring non-human (“spontaneous”) animal disease analogs for VBD were identified in the retrieved sources.
Although VBD itself is caused by a regulatory deletion, experimental Sost loss-of-function and Sost enhancer perturbation models are widely used to study sclerostin biology. - Functional dissection of the VBD deletion interval identified bone enhancer activity (ECR5) in vivo and in vitro. (loots2005genomicdeletionof pages 3-4) - A 2023 study used Sost loss-of-function high-bone-mass mice to demonstrate porcupine inhibition reduces bone mass, supporting the Wnt-dependence of the phenotype. ()
References
(balemans2002identificationofa pages 1-2): W. Balemans, Neela M. Patel, M. Ebeling, E. Hul, W. Wuyts, C. Lacza, M. Dioszegi, F. Dikkers, P. Hildering, P. Willems, J. Verheij, K. Lindpaintner, B. Vickery, D. Foernzler, and W. Hul. Identification of a 52 kb deletion downstream of the sost gene in patients with van buchem disease. Journal of Medical Genetics, 39:91-97, Feb 2002. URL: https://doi.org/10.1136/jmg.39.2.91, doi:10.1136/jmg.39.2.91. This article has 834 citations and is from a domain leading peer-reviewed journal.
(loots2005genomicdeletionof pages 3-4): Gabriela G. Loots, Michaela Kneissel, Hansjoerg Keller, Myma Baptist, Jessie Chang, Nicole M. Collette, Dmitriy Ovcharenko, Ingrid Plajzer-Frick, and Edward M. Rubin. Genomic deletion of a long-range bone enhancer misregulates sclerostin in van buchem disease. Genome Research, 15:928-935, Jun 2005. URL: https://doi.org/10.1101/gr.3437105, doi:10.1101/gr.3437105. This article has 541 citations and is from a highest quality peer-reviewed journal.
(lierop2013vanbuchemdisease pages 1-2): Antoon H van Lierop, Neveen AT Hamdy, Martje E van Egmond, Egbert Bakker, Freek G Dikkers, and Socrates E Papapoulos. Van buchem disease: clinical, biochemical, and densitometric features of patients and disease carriers. Journal of Bone and Mineral Research, 28:848-854, Apr 2013. URL: https://doi.org/10.1002/jbmr.1794, doi:10.1002/jbmr.1794. This article has 156 citations and is from a highest quality peer-reviewed journal.
(appelmandijkstra2026sclerosingbonedysplasias pages 1-3): N Appelman-Dijkstra and A Van Lierop. Sclerosing bone dysplasias. Genetics of Bone Biology and Skeletal Disease, pages 651-668, Jan 2026. URL: https://doi.org/10.1016/b978-0-443-13683-2.00039-6, doi:10.1016/b978-0-443-13683-2.00039-6. This article has 17 citations.
(appelmandijkstra2026sclerosingbonedysplasias pages 17-18): N Appelman-Dijkstra and A Van Lierop. Sclerosing bone dysplasias. Genetics of Bone Biology and Skeletal Disease, pages 651-668, Jan 2026. URL: https://doi.org/10.1016/b978-0-443-13683-2.00039-6, doi:10.1016/b978-0-443-13683-2.00039-6. This article has 17 citations.
(staehling‐hampton2002a52kbdeletion pages 9-9): Karen Staehling‐Hampton, Sean Proll, Bryan W. Paeper, Lei Zhao, Patrick Charmley, Analisa Brown, Jessica C. Gardner, David Galas, Randall C. Schatzman, Peter Beighton, Socrates Papapoulos, Herman Hamersma, and Mary E. Brunkow. A 52-kb deletion in the sost-meox1 intergenic region on 17q12-q21 is associated with van buchem disease in the dutch population. American journal of medical genetics, 110 2:144-52, Jun 2002. URL: https://doi.org/10.1002/ajmg.10401, doi:10.1002/ajmg.10401. This article has 354 citations.
(appelmandijkstra2026sclerosingbonedysplasias pages 8-9): N Appelman-Dijkstra and A Van Lierop. Sclerosing bone dysplasias. Genetics of Bone Biology and Skeletal Disease, pages 651-668, Jan 2026. URL: https://doi.org/10.1016/b978-0-443-13683-2.00039-6, doi:10.1016/b978-0-443-13683-2.00039-6. This article has 17 citations.
(dixon1982twocasesof pages 1-3): J M Dixon, R E Cull, and P Gamble. Two cases of van buchem's disease. Journal of Neurology, Neurosurgery & Psychiatry, 45:913-918, Oct 1982. URL: https://doi.org/10.1136/jnnp.45.10.913, doi:10.1136/jnnp.45.10.913. This article has 45 citations.
(lierop2013vanbuchemdisease pages 2-3): Antoon H van Lierop, Neveen AT Hamdy, Martje E van Egmond, Egbert Bakker, Freek G Dikkers, and Socrates E Papapoulos. Van buchem disease: clinical, biochemical, and densitometric features of patients and disease carriers. Journal of Bone and Mineral Research, 28:848-854, Apr 2013. URL: https://doi.org/10.1002/jbmr.1794, doi:10.1002/jbmr.1794. This article has 156 citations and is from a highest quality peer-reviewed journal.
(dixon1982twocasesof pages 3-5): J M Dixon, R E Cull, and P Gamble. Two cases of van buchem's disease. Journal of Neurology, Neurosurgery & Psychiatry, 45:913-918, Oct 1982. URL: https://doi.org/10.1136/jnnp.45.10.913, doi:10.1136/jnnp.45.10.913. This article has 45 citations.
(staehling‐hampton2002a52kbdeletion pages 4-5): Karen Staehling‐Hampton, Sean Proll, Bryan W. Paeper, Lei Zhao, Patrick Charmley, Analisa Brown, Jessica C. Gardner, David Galas, Randall C. Schatzman, Peter Beighton, Socrates Papapoulos, Herman Hamersma, and Mary E. Brunkow. A 52-kb deletion in the sost-meox1 intergenic region on 17q12-q21 is associated with van buchem disease in the dutch population. American journal of medical genetics, 110 2:144-52, Jun 2002. URL: https://doi.org/10.1002/ajmg.10401, doi:10.1002/ajmg.10401. This article has 354 citations.
(lierop2012theroleof pages 66-73): A. H. van Lierop, N. A. T. Hamdy, R. L. van Bezooijen, C. W. Löwik, and S. E. Papapoulos. The role of sclerostin in the pathophysiology of sclerosing bone dysplasias. Clinical Reviews in Bone and Mineral Metabolism, 10:108-116, Jun 2012. URL: https://doi.org/10.1007/s12018-011-9123-5, doi:10.1007/s12018-011-9123-5. This article has 22 citations.
(lierop2012theroleof pages 82-85): A. H. van Lierop, N. A. T. Hamdy, R. L. van Bezooijen, C. W. Löwik, and S. E. Papapoulos. The role of sclerostin in the pathophysiology of sclerosing bone dysplasias. Clinical Reviews in Bone and Mineral Metabolism, 10:108-116, Jun 2012. URL: https://doi.org/10.1007/s12018-011-9123-5, doi:10.1007/s12018-011-9123-5. This article has 22 citations.
(appelmandijkstra2026sclerosingbonedysplasias pages 6-8): N Appelman-Dijkstra and A Van Lierop. Sclerosing bone dysplasias. Genetics of Bone Biology and Skeletal Disease, pages 651-668, Jan 2026. URL: https://doi.org/10.1016/b978-0-443-13683-2.00039-6, doi:10.1016/b978-0-443-13683-2.00039-6. This article has 17 citations.
(appelmandijkstra2026sclerosingbonedysplasias pages 9-11): N Appelman-Dijkstra and A Van Lierop. Sclerosing bone dysplasias. Genetics of Bone Biology and Skeletal Disease, pages 651-668, Jan 2026. URL: https://doi.org/10.1016/b978-0-443-13683-2.00039-6, doi:10.1016/b978-0-443-13683-2.00039-6. This article has 17 citations.
(appelmandijkstra2026sclerosingbonedysplasias pages 3-6): N Appelman-Dijkstra and A Van Lierop. Sclerosing bone dysplasias. Genetics of Bone Biology and Skeletal Disease, pages 651-668, Jan 2026. URL: https://doi.org/10.1016/b978-0-443-13683-2.00039-6, doi:10.1016/b978-0-443-13683-2.00039-6. This article has 17 citations.
(sebastian2018geneticsofsostsost pages 7-11): Aimy Sebastian and Gabriela G. Loots. Genetics of sost/sost in sclerosteosis and van buchem disease animal models. Metabolism, 80:38-47, Mar 2018. URL: https://doi.org/10.1016/j.metabol.2017.10.005, doi:10.1016/j.metabol.2017.10.005. This article has 105 citations.
(sebastian2018geneticsofsostsost pages 1-7): Aimy Sebastian and Gabriela G. Loots. Genetics of sost/sost in sclerosteosis and van buchem disease animal models. Metabolism, 80:38-47, Mar 2018. URL: https://doi.org/10.1016/j.metabol.2017.10.005, doi:10.1016/j.metabol.2017.10.005. This article has 105 citations.
(charoenngam2022hereditarymetabolicbone pages 11-13): N Charoenngam, A Nasr, A Shirvani, and MF Holick. Hereditary metabolic bone diseases: a review of pathogenesis, diagnosis and management. genes 2022; 13: 1880. Unknown journal, 2022.
(balemans2002identificationofa pages 7-8): W. Balemans, Neela M. Patel, M. Ebeling, E. Hul, W. Wuyts, C. Lacza, M. Dioszegi, F. Dikkers, P. Hildering, P. Willems, J. Verheij, K. Lindpaintner, B. Vickery, D. Foernzler, and W. Hul. Identification of a 52 kb deletion downstream of the sost gene in patients with van buchem disease. Journal of Medical Genetics, 39:91-97, Feb 2002. URL: https://doi.org/10.1136/jmg.39.2.91, doi:10.1136/jmg.39.2.91. This article has 834 citations and is from a domain leading peer-reviewed journal.
(staehling‐hampton2002a52kbdeletion pages 8-9): Karen Staehling‐Hampton, Sean Proll, Bryan W. Paeper, Lei Zhao, Patrick Charmley, Analisa Brown, Jessica C. Gardner, David Galas, Randall C. Schatzman, Peter Beighton, Socrates Papapoulos, Herman Hamersma, and Mary E. Brunkow. A 52-kb deletion in the sost-meox1 intergenic region on 17q12-q21 is associated with van buchem disease in the dutch population. American journal of medical genetics, 110 2:144-52, Jun 2002. URL: https://doi.org/10.1002/ajmg.10401, doi:10.1002/ajmg.10401. This article has 354 citations.
(loots2005genomicdeletionof media ef8ab351): Gabriela G. Loots, Michaela Kneissel, Hansjoerg Keller, Myma Baptist, Jessie Chang, Nicole M. Collette, Dmitriy Ovcharenko, Ingrid Plajzer-Frick, and Edward M. Rubin. Genomic deletion of a long-range bone enhancer misregulates sclerostin in van buchem disease. Genome Research, 15:928-935, Jun 2005. URL: https://doi.org/10.1101/gr.3437105, doi:10.1101/gr.3437105. This article has 541 citations and is from a highest quality peer-reviewed journal.
(loots2005genomicdeletionof media 6d141620): Gabriela G. Loots, Michaela Kneissel, Hansjoerg Keller, Myma Baptist, Jessie Chang, Nicole M. Collette, Dmitriy Ovcharenko, Ingrid Plajzer-Frick, and Edward M. Rubin. Genomic deletion of a long-range bone enhancer misregulates sclerostin in van buchem disease. Genome Research, 15:928-935, Jun 2005. URL: https://doi.org/10.1101/gr.3437105, doi:10.1101/gr.3437105. This article has 541 citations and is from a highest quality peer-reviewed journal.
(lierop2012theroleof pages 77-82): A. H. van Lierop, N. A. T. Hamdy, R. L. van Bezooijen, C. W. Löwik, and S. E. Papapoulos. The role of sclerostin in the pathophysiology of sclerosing bone dysplasias. Clinical Reviews in Bone and Mineral Metabolism, 10:108-116, Jun 2012. URL: https://doi.org/10.1007/s12018-011-9123-5, doi:10.1007/s12018-011-9123-5. This article has 22 citations.
(lierop2012theroleof pages 97-100): A. H. van Lierop, N. A. T. Hamdy, R. L. van Bezooijen, C. W. Löwik, and S. E. Papapoulos. The role of sclerostin in the pathophysiology of sclerosing bone dysplasias. Clinical Reviews in Bone and Mineral Metabolism, 10:108-116, Jun 2012. URL: https://doi.org/10.1007/s12018-011-9123-5, doi:10.1007/s12018-011-9123-5. This article has 22 citations.