Hyperostosis corticalis generalisata

Summary

Hyperostosis corticalis generalisata (MONDO:0009395) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• Phenotypes (HPO): 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0000303	Mandibular prognathia	Very frequent (80-99%)
HP:0000889	Abnormality of the clavicle	Very frequent (80-99%)
HP:0003103	Abnormal cortical bone morphology	Very frequent (80-99%)
HP:0004437	Cranial hyperostosis	Very frequent (80-99%)
HP:0005019	Diaphyseal thickening	Very frequent (80-99%)
HP:0005789	Generalized osteosclerosis	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperostosis corticalis generalisata
Mondo ID	MONDO:0009395
OMIM	239100
Orphanet	3416
DOID	DOID:0080036
ICD-11	241514592
NCIT	C131812
SNOMED CT	59763006
UMLS	C0432272
MedGen	98484
GARD	0002833
Is cancer (heuristic)	no

Also known as: endosteal hyperostosis · endosteal hyperostosis autosomal recessive · hyperostosis corticalis generalisata · hyperphosphatasemia tarda · Van Buchem disease · van Buchem disease · van Buchem disease type 1 · VBCH

Data availability: 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone remodeling disease › hyperostosis › hyperostosis corticalis generalisata

Related subtypes (8): exostosis, bone Paget disease, diffuse idiopathic skeletal hyperostosis, Caffey disease, autosomal dominant osteosclerosis, Worth type, craniodiaphyseal dysplasia, X-linked calvarial hyperostosis, sclerosteosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 34 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
LRP5	Supportive	Autosomal dominant	hyperostosis corticalis generalisata	26
SOST	Supportive	Autosomal dominant	hyperostosis corticalis generalisata	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOST	Orphanet:1513	Craniodiaphyseal dysplasia
SOST	Orphanet:3152	Sclerosteosis
SOST	Orphanet:3416	Hyperostosis corticalis generalisata
LRP5	Orphanet:178377	Osteosclerosis-developmental delay-craniosynostosis syndrome
LRP5	Orphanet:2783	Autosomal dominant osteopetrosis type 1
LRP5	Orphanet:2788	Osteoporosis-pseudoglioma syndrome
LRP5	Orphanet:2790	Endosteal hyperostosis, Worth type
LRP5	Orphanet:2924	Isolated polycystic liver disease
LRP5	Orphanet:3416	Hyperostosis corticalis generalisata
LRP5	Orphanet:498481	LRP5-related primary osteoporosis
LRP5	Orphanet:891	Familial exudative vitreoretinopathy
LRP5	Orphanet:90050	Retinopathy of prematurity

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOST	HGNC:13771	ENSG00000167941	Q9BQB4	Sclerostin	gencc
LRP5	HGNC:6697	ENSG00000162337	O75197	Low-density lipoprotein receptor-related protein 5	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOST	Sclerostin	Negative regulator of bone growth that acts through inhibition of Wnt signaling and bone formation.
LRP5	Low-density lipoprotein receptor-related protein 5	Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOST	Other/Unknown	no		Cys_knot_C, Sclerostin/SOSTDC1, Cystine-knot_cytokine
LRP5	Other/Unknown	no		LDLR_classB_rpt, EGF, LDrepeatLR_classA_rpt

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
descending thoracic aorta	1
male germ line stem cell (sensu Vertebrata) in testis	1
trabecular bone tissue	1
ascending aorta	1
mucosa of transverse colon	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOST	73	broad	marker	trabecular bone tissue, descending thoracic aorta, male germ line stem cell (sensu Vertebrata) in testis
LRP5	224	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRP5	2,619
SOST	2,417

Intra-cohort edges

A	B	Sources
LRP5	SOST	biogrid_interaction, intact, string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SOST	Q9BQB4	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRP5	O75197	78.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	2	713.8×	2e-05	SOST, LRP5
TCF dependent signaling in response to WNT	2	117.7×	3e-04	SOST, LRP5
Signaling by WNT	2	112.0×	3e-04	SOST, LRP5
Signaling by LRP5 mutants	1	815.7×	0.003	LRP5
Signaling by RNF43 mutants	1	634.4×	0.003	LRP5
Signaling by WNT in cancer	1	300.5×	0.006	LRP5
Regulation of FZD by ubiquitination	1	259.6×	0.006	LRP5
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	178.4×	0.008	LRP5
Signal Transduction	2	10.2×	0.012	SOST, LRP5
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.038	LRP5
Disease	1	6.5×	0.147	LRP5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
canonical Wnt signaling pathway	2	153.2×	0.002	SOST, LRP5
cell-cell signaling involved in mammary gland development	1	2808.7×	0.004	LRP5
mesodermal cell migration	1	1685.2×	0.004	LRP5
extracellular matrix-cell signaling	1	1685.2×	0.004	LRP5
anatomical structure regression	1	1685.2×	0.004	LRP5
Norrin signaling pathway	1	1685.2×	0.004	LRP5
apoptotic process involved in blood vessel morphogenesis	1	1404.3×	0.004	LRP5
establishment of blood-retinal barrier	1	1404.3×	0.004	LRP5
glucose catabolic process	1	1203.7×	0.004	LRP5
retinal blood vessel morphogenesis	1	1203.7×	0.004	LRP5
retina morphogenesis in camera-type eye	1	936.2×	0.004	LRP5
cell migration involved in gastrulation	1	766.0×	0.004	LRP5
bone marrow development	1	766.0×	0.004	LRP5
osteoblast proliferation	1	702.2×	0.004	LRP5
branching involved in mammary gland duct morphogenesis	1	702.2×	0.004	LRP5
establishment of blood-brain barrier	1	702.2×	0.004	LRP5
cellular response to parathyroid hormone stimulus	1	702.2×	0.004	SOST
positive regulation of DNA-templated transcription	2	27.9×	0.004	SOST, LRP5
positive regulation of osteoblast proliferation	1	601.9×	0.005	LRP5
osteoblast development	1	495.6×	0.005	LRP5
gastrulation with mouth forming second	1	468.1×	0.005	LRP5
bone remodeling	1	468.1×	0.005	LRP5
regulation of insulin secretion involved in cellular response to glucose stimulus	1	468.1×	0.005	LRP5
negative regulation of ossification	1	312.1×	0.007	SOST
positive regulation of mesenchymal cell proliferation	1	300.9×	0.007	LRP5
bone morphogenesis	1	300.9×	0.007	LRP5
positive regulation of mitotic nuclear division	1	271.8×	0.007	LRP5
negative regulation of protein-containing complex assembly	1	227.7×	0.008	SOST
adipose tissue development	1	200.6×	0.009	LRP5
response to peptide hormone	1	195.9×	0.009	LRP5

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SOST	CIANIDANOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOST	2	4
LRP5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CIANIDANOL	4	SOST
COUMARIN	4	SOST

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SOST	9	Binding:9
LRP5	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CIANIDANOL	4	SOST
COUMARIN	4	SOST

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SOST
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LRP5

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LRP5	1	SOST

Clinical trials & evidence

Clinical trials

Clinical trials: 0.