juvenile Paget disease

Summary

juvenile Paget disease (MONDO:0009394) is a disease caused by TNFRSF11B (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TNFRSF11B (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 61
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000164	Abnormality of the dentition	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000889	Abnormality of the clavicle	Very frequent (80-99%)
HP:0000939	Osteoporosis	Very frequent (80-99%)
HP:0002149	Hyperuricemia	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004437	Cranial hyperostosis	Very frequent (80-99%)
HP:0006487	Bowing of the long bones	Very frequent (80-99%)
HP:0100670	Rough bone trabeculation	Very frequent (80-99%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0007703	Abnormality of retinal pigmentation	Frequent (30-79%)
HP:0000995	Melanocytic nevus	Occasional (5-29%)
HP:0001482	Subcutaneous nodule	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	juvenile Paget disease
Mondo ID	MONDO:0009394
MeSH	C537701
OMIM	239000
Orphanet	2801
DOID	DOID:0081368
ICD-11	762002965
NCIT	C131861
SNOMED CT	9723006
UMLS	C0268414
MedGen	75678
GARD	0002831
NORD	1230
Is cancer (heuristic)	no

Also known as: familial hyperphosphatasia · familial osteoectasia · Hereditary Hyperphosphatasia · hereditary hyperphosphatasia · hyperostosid corticalis deformans juvenilis · hyperostosis corticalis deformans juvenilis · JPD · JPG · juvenile Paget disease · juvenile Paget’s disease · juvenile Pagets disease · Paget disease juvenile type · Paget disease of bone 5, juvenile-onset · PDB5

Data availability: 61 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

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 › bone Paget disease › juvenile Paget disease

Related subtypes (4): Paget disease of bone 3, Paget disease of bone 2, early-onset, paget disease of bone 4, Paget disease of bone 6

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

ClinVar germline variants

61 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 13 benign, 7 pathogenic, 5 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
6968	nsv513786	COLEC10	Pathogenic	no assertion criteria provided
208808	NC_000008.11:g.(118690580_118696647)_(118950613_118950848)del	TNFRSF11B	Pathogenic	no assertion criteria provided
208809	NM_002546.4(TNFRSF11B):c.226A>C (p.Thr76Pro)	TNFRSF11B	Pathogenic	no assertion criteria provided
6969	NM_002546.4(TNFRSF11B):c.544_546del (p.Asp182del)	TNFRSF11B	Pathogenic	no assertion criteria provided
6970	NM_002546.4(TNFRSF11B):c.260G>A (p.Cys87Tyr)	TNFRSF11B	Pathogenic	no assertion criteria provided
6972	NM_002546.4(TNFRSF11B):c.966_969delinsCTT (p.Asp323fs)	TNFRSF11B	Pathogenic	no assertion criteria provided
802437	NM_002546.4(TNFRSF11B):c.997C>T (p.Arg333Ter)	TNFRSF11B	Pathogenic	criteria provided, single submitter
3062042	NM_002546.4(TNFRSF11B):c.419_420del (p.Thr140fs)	TNFRSF11B	Likely pathogenic	criteria provided, single submitter
281427	NM_002546.4(TNFRSF11B):c.96C>T (p.Asp32=)	TNFRSF11B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
361694	NM_002546.4(TNFRSF11B):c.234C>T (p.Asp78=)	TNFRSF11B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
759904	NM_002546.4(TNFRSF11B):c.840C>T (p.Ser280=)	TNFRSF11B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908220	NM_002546.4(TNFRSF11B):c.621C>T (p.Phe207=)	TNFRSF11B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
912224	NM_002546.4(TNFRSF11B):c.853A>G (p.Ile285Val)	TNFRSF11B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1380343	NM_002546.4(TNFRSF11B):c.1026G>C (p.Leu342Phe)	TNFRSF11B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1396908	NM_002546.4(TNFRSF11B):c.256G>A (p.Val86Met)	TNFRSF11B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1420847	NM_002546.4(TNFRSF11B):c.97G>A (p.Glu33Lys)	TNFRSF11B	Uncertain significance	criteria provided, multiple submitters, no conflicts
285282	NM_002546.4(TNFRSF11B):c.729A>T (p.Gln243His)	TNFRSF11B	Uncertain significance	criteria provided, multiple submitters, no conflicts
361682	NM_002546.4(TNFRSF11B):c.*682T>C	TNFRSF11B	Uncertain significance	criteria provided, single submitter
361686	NM_002546.4(TNFRSF11B):c.*207C>G	TNFRSF11B	Uncertain significance	criteria provided, single submitter
361687	NM_002546.4(TNFRSF11B):c.*67C>T	TNFRSF11B	Uncertain significance	criteria provided, single submitter
361690	NM_002546.4(TNFRSF11B):c.700G>A (p.Ala234Thr)	TNFRSF11B	Uncertain significance	criteria provided, multiple submitters, no conflicts
361691	NM_002546.4(TNFRSF11B):c.699C>A (p.Asn233Lys)	TNFRSF11B	Uncertain significance	criteria provided, multiple submitters, no conflicts
361692	NM_002546.4(TNFRSF11B):c.400+15G>A	TNFRSF11B	Uncertain significance	criteria provided, single submitter
361693	NM_002546.4(TNFRSF11B):c.400+5G>A	TNFRSF11B	Uncertain significance	criteria provided, single submitter
3892681	NM_002546.4(TNFRSF11B):c.783C>A (p.Asn261Lys)	TNFRSF11B	Uncertain significance	criteria provided, single submitter
6971	NM_002546.4(TNFRSF11B):c.349T>C (p.Phe117Leu)	TNFRSF11B	Uncertain significance	criteria provided, single submitter
816653	NM_002546.4(TNFRSF11B):c.884T>C (p.Leu295Pro)	TNFRSF11B	Uncertain significance	criteria provided, single submitter
908146	NM_002546.4(TNFRSF11B):c.*799G>A	TNFRSF11B	Uncertain significance	criteria provided, single submitter
910101	NM_002546.4(TNFRSF11B):c.*609G>A	TNFRSF11B	Uncertain significance	criteria provided, single submitter
910102	NM_002546.4(TNFRSF11B):c.*505A>G	TNFRSF11B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
BTF3P11	Strong	Autosomal recessive	juvenile Paget disease	3
TNFRSF11B	Strong	Autosomal recessive	juvenile Paget disease	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNFRSF11B	Orphanet:1416	Familial calcium pyrophosphate deposition
TNFRSF11B	Orphanet:2801	Juvenile Paget disease
COLEC10	Orphanet:293843	3MC syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BTF3P11	HGNC:1126	ENSG00000118903		basic transcription factor 3 pseudogene 11	gencc,clinvar
TNFRSF11B	HGNC:11909	ENSG00000164761	O00300	Tumor necrosis factor receptor superfamily member 11B	gencc,clinvar
COLEC10	HGNC:2220	ENSG00000184374	Q9Y6Z7	Collectin-10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNFRSF11B	Tumor necrosis factor receptor superfamily member 11B	Acts as a decoy receptor for TNFSF11/RANKL and thereby neutralizes its function in osteoclastogenesis.
COLEC10	Collectin-10	Lectin that binds to various sugars: galactose > mannose = fucose > N-acetylglucosamine > N-acetylgalactosamine.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BTF3P11	Other/Unknown	no
TNFRSF11B	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, DEATH-like_dom_sf
COLEC10	Other/Unknown	no		C-type_lectin-like, Collagen, C-type_lectin-like/link_sf

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
Brodmann (1909) area 10	1
endometrium epithelium	1
ascending aorta	1
cartilage tissue	1
thoracic aorta	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BTF3P11	76		yes	male germ line stem cell (sensu Vertebrata) in testis, endometrium epithelium, Brodmann (1909) area 10
TNFRSF11B	201	ubiquitous	marker	cartilage tissue, ascending aorta, thoracic aorta
COLEC10	91	tissue_specific	marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNFRSF11B	1,542
COLEC10	839
BTF3P11	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFRSF11B	O00300	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COLEC10	Q9Y6Z7	81.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 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
Lectin pathway of complement activation	1	634.4×	0.005	COLEC10
Initial triggering of complement	1	300.5×	0.005	COLEC10
TNFs bind their physiological receptors	1	196.9×	0.005	TNFRSF11B

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
negative regulation of odontogenesis of dentin-containing tooth	1	4213.0×	0.003	TNFRSF11B
complement activation, lectin pathway	1	842.6×	0.004	COLEC10
positive regulation of opsonization	1	842.6×	0.004	COLEC10
cell surface pattern recognition receptor signaling pathway	1	702.2×	0.004	COLEC10
cranial skeletal system development	1	468.1×	0.005	COLEC10
negative regulation of osteoclast differentiation	1	271.8×	0.007	TNFRSF11B
negative regulation of tumor necrosis factor-mediated signaling pathway	1	227.7×	0.008	TNFRSF11B
skeletal system development	1	62.9×	0.022	TNFRSF11B
extracellular matrix organization	1	61.1×	0.022	TNFRSF11B
proteolysis	1	17.1×	0.069	COLEC10
apoptotic process	1	14.3×	0.075	TNFRSF11B
signal transduction	1	8.0×	0.121	TNFRSF11B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BTF3P11	0	0
TNFRSF11B	0	0
COLEC10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	3	BTF3P11, TNFRSF11B, COLEC10

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BTF3P11	0	—
TNFRSF11B	0	—
COLEC10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.