Familial expansile osteolysis

Summary

Familial expansile osteolysis (MONDO:0008275) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial expansile osteolysis
Mondo ID	MONDO:0008275
MeSH	C536335
OMIM	174810
Orphanet	85195
DOID	DOID:0111542
ICD-11	1161028858
SNOMED CT	254153009
UMLS	C0432292
MedGen	96593
GARD	0009168
Is cancer (heuristic)	no

Also known as: EOF · familial expansile osteolysis · FEO · HEPOD · hereditary expansile polyostotic osteolytic dysplasia · McCabe disease · osteolysis, familial expansile

Data availability: 12 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › primary osteolysis › familial expansile osteolysis

Related subtypes (13): acroosteolysis, multicentric carpo-tarsal osteolysis with or without nephropathy, pacman dysplasia, Hutchinson-Gilford progeria syndrome, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, hyaline fibromatosis syndrome, autosomal recessive distal osteolysis syndrome, Paget disease of bone 2, early-onset, talo-patello-scaphoid osteolysis, Nestor-Guillermo progeria syndrome, mandibuloacral dysplasia, phalangeal microgeodic syndrome, multicentric osteolysis-nodulosis-arthropathy spectrum

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

12 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 2 conflicting classifications of pathogenicity, 1 pathogenic, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208143	NM_003839.4(TNFRSF11A):c.45_62dup (p.Leu16_Leu21dup)	LOC130062628	Pathogenic	criteria provided, multiple submitters, no conflicts
6299	NM_003839.4(TNFRSF11A):c.46_63dup (p.Leu16_Leu21dup)	LOC130062628	Likely pathogenic	criteria provided, single submitter
1442005	NM_003839.4(TNFRSF11A):c.637G>A (p.Gly213Ser)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287370	NM_003839.4(TNFRSF11A):c.718A>G (p.Lys240Glu)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030713	NM_003839.4(TNFRSF11A):c.338C>T (p.Ala113Val)	TNFRSF11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031361	NM_003839.4(TNFRSF11A):c.1370G>A (p.Cys457Tyr)	TNFRSF11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031362	NM_003839.4(TNFRSF11A):c.1703G>A (p.Arg568His)	TNFRSF11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1285402	NM_003839.4(TNFRSF11A):c.1544C>A (p.Pro515His)	TNFRSF11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1354871	NM_003839.4(TNFRSF11A):c.1054A>G (p.Arg352Gly)	TNFRSF11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1446865	NM_003839.4(TNFRSF11A):c.134G>A (p.Arg45Gln)	TNFRSF11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1915163	NM_003839.4(TNFRSF11A):c.1442AAG[2] (p.Glu483del)	TNFRSF11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
259183	NM_003839.4(TNFRSF11A):c.933A>G (p.Thr311=)	TNFRSF11A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · 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
TNFRSF11A	Moderate	Autosomal dominant	familial expansile osteolysis	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNFRSF11A	Orphanet:1782	Dysosteosclerosis
TNFRSF11A	Orphanet:178389	Osteopetrosis-hypogammaglobulinemia syndrome
TNFRSF11A	Orphanet:2801	Juvenile Paget disease
TNFRSF11A	Orphanet:391490	Adult-onset myasthenia gravis
TNFRSF11A	Orphanet:85195	Familial expansile osteolysis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNFRSF11A	HGNC:11908	ENSG00000141655	Q9Y6Q6	Tumor necrosis factor receptor superfamily member 11A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNFRSF11A	Tumor necrosis factor receptor superfamily member 11A	Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNFRSF11A	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_11, TNFR_11A

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
mucosa of sigmoid colon	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNFRSF11A	221	broad	marker	parotid gland, mucosa of sigmoid colon, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNFRSF11A	1,186

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFRSF11A	Q9Y6Q6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	671.8×	0.003	TNFRSF11A
TNFR2 non-canonical NF-kB pathway	1	181.3×	0.006	TNFRSF11A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of fever generation by positive regulation of prostaglandin secretion	1	8426.0×	0.002	TNFRSF11A
circadian temperature homeostasis	1	5617.3×	0.002	TNFRSF11A
multinuclear osteoclast differentiation	1	5617.3×	0.002	TNFRSF11A
cellular response to zinc ion starvation	1	2407.4×	0.003	TNFRSF11A
positive regulation of bone resorption	1	991.3×	0.004	TNFRSF11A
mammary gland alveolus development	1	991.3×	0.004	TNFRSF11A
lymph node development	1	802.5×	0.004	TNFRSF11A
response to tumor necrosis factor	1	624.1×	0.004	TNFRSF11A
monocyte chemotaxis	1	581.1×	0.004	TNFRSF11A
positive regulation of osteoclast differentiation	1	581.1×	0.004	TNFRSF11A
response to interleukin-1	1	510.7×	0.005	TNFRSF11A
osteoclast differentiation	1	343.9×	0.006	TNFRSF11A
tumor necrosis factor-mediated signaling pathway	1	330.4×	0.006	TNFRSF11A
response to mechanical stimulus	1	300.9×	0.006	TNFRSF11A
positive regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.007	TNFRSF11A
response to insulin	1	230.8×	0.007	TNFRSF11A
ossification	1	227.7×	0.007	TNFRSF11A
positive regulation of JNK cascade	1	163.6×	0.009	TNFRSF11A
response to ethanol	1	146.5×	0.009	TNFRSF11A
response to lipopolysaccharide	1	124.8×	0.010	TNFRSF11A
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.014	TNFRSF11A
adaptive immune response	1	84.3×	0.014	TNFRSF11A
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	TNFRSF11A
cell-cell signaling	1	69.6×	0.016	TNFRSF11A
positive regulation of cell population proliferation	1	33.6×	0.031	TNFRSF11A
signal transduction	1	16.1×	0.062	TNFRSF11A

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
TNFRSF11A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	TNFRSF11A

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)
TNFRSF11A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.