Hyaline fibromatosis syndrome

Summary

Hyaline fibromatosis syndrome (MONDO:0009229) is a disease caused by ANTXR2 (GenCC Definitive), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include celecoxib and uracil.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ANTXR2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 184
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		150	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hyaline fibromatosis syndrome
Mondo ID	MONDO:0009229
OMIM	228600
Orphanet	498474
DOID	DOID:0111669
UMLS	C5574677
MedGen	1805033
GARD	0022029
Is cancer (heuristic)	no

Also known as: HFS · hyaline fibromatosis syndrome · infantile systemic hyalinosis (former subtype) · inherited systemic hyalinosis · juvenile hyaline fibromatosis (former subtype)

Data availability: 184 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › primary osteolysis › hyaline fibromatosis syndrome

Related subtypes (13): acroosteolysis, multicentric carpo-tarsal osteolysis with or without nephropathy, pacman dysplasia, familial expansile osteolysis, Hutchinson-Gilford progeria syndrome, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, 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

Subtypes (2): juvenile hyaline fibromatosis, infantile systemic hyalinosis

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

184 retrieved; paginated sample, class counts are floors:

101 uncertain significance, 26 benign, 16 likely pathogenic, 16 pathogenic, 13 likely benign, 5 benign/likely benign, 4 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3255468	NM_058172.6(ANTXR2):c.[1073dup];[1074del]		Pathogenic	criteria provided, single submitter
1332786	NM_058172.6(ANTXR2):c.1073del (p.Pro358fs)	ANTXR2	Pathogenic	criteria provided, single submitter
209132	NM_058172.6(ANTXR2):c.1305del (p.Thr436fs)	ANTXR2	Pathogenic	criteria provided, single submitter
2581430	NM_058172.6(ANTXR2):c.1294C>T (p.Arg432Ter)	ANTXR2	Pathogenic	criteria provided, single submitter
2585639	NM_058172.6(ANTXR2):c.1139del (p.Tyr380fs)	ANTXR2	Pathogenic	criteria provided, single submitter
2598	NM_058172.6(ANTXR2):c.1179G>A (p.Glu393=)	ANTXR2	Pathogenic	no assertion criteria provided
2599	NM_058172.6(ANTXR2):c.1142A>G (p.Tyr381Cys)	ANTXR2	Pathogenic	no assertion criteria provided
2600	NM_058172.6(ANTXR2):c.314G>A (p.Gly105Asp)	ANTXR2	Pathogenic	no assertion criteria provided
2601	NM_058172.6(ANTXR2):c.986T>G (p.Leu329Arg)	ANTXR2	Pathogenic	no assertion criteria provided
2602	NM_058172.6(ANTXR2):c.658G>T (p.Glu220Ter)	ANTXR2	Pathogenic	no assertion criteria provided
2603	NM_058172.6(ANTXR2):c.566T>C (p.Ile189Thr)	ANTXR2	Pathogenic	no assertion criteria provided
2604	NM_058172.6(ANTXR2):c.1073dup (p.Ala359fs)	ANTXR2	Pathogenic	criteria provided, multiple submitters, no conflicts
280129	NM_058172.6(ANTXR2):c.134T>C (p.Leu45Pro)	ANTXR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
419342	NM_058172.6(ANTXR2):c.1074del (p.Ala359fs)	ANTXR2	Pathogenic	criteria provided, multiple submitters, no conflicts
4277999	NM_058172.6(ANTXR2):c.1347+1G>T	ANTXR2	Pathogenic	criteria provided, single submitter
446525	NM_058172.6(ANTXR2):c.903dup (p.Ser302fs)	ANTXR2	Pathogenic	no assertion criteria provided
974886	NM_058172.6(ANTXR2):c.652T>C (p.Cys218Arg)	ANTXR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982062	NM_058172.6(ANTXR2):c.1069del (p.Ala357fs)	ANTXR2	Pathogenic	criteria provided, single submitter
982063	NM_058172.6(ANTXR2):c.720del (p.Ser240fs)	ANTXR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323915	NM_058172.6(ANTXR2):c.297-2del	ANTXR2	Likely pathogenic	criteria provided, single submitter
1723454	NM_058172.6(ANTXR2):c.496_497del (p.Ser166fs)	ANTXR2	Likely pathogenic	no assertion criteria provided
209133	NM_058172.6(ANTXR2):c.241T>C (p.Ser81Pro)	ANTXR2	Likely pathogenic	criteria provided, single submitter
2431432	NM_058172.6(ANTXR2):c.1287_1288del (p.Arg429fs)	ANTXR2	Likely pathogenic	criteria provided, single submitter
2431563	NM_058172.6(ANTXR2):c.487-2A>G	ANTXR2	Likely pathogenic	criteria provided, single submitter
2434220	NM_058172.6(ANTXR2):c.297-1G>A	ANTXR2	Likely pathogenic	criteria provided, single submitter
2445864	NM_058172.6(ANTXR2):c.1087-1G>A	ANTXR2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2585304	NM_058172.6(ANTXR2):c.211del (p.Glu71fs)	ANTXR2	Likely pathogenic	criteria provided, single submitter
3393145	NM_058172.6(ANTXR2):c.698-2A>G	ANTXR2	Likely pathogenic	criteria provided, single submitter
3591243	NM_058172.6(ANTXR2):c.1179+1G>C	ANTXR2	Likely pathogenic	criteria provided, single submitter
3591244	NM_058172.6(ANTXR2):c.1114_1115dup (p.Trp373fs)	ANTXR2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
ANTXR2	Definitive	Autosomal recessive	hyaline fibromatosis syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANTXR2	Orphanet:2028	Juvenile hyaline fibromatosis
ANTXR2	Orphanet:2176	Infantile systemic hyalinosis

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
ANTXR2	HGNC:21732	ENSG00000163297	P58335	Anthrax toxin receptor 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANTXR2	Anthrax toxin receptor 2	Necessary for cellular interactions with laminin and the extracellular matrix.

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)
ANTXR2	Other/Unknown	no		VWF_A, Anthrax_toxin_rcpt_C, Anthrax_toxin_rcpt_extracel

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
decidua	1
mucosa of stomach	1
smooth muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANTXR2	243	ubiquitous	marker	mucosa of stomach, decidua, smooth muscle tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANTXR2	1,270

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANTXR2	P58335	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Uptake and function of anthrax toxins	1	951.7×	0.001	ANTXR2

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
uterus development	1	802.5×	0.004	ANTXR2
collagen fibril organization	1	224.7×	0.005	ANTXR2
single fertilization	1	183.2×	0.005	ANTXR2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ANTXR2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ANTXR2	3	Binding:3

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	ANTXR2

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)
ANTXR2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05327751	PHASE3	UNKNOWN	Possible Protective Effect of Celecoxib Against Capecitabine Induced Hand and Foot Syndrome in Patients With Colorectal Cancer
NCT07501442	Not specified	NOT_YET_RECRUITING	Clinical Trial Evaluating the Efficacy and Safety of Uracil 0,5% Plasters in Oncology Patients Affected by Hand-foot Syndrome (HFS)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CELECOXIB	4	1
URACIL	3	1