Familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome

Summary

Familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome (MONDO:0100251) is a disease caused by FGF23 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: FGF23 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome
Mondo ID	MONDO:0100251
Orphanet	306661
DOID	DOID:0111063
NCIT	C131851
UMLS	C1876187
MedGen	360297
GARD	0010879
Is cancer (heuristic)	no

Also known as: familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome · HFTC · HHS · hypercalcemic tumoral calcinosis · hyperphosphatemic familial tumoral calcinosis · tumoral calcinosis, hyperphosphatemic, familial, 1

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › skin neoplasm › familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome

Related subtypes (16): dermoid cyst of skin, eyelid neoplasm, epidermal appendage tumor, dermis tumor, skin cancer, benign dermal neurilemmoma, actinic keratosis, familial Dupuytren contracture, schwannomatosis, familial multiple discoid fibromas, Maffucci syndrome, hemangiopericytoma of skin, benign neoplasm of skin, melanocytic skin neoplasm, epithelial skin neoplasm, calcifying epithelial odontogenic tumor

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

2 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
216929	NM_020638.3(FGF23):c.260G>A (p.Gly87Asp)	FGF23	Likely pathogenic	criteria provided, single submitter
5027	NM_020638.3(FGF23):c.211A>G (p.Ser71Gly)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
FGF23	Strong	Autosomal recessive	tumoral calcinosis, hyperphosphatemic, familial, 2	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGF23	Orphanet:306661	Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome
FGF23	Orphanet:89937	Autosomal dominant hypophosphatemic rickets

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
FGF23	HGNC:3680	ENSG00000118972	Q9GZV9	Fibroblast growth factor 23	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGF23	Fibroblast growth factor 23	Regulator of phosphate homeostasis.

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)
FGF23	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF

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
hair follicle	1
primordial germ cell in gonad	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGF23	44	tissue_specific	marker	sural nerve, primordial germ cell in gonad, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF23	1,533

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGF23	Q9GZV9	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. 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
FGFR1c and Klotho ligand binding and activation	1	2855.0×	0.003	FGF23
Signaling by activated point mutants of FGFR1	1	951.7×	0.003	FGF23
Signaling by activated point mutants of FGFR3	1	951.7×	0.003	FGF23
FGFR3c ligand binding and activation	1	878.5×	0.003	FGF23
FGFR2c ligand binding and activation	1	878.5×	0.003	FGF23
Phospholipase C-mediated cascade; FGFR3	1	878.5×	0.003	FGF23
FGFRL1 modulation of FGFR1 signaling	1	878.5×	0.003	FGF23
FGFR4 ligand binding and activation	1	815.7×	0.003	FGF23
FGFR1c ligand binding and activation	1	761.3×	0.003	FGF23
Phospholipase C-mediated cascade; FGFR4	1	761.3×	0.003	FGF23
Activated point mutants of FGFR2	1	671.8×	0.003	FGF23
Phospholipase C-mediated cascade: FGFR1	1	671.8×	0.003	FGF23
Phospholipase C-mediated cascade; FGFR2	1	634.4×	0.003	FGF23
PI-3K cascade:FGFR3	1	634.4×	0.003	FGF23
SHC-mediated cascade:FGFR3	1	601.0×	0.003	FGF23
PI-3K cascade:FGFR4	1	571.0×	0.003	FGF23
Downstream signaling of activated FGFR1	1	543.8×	0.003	FGF23
FRS-mediated FGFR3 signaling	1	543.8×	0.003	FGF23
SHC-mediated cascade:FGFR4	1	543.8×	0.003	FGF23
PI-3K cascade:FGFR1	1	519.1×	0.003	FGF23
SHC-mediated cascade:FGFR1	1	496.5×	0.003	FGF23
PI-3K cascade:FGFR2	1	496.5×	0.003	FGF23
FRS-mediated FGFR4 signaling	1	496.5×	0.003	FGF23
Signaling by FGFR3 in disease	1	496.5×	0.003	FGF23
SHC-mediated cascade:FGFR2	1	475.8×	0.003	FGF23
FRS-mediated FGFR1 signaling	1	456.8×	0.003	FGF23
FRS-mediated FGFR2 signaling	1	439.2×	0.003	FGF23
Negative regulation of FGFR3 signaling	1	439.2×	0.003	FGF23
Negative regulation of FGFR4 signaling	1	407.9×	0.003	FGF23
Negative regulation of FGFR1 signaling	1	368.4×	0.004	FGF23

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
obsolete positive regulation of vitamin D 24-hydroxylase activity	1	16852.0×	0.001	FGF23
regulation of phosphate transport	1	5617.3×	0.002	FGF23
vitamin D catabolic process	1	4213.0×	0.002	FGF23
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	1	2808.7×	0.002	FGF23
negative regulation of hormone secretion	1	1872.4×	0.002	FGF23
response to sodium phosphate	1	1685.2×	0.002	FGF23
intracellular phosphate ion homeostasis	1	1532.0×	0.002	FGF23
cellular response to leptin stimulus	1	1532.0×	0.002	FGF23
cellular response to vitamin D	1	1532.0×	0.002	FGF23
response to magnesium ion	1	1404.3×	0.002	FGF23
cellular response to parathyroid hormone stimulus	1	1404.3×	0.002	FGF23
phosphate ion homeostasis	1	1053.2×	0.002	FGF23
cellular response to interleukin-6	1	991.3×	0.002	FGF23
negative regulation of bone mineralization	1	936.2×	0.002	FGF23
calcium ion homeostasis	1	443.5×	0.004	FGF23
ERK1 and ERK2 cascade	1	318.0×	0.005	FGF23
negative regulation of osteoblast differentiation	1	295.6×	0.005	FGF23
fibroblast growth factor receptor signaling pathway	1	285.6×	0.005	FGF23
neurogenesis	1	208.1×	0.006	FGF23
regulation of cell migration	1	157.5×	0.008	FGF23
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.013	FGF23
positive regulation of MAPK cascade	1	80.6×	0.014	FGF23
positive regulation of cell population proliferation	1	33.6×	0.031	FGF23
positive regulation of DNA-templated transcription	1	27.9×	0.036	FGF23

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
FGF23	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
FGF23	2	Binding:2

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	FGF23

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)
FGF23	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.