Autosomal dominant hypophosphatemic rickets

Summary

Autosomal dominant hypophosphatemic rickets (MONDO:0008660) is a disease caused by FGF23 (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FGF23 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 104
• Phenotypes (HPO): 15
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0002148	Hypophosphatemia	Very frequent (80-99%)
HP:0003109	Hyperphosphaturia	Very frequent (80-99%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001891	Iron deficiency anemia	Frequent (30-79%)
HP:0002653	Bone pain	Frequent (30-79%)
HP:0002748	Rickets	Frequent (30-79%)
HP:0002749	Osteomalacia	Frequent (30-79%)
HP:0002979	Bowing of the legs	Frequent (30-79%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0030757	Tooth abscess	Frequent (30-79%)
HP:0100512	Low levels of vitamin D	Frequent (30-79%)
HP:0020110	Bone fracture	Occasional (5-29%)
HP:0002901	Hypocalcemia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant hypophosphatemic rickets
Mondo ID	MONDO:0008660
MeSH	C562791
OMIM	193100
Orphanet	89937
DOID	DOID:0050948
SNOMED CT	237889002
UMLS	C0342642
MedGen	83346
GARD	0016781
Is cancer (heuristic)	no

Also known as: ADHR · autosomal dominant hereditary hypophosphatemic rickets · autosomal dominant hypophosphatemia · autosomal dominant hypophosphatemic rickets · hereditary hypophosphatemic rickets, autosomal dominant · hypophosphatemic rickets, autosomal dominant

Data availability: 104 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary hypophosphatemic rickets › autosomal dominant hypophosphatemic rickets

Related subtypes (3): hereditary hypophosphatemic rickets with hypercalciuria, autosomal recessive hypophosphatemic rickets, X-linked hypophosphatemic rickets

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

104 retrieved; paginated sample, class counts are floors:

60 uncertain significance, 13 conflicting classifications of pathogenicity, 11 benign, 8 benign/likely benign, 4 likely benign, 3 pathogenic, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179114	GRCh37/hg19 12p13.32(chr12:4477393-4488878)	FGF23	Pathogenic	no assertion criteria provided
36135	NM_020638.3(FGF23):c.536G>A (p.Arg179Gln)	FGF23	Pathogenic	criteria provided, multiple submitters, no conflicts
5025	NM_020638.3(FGF23):c.527G>A (p.Arg176Gln)	FGF23	Pathogenic	criteria provided, single submitter
5026	NM_020638.3(FGF23):c.535C>T (p.Arg179Trp)	FGF23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279873	NM_000444.6(PHEX):c.2239C>T (p.Arg747Ter)	PHEX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2681728	NM_020638.3(FGF23):c.515_529del (p.Pro172_Arg176del)	FGF23	Likely pathogenic	criteria provided, single submitter
3574584	NM_020638.3(FGF23):c.211+1G>A	FGF23	Likely pathogenic	criteria provided, single submitter
36134	NM_020638.3(FGF23):c.162G>C (p.Gln54His)	FGF23	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1427539	NM_020638.3(FGF23):c.559C>G (p.Arg187Gly)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308775	NM_020638.3(FGF23):c.*1886C>A	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308776	NM_020638.3(FGF23):c.*1803C>T	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308777	NM_020638.3(FGF23):c.*1772G>A	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308805	NM_020638.3(FGF23):c.551A>G (p.Asp184Gly)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308806	NM_020638.3(FGF23):c.515C>T (p.Pro172Leu)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308807	NM_020638.3(FGF23):c.331G>A (p.Glu111Lys)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5027	NM_020638.3(FGF23):c.211A>G (p.Ser71Gly)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880634	NM_020638.3(FGF23):c.*1398T>A	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882110	NM_020638.3(FGF23):c.*235C>T	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882162	NM_020638.3(FGF23):c.249G>A (p.Val83=)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882164	NM_020638.3(FGF23):c.138A>G (p.Thr46=)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
930793	NM_020638.3(FGF23):c.88C>T (p.Pro30Ser)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025781	NM_020638.3(FGF23):c.64C>T (p.Leu22Phe)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1049194	NM_020638.3(FGF23):c.673G>A (p.Gly225Arg)	FGF23	Uncertain significance	criteria provided, single submitter
1406065	NM_020638.3(FGF23):c.686G>A (p.Gly229Asp)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1419246	NM_020638.3(FGF23):c.559C>T (p.Arg187Trp)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1472123	NM_020638.3(FGF23):c.46G>A (p.Val16Ile)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1504076	NM_020638.3(FGF23):c.636C>A (p.Ser212Arg)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1505152	NM_020638.3(FGF23):c.313T>A (p.Ser105Thr)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1950107	NM_020638.3(FGF23):c.706G>C (p.Ala236Pro)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1986419	NM_020638.3(FGF23):c.550G>A (p.Asp184Asn)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
FGF23	Strong	Autosomal dominant	autosomal dominant hypophosphatemic rickets	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
PHEX	Orphanet:89936	X-linked hypophosphatemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGF23	HGNC:3680	ENSG00000118972	Q9GZV9	Fibroblast growth factor 23	gencc,clinvar
LRRC41	HGNC:16917	ENSG00000132128	Q15345	Leucine-rich repeat-containing protein 41	clinvar
PHEX	HGNC:8918	ENSG00000102174	P78562	Phosphate-regulating neutral endopeptidase PHEX	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.
LRRC41	Leucine-rich repeat-containing protein 41	Probable substrate recognition component of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
PHEX	Phosphate-regulating neutral endopeptidase PHEX	Peptidase that cleaves SIBLING (small integrin-binding ligand, N-linked glycoprotein)-derived ASARM peptides, thus regulating their biological activity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGF23	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
LRRC41	Other/Unknown	no		Leu_rpt_41, LRR_dom_sf
PHEX	Protease	yes	3.4.24.B15	Peptidase_M13, Peptidase_M13_N, Peptidase_M13_C

Expression context

Cohort genes with no expression data: 0.

3 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
hair follicle	1
primordial germ cell in gonad	1
sural nerve	1
adenohypophysis	1
left uterine tube	1
right uterine tube	1
oocyte	1
secondary oocyte	1
tibia	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
LRRC41	281	ubiquitous	marker	right uterine tube, left uterine tube, adenohypophysis
PHEX	139	tissue_specific	marker	secondary oocyte, tibia, oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF23	1,533
PHEX	856
LRRC41	683

Intra-cohort edges

A	B	Sources
FGF23	PHEX	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGF23	Q9GZV9	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PHEX	P78562	94.58
LRRC41	Q15345	71.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. 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
FGFR1c and Klotho ligand binding and activation	1	1427.5×	0.008	FGF23
RHOBTB3 ATPase cycle	1	571.0×	0.008	LRRC41
Signaling by activated point mutants of FGFR1	1	475.8×	0.008	FGF23
Signaling by activated point mutants of FGFR3	1	475.8×	0.008	FGF23
FGFR3c ligand binding and activation	1	439.2×	0.008	FGF23
FGFR2c ligand binding and activation	1	439.2×	0.008	FGF23
Phospholipase C-mediated cascade; FGFR3	1	439.2×	0.008	FGF23
FGFRL1 modulation of FGFR1 signaling	1	439.2×	0.008	FGF23
FGFR4 ligand binding and activation	1	407.9×	0.008	FGF23
FGFR1c ligand binding and activation	1	380.7×	0.008	FGF23
Phospholipase C-mediated cascade; FGFR4	1	380.7×	0.008	FGF23
Activated point mutants of FGFR2	1	335.9×	0.008	FGF23
Phospholipase C-mediated cascade: FGFR1	1	335.9×	0.008	FGF23
Phospholipase C-mediated cascade; FGFR2	1	317.2×	0.008	FGF23
PI-3K cascade:FGFR3	1	317.2×	0.008	FGF23
SHC-mediated cascade:FGFR3	1	300.5×	0.008	FGF23
PI-3K cascade:FGFR4	1	285.5×	0.008	FGF23
Downstream signaling of activated FGFR1	1	271.9×	0.008	FGF23
FRS-mediated FGFR3 signaling	1	271.9×	0.008	FGF23
SHC-mediated cascade:FGFR4	1	271.9×	0.008	FGF23
PI-3K cascade:FGFR1	1	259.6×	0.008	FGF23
SHC-mediated cascade:FGFR1	1	248.3×	0.008	FGF23
PI-3K cascade:FGFR2	1	248.3×	0.008	FGF23
FRS-mediated FGFR4 signaling	1	248.3×	0.008	FGF23
Signaling by FGFR3 in disease	1	248.3×	0.008	FGF23
SHC-mediated cascade:FGFR2	1	237.9×	0.008	FGF23
FRS-mediated FGFR1 signaling	1	228.4×	0.008	FGF23
FRS-mediated FGFR2 signaling	1	219.6×	0.008	FGF23
Negative regulation of FGFR3 signaling	1	219.6×	0.008	FGF23
Negative regulation of FGFR4 signaling	1	203.9×	0.008	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to sodium phosphate	2	1123.5×	2e-05	FGF23, PHEX
cellular response to vitamin D	2	1021.3×	2e-05	FGF23, PHEX
cellular response to parathyroid hormone stimulus	2	936.2×	2e-05	FGF23, PHEX
obsolete positive regulation of vitamin D 24-hydroxylase activity	1	5617.3×	0.001	FGF23
organophosphate metabolic process	1	5617.3×	0.001	PHEX
regulation of phosphate transport	1	1872.4×	0.003	FGF23
vitamin D catabolic process	1	1404.3×	0.004	FGF23
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	1	936.2×	0.004	FGF23
response to insulin-like growth factor stimulus	1	936.2×	0.004	PHEX
negative regulation of hormone secretion	1	624.1×	0.006	FGF23
intracellular phosphate ion homeostasis	1	510.7×	0.006	FGF23
cellular response to leptin stimulus	1	510.7×	0.006	FGF23
response to magnesium ion	1	468.1×	0.006	FGF23
response to growth hormone	1	374.5×	0.007	PHEX
phosphate ion homeostasis	1	351.1×	0.007	FGF23
cellular response to interleukin-6	1	330.4×	0.007	FGF23
negative regulation of bone mineralization	1	312.1×	0.007	FGF23
odontogenesis	1	175.5×	0.012	PHEX
calcium ion homeostasis	1	147.8×	0.013	FGF23
ERK1 and ERK2 cascade	1	106.0×	0.017	FGF23
negative regulation of osteoblast differentiation	1	98.5×	0.017	FGF23
fibroblast growth factor receptor signaling pathway	1	95.2×	0.017	FGF23
bone development	1	92.1×	0.017	PHEX
bone mineralization	1	90.6×	0.017	PHEX
protein modification process	1	81.4×	0.018	PHEX
neurogenesis	1	69.3×	0.020	FGF23
lung development	1	66.1×	0.021	PHEX
protein processing	1	56.7×	0.023	PHEX
regulation of cell migration	1	52.5×	0.024	FGF23
skeletal system development	1	41.9×	0.029	PHEX

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
LRRC41	0	0
PHEX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FGF23	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PHEX	3.4.24.B15

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	1	PHEX
E	Difficult family or no structure, no drug	2	FGF23, LRRC41

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)
FGF23	2	—
LRRC41	0	—
PHEX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02233322	Not specified	COMPLETED	Iron Therapy for Autosomal Dominant Hypophosphatemic Rickets: A Pilot Project.