Autosomal recessive hypophosphatemic rickets

Summary

Autosomal recessive hypophosphatemic rickets (MONDO:0017324) is a disease with 2 cohort genes and 7 clinical trials. Top therapeutic interventions include inz-701.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• Phenotypes (HPO): 37
• Clinical trials: 7

Clinical features

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0004912	Hypophosphatemic rickets	Obligate (100%)
HP:0000117	Renal phosphate wasting	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000684	Delayed eruption of teeth	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002749	Osteomalacia	Very frequent (80-99%)
HP:0002812	Coxa vara	Very frequent (80-99%)
HP:0002814	Abnormality of the lower limb	Very frequent (80-99%)
HP:0002970	Genu varum	Very frequent (80-99%)
HP:0003020	Enlargement of the wrists	Very frequent (80-99%)
HP:0003109	Hyperphosphaturia	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004576	Sclerotic vertebral endplates	Very frequent (80-99%)
HP:0005096	Distal femoral bowing	Very frequent (80-99%)
HP:0005764	Polyarticular arthritis	Very frequent (80-99%)
HP:0006463	Rickets of the lower limbs	Very frequent (80-99%)
HP:0008732	Renal hypophosphatemia	Very frequent (80-99%)
HP:0010639	Elevated alkaline phosphatase of bone origin	Very frequent (80-99%)
HP:0011001	Increased bone mineral density	Very frequent (80-99%)
HP:0011036	Abnormality of renal excretion	Very frequent (80-99%)
HP:0012052	Low serum calcitriol	Very frequent (80-99%)
HP:0100511	Abnormality of vitamin D metabolism	Very frequent (80-99%)
HP:0100559	Lower limb asymmetry	Very frequent (80-99%)
HP:0100671	Abnormal trabecular bone morphology	Very frequent (80-99%)
HP:0001363	Craniosynostosis	Frequent (30-79%)
HP:0002024	Malabsorption	Frequent (30-79%)
HP:0002982	Tibial bowing	Frequent (30-79%)
HP:0003416	Spinal canal stenosis	Frequent (30-79%)
HP:0030757	Tooth abscess	Frequent (30-79%)
HP:0100036	Pseudo-fractures	Frequent (30-79%)
HP:0100686	Enthesitis	Frequent (30-79%)
HP:0100781	Abnormality of the sacroiliac joint	Frequent (30-79%)
HP:0001250	Seizure	Excluded (0%)
HP:0001324	Muscle weakness	Excluded (0%)
HP:0003472	Hypocalcemic tetany	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive hypophosphatemic rickets
Mondo ID	MONDO:0017324
Orphanet	289176
DOID	DOID:0050949
SNOMED CT	90505000
UMLS	C0342643
MedGen	137975
GARD	0017320
Is cancer (heuristic)	no

Also known as: ARHR · autosomal recessive hereditary hypophosphatemic rickets · hereditary hypophosphatemic rickets, autosomal recessive · hypophosphatemic rickets, autosomal recessive

Data availability: 2 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 › hereditary hypophosphatemic rickets › autosomal recessive hypophosphatemic rickets

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

Subtypes (2): hypophosphatemic rickets, autosomal recessive, 1, hypophosphatemic rickets, autosomal recessive, 2

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · 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
DMP1	Definitive	Autosomal recessive	hypophosphatemic rickets, autosomal recessive, 1	5
ENPP1	Strong	Autosomal recessive	hypophosphatemic rickets, autosomal recessive, 2	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DMP1	Orphanet:289176	Autosomal recessive hypophosphatemic rickets
ENPP1	Orphanet:289176	Autosomal recessive hypophosphatemic rickets
ENPP1	Orphanet:324561	Hypopigmentation-punctate palmoplantar keratoderma syndrome
ENPP1	Orphanet:51608	Generalized arterial calcification of infancy
ENPP1	Orphanet:758	Pseudoxanthoma elasticum

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DMP1	HGNC:2932	ENSG00000152592	Q13316	Dentin matrix acidic phosphoprotein 1	gencc
ENPP1	HGNC:3356	ENSG00000197594	P22413	Ectonucleotide pyrophosphatase/phosphodiesterase family member 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DMP1	Dentin matrix acidic phosphoprotein 1	May have a dual function during osteoblast differentiation.
ENPP1	Ectonucleotide pyrophosphatase/phosphodiesterase family member 1	Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Phosphatase	1	42.0×	0.047
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DMP1	Other/Unknown	no		DMP1
ENPP1	Phosphatase	yes	3.6.1.9	Somatomedin_B_dom, Endo_G_ENPP1-like_dom, Phosphodiest/P_Trfase

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibia	2
male germ line stem cell (sensu Vertebrata) in testis	1
periodontal ligament	1
cartilage tissue	1
decidua	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DMP1	40	tissue_specific	marker	periodontal ligament, tibia, male germ line stem cell (sensu Vertebrata) in testis
ENPP1	227	ubiquitous	marker	tibia, decidua, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ENPP1	1,911
DMP1	850

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ENPP1	P22413	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DMP1	Q13316	47.80

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 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
Vitamin B2 (riboflavin) metabolism	1	815.7×	0.006	ENPP1
Vitamin B5 (pantothenate) metabolism	1	380.7×	0.007	ENPP1
ECM proteoglycans	1	75.1×	0.022	DMP1
Post-translational protein phosphorylation	1	50.1×	0.023	DMP1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.023	DMP1

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
obsolete negative regulation of hh target transcription factor activity	1	8426.0×	0.003	ENPP1
inorganic diphosphate transport	1	4213.0×	0.003	ENPP1
regulation of enamel mineralization	1	2808.7×	0.003	DMP1
nucleoside triphosphate catabolic process	1	1685.2×	0.004	ENPP1
nucleic acid metabolic process	1	1404.3×	0.004	ENPP1
negative regulation of glycogen biosynthetic process	1	1053.2×	0.004	ENPP1
intracellular phosphate ion homeostasis	1	766.0×	0.005	ENPP1
negative regulation of D-glucose import across plasma membrane	1	601.9×	0.005	ENPP1
3’-phosphoadenosine 5’-phosphosulfate metabolic process	1	561.7×	0.005	ENPP1
phosphate ion homeostasis	1	526.6×	0.005	ENPP1
phosphate-containing compound metabolic process	1	495.6×	0.005	ENPP1
response to ATP	1	495.6×	0.005	ENPP1
negative regulation of bone mineralization	1	468.1×	0.005	ENPP1
melanocyte differentiation	1	401.2×	0.005	ENPP1
regulation of bone mineralization	1	366.4×	0.005	ENPP1
biomineral tissue development	1	324.1×	0.005	DMP1
positive regulation of cell-substrate adhesion	1	247.8×	0.007	DMP1
ATP metabolic process	1	234.1×	0.007	ENPP1
negative regulation of insulin receptor signaling pathway	1	187.2×	0.008	ENPP1
generation of precursor metabolites and energy	1	172.0×	0.008	ENPP1
negative regulation of fat cell differentiation	1	156.0×	0.009	ENPP1
bone mineralization	1	135.9×	0.009	ENPP1
ossification	1	113.9×	0.011	DMP1
cellular response to insulin stimulus	1	85.1×	0.014	ENPP1
negative regulation of cell growth	1	72.0×	0.015	ENPP1
extracellular matrix organization	1	61.1×	0.018	DMP1
gene expression	1	39.9×	0.026	ENPP1
immune response	1	23.5×	0.042	ENPP1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ENPP1	1	3
DMP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN	3	ENPP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ENPP1	167	Binding:154, ADMET:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ENPP1	3.6.1.9	nucleotide diphosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ENPP1	167

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
SURAMIN	3	ENPP1

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	1	ENPP1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DMP1

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)
DMP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
Not specified	2
PHASE1/PHASE2	1
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06046820	PHASE3	ACTIVE_NOT_RECRUITING	The ENERGY 3 Study: Evaluation of Efficacy and Safety of INZ-701 in Children With ENPP1 Deficiency
NCT07473973	PHASE3	RECRUITING	ENERGY 2: Evaluation of the Efficacy and Safety of INZ-701 in Infants With ENPP1 Deficiency
NCT04686175	PHASE1/PHASE2	COMPLETED	Evaluation of Safety, Tolerability, and Efficacy of INZ-701 in Adults With ENPP1 Deficiency
NCT06739980	PHASE2	WITHDRAWN	The ENABLE Study: Safety and Efficacy Study of INZ-701 in Patients With ENPP1 Deficiency
NCT05734196	PHASE1	RECRUITING	The ENERGY Study: Evaluation of Safety and Tolerability of INZ-701 in Infants With ENPP1 Deficiency or ABCC6 Deficiency
NCT03758534	Not specified	UNKNOWN	Natural History of GACI With or Without ARHR2 or PXE
NCT05050669	Not specified	COMPLETED	Natural History Study of ENPP1 Deficiency and the Early-onset Form of ABCC6 Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
INZ-701	3	5