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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic DMP1 variants cause ARHR1, usually homozygous in reported families, with compound heterozygosity also established. Carrier parents may be clinically and biochemically normal; mild phosphate, density or histomorphometric abnormalities have been documented in selected families. These carrier observations do not quantify biallelic penetrance or establish dominant disease.

Autosomal recessive inheritance Penetrance: UNKNOWN Expressivity: VARIABLE

Show evidence (5 references)

PMID:17033625 SUPPORT PRIMARY RESULT Human Clinical

"Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes."

The discovery study mapped the disorder as autosomal recessive and found homozygous DMP1 mutations in the affected individuals.

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"The parents and available unaffected siblings were heterozygous for c.485Tdel."

Heterozygous parents and siblings were unaffected, the segregation pattern of a recessive trait.

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"the parents of the three affected children are first-degree cousins"

Consanguinity was documented in these three affected children; the report does not estimate its frequency across all ARHR1.

+ 2 more references

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Discussions and Knowledge Gaps

4

By what molecular route does loss of an extracellular matrix phosphoprotein in the osteocyte de-repress Fgf23 transcription, and is the FGFR-dependent mechanism shown in mouse bone cells the one operating in human ARHR1?

KNOWLEDGE GAP OPEN arhr1_dmp1_to_fgf23_coupling

Attached to

pathophysiology#Biallelic DMP1 Loss of Function pathophysiology#Increased Bone FGFR Signaling pathophysiology#Increased Osteocytic FGF23 Production

Mouse bone shows increased FGFR1/FRS2/PI3K phosphorylation, and an FGFR inhibitor suppresses Fgf23 induction in mutant marrow stromal cultures. These results implicate FGFR signaling but do not identify how extracellular DMP1 loss activates it, exclude other FGFRs or demonstrate the mechanism in human osteocytes. Non-additivity with Phex loss supports pathway convergence without proving a direct DMP1-PHEX interaction. Matrix/integrin signaling, phosphate sensing and maturation state remain candidate intermediates.

Proposed experiments

FGFR dependence of FGF23 induction in human DMP1-deficient osteocytes

arhr1_human_osteocyte_fgfr_dependence

Differentiate osteocytes from patient-derived or DMP1-edited human iPSCs and test whether FGF23 induction is abolished by FGFR1 inhibition, and whether it is restored by exogenous 57-kDa C-terminal DMP1 added to the matrix, to establish that the mouse pathway operates in human cells and that the extracellular fragment is sufficient.

Show evidence (2 references)

PMID:21507898 SUPPORT PRIMARY RESULT Model Organism

"The mechanisms whereby PHEX and DMP1 regulate Fgf23 expression are unknown."

The gap stated in the paper that came closest to closing it.

PMID:17033625 SUPPORT PRIMARY RESULT Human Clinical

"suggesting that DMP1 may regulate FGF23 expression"

The hypothesis as first stated; it has been confirmed as a relationship but not explained as a mechanism.

In the Dmp1-null mouse, removing osteocytic Fgf23 normalizes serum phosphate but leaves part of the bone phenotype uncorrected; does the same residual, DMP1-intrinsic mineralization defect limit what burosumab can achieve in patients with ARHR1?

KNOWLEDGE GAP OPEN arhr1_fgf23_blockade_versus_matrix_defect

Attached to

pathophysiology#Skeletal Mineralization Failure treatments#Burosumab

Partial human clinical benefit is compatible with partial rescue in mouse models. The 2023 lineage-specific deletion leaves residual circulating FGF23 excess, so persistent bone defects cannot all be assigned to DMP1-independent-of-FGF23 effects from that experiment alone. Its cultured-cell results distinguish FGF23-sensitive differentiation from persistent matrix mineralization failure. Earlier newborn calvarial cultures mineralized with sufficient phosphate, indicating that age, cell source and culture conditions matter. The two-brother human report documents clinical and radiographic improvement but not paired bone histomorphometry. The later adult report is available here only as an abstract. Whether clinically important residual matrix defects persist after adequate FGF23 blockade remains unresolved.

Proposed experiments

Paired bone histomorphometry before and after burosumab in ARHR1

arhr1_burosumab_histomorphometry

Where clinically justified and consented, compare paired bone histomorphometry and imaging before and after specialist-directed burosumab, with phosphate, PTH, drug exposure, genotype, age and prior therapy documented. Residual osteoid would establish incomplete response, but would not by itself prove a solely DMP1-intrinsic cause. Complement clinical observations with matched patient-derived matrix and differentiation assays.

Show evidence (3 references)

PMID:37943605 SUPPORT PRIMARY RESULT Model Organism

"Our data suggest that combined DMP1 repletion and FGF23 blockade could effectively correct ARHR-associated mineral and bone disorders."

The authors' inference that FGF23 blockade alone will be incomplete in ARHR1.

PMID:35896139 SUPPORT PRIMARY RESULT Human Clinical

"The present report highlights the beneficial biochemical and clinical outcomes associated with the use of burosumab in patients with ARHR1."

Human clinical benefit is compatible with incomplete skeletal correction; this is not a demonstrated human-model contradiction.

PMID:21542006 SUPPORT PRIMARY RESULT In Vitro

"This defect in osteoblast differentiation apparently is caused by hypophosphatemia because the isolated calvarial osteoblasts mineralize normally ex vivo if sufficient phosphate is provided (Fig. 3D)."

Earlier neonatal calvarial cultures differ from the 2023 marrow stromal cultures; this is the authors' interpretation of their experiment, not a universal conclusion.

Why do adults with a mineralization-failure disease develop cranial hyperostosis, a high axial bone density and ossifying enthesopathy severe enough to immobilize the spine, and are these one process or several?

KNOWLEDGE GAP OPEN arhr1_hyperostosis_osteosclerosis_mechanism

Attached to

phenotypes#Increased Axial Bone Density phenotypes#Generalized Osteosclerosis phenotypes#Cranial Hyperostosis phenotypes#Enthesopathy phenotypes#Paraspinal Ligament Ossification

Increased axial areal density can coexist with poor peripheral microstructure and mineralization defects. Cortical thickening and extraosseous calcification can complicate DXA interpretation; unmineralized osteoid itself is not a demonstrated cause of increased measured mineral density. One untreated Finnish adult also developed extensive ossification, so conventional therapy is not a sufficient explanation. Reduced osteoclast support and age-dependent bony protuberances in mice suggest candidate remodeling mechanisms, but their relationship to human enthesopathy is unresolved. The Indian family carried an SPP1 variant of uncertain significance; no modifier effect was established. Clinical improvement with burosumab does not establish prevention or reversal of ectopic ossification.

Proposed experiments

Volumetric density, microstructure and histology of sclerotic ARHR1 bone

arhr1_bone_quality_hrpqct_histology

Compare volumetric density, peripheral microstructure and, when available, undecalcified histomorphometry with osteoclast counts in adults with radiographic sclerosis. Distinguish mineralized bone quantity from excess osteoid and adjacent ligament ossification; assess longitudinal relationships to age, genotype, treatment and FGF23 rather than inferring strength from DXA alone.

Show evidence (3 references)

PMID:25180662 SUPPORT PRIMARY RESULT Human Clinical

"Our cases show that some ARHR cases may develop with age an unaccountable increase in bone density and bone overgrowth."

The gap as stated by the reporters.

PMID:32920683 SUPPORT PRIMARY RESULT Human Clinical

"High aBMD and local osteosclerosis in axial bone with low vBMD and damaged microstructure in peripheral bone were featured."

The axial-peripheral discordance that makes the sclerosis hard to interpret.

PMID:21542006 SUPPORT PRIMARY RESULT Model Organism

"We showed (1) that abnormal bone remodeling in Dmp1 null mice is due to reduced osteoclast number, which is secondary to a reduced ratio of RANKL/OPG expressed by osteoclast supporting cells"

A candidate mechanism, reduced resorption, from the model.

Is the DMP1 heterozygous carrier state a subclinical bone disorder that warrants surveillance, and does it explain the carriers with mild hypophosphatemia?

KNOWLEDGE GAP OPEN arhr1_carrier_phenotype

Attached to

genetic#Biallelic DMP1 Pathogenic Variants

Selected families show mild carrier biochemical or histomorphometric abnormalities, whereas other carrier relatives are clinically and biochemically normal. The 2026 report describes normal biochemistry with differing bone density between families and one carrier biopsy showing a mild mineralization defect. These observations warrant study of an unselected carrier cohort; they do not estimate penetrance, change biallelic ARHR1 to dominant inheritance or establish routine bone-density screening for all carriers. In heterozygous mice, normal phosphate and mineral-to-matrix ratio coexist with altered mineral crystallinity and reduced serum calcium; they are not normal in every measured bone endpoint.

Show evidence (4 references)

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia."

The first report of a carrier phenotype.

PMID:41820620 SUPPORT PRIMARY RESULT Human Clinical

"These data expand the description of the clinical phenotype in fully affected individuals with ARHR1 and provide further evidence of a subclinical phenotype in the ARHR1 carrier state."

Independent confirmation of a subclinical carrier phenotype.

PMID:16294270 SUPPORT PRIMARY RESULT Model Organism

"Dmp1 KO mice had significantly lower ionic calcium and phosphate concentrations relative to WT, whereas in the HET, values for phosphate were equivalent, and calcium values were decreased relative to WT values."

Heterozygous mice keep normal phosphate, so the human carrier hypophosphatemia is not reproduced by the model.

+ 1 more reference

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Pathophysiology

13

Biallelic DMP1 Loss of Function

Homozygous or compound heterozygous DMP1 variants impair a SIBLING-family matrix protein expressed by mineralizing cells. Nonsense, frameshift, splice-site, start-codon and deletion alleles are reported. The c.1A>G construct is retained intracellularly, whereas a C-terminal frameshift product is secreted with altered processing. The distinct c.1A>T start-loss construct produces a shorter, secreted protein initiated at a downstream start site, with reduced abundance and absent detectable C-terminal cleavage fragment. These allele-specific results support loss of normal function without assuming universal protein absence or identical trafficking defects. A large deletion can involve adjacent SIBLING genes; its full phenotypic contribution cannot be inferred from DMP1 alone.

osteocyte CL:0000137 osteoblast CL:0000062 odontoblast CL:0000060

DMP1 hgnc:2932

Genetic context DMP1 hgnc:2932 variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic germline loss of function; homozygous in most families, compound heterozygous in one reported patient.

Downstream

Defective Osteocyte Maturation DMP1 loss impairs osteoblast-to-osteocyte maturation and the organization of the lacunocanalicular network.

DMP1-Dependent Matrix Mineralization Defect Loss of functional extracellular DMP1 impairs matrix mineralization independently of phosphate substrate and excess FGF23 in culture.

Increased Bone FGFR Signaling DMP1 deficiency is associated with increased FGFR pathway activation in bone; upstream intermediates are unknown.

Show evidence (7 references)

PMID:17033621 SUPPORT PRIMARY RESULT Human Clinical

"Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus."

One of the two simultaneous discovery reports; identifies the start-codon and C-terminal deletion alleles.

PMID:17033625 SUPPORT PRIMARY RESULT Human Clinical

"identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes"

The companion discovery report; establishes the gene and its expression in the mineralizing lineage.

PMID:19007919 SUPPORT PRIMARY RESULT In Vitro

"These analyses showed that the M1V DMP1 mutant was not sorted to the trans-Golgi network (TGN) and secretory pathway, but filled the entire cytoplasm."

Direct cellular demonstration that the start-codon allele is a loss of the secreted protein.

+ 4 more references

Defective Osteocyte Maturation

Dmp1-null osteocytes retain osteoblast and early osteocyte markers and have enlarged, disorganized lacunae and abnormal canaliculi. These observations support impaired osteoblast-to-osteocyte maturation. The separate contribution of matrix mineralization and FGF23 signaling to that maturation defect is incompletely resolved; carrier biopsy observations do not establish a uniform haploinsufficiency phenotype.

osteocyte CL:0000137

osteoblast to osteocyte differentiation GO:0001649 ↓ DECREASED

Animal models

Dmp1-null mouse Mouse recapitulates The osteocyte maturation arrest and lacunocanalicular defect were defined in this model and are DMP1-dependent, since bone-cell DMP1 expression rescues them.

Show evidence (2 references)

PMID:17033621 SUPPORT PRIMARY RESULT Model Organism

"Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization."

Establishes defective osteocyte maturation as the primary cellular lesion in the null mouse.

PMID:20734454 SUPPORT PRIMARY RESULT Model Organism

"This included rescue of growth plate defects, osteomalacia, abnormal osteocyte maturation, and the abnormal osteocyte lacunocanalicular system."

Names the abnormal osteocyte maturation and lacunocanalicular system as DMP1-dependent, since restoring DMP1 in bone cells corrects them.

DMP1-Dependent Matrix Mineralization Defect

DMP1-deficient osteoblast cultures mineralize poorly despite adequate phosphate substrate and correction of excess FGF23 by lineage-specific deletion. Exogenous DMP1 supplied in coculture restores mineralization. This supports an extracellular DMP1-dependent defect; it should not be described as strictly cell-autonomous or inferred solely from incomplete whole-animal rescue.

bone mineralization GO:0030282 ↓ DECREASED

Animal models

Dmp1-null mouse Mouse recapitulates Dmp1-null tibias have reduced mineral-to-matrix ratio at 4 and 16 weeks by FTIR imaging.

Downstream

Skeletal Mineralization Failure The local DMP1-dependent defect contributes to failure to mineralize bone matrix.

Show evidence (1 reference)

PMID:37943605 SUPPORT PRIMARY RESULT In Vitro

"In the present study, although genetic deletion of Fgf23 restored osteoblast differentiation, it did not correct the impaired mineralization observed in Dmp1-null osteoblast cultures, suggesting that DMP1 deficiency directly contributes to the mineralization defect despite adequate Pi supply and..."

Mineralization remained impaired after differentiation and FGF23 production were corrected in cultured cells.

Increased Bone FGFR Signaling

Dmp1-null and Phex-deficient mouse cortical bone show increased phosphorylation of FGFR1, FRS2 and PI3K. A common pathway is supported by nonadditive double-mutant phenotypes and inhibition experiments in marrow stromal cultures. The molecular steps connecting DMP1 loss to receptor activation, and the relative contributions of FGFR1 versus other receptors, remain unresolved.

fibroblast growth factor receptor signaling pathway GO:0008543 ↑ INCREASED

Downstream

Increased Osteocytic FGF23 Production FGFR inhibition lowers the abnormal Fgf23 promoter activity and endogenous mRNA in mutant stromal-cell cultures.

Show evidence (1 reference)

PMID:21507898 SUPPORT PRIMARY RESULT Model Organism

"we confirmed by Western blot analysis that FGFR1 pathway was activated in Hyp and Dmp1−/− (Fig. 5) by showing increased phosphorylation of FGFR1, FRS2, and PI3K in these bones."

Protein phosphorylation was measured in mutant mouse bone; this is distinct from the cultured-cell SU5402 intervention.

Increased Osteocytic FGF23 Production

Bone Fgf23 transcription and circulating hormone are increased in Dmp1-null models. SU5402 suppresses the high Fgf23 expression in Dmp1-null marrow stromal cultures, supporting FGFR-dependent production. Fold changes vary by assay, tissue and culture condition. Human biopsies show increased bone FGF23 staining in affected individuals and in a carrier from one family. Mouse studies also support altered phosphate responsiveness and reduced cleavage of FGF23; these are not equivalent to a demonstrated human cleavage defect.

osteocyte CL:0000137

FGF23 hgnc:3680

Animal models

Dmp1-null mouse Mouse recapitulates Osteocytic Fgf23 induction, its FGFR dependence and its non-additivity with Phex loss were all established in this model.

Downstream

Elevated Circulating Intact FGF23 Increased bone production contributes to raised circulating intact hormone; altered processing can also affect circulating concentrations.

FGF23-Induced Impairment of Osteoprogenitor Differentiation Excess FGF23 can directly suppress osteoblast-lineage differentiation in culture independently of systemic hypophosphatemia.

Show evidence (4 references)

PMID:21507898 SUPPORT PRIMARY RESULT In Vitro

"Furthermore, inhibiting FGFR signaling using SU5402 in Hyp- and Dmp1(-/-)-derived bone marrow stromal cells prevented the increase in Fgf23 mRNA expression (129- and 124-fold increase in Hyp and Dmp1(-/-) vs. 1.3-fold in Hyp+SU5402 and 2.5-fold in Dmp1(-/-)+SU5402, P<0.05)."

SU5402 blocked induction of Fgf23 in mouse-derived marrow stromal cells cultured under osteoblast differentiation conditions, not in a treated whole animal.

PMID:28005411 SUPPORT PRIMARY RESULT Model Organism

"In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD)."

Increased bone Fgf23 expression with intact, uncleaved hormone in the null mouse.

PMID:28005411 SUPPORT PRIMARY RESULT Model Organism

"These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression."

The set-point shift explains why phosphate loading drives FGF23 higher rather than correcting the disease.

+ 1 more reference

FGF23-Induced Impairment of Osteoprogenitor Differentiation

In Dmp1-null marrow-derived cultures, Fgf23 deletion improves osteoblast differentiation despite persistent DMP1-dependent mineralization failure. Recombinant FGF23 suppresses osteoblast differentiation markers in MC3T3-E1 cells, and FGF23-rich coculture reduces alkaline phosphatase activity. Transcriptomic pathways and inferred differentiation trajectories support candidate mechanisms but are not direct biochemical measurements or lineage tracing. A corresponding direct effect has not been established in treated human bone.

osteoblast differentiation GO:0001649 ↓ DECREASED

Show evidence (1 reference)

PMID:37943605 SUPPORT PRIMARY RESULT In Vitro

"In vitro, we show that FGF23 directly impaired osteoprogenitors' differentiation and that DMP1 deficiency contributed to impaired mineralization independent of FGF23 or Pi levels."

Controlled cell experiments separate FGF23-dependent differentiation from the DMP1-dependent mineralization defect.

Elevated Circulating Intact FGF23

Intact FGF23 may be elevated or inappropriately normal for the degree of hypophosphatemia. Assay type matters: C-terminal assays also measure fragments and must not be described as intact-only measurements. Treatment and sampling conditions affect interpretation. Nonadditive Phex/Dmp1 mouse phenotypes support overlapping regulation, without proving every function is shared.

phosphate ion homeostasis GO:0055062 ⚠ ABNORMAL

Downstream

Reduced Proximal Tubular Phosphate Reabsorption FGF23 acting through FGFR1c and alpha-Klotho in the proximal tubule removes the NaPi-IIa and NaPi-IIc cotransporters from the apical membrane.

Suppressed Renal Calcitriol Synthesis FGF23 suppresses CYP27B1 and induces CYP24A1 in the proximal tubule.

Elevated Circulating FGF23 The measured elevation is the biochemical phenotype of excess circulating intact hormone; other patients have inappropriately normal values.

Show evidence (2 references)

PMID:17033625 SUPPORT PRIMARY RESULT Human Clinical

"Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression."

First human measurement of elevated intact FGF23 in the disorder, with the interpretation that it drives the phosphaturia.

PMID:21507898 SUPPORT PRIMARY RESULT Model Organism

"Compared to single-mutant littermates, compound-mutant Hyp/Dmp1(-/-) mice displayed nonadditive elevations of serum FGF23 (1912 ± 183, 1715 ± 178, and 1799 ± 181 pg/ml), hypophosphatemia (P(i): 6.0 ± 0.3, 5.8 ± 0.2, and 5.4 ± 0.1 mg/dl), and severity of rickets/osteomalacia (bone mineral..."

Serum FGF23 elevation in the Dmp1-null mouse, non-additive with Phex loss.

Reduced Proximal Tubular Phosphate Reabsorption

FGF23 reduces proximal tubular sodium-phosphate transport, causing inappropriate renal phosphate loss. Normocalciuria and normal calcium/PTH occur in discovery families, but are not obligatory; secondary hyperparathyroidism can further promote phosphate wasting. This is generally an isolated phosphate-handling defect rather than generalized Fanconi syndrome.

proximal tubule epithelial cell CL:0002306

tubular phosphate reabsorption GO:0097291 ↓ DECREASED

renal proximal tubule UBERON:0004134

Downstream

Chronic Hypophosphatemia Renal phosphate loss lowers serum phosphate relative to age-specific reference ranges; treatment may correct the measured concentration.

Show evidence (3 references)

PMID:17033621 SUPPORT PRIMARY RESULT Human Clinical

"Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria."

Isolated renal phosphate wasting with normocalciuria in patients, the defining renal finding.

PMID:20213538 SUPPORT PRIMARY RESULT Human Clinical

"Serum calcium, parathyroid hormone, and urinary calcium excretion were within the normal range, leading to clinical diagnosis of ARHR."

Normal calcium, PTH and calciuria alongside renal phosphate loss, distinguishing this arm from calciopenic and tubulopathic causes.

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"showed hypophosphatemia due to insufficient renal phosphate retention"

Renal phosphate wasting documented at presentation in a child.

Suppressed Renal Calcitriol Synthesis

FGF23 restrains renal calcitriol production and promotes its catabolism, often leaving calcitriol inappropriately normal or low for hypophosphatemia. This is a regulatory effect, not an obligatory low serum value: PTH, age and treatment modify net concentrations. The 12-week Dmp1-null model had increased Cyp27b1 and approximately threefold higher calcitriol, with persistent hyperparathyroidism; a human compound-heterozygote also had elevated measured calcitriol.

renal 1,25-dihydroxyvitamin D synthesis GO:0042359 ↓ DECREASED

Downstream

Skeletal Mineralization Failure Blunted calcitriol removes the intestinal compensation that would otherwise partly offset renal phosphate loss, deepening the substrate deficit at the mineralization front.

Show evidence (3 references)

PMID:17033625 SUPPORT PRIMARY RESULT Human Clinical

"providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels"

Inappropriately normal calcitriol for the degree of hypophosphatemia in the discovery families, attributed to FGF23.

PMID:20213538 SUPPORT PRIMARY RESULT Human Clinical

"Biochemical examination revealed hypophosphatemia with renal phosphate excretion and low levels of 1,25(OH)(2)D."

Frankly low calcitriol in the Japanese siblings.

PMID:37943605 REFUTE PRIMARY RESULT Model Organism

"At 12 weeks, Dmp1KO mice also displayed hyperparathyroidism and a surprising 3-fold increase in 1,25(OH)2D levels"

Adult mouse findings limit any claim that calcitriol must be low across all models or contexts.

Chronic Hypophosphatemia

Inappropriately high renal phosphate loss creates a systemic substrate deficit for mineralization. Serum phosphate must be interpreted using age-specific ranges and treatment timing. High-phosphate diet from 6 to 12 weeks worsened FGF23 excess, hyperparathyroidism and osteomalacia in adult Dmp1-null mice, whereas earlier dietary rescue improved some skeletal endpoints. These stage-dependent experiments do not replace clinical evidence for combined phosphate and active-vitamin-D treatment.

Animal models

Dmp1-null mouse Mouse recapitulates Hypophosphatemia with a lowered set point that is maintained through Fgf23 expression and cleavage; raising phosphate provokes more FGF23.

Downstream

Skeletal Mineralization Failure Low extracellular phosphate lowers the calcium-phosphate product at the mineralization front.

Growth Plate Hypertrophic Zone Expansion Phosphate is required for apoptosis of terminal hypertrophic chondrocytes; the module carries this direct arm separately from matrix mineralization.

Hypophosphatemia The systemic state is expressed clinically as the laboratory phenotype hypophosphatemia.

Dentin Hypomineralization Chronic hypophosphatemia contributes to dentin hypomineralization, as in XLH; the relative weight of systemic phosphate and local DMP1 loss in the odontoblast is not resolved.

Show evidence (3 references)

PMID:20213538 SUPPORT BACKGROUND Other

"characterized by hypophosphatemia resulting from renal phosphate wasting"

Defines the systemic state this node represents.

PMID:37943605 SUPPORT PRIMARY RESULT Model Organism

"At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia."

The null mouse reproduces the hypophosphatemia; note that adult mice, unlike most patients, also show raised parathyroid hormone.

PMID:37943605 SUPPORT PRIMARY RESULT Model Organism

"Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion, and osteomalacia."

Phosphate loading alone worsens the disease in the model, consistent with the shifted set point.

Skeletal Mineralization Failure

Insufficient phosphate availability and a DMP1-dependent matrix defect impair mineral deposition into osteoid. Osteomalacia can occur in children and adults; rickets is the growth-plate lesion of the growing skeleton. Persistent bone abnormalities after partial FGF23 reduction cannot be assigned exclusively to DMP1 because FGF23 remains elevated; controlled cultures more directly demonstrate the local mineralization contribution.

osteoblast CL:0000062 osteocyte CL:0000137

bone mineralization GO:0030282 ↓ DECREASED

bone UBERON:0001474

Animal models

Dmp1-null mouse Mouse recapitulates Osteomalacia and excess osteoid are partly corrected by osteocytic Fgf23 deletion even when phosphate normalizes. Residual FGF23 and PTH elevation limit causal attribution solely to a local matrix defect.

Downstream

Growth Plate Hypertrophic Zone Expansion In the growing skeleton the mineralization defect is expressed at the growth plate.

Osteomalacia Failure to mineralize osteoid produces osteomalacia at any age.

Pathologic Fractures Poorly mineralized bone is susceptible to pathologic fractures.

Bone Pain Active osteomalacia is a pain generator; enthesopathy and deformity add others.

Pseudofractures Osteomalacic bone develops pseudofractures; healing after anti-FGF23 treatment supports a mineralization-related contribution.

Show evidence (3 references)

PMID:17033621 SUPPORT PRIMARY RESULT Human Clinical

"Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria."

Rickets and osteomalacia, the two expressions of mineralization failure, in patients and mice.

PMID:37943605 SUPPORT PRIMARY RESULT Model Organism

"In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice."

The two-route structure of this node, endocrine and local, is the paper's stated conclusion.

PMID:16294270 SUPPORT PRIMARY RESULT Model Organism

"Histological analysis and muCT 3-D images suggested that dmp1 KO mice had osteomalacia."

Histological osteomalacia in the null mouse.

Growth Plate Hypertrophic Zone Expansion

In the growing skeleton the hypertrophic chondrocyte layer fails to involute, giving the expanded, disorganized growth plate with poorly calcified cartilage and delayed vascular invasion seen in Dmp1-null mice, and the widened, cupped metaphyses of rickets on radiographs. Reinstating DMP1 or its 57-kDa fragment in bone cells rescues the growth plate defect in the model.

hypertrophic chondrocyte CL:0000743

growth plate cartilage development GO:0003417 ⚠ ABNORMAL

growth plate UBERON:0002516

Animal models

Dmp1-null mouse Mouse recapitulates Expanded, disorganized growth plates with rickets, rescued by bone-cell expression of DMP1 or its 57-kDa fragment, and shown to be phosphate-dependent in metatarsal organ culture.

Downstream

Rickets The growth plate lesion is rickets.

Short Stature Persistent growth plate disease shortens the limbs disproportionately.

Lower-Limb Bowing Weight bearing on undermineralized growing bone bows the legs.

Show evidence (2 references)

PMID:20734454 SUPPORT PRIMARY RESULT Model Organism

"This included rescue of growth plate defects, osteomalacia, abnormal osteocyte maturation, and the abnormal osteocyte lacunocanalicular system."

The growth plate defect of the null mouse is DMP1-dependent, since bone-cell DMP1 expression rescues it.

PMID:37943605 SUPPORT PRIMARY RESULT Model Organism

"At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia."

Rickets and impaired growth in the model, the tissue expression of this node.

Dentin Hypomineralization

Affected children in one family had thin dentin and enlarged pulp chambers, with post-eruption attrition and trauma-associated tooth injury. Both systemic phosphate deficit and local DMP1 loss may contribute; the relative mechanisms remain uncertain. Recurrent abscesses and tooth loss are documented, while a later single adult jaw-necrosis report does not establish the same causal pathway.

odontoblast CL:0000060

dentin mineralization GO:0097188 ↓ DECREASED

tooth UBERON:0001091

Downstream

Dental Abscesses Abnormal dental structure plausibly predisposes to injury and infection; the case reports do not isolate its contribution from trauma and other factors.

Premature Loss of Primary Teeth Abnormal dentin structure contributes to the dental phenotype; the relative contributions of systemic phosphate and local DMP1 function remain uncertain.

Enlarged Dental Pulp Chambers Abnormal dentin structure contributes to the dental phenotype; the relative contributions of systemic phosphate and local DMP1 function remain uncertain.

Show evidence (2 references)

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent and deciduous teeth displayed enlarged pulp chambers."

The characteristic dental finding in three affected children.

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"Furthermore, DMP-1 mutations appear to contribute, through yet unknown mechanisms, to tooth development."

The authors attribute the dental phenotype to DMP1 loss while leaving the mechanism open.

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Pathograph

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Phenotypes

22

Ear 1

Hearing Impairment HP:0000365

Show evidence (2 references)

PMID:41820620 SUPPORT BACKGROUND Other

"A variable clinical spectrum has been described in this condition, including features of rickets (in children), hyperostotic osteomalacia (in children and adults), bone pain, short stature, lower limb deformities, recurrent dental abscesses, and hearing defects."

Hearing defects listed in the described spectrum; no frequency is assigned.

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"She has a hearing deficit."

Direct observation in the Finnish affected woman; no hearing-loss subtype is specified.

Endocrine 1

Elevated Circulating FGF23 Elevated circulating fibroblast growth factor 23 concentration HP:6000407

Show evidence (2 references)

PMID:17033625 SUPPORT PRIMARY RESULT Human Clinical

"Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals"

Intact FGF23 was elevated in two of four individuals at discovery; other values were inappropriately normal for the hypophosphatemia.

PMID:32920683 SUPPORT PRIMARY RESULT Human Clinical

"Hypophosphatemia, elevated alkaline phosphatase, high intact fibroblast growth factor 23 and sclerostin were found."

High intact FGF23 in the Chinese series.

Head and Neck 4

Cranial Hyperostosis HP:0004437

Show evidence (2 references)

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments."

Significant cranial hyperostosis in both adult siblings.

PMID:25180662 SUPPORT PRIMARY RESULT Human Clinical

"Patients aged 45 and 47years old presented with short stature, severe genu varum, cranial hyperostosis and a very high bone density that led to a diagnosis of a familial sclerosing bone dysplasia."

Cranial hyperostosis was reported in a second, unrelated adult sibship.

Dental Abscesses Tooth abscess HP:0030757

Show evidence (2 references)

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"The patient had significant dental problems, with recurrent gingival abscess formation, and required a dental prosthesis since age 50."

Recurrent abscesses were documented in the affected Finnish woman.

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"However, after another minor trauma, his lower central incisor fractured, leading to recurrent dental abscesses."

The Turkish index case developed recurrent abscesses after incisor fracture.

Premature Loss of Primary Teeth HP:0006323

Show evidence (2 references)

PMID:36334264 SUPPORT PRIMARY RESULT Human Clinical

"The proband is a 4-year-old boy, who developed genu varum when he was able to walk at age 1 year and tooth loss after a mild hit at age 3.5 years."

Early childhood tooth loss in the compound-heterozygote.

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"Review of the dental history of the index case (#5) revealed that the loss of deciduous central incisors had occurred at the age of 4.5 years after moderate trauma to the chin."

Explicit primary-tooth loss in the Turkish index case.

Enlarged Dental Pulp Chambers Abnormal dental pulp morphology HP:0006479

Show evidence (1 reference)

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent and deciduous teeth displayed enlarged pulp chambers."

Radiographic pulp chamber enlargement in the family.

Limbs 1

Lower-Limb Bowing Bowing of the legs HP:0002979

Show evidence (2 references)

PMID:35896139 SUPPORT BACKGROUND Other

"Short stature, prominent bowing of the legs, fractures/pseudofractures, and severe enthesopathy are prominent in this patient population."

Bowing described as prominent across the patient population.

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood."

Varus deformity from early childhood in both siblings.

Metabolism 2

Hypophosphatemia HP:0002148

Show evidence (3 references)

PMID:20213538 SUPPORT BACKGROUND Other

"Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting."

Renal phosphate wasting and hypophosphatemia characterize the disorder; treatment and sampling time affect measured phosphate.

PMID:32920683 SUPPORT PRIMARY RESULT Human Clinical

"Hypophosphatemia, elevated alkaline phosphatase, high intact fibroblast growth factor 23 and sclerostin were found."

Present in all five Chinese patients.

PMID:25180662 REFUTE PRIMARY RESULT Human Clinical

"Biochemical analysis was consistent with normal serum calcium and 1-25(OH)2D levels, low to normal serum phosphorus and elevated PTH values."

The two adult sisters had low-to-normal phosphate values, limiting an obligatory lifelong low-concentration claim.

Elevated Alkaline Phosphatase Elevated circulating alkaline phosphatase concentration HP:0003155

Show evidence (3 references)

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"Serum alkaline phosphatase activity was elevated, with initially normal PTH."

Elevated ALP with normal PTH at presentation.

PMID:32920683 SUPPORT PRIMARY RESULT Human Clinical

"Hypophosphatemia, elevated alkaline phosphatase, high intact fibroblast growth factor 23 and sclerostin were found."

Elevated in all five patients of the Chinese series.

PMID:39011543 REFUTE PRIMARY RESULT Human Clinical

"Biochemical tests revealed hypophosphatemia (0.71 mmol/L, normal 0.80–1.5), normal alkaline phosphatase (105 IU/L, normal 48–130 IU/L), increased parathyroid hormone (10.3 pmol/L, normal 1.6–6.9 pmol/L), and normal 25-hydroxyvitamin D (54.5 nmol/L, normal 30–100 nmol/L) and calcium (2.4 mmol/L,..."

The DMP1 p.Tyr374Ter adolescent had normal ALP during long-term treatment and elevated PTH.

Musculoskeletal 9

Rickets HP:0002748

Show evidence (2 references)

PMID:17033621 SUPPORT PRIMARY RESULT Human Clinical

"Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria."

Rickets is the defining childhood manifestation named in the disorder itself.

PMID:35896139 SUPPORT BACKGROUND Other

"leading to impaired bone mineralization (rickets and osteomalacia)"

Rickets is the skeletal mineralization manifestation described by this source.

Osteomalacia HP:0002749

Show evidence (2 references)

PMID:17033621 SUPPORT PRIMARY RESULT Human Clinical

"Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria."

Osteomalacia named as a manifestation in the discovery families.

PMID:32920683 SUPPORT PRIMARY RESULT Human Clinical

"X-ray uncovered coexistence of osteomalacia and osteosclerosis."

Radiographic osteomalacia in the Chinese cases, coexisting with sclerosis.

Pathologic Fractures HP:0002756

Show evidence (1 reference)

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"patient 2 had a pathologic fracture of the left femoral neck"

Radiographic fracture in one Finnish affected adult.

Joint Contractures HP:0034392

Show evidence (1 reference)

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine."

Both adults in this selected family had contractures; no population frequency is inferred.

Increased Axial Bone Density Increased bone mineral density HP:0011001

Show evidence (2 references)

PMID:32920683 SUPPORT PRIMARY RESULT Human Clinical

"Although areal bone mineral density (aBMD) of axial bone measured by dual-energy X-ray absorptiometry was relatively high in all patients, volumetric BMD (vBMD) and microstructure of one adult patient's peripheral bone detected by HR-pQCT were damaged."

High axial areal density in all five Chinese patients, with damaged peripheral microstructure in the one adult examined.

PMID:25180662 SUPPORT PRIMARY RESULT Human Clinical

"Our cases show that some ARHR cases may develop with age an unaccountable increase in bone density and bone overgrowth."

The sclerosing phenotype developing with age; the authors call it unaccountable, which is why it carries no causal edge.

Pseudofractures HP:0100036

Show evidence (1 reference)

PMID:35896139 SUPPORT PRIMARY RESULT Human Clinical

"A computed tomography scan of the right hip and pelvis revealed marked bone demineralization, and a horizontal line with sclerotic edges at the level of the lesser trochanter, consistent with a pseudofracture"

Imaging documents a pseudofracture before burosumab treatment.

Paraspinal Ligament Ossification Ectopic ossification HP:0011986

Show evidence (1 reference)

PMID:35896139 SUPPORT PRIMARY RESULT Human Clinical

"there was ossification of the posterior longitudinal ligament (seeFig.1A) resulting in canal stenosis throughout the cervical spine"

CT findings in the 50-year-old treated brother.

Spinal Ankylosis HP:0031013

Show evidence (1 reference)

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"She has complete spinal ankylosis with calcification of the spinal ligaments and dural ectasia, lower limb deformities, and contractures."

Clinical description of the affected Finnish woman.

Generalized Osteosclerosis HP:0005789

Show evidence (1 reference)

PMID:31843680 SUPPORT PRIMARY RESULT Human Clinical

"Both our patients manifested osteosclerosis and hyperostosis, enthesopathy, tooth loss, and findings in keeping with severe rickets during childhood together with elevated circulating levels of FGF23, renal Pi wasting, and hypophosphatemia."

Generalized radiographic sclerosis in two related DMP1 cases; the additional SPP1 variant is a possible, unproven modifier.

Constitutional 1

Bone Pain HP:0002653

Show evidence (2 references)

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood."

Lifelong bone pain in both siblings.

PMID:41820620 SUPPORT BACKGROUND Other

"A variable clinical spectrum has been described in this condition, including features of rickets (in children), hyperostotic osteomalacia (in children and adults), bone pain, short stature, lower limb deformities, recurrent dental abscesses, and hearing defects."

Bone pain among the features of the described clinical spectrum.

Growth 1

Short Stature HP:0004322

Show evidence (3 references)

PMID:32920683 SUPPORT PRIMARY RESULT Human Clinical

"Five Chinese patients from three unrelated pedigrees presented with lower extremity deformity and short stature."

All five patients in these three selected families had short stature; this does not estimate population-wide penetrance.

PMID:20213538 SUPPORT PRIMARY RESULT Human Clinical

"The patients were a 53-year-old woman and a 50-year-old man with short stature and skeletal deformities who were the offspring of a first-cousin marriage."

Short stature persisting into adulthood.

PMID:17033621 REFUTE PRIMARY RESULT Human Clinical

"The affected individual in F-2 had a final adult height of 172 cm (90th–95th percentile), 3 cm above the upper limit of her genetic target."

The discovery report documents a 172-cm affected adult, showing short stature is not obligatory.

Other 2

Enthesopathy

Show evidence (2 references)

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments."

Radiographic enthesopathy and paraspinal ligament calcification in both adult siblings.

PMID:31843680 SUPPORT PRIMARY RESULT Human Clinical

"Herein, we describe severe hypophosphatemic osteosclerosis and hyperostosis associated with skeletal deformity, short stature, enthesopathy, tooth loss, and high circulating FGF23 levels in a middle-aged man and young woman from an endogamous family living in southern India."

Enthesopathy in a further DMP1 family; note these patients also carried a homozygous SPP1 variant, so the report is read as supporting the association rather than as a pure DMP1 case.

Osteonecrosis of the Jaw

Show evidence (1 reference)

PMID:41820620 SUPPORT PRIMARY RESULT Human Clinical

"The purpose of this report is to describe the clinical evolution in an adult with a bi-allelic, loss of function pathogenic variant in DMP1 who developed an unusual feature of the condition—osteonecrosis of the jaw—as well as her clinical response to conventional therapy (phosphate..."

Single affected-adult observation; abstract-only access limits etiologic and treatment-outcome inference.

🧬

Genetic Associations

1

Biallelic DMP1 Pathogenic Variants (Causative)

Gene: DMP1 hgnc:2932 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (12 references)

PMID:17033625 SUPPORT PRIMARY RESULT Human Clinical

"Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes."

Linkage mapping and homozygous mutation identification establishing DMP1 as the causal gene.

PMID:17033621 SUPPORT PRIMARY RESULT Human Clinical

"Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus."

Independent simultaneous identification of the gene with two allele classes.

PMID:19007919 SUPPORT PRIMARY RESULT Human Clinical

"At a minimum, this deletion encompassed 49 kb between DMP1 exon 3 and an intergenic region 5' to the next telomeric gene, integrin-binding sialoprotein (IBSP)."

A large biallelic deletion, confirming loss of function as the mechanism.

+ 9 more references

💊

Medical Actions

7

Oral Phosphate with Active Vitamin D

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: phosphate CHEBI:26020 calcitriol CHEBI:17823 alfacalcidol CHEBI:31186

Platform: Small molecule

Divided oral phosphate with calcitriol or alfacalcidol is conventional treatment for FGF23-mediated rickets, including ARHR1. Adjust treatment to growth, symptoms, healing and ALP/PTH while monitoring calcium, urinary calcium and renal function; sustained normal phosphate is not the sole target. Clinical reports document healing of rickets but variable growth and residual disease. Gastrointestinal intolerance, hypercalciuria, nephrocalcinosis and hyperparathyroidism limit treatment. Adult mouse phosphate loading without active vitamin D worsened disease under that protocol; this does not by itself define a human regimen.

Mechanism Target:

MODULATES Chronic Hypophosphatemia — Divided phosphate doses transiently raise available phosphate without correcting the upstream FGF23 excess or the lowered set point.

BYPASSES Suppressed Renal Calcitriol Synthesis — Active vitamin D supports intestinal mineral absorption in the setting of FGF23-mediated suppression of renal calcitriol production; measured calcitriol is not invariably low.

MODULATES Skeletal Mineralization Failure — Together phosphate and active vitamin D partly improve rickets and osteomalacia.

Show evidence (1 reference)

PMID:35896139 SUPPORT BACKGROUND Other

"Traditionally, treatment consists of oral phosphate replacement and the addition of calcitriol but this approach is limited by modest efficacy and potential renal and gastrointestinal side effects."

Conventional therapy acts on the mineralization defect with modest efficacy, which is what the MODULATES effect records.

Show evidence (5 references)

PMID:35896139 SUPPORT BACKGROUND Other

"Traditionally, treatment consists of oral phosphate replacement and the addition of calcitriol but this approach is limited by modest efficacy and potential renal and gastrointestinal side effects."

States the conventional regimen for ARHR1 and its limits.

PMID:35352187 SUPPORT REVIEW SYNTHESIS Other

"Fibroblast-growth factor 23 (FGF23)-associated hypophosphatemic rickets was historically treated with frequent doses of oral phosphate salts in combination with active vitamin D, whereas tumor-induced osteomalacia (TIO) should primarily undergo tumor resection, if possible."

Guidance for the FGF23-associated class to which ARHR1 belongs. Evidence source is OTHER because this is a guidance document.

PMID:35352187 SUPPORT REVIEW SYNTHESIS Other

"Adjustment of medication should be done with consideration of treatment-associated side effects, including diarrhea, gastrointestinal discomfort, hypercalciuria, secondary hyperparathyroidism, and development of nephrocalcinosis or nephrolithiasis."

The monitoring trade-off of conventional therapy. Evidence source is OTHER because this is a guidance document.

+ 2 more references

Burosumab

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: burosumab NCIT:C119744

Platform: Monoclonal antibody

FGF23-neutralizing antibody used off-label for ARHR1 in specialist care. The August 2025 US label covers XLH from six months and unresectable or unlocalizable phosphaturic-mesenchymal-tumor-associated TIO from two years; it does not include ARHR1. Two adult brothers receiving monthly treatment had improved pain/function and phosphate, with near-healing of one pseudofracture after five months. The younger brother still had subnormal phosphate before the next dose; improvement in mouth opening followed concurrent corrective surgery and does not establish reversal of ossification by the drug. Follow-up was one and two years, with no reported adverse effects; these cases cannot establish long-term safety or pediatric efficacy. A later adult report describes treatment after conventional therapy, but its available abstract does not quantify response. Genetic reduction of osteocytic FGF23 in mice is not equivalent to antibody treatment and left residual FGF23 excess and skeletal defects.

Mechanism Target:

INHIBITS Elevated Circulating Intact FGF23 — Burosumab binds circulating FGF23 and blocks its renal phosphaturic and calcitriol-suppressing actions.

Show evidence (1 reference)

PMID:35896139 SUPPORT PRIMARY RESULT Human Clinical

"Monthly administration of burosumab to 2 brothers afflicted with the disorder resulted in normalization of serum phosphate, healing of pseudofracture, diminished fatigue, less bone pain, and reduced incapacity arising from the extensive enthesopathy and soft tissue fibrosis/calcification that..."

Phosphate normalized when FGF23 was neutralized, the on-target effect in ARHR1 patients.

Show evidence (9 references)

PMID:35896139 SUPPORT BACKGROUND Other

"The advent of burosumab (Crysvita), a fully humanized monoclonal antibody to FGF23 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, offers a unique opportunity to evaluate its safety and efficacy in patients with ARHR1."

Historical background motivating ARHR1 treatment, not the current regulatory authority.

PMID:35896139 SUPPORT PRIMARY RESULT Human Clinical

"No adverse effects were reported following burosumab administration."

Short-term tolerability in two patients; not a safety study.

PMID:41820620 SUPPORT PRIMARY RESULT Human Clinical

"as well as her clinical response to conventional therapy (phosphate supplementation and active vitamin D) followed by burosumab"

A further adult treated with burosumab after conventional therapy.

+ 6 more references

Corrective Orthopedic Surgery

Category: Therapeutic Action: Orthopedic Surgical Procedure NCIT:C16186

Platform: Surgery

Osteotomy or guided growth for persistent lower-limb deformity after metabolic treatment has been optimized, and fracture fixation, joint replacement or spinal decompression in adults with advanced disease. The Finnish patient underwent osteotomies from age six and more than thirty orthopedic procedures over her life. Surgery does not alter the biochemical disease.

Target Phenotypes: Bowing of the legs HP:0002979

Show evidence (1 reference)

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"Lower limb osteotomies were first performed at age 6 years, and subsequently, numerous (>30) orthopedic procedures were needed to correct lower limb deformities, to repair bilateral femoral neck fractures, and to treat cervical spinal stenosis."

Direct operative history in an affected adult supports surgery for established deformity and disability.

Dental Surveillance and Care

Category: Therapeutic Action: Dental Procedure NCIT:C38052

Platform: Other

Regular dental examination after tooth eruption and prompt treatment of infection or abscess address the documented dentin/pulp abnormalities. Twice-yearly review is suggested by general rickets guidance and extrapolated to ARHR1; no ARHR1-specific surveillance trial establishes an optimal interval. Dental and metabolic teams should coordinate care.

Target Phenotypes: Tooth abscess HP:0030757

Show evidence (2 references)

PMID:19796717 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent and deciduous teeth displayed enlarged pulp chambers."

The structural dental defect that makes surveillance necessary. Indirect, since the source documents the finding rather than the care.

PMID:35352187 SUPPORT REVIEW SYNTHESIS Other

"Dental examinationTwice-yearly after tooth eruptionTwice-yearlyTwice-yearly"

Table 1 recommends twice-yearly dental examination in children requiring long-term rickets treatment; applied as class-level guidance.

Genetic Counseling and Family Testing

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

When both parents carry a pathogenic DMP1 allele, each pregnancy has a 25% risk of biallelic disease, 50% chance of carrier status and 25% chance of inheriting neither familial allele. Confirm parental segregation and offer targeted family and reproductive-partner testing with genetic counseling. Evaluate at-risk children early. Apparent homozygosity without the expected parental allele requires consideration of a deletion, as demonstrated in a compound-heterozygous family. Mild findings in selected carriers do not establish dominant ARHR1 or a universal carrier-surveillance protocol.

Show evidence (2 references)

PMID:36315908 SUPPORT BACKGROUND Other

"In recessive forms, both parents are carriers and the risk of recurrence is 25% for new children of the couple."

Conditional recurrence risk for a couple in which both parents carry an ARHR1 allele.

PMID:39011543 SUPPORT BACKGROUND Other

"Hypophosphatemic rickets, which is often hereditary, is still under- or misdiagnosed in both children and adults, denying these individuals access to optimal management and genetic counseling."

Misdiagnosis denies families counselling, the reason molecular diagnosis is sought.

Metabolic and Renal Surveillance

Category: Monitoring

Monitor growth, limb alignment, pain, mobility, dental status and hearing symptoms alongside age-adjusted phosphate, ALP, calcium, PTH, renal function, vitamin D status and urinary calcium. General rickets guidance suggests kidney ultrasonography every one to two years during phosphate, active vitamin D or burosumab treatment, adjusted to individual findings. Biochemical improvement alone does not exclude progressive enthesopathy or skeletal disability.

Show evidence (2 references)

PMID:35352187 SUPPORT REVIEW SYNTHESIS Other

"Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate, calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets, parathyroid hormone, 25-hydroxyvitamin D3, and calciuria."

General management guidance applies to long-term monitoring of ARHR1.

PMID:35352187 SUPPORT REVIEW SYNTHESIS Other

"Kidney ultrasonographyEvery 1–2 years on phosphate, active vitamin D or burosumab treatment"

Table 1 surveillance interval, extrapolated from general rickets guidance.

Cinacalcet (Reported Adjunctive Trial)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Cinacalcet NCIT:C74100

Platform: Small molecule

One adult received adjunctive cinacalcet with active/native vitamin D and dietary calcium before burosumab. PTH fell and phosphate trended upward, but the authors judged the changes clinically minor; higher doses were not tolerated and treatment stopped. This unsuccessful individual treatment course does not establish routine efficacy or an ARHR1-specific recommended regimen.

Show evidence (1 reference)

PMID:35896139 SUPPORT PRIMARY RESULT Human Clinical

"Although PTH levels did decrease and serum PO4levels trended higher, the changes were judged to be of minor clinical significance. Higher doses of cinacalcet were not tolerated and treatment with cinacalcet was terminated."

Direct negative/limited treatment experience in the younger brother, with concomitant therapy and intolerance.

🔬

Biochemical Markers

6

Serum Phosphate (Decreased below the age-related reference range)

Context: Fasting, interpreted against age-specific intervals; in the pooled series mean serum phosphate was 0.70 mmol/L with C-terminal alleles and 0.84 mmol/L with N-terminal alleles.

Show evidence (1 reference)

PMID:20213538 SUPPORT PRIMARY RESULT Human Clinical

"Biochemical examination revealed hypophosphatemia with renal phosphate excretion and low levels of 1,25(OH)(2)D."

The core biochemical finding.

Renal Phosphate Wasting (TmP/GFR) (Decreased tubular reabsorption of phosphate despite hypophosphatemia)

Context: Paired fasting serum and urine phosphate and creatinine give TmP/GFR; phosphate wasting is isolated, without glycosuria, aminoaciduria or acidosis, and with normal calcium excretion.

Show evidence (2 references)

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"showed hypophosphatemia due to insufficient renal phosphate retention"

Renal phosphate wasting documented at presentation.

PMID:17033621 SUPPORT PRIMARY RESULT Human Clinical

"isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria"

Isolated wasting with normocalciuria distinguishes it from generalized tubulopathy and from calciopenic rickets.

Intact FGF23 (Elevated or inappropriately normal for the degree of hypophosphatemia)

Show evidence (1 reference)

PMID:17033625 SUPPORT PRIMARY RESULT Human Clinical

"Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals"

Elevated in half of the discovery cohort, inappropriately normal in the rest.

1,25-Dihydroxyvitamin D (Often inappropriately normal or low; elevated values can occur)

Context: FGF23 restrains calcitriol synthesis and increases catabolism, but net levels depend on PTH, age and treatment. Elevated calcitriol was measured in the compound-heterozygote and in adult Dmp1-null mice.

Show evidence (2 references)

PMID:17033625 SUPPORT PRIMARY RESULT Human Clinical

"providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels"

Inappropriately normal calcitriol in the discovery families.

PMID:20213538 SUPPORT PRIMARY RESULT Human Clinical

"Biochemical examination revealed hypophosphatemia with renal phosphate excretion and low levels of 1,25(OH)(2)D."

Frankly low calcitriol in the Japanese siblings.

Alkaline Phosphatase (Elevated with active rickets or osteomalacia)

Context: Interpret with age-specific ranges and clinical response. Total ALP may reflect liver disease; bone-specific measurements can help. During conventional treatment, normalization of serum phosphate is not the sole therapeutic target.

Show evidence (1 reference)

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"Serum alkaline phosphatase activity was elevated, with initially normal PTH."

Elevated ALP at diagnosis.

Parathyroid Hormone and Calcium (Calcium and PTH may be normal; secondary hyperparathyroidism or hypocalcemia can occur)

Context: Normal PTH supports a phosphopenic pattern but does not distinguish all cases. Elevated PTH occurs in affected children and adults and can reflect phosphate treatment, inadequate calcium/vitamin D or the disease context. Monitor both minerals and PTH during therapy.

Show evidence (2 references)

PMID:20213538 SUPPORT PRIMARY RESULT Human Clinical

"Serum calcium, parathyroid hormone, and urinary calcium excretion were within the normal range, leading to clinical diagnosis of ARHR."

Normal calcium, PTH and calciuria in the Japanese siblings.

PMID:25180662 SUPPORT PRIMARY RESULT Human Clinical

"Biochemical analysis was consistent with normal serum calcium and 1-25(OH)2D levels, low to normal serum phosphorus and elevated PTH values."

Elevated PTH in the Lebanese adult sisters, the exception that the presence field records.

🔬

Diagnosis

2

Clinical and Biochemical Evaluation for FGF23-Mediated Phosphate Wasting

Evaluate rickets, limb deformity or adult osteomalacia with age-adjusted fasting serum phosphate, paired urine/serum measurements for renal phosphate handling, calcium, ALP, PTH, vitamin D status, renal function and FGF23 interpreted by assay. Normal calcium/PTH and inappropriately normal or low calcitriol are common patterns, not requirements. A recessive pedigree is suggestive but absent family history does not exclude compound heterozygosity. Assess generalized tubular abnormalities, nutritional causes and other genetic phosphate-wasting disorders.

Clinical Evaluation NCIT:C124351

Results: Inappropriate renal phosphate loss and nonsuppressed FGF23 support an FGF23-mediated disorder; molecular testing distinguishes DMP1 from phenocopies.

Show evidence (1 reference)

PMID:20213538 SUPPORT PRIMARY RESULT Human Clinical

"Serum calcium, parathyroid hormone, and urinary calcium excretion were within the normal range, leading to clinical diagnosis of ARHR."

The biochemical pattern that led to the clinical diagnosis before sequencing.

DMP1 Molecular Genetic Testing

Confirm biallelic pathogenic or likely pathogenic DMP1 variants, with segregation/phase assessment. Use a hereditary hypophosphatemia panel or exome analysis that includes copy-number detection, with orthogonal confirmation of deletions when indicated. A deletion may make the remaining allele appear homozygous; discordant parental segregation should prompt investigation. A VUS alone is not diagnostic. Broader analysis helps distinguish PHEX, FGF23, ENPP1, FAM20C and transporter-gene disease.

Genetic Testing NCIT:C15709

Results: Homozygous or compound heterozygous pathogenic DMP1 variants, with deletion analysis.

Show evidence (3 references)

PMID:36334264 SUPPORT PRIMARY RESULT Human Clinical

"The maternally inherited deletion was validated by Cytoscan and qPCR, and the breakpoint was finally identified by long-range PCR and Sanger sequencing."

Shows that copy-number analysis was needed to find the second allele.

PMID:39011543 SUPPORT PRIMARY RESULT Human Clinical

"Our cases prompt consideration of the (i) frequent misdiagnosis of hypophosphatemic rickets in clinical practice and the importance of comprehensive genetic testing"

Real-world series including a DMP1 case, arguing for comprehensive rather than restricted testing.

url:https://oup.silverchair-cdn.com/article-minimal/6806102 SUPPORT PRIMARY RESULT Human Clinical

"this mutation was absent in the proband’s mother (I-2), suggesting that the existence of the CNV in the proband that he might have inherited from his mother made the mutation appear homozygous in the proband."

The apparently homozygous start-codon call was resolved to paternal sequence variant plus maternal deletion by copy-number and segregation studies.

📈

Progression

2

Early childhood onset

Age: Infancy through childhood

Leg bowing and rickets often become apparent after walking begins, but onset or recognition at school age is documented. Growth, biochemical abnormalities and response to early treatment vary.

Show evidence (2 references)

PMID:19796717 SUPPORT PRIMARY RESULT Human Clinical

"The index case presented at the age of 3 years with bowing of his legs and showed hypophosphatemia due to insufficient renal phosphate retention."

Typical age and mode of presentation in a family report.

PMID:36334264 SUPPORT PRIMARY RESULT Human Clinical

"The proband is a 4-year-old boy, who developed genu varum when he was able to walk at age 1 year and tooth loss after a mild hit at age 3.5 years."

Onset with walking, and early dental involvement, in an independent case.

Adult disease

Age: Adulthood into the seventh and eighth decades

Osteomalacia, pseudofractures and bone pain persist, and in the longest followed family joint pain, contractures, cranial hyperostosis, enthesopathy, paraspinal ligament calcification and complete spinal immobilization accumulated over decades. Survival into old age is documented; mortality has not been quantified.

Show evidence (2 references)

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine."

Documents the progressive adult musculoskeletal course in the 78-year-old and 66-year-old siblings.

PMID:20499351 SUPPORT PRIMARY RESULT Human Clinical

"The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets."

The authors' own comparison with XLH and ADHR, drawn from the adult course.

📊

Prevalence

1

Worldwide, reported cases

Cases In Literature

No population prevalence or incidence is established. The 2020 series pooled five new Chinese patients with 25 published cases; the later compound-heterozygote paper repeated a 30-case background count. These are historical, overlapping literature censuses, not independent estimates or a current total.

Show evidence (3 references)

PMID:36334264 SUPPORT BACKGROUND Other

"autosomal recessive hypophosphatemic rickets type 1 (ARHR1), caused by a homozygous mutation of dentin matrix protein 1 (DMP1), is extremely rare, with only 30 reported patients"

Gives the literature case count that supports the ultra-rare class and the cases-in-literature measure.

PMID:32920683 SUPPORT PRIMARY RESULT Human Clinical

"Genotype-phenotype correlation analysis including 30 cases (25 from literature review and 5 from our study)"

An independent 2020 literature census reaches the same order of magnitude.

PMID:20213538 SUPPORT BACKGROUND Other

"Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting."

Qualitative rarity statement from a family report.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Hypophosphatemic Rickets 1:

X-Linked Hypophosphatemia MONDO:0010619

Overlapping Features The common FGF23-mediated phosphate-wasting rickets, biochemically indistinguishable from ARHR1; PHEX and DMP1 restrain FGF23 through a common osteocyte pathway.

Distinguishing Features

X-linked dominant pedigree with affected heterozygous females, versus unaffected carrier parents.
PHEX rather than biallelic DMP1 variants.
The adult hyperostotic-osteosclerotic and severe enthesopathic phenotype is more prominent in ARHR1 families.

Show evidence (1 reference)

PMID:21507898 SUPPORT PRIMARY RESULT Model Organism

"These findings indicate that PHEX and DMP1 control a common pathway regulating bone mineralization and FGF23 production, the latter involving activation of the FGFR signaling in osteocytes."

Explains why the two disorders are biochemically alike and must be separated by pedigree and genotype.

Autosomal Recessive Hypophosphatemic Rickets 2 Not Yet Curated MONDO:0013219

Overlapping Features The ENPP1-related recessive form, with the same FGF23-driven renal phenotype but a different initiating lesion in pyrophosphate metabolism.

Distinguishing Features

Biallelic ENPP1 rather than DMP1 variants.
ENPP1 disease spans neonatal arterial calcification to rickets or osteoporosis; arterial calcification is not a feature of ARHR1.

Show evidence (2 references)

PMID:42412262 SUPPORT REVIEW SYNTHESIS Other

"Variants in multiple genes cause dominant (FGF23, SGK3, FGFR1), recessive (DMP1, ENPP1, FAM20C, INPPL1) or even somatic (NRAS, HRAS, GNAS, gene fusions) conditions of FGF23 excess, with important phenotypic differences."

Places DMP1 and ENPP1 as separate recessive causes of FGF23 excess. Evidence source is OTHER because this is a review article.

PMID:42412262 SUPPORT REVIEW SYNTHESIS Other

"ENPP1 variants cause phenotypes ranging from severe neonatal vascular calcifications to rickets or osteoporosis"

The vascular calcification spectrum that separates ARHR2 clinically. Evidence source is OTHER because this is a review article.

Sclerosing Bone Dysplasias

Overlapping Features Adult ARHR1 with cranial hyperostosis and high axial bone density has been misdiagnosed as a familial sclerosing bone dysplasia and worked up for osteopetrosis.

Distinguishing Features

Hypophosphatemia with renal phosphate wasting and elevated FGF23 are absent in the primary sclerosing dysplasias.
Childhood rickets and osteomalacia precede the sclerosis.

Show evidence (1 reference)

PMID:25180662 SUPPORT PRIMARY RESULT Human Clinical

"Molecular analysis of known genes involved in osteopetrosis showed normal results."

The sisters were first investigated as a sclerosing dysplasia before exome sequencing found DMP1.

🐁

Animal Models

1

Dmp1-null mouse

Dmp1-null mice reproduce osteocyte maturation defects, impaired matrix mineralization, increased bone Fgf23, phosphate wasting, rickets and osteomalacia. Transgenic full-length DMP1 or its 57-kDa fragment rescues several skeletal and biochemical endpoints. Early anti-FGF23 antibody treatment improves growth plates and secondary ossification more fully than cortical mineralization; adult osteocytic Fgf23 deletion reduces excess hormone and partly corrects bone despite normalized phosphate. Outcomes depend on developmental timing, genetic background, diet and intervention.

Species

Mouse

Genotype

Dmp1 homozygous null

Genes

Dmp1 hgnc:2932

Publication

PMID:17033621

Pathograph links

Defective Osteocyte Maturation recapitulates fidelity: high observes: cellular The osteocyte maturation arrest and lacunocanalicular defect were defined in this model and are DMP1-dependent, since bone-cell DMP1 expression rescues them.

Limitations: Complete null alleles and transgenic rescue do not reproduce every human start-loss or C-terminal allele.

Show evidence (1 reference)

PMID:17033621 SUPPORT PRIMARY RESULT Model Organism

"Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization."

The model defines this node.

DMP1-Dependent Matrix Mineralization Defect recapitulates fidelity: high observes: tissue Dmp1-null tibias have reduced mineral-to-matrix ratio at 4 and 16 weeks by FTIR imaging.

Limitations: FTIR is a matrix endpoint, distinct from osteocyte maturation markers. Relative mineral content does not measure every aspect of mineral crystal composition.

Readouts

Tibial mineral-to-matrix ratio by FTIR imaging

Direction: DECREASED

Interpretation: Relative mineral content of bone matrix in the null mouse at 4 and 16 weeks.

Show evidence (1 reference)

PMID:16294270 SUPPORT PRIMARY RESULT Model Organism

"The mineral-to-matrix ratios (spectroscopic parameter of relative mineral content) were significantly lower in dmp1 KO mice tibias compared with WT and HET at 4 and 16 weeks."

The measurement behind this readout.

Show evidence (1 reference)

PMID:16294270 SUPPORT PRIMARY RESULT Model Organism

"The mineral-to-matrix ratios (spectroscopic parameter of relative mineral content) were significantly lower in dmp1 KO mice tibias compared with WT and HET at 4 and 16 weeks."

The measurement behind this readout.

Increased Osteocytic FGF23 Production recapitulates fidelity: high observes: cellular Osteocytic Fgf23 induction, its FGFR dependence and its non-additivity with Phex loss were all established in this model.

Limitations: The magnitude of induction in the null mouse exceeds what is inferred from human bone, where FGF23 expression is increased but has not been quantified; whether FGFR signalling drives human osteocytic FGF23 is not demonstrated.

Readouts

Fgf23 mRNA in bone marrow stromal cells

Direction: INCREASED

Interpretation: 124-fold induction in differentiated marrow stromal cultures; SU5402 reduced this to 2.5-fold. This is an in-vitro assay using cells derived from mutant mice.

Show evidence (1 reference)

PMID:21507898 SUPPORT PRIMARY RESULT In Vitro

"Furthermore, inhibiting FGFR signaling using SU5402 in Hyp- and Dmp1(-/-)-derived bone marrow stromal cells prevented the increase in Fgf23 mRNA expression (129- and 124-fold increase in Hyp and Dmp1(-/-) vs. 1.3-fold in Hyp+SU5402 and 2.5-fold in Dmp1(-/-)+SU5402, P<0.05)."

The measurement behind this readout.

Show evidence (1 reference)

PMID:28005411 SUPPORT PRIMARY RESULT Model Organism

"In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD)."

Increased bone Fgf23 expression driving hypophosphatemia in the model.

Chronic Hypophosphatemia recapitulates fidelity: high observes: organism Hypophosphatemia with a lowered set point that is maintained through Fgf23 expression and cleavage; raising phosphate provokes more FGF23.

Limitations: Adult null mice also develop hyperparathyroidism, which most patients do not; the mouse therefore overstates the calciopenic component.

Readouts

Serum phosphate

Direction: DECREASED

Interpretation: Hypophosphatemia at 12 weeks with elevated serum FGF23 and PTH.

Show evidence (1 reference)

PMID:37943605 SUPPORT PRIMARY RESULT Model Organism

"At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia."

The measurement behind this readout.

Show evidence (1 reference)

PMID:28005411 SUPPORT PRIMARY RESULT Model Organism

"These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression."

Characterizes the hypophosphatemia as a set-point defect, which is the informative feature of the model for this node.

Skeletal Mineralization Failure recapitulates fidelity: high observes: tissue Osteomalacia and excess osteoid are partly corrected by osteocytic Fgf23 deletion even when phosphate normalizes. Residual FGF23 and PTH elevation limit causal attribution solely to a local matrix defect.

Limitations: A 2011 study observed age-dependent bony protuberances at one year, but this does not establish equivalence to every adult human sclerosis or enthesopathy phenotype. Different treatment ages and endpoints limit comparison of experiments.

Show evidence (1 reference)

PMID:37943605 SUPPORT PRIMARY RESULT Model Organism

"In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice."

The two-route result that makes this model informative for the node.

Growth Plate Hypertrophic Zone Expansion recapitulates fidelity: high observes: tissue Expanded, disorganized growth plates with rickets, rescued by bone-cell expression of DMP1 or its 57-kDa fragment, and shown to be phosphate-dependent in metatarsal organ culture.

Limitations: Neonatal organ culture and early postnatal mouse antibody treatment test developing growth plates; these endpoints cannot measure reversal of established adult human enthesopathy.

Show evidence (2 references)

PMID:20734454 SUPPORT PRIMARY RESULT Model Organism

"This included rescue of growth plate defects, osteomalacia, abnormal osteocyte maturation, and the abnormal osteocyte lacunocanalicular system."

The growth plate defect of the model and its DMP1 dependence.

+ 1 more reference

Notes

Related experiments include Dmp1/Galnt3 double knockout, which changes Fgf23 cleavage and phosphate responsiveness, and non-additive Hyp/Dmp1 double mutants. Rescue by a 3.6-kb Col1a1-driven 57-kDa DMP1 fragment establishes experimental sufficiency, not a human replacement therapy. The 2011 culture study found normal mineralization with sufficient phosphate in neonatal calvarial cells, whereas the 2023 marrow stromal cultures retained impaired matrix mineralization; these differ in cell source, age and protocol. FTIR analysis used female mice at four and sixteen weeks; heterozygotes had altered crystallinity despite preserved mineral-to-matrix ratio. A separate 2011 study used CD-1 mice and observed bony protuberances by one year.

Show evidence (3 references)

PMID:17033621 SUPPORT PRIMARY RESULT Model Organism

"Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype."

Establishes the model and its baseline phenotype.

PMID:21542006 SUPPORT PRIMARY RESULT Model Organism

"We showed (1) that abnormal bone remodeling in Dmp1 null mice is due to reduced osteoclast number, which is secondary to a reduced ratio of RANKL/OPG expressed by osteoclast supporting cells"

Reduced osteoclast number and remodeling in the model, a feature with no established human counterpart that is recorded here rather than as a human node.

PMID:21542006 SUPPORT PRIMARY RESULT Model Organism

"In the aged animal at 1 year, the development of large bony protuberances occurs in all bones examined (Fig. 1C, middle and right panels, D and Supplemental Fig. S1), suggesting that the abnormality of bone remodeling progresses with age."

Age-dependent remodeling abnormalities were followed to one year; equivalence to specific human enthesopathy remains uncertain.

{ }

Source YAML

click to show

name: Autosomal Recessive Hypophosphatemic Rickets 1
creation_date: "2026-09-04T23:23:40Z"
category: Mendelian
description: >-
  Autosomal recessive hypophosphatemic rickets 1 (ARHR1) is a DMP1-related disorder of skeletal mineralization
  and FGF23-mediated renal phosphate wasting. Biallelic loss-of-function variants impair a secreted matrix
  protein required for normal osteocyte maturation and mineralization. Depending on the allele, protein secretion,
  abundance or processing is altered; complete protein absence is not universal. Increased bone FGF23 production
  promotes renal phosphate loss and restrains the expected calcitriol response to hypophosphatemia. Calcium
  and PTH can be normal, but secondary hyperparathyroidism and variable calcitriol concentrations occur.

  Model experiments distinguish systemic phosphate deficiency, direct FGF23 effects on osteoprogenitor differentiation,
  and a DMP1-dependent mineralization defect. Correction of serum phosphate alone does not isolate these mechanisms,
  because residual FGF23 excess may persist. Cultured-cell rescue experiments provide stronger evidence for
  a mineralization defect independent of phosphate availability and FGF23 production. PHEX-related disease
  also has intrinsic bone abnormalities; this is not a clean distinction between local and purely endocrine
  disease.

  Reported manifestations range from childhood rickets and limb deformity to adult osteomalacia, pain, fractures
  or pseudofractures, dental abnormalities and hearing impairment. Some older patients develop marked cranial
  hyperostosis, enthesopathy, ligament ossification and spinal ankylosis. High axial areal bone density can
  coexist with impaired mineralization and poor peripheral bone microstructure. Short stature and severe adult
  disability are variable. Conventional treatment combines phosphate and active vitamin D, with monitoring
  for renal and parathyroid complications. Burosumab use in ARHR1 is supported by limited case reports; long-term
  effects on established enthesopathy remain uncertain.
disease_term:
  preferred_term: Autosomal Recessive Hypophosphatemic Rickets 1
  term:
    id: MONDO:0009430
    label: hypophosphatemic rickets, autosomal recessive, 1
synonyms:
- ARHR1
- ARHR type 1
- ARHP
- DMP1-related hypophosphatemic rickets
- DMP1 autosomal recessive hypophosphatemic rickets
- autosomal recessive hypophosphatemia
- hypophosphatemic rickets, autosomal recessive, type 1
parents:
- Metabolic Bone Disorders
- Hereditary Hypophosphatemic Rickets
- FGF23-Mediated Hypophosphatemia
notes: >-
  This entry covers biallelic DMP1-related ARHR1 (MONDO:0009430; OMIM 241520). PHEX-, ENPP1- and FAM20C-related
  disorders are differential diagnoses, not subtypes of this disease. Subclinical findings in some heterozygous
  carriers are recorded separately from the biallelic clinical disorder and do not establish dominant ARHR1.
  The phosphopenic downstream mechanisms conform to the defective skeletal mineralization module. The causes
  of the adult hyperostotic and enthesopathic phenotype remain incompletely resolved.
references:
- reference: PMID:17033621
  title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
- reference: PMID:17033625
  title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
- reference: PMID:20499351
  title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
- reference: PMID:37943605
  title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
- reference: PMID:35896139
  title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
- reference: url:https://oup.silverchair-cdn.com/article-minimal/6806102
  title: "https://oup.silverchair-cdn.com/article-minimal/6806102"
  findings:
  - statement: >-
      Publisher full text of Ni et al., The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal
      Recessive Hypophosphatemic Rickets Type 1 (PMID:36334264; DOI:10.1210/clinem/dgac638).
- reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761068s009lbl.pdf
  title: "https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761068s009lbl.pdf"
  findings:
  - statement: >-
      US FDA CRYSVITA prescribing information, revised August 2025; indication and safety reference, not an
      ARHR1 efficacy study.
- reference: PMID:21507898
  title: Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.
- reference: PMID:20734454
  title: The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa C-terminal fragment.
- reference: PMID:21542006
  title: Unique roles of phosphorus in endochondral bone formation and osteocyte maturation.
- reference: PMID:16294270
  title: "DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis."
- reference: PMID:19007919
  title: Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets.
- reference: PMID:19796717
  title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
- reference: PMID:32920683
  title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
- reference: PMID:36334264
  title: The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1.
- reference: PMID:39011543
  title: Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets.
- reference: PMID:41820620
  title: Expanding the Autosomal Recessive Hypophosphatemic Rickets Type I Carrier Phenotype and Adult Treatment with Burosumab.
- reference: PMID:29901142
  title: Targeted resequencing of phosphorus metabolism‑related genes in 86 patients with hypophosphatemic rickets/osteomalacia.
- reference: PMID:35352187
  title: "Rickets guidance: part II-management."
- reference: url:https://www.spandidos-publications.com/10.3892/ijmm.2018.3730/download
  title: https://www.spandidos-publications.com/10.3892/ijmm.2018.3730/download
  findings:
  - statement: >-
      Full text of Gu et al. 2018, PMID:29901142; DMP1 c.730G>T segregation and selected-cohort clinical findings.
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      A disorder of phosphate homeostasis and mineral metabolism, managed by
      metabolic bone and endocrine services.
    evidence:
    - reference: PMID:35896139
      reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Autosomal recessive hypophosphatemic rickets (ARHR) are rare, heritable renal phosphate-wasting disorders that arise from overexpression of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) leading to impaired bone mineralization (rickets and osteomalacia)."
      explanation: Frames the disorder as a hormone-driven disorder of phosphate metabolism, the endocrine and metabolic home.
      quote_role: BACKGROUND
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Mendelian, autosomal recessive, caused by biallelic DMP1 loss of function.
    evidence:
    - reference: PMID:20213538
      reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting."
      explanation: States the Mendelian recessive inheritance that places the disorder in the genetics Part.
      quote_role: BACKGROUND
  isds_skeletal_category:
  - classification_value: abnormal_mineralization
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2023
      revision (Unger et al., PMID:36779427), group 27 "Disorders of bone
      mineralisation", which holds the hereditary hypophosphataemic rickets;
      ARHR1 is the DMP1-related autosomal recessive member, alongside the
      PHEX-related X-linked form curated in `X-Linked_Hypophosphatemia`.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: UNKNOWN
  expressivity: VARIABLE
  description: >-
    Biallelic DMP1 variants cause ARHR1, usually homozygous in reported families, with compound heterozygosity
    also established. Carrier parents may be clinically and biochemically normal; mild phosphate, density or
    histomorphometric abnormalities have been documented in selected families. These carrier observations do
    not quantify biallelic penetrance or establish dominant disease.
  evidence:
  - reference: PMID:17033625
    reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes."
    explanation: The discovery study mapped the disorder as autosomal recessive and found homozygous DMP1 mutations in the affected individuals.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The parents and available unaffected siblings were heterozygous for c.485Tdel."
    explanation: Heterozygous parents and siblings were unaffected, the segregation pattern of a recessive trait.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the parents of the three affected children are first-degree cousins"
    explanation: >-
      Consanguinity was documented in these three affected children; the report does not estimate its frequency
      across all ARHR1.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia."
    explanation: >-
      Two carriers in one family had mild biochemical abnormalities, with focal biopsy changes in one. Biallelic
      penetrance is unknown because no unselected genotype cohort was evaluated, not because carrier findings
      invalidate recessive inheritance.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36334264
    reference_title: The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report for the first time compound heterozygous DMP1 mutations consisting of a large deletion and a novel start codon mutation (c.1A > T, p.Met1Leu) in a Chinese patient with ARHR1."
    explanation: Compound heterozygosity in a non-consanguineous family confirms that biallelic loss, not homozygosity per se, is what causes disease.
    quote_role: PRIMARY_RESULT
prevalence:
- population: Worldwide, reported cases
  measure_type: CASES_IN_LITERATURE
  notes: >-
    No population prevalence or incidence is established. The 2020 series pooled five new Chinese patients
    with 25 published cases; the later compound-heterozygote paper repeated a 30-case background count. These
    are historical, overlapping literature censuses, not independent estimates or a current total.
  evidence:
  - reference: PMID:36334264
    reference_title: The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "autosomal recessive hypophosphatemic rickets type 1 (ARHR1), caused by a homozygous mutation of dentin matrix protein 1 (DMP1), is extremely rare, with only 30 reported patients"
    explanation: Gives the literature case count that supports the ultra-rare class and the cases-in-literature measure.
    quote_role: BACKGROUND
  - reference: PMID:32920683
    reference_title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genotype-phenotype correlation analysis including 30 cases (25 from literature review and 5 from our study)"
    explanation: An independent 2020 literature census reaches the same order of magnitude.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting."
    explanation: Qualitative rarity statement from a family report.
    quote_role: BACKGROUND
progression:
- phase: Early childhood onset
  age_range: Infancy through childhood
  notes: >-
    Leg bowing and rickets often become apparent after walking begins, but onset or recognition at school age
    is documented. Growth, biochemical abnormalities and response to early treatment vary.
  evidence:
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The index case presented at the age of 3 years with bowing of his legs and showed hypophosphatemia due to insufficient renal phosphate retention."
    explanation: Typical age and mode of presentation in a family report.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36334264
    reference_title: The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband is a 4-year-old boy, who developed genu varum when he was able to walk at age 1 year and tooth loss after a mild hit at age 3.5 years."
    explanation: Onset with walking, and early dental involvement, in an independent case.
    quote_role: PRIMARY_RESULT
- phase: Adult disease
  age_range: Adulthood into the seventh and eighth decades
  notes: >-
    Osteomalacia, pseudofractures and bone pain persist, and in the longest
    followed family joint pain, contractures, cranial hyperostosis,
    enthesopathy, paraspinal ligament calcification and complete spinal
    immobilization accumulated over decades. Survival into old age is
    documented; mortality has not been quantified.
  evidence:
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine."
    explanation: Documents the progressive adult musculoskeletal course in the 78-year-old and 66-year-old siblings.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets."
    explanation: The authors' own comparison with XLH and ADHR, drawn from the adult course.
    quote_role: PRIMARY_RESULT
pathophysiology:
- name: Biallelic DMP1 Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Homozygous or compound heterozygous DMP1 variants impair a SIBLING-family matrix protein expressed by mineralizing
    cells. Nonsense, frameshift, splice-site, start-codon and deletion alleles are reported. The c.1A>G construct
    is retained intracellularly, whereas a C-terminal frameshift product is secreted with altered processing.
    The distinct c.1A>T start-loss construct produces a shorter, secreted protein initiated at a downstream
    start site, with reduced abundance and absent detectable C-terminal cleavage fragment. These allele-specific
    results support loss of normal function without assuming universal protein absence or identical trafficking
    defects. A large deletion can involve adjacent SIBLING genes; its full phenotypic contribution cannot be
    inferred from DMP1 alone.
  genes:
  - preferred_term: DMP1
    term:
      id: hgnc:2932
      label: DMP1
  genetic_context:
    gene:
      preferred_term: DMP1
      term:
        id: hgnc:2932
        label: DMP1
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    description: >-
      Biallelic germline loss of function; homozygous in most families, compound
      heterozygous in one reported patient.
  cell_types:
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: odontoblast
    term:
      id: CL:0000060
      label: odontoblast
  evidence:
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus."
    explanation: One of the two simultaneous discovery reports; identifies the start-codon and C-terminal deletion alleles.
    quote_role: PRIMARY_RESULT
  - reference: PMID:17033625
    reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes"
    explanation: The companion discovery report; establishes the gene and its expression in the mineralizing lineage.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19007919
    reference_title: Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These analyses showed that the M1V DMP1 mutant was not sorted to the trans-Golgi network (TGN) and secretory pathway, but filled the entire cytoplasm."
    explanation: Direct cellular demonstration that the start-codon allele is a loss of the secreted protein.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19007919
    reference_title: Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analyses of this family demonstrated that the affected members had elevated serum FGF23 and carried a large, biallelic deletion that removed the majority of DMP1."
    explanation: >-
      Affected siblings carried a deletion of most of DMP1, supporting loss of function; the mapped deletion
      was at least 49 kb, not an exactly resolved 49-kb whole-gene deletion. Possible effects on adjacent regulatory
      sequence were unresolved.
    quote_role: PRIMARY_RESULT
  - reference: PMID:32920683
    reference_title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients harboring mutations affecting C-terminal fragment of DMP1 presented with shorter stature (Z score of height = - 3.4 ± 1.6 vs - 1.0 ± 1.6, p = 0.001) and lower serum phosphate level (0.70 ± 0.15 vs 0.84 ± 0.16, p = 0.03) than those harboring mutations only affecting N-terminal fragment"
    explanation: >-
      A selected 30-case pooled analysis associates C-terminal-affecting alleles with shorter stature and lower
      phosphate. Relatedness, age and treatment history limit causal domain-specific or individual prognostic
      inference.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20734454
    reference_title: The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa C-terminal fragment.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Not only did expression of the full-length DMP-1 in bone cells fully rescue the skeletal abnormalities of Dmp1 null mice, but the 57-kDa fragment also had similar results."
    explanation: >-
      Transgenic expression of the C-terminal fragment rescued the null mouse, demonstrating rescue capacity
      in this model rather than a validated human genotype-severity rule.
    quote_role: PRIMARY_RESULT
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6806102
    reference_title: "https://oup.silverchair-cdn.com/article-minimal/6806102"
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Consistent with this speculation, LC-MS analysis confirmed the reinitiated translation of MT DMP1 by
      the downstream alternative start site.
    explanation: >-
      Mass spectrometry in transfected cells establishes alternative initiation for c.1A>T; the paper's p.Met1Leu
      shorthand does not describe a simple full-length amino-acid substitution.
  downstream:
  - target: Defective Osteocyte Maturation
    causal_link_type: DIRECT
    description: >-
      DMP1 loss impairs osteoblast-to-osteocyte maturation and the organization of the lacunocanalicular network.
    evidence:
    - reference: PMID:17033621
      reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization."
      explanation: States the causal step from DMP1 absence to defective osteocyte maturation.
      quote_role: PRIMARY_RESULT
  - target: DMP1-Dependent Matrix Mineralization Defect
    causal_link_type: DIRECT
    description: >-
      Loss of functional extracellular DMP1 impairs matrix mineralization independently of phosphate substrate
      and excess FGF23 in culture.
    evidence:
    - reference: PMID:37943605
      reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        In the present study, although genetic deletion of Fgf23 restored osteoblast differentiation, it did
        not correct the impaired mineralization observed in Dmp1-null osteoblast cultures, suggesting that
        DMP1 deficiency directly contributes to the mineralization defect despite adequate Pi supply and normal
        FGF23 production.
      explanation: >-
        Mineralization remained impaired after differentiation and FGF23 production were corrected in cultured
        cells.
  - target: Increased Bone FGFR Signaling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      DMP1 deficiency is associated with increased FGFR pathway activation in bone; upstream intermediates
      are unknown.
    evidence:
    - reference: PMID:21507898
      reference_title: Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        we confirmed by Western blot analysis that FGFR1 pathway was activated in Hyp and Dmp1−/− (Fig. 5)
        by showing increased phosphorylation of FGFR1, FRS2, and PI3K in these bones.
      explanation: >-
        Protein phosphorylation was measured in mutant mouse bone; this is distinct from the cultured-cell
        SU5402 intervention.
- name: Defective Osteocyte Maturation
  biological_scale: CELLULAR
  description: >-
    Dmp1-null osteocytes retain osteoblast and early osteocyte markers and have enlarged, disorganized lacunae
    and abnormal canaliculi. These observations support impaired osteoblast-to-osteocyte maturation. The separate
    contribution of matrix mineralization and FGF23 signaling to that maturation defect is incompletely resolved;
    carrier biopsy observations do not establish a uniform haploinsufficiency phenotype.
  cell_types:
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: osteoblast to osteocyte differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization."
    explanation: Establishes defective osteocyte maturation as the primary cellular lesion in the null mouse.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20734454
    reference_title: The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa C-terminal fragment.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This included rescue of growth plate defects, osteomalacia, abnormal osteocyte maturation, and the abnormal osteocyte lacunocanalicular system."
    explanation: Names the abnormal osteocyte maturation and lacunocanalicular system as DMP1-dependent, since restoring DMP1 in bone cells corrects them.
    quote_role: PRIMARY_RESULT
- name: DMP1-Dependent Matrix Mineralization Defect
  biological_scale: TISSUE
  description: >-
    DMP1-deficient osteoblast cultures mineralize poorly despite adequate phosphate substrate and correction
    of excess FGF23 by lineage-specific deletion. Exogenous DMP1 supplied in coculture restores mineralization.
    This supports an extracellular DMP1-dependent defect; it should not be described as strictly cell-autonomous
    or inferred solely from incomplete whole-animal rescue.
  biological_processes:
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  evidence:
  - reference: PMID:37943605
    reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      In the present study, although genetic deletion of Fgf23 restored osteoblast differentiation, it did
      not correct the impaired mineralization observed in Dmp1-null osteoblast cultures, suggesting that DMP1
      deficiency directly contributes to the mineralization defect despite adequate Pi supply and normal FGF23
      production.
    explanation: >-
      Mineralization remained impaired after differentiation and FGF23 production were corrected in cultured
      cells.
  downstream:
  - target: Skeletal Mineralization Failure
    causal_link_type: DIRECT
    description: >-
      The local DMP1-dependent defect contributes to failure to mineralize bone matrix.
    evidence:
    - reference: PMID:37943605
      reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        In the present study, although genetic deletion of Fgf23 restored osteoblast differentiation, it did
        not correct the impaired mineralization observed in Dmp1-null osteoblast cultures, suggesting that
        DMP1 deficiency directly contributes to the mineralization defect despite adequate Pi supply and normal
        FGF23 production.
      explanation: >-
        Mineralization remained impaired after differentiation and FGF23 production were corrected in cultured
        cells.
- name: Increased Bone FGFR Signaling
  biological_scale: CELLULAR
  description: >-
    Dmp1-null and Phex-deficient mouse cortical bone show increased phosphorylation of FGFR1, FRS2 and PI3K.
    A common pathway is supported by nonadditive double-mutant phenotypes and inhibition experiments in marrow
    stromal cultures. The molecular steps connecting DMP1 loss to receptor activation, and the relative contributions
    of FGFR1 versus other receptors, remain unresolved.
  biological_processes:
  - preferred_term: fibroblast growth factor receptor signaling pathway
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:21507898
    reference_title: Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      we confirmed by Western blot analysis that FGFR1 pathway was activated in Hyp and Dmp1−/− (Fig. 5) by
      showing increased phosphorylation of FGFR1, FRS2, and PI3K in these bones.
    explanation: >-
      Protein phosphorylation was measured in mutant mouse bone; this is distinct from the cultured-cell SU5402
      intervention.
  downstream:
  - target: Increased Osteocytic FGF23 Production
    causal_link_type: DIRECT
    description: >-
      FGFR inhibition lowers the abnormal Fgf23 promoter activity and endogenous mRNA in mutant stromal-cell
      cultures.
    evidence:
    - reference: PMID:21507898
      reference_title: Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Furthermore, inhibiting FGFR signaling using SU5402 in Hyp- and Dmp1(-/-)-derived bone marrow stromal cells prevented the increase in Fgf23 mRNA expression (129- and 124-fold increase in Hyp and Dmp1(-/-) vs. 1.3-fold in Hyp+SU5402 and 2.5-fold in Dmp1(-/-)+SU5402, P<0.05)."
      explanation: >-
        SU5402 blocked induction of Fgf23 in mouse-derived marrow stromal cells cultured under osteoblast differentiation
        conditions, not in a treated whole animal.
      quote_role: PRIMARY_RESULT
- name: Increased Osteocytic FGF23 Production
  biological_scale: CELLULAR
  description: >-
    Bone Fgf23 transcription and circulating hormone are increased in Dmp1-null models. SU5402 suppresses the
    high Fgf23 expression in Dmp1-null marrow stromal cultures, supporting FGFR-dependent production. Fold
    changes vary by assay, tissue and culture condition. Human biopsies show increased bone FGF23 staining
    in affected individuals and in a carrier from one family. Mouse studies also support altered phosphate
    responsiveness and reduced cleavage of FGF23; these are not equivalent to a demonstrated human cleavage
    defect.
  cell_types:
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  genes:
  - preferred_term: FGF23
    term:
      id: hgnc:3680
      label: FGF23
  evidence:
  - reference: PMID:21507898
    reference_title: Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, inhibiting FGFR signaling using SU5402 in Hyp- and Dmp1(-/-)-derived bone marrow stromal cells prevented the increase in Fgf23 mRNA expression (129- and 124-fold increase in Hyp and Dmp1(-/-) vs. 1.3-fold in Hyp+SU5402 and 2.5-fold in Dmp1(-/-)+SU5402, P<0.05)."
    explanation: >-
      SU5402 blocked induction of Fgf23 in mouse-derived marrow stromal cells cultured under osteoblast differentiation
      conditions, not in a treated whole animal.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28005411
    reference_title: A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD)."
    explanation: Increased bone Fgf23 expression with intact, uncleaved hormone in the null mouse.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28005411
    reference_title: A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression."
    explanation: The set-point shift explains why phosphate loading drives FGF23 higher rather than correcting the disease.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In bone, DMP1 expression was absent in the homozygote but normal in the heterozygote, whereas FGF-23 expression was increased in both subjects but higher in the ARHP patient."
    explanation: >-
      Bone immunostaining was increased in the sampled affected individual and carrier; this small family comparison
      does not establish a general linear gene-dosage relationship.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Elevated Circulating Intact FGF23
    causal_link_type: DIRECT
    description: >-
      Increased bone production contributes to raised circulating intact hormone; altered processing can also
      affect circulating concentrations.
    evidence:
    - reference: PMID:17033621
      reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        The elevated circulating Fgf23 concentration in Dmp1-null mice was associated with increased bone Fgf23
        mRNA expression, as measured by real-time PCR (Fig. 2b), and increased Fgf23 mRNA levels in osteocytes,
        as measured by in situ hybridization (Fig. 2c).
      explanation: >-
        Bone and osteocyte Fgf23 expression accompanied increased circulating Fgf23 in the discovery mouse
        experiments.
  - target: FGF23-Induced Impairment of Osteoprogenitor Differentiation
    causal_link_type: DIRECT
    description: >-
      Excess FGF23 can directly suppress osteoblast-lineage differentiation in culture independently of systemic
      hypophosphatemia.
    evidence:
    - reference: PMID:37943605
      reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        In vitro, we show that FGF23 directly impaired osteoprogenitors' differentiation and that DMP1 deficiency
        contributed to impaired mineralization independent of FGF23 or Pi levels.
      explanation: >-
        Controlled cell experiments separate FGF23-dependent differentiation from the DMP1-dependent mineralization
        defect.
- name: FGF23-Induced Impairment of Osteoprogenitor Differentiation
  biological_scale: CELLULAR
  description: >-
    In Dmp1-null marrow-derived cultures, Fgf23 deletion improves osteoblast differentiation despite persistent
    DMP1-dependent mineralization failure. Recombinant FGF23 suppresses osteoblast differentiation markers
    in MC3T3-E1 cells, and FGF23-rich coculture reduces alkaline phosphatase activity. Transcriptomic pathways
    and inferred differentiation trajectories support candidate mechanisms but are not direct biochemical measurements
    or lineage tracing. A corresponding direct effect has not been established in treated human bone.
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:37943605
    reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      In vitro, we show that FGF23 directly impaired osteoprogenitors' differentiation and that DMP1 deficiency
      contributed to impaired mineralization independent of FGF23 or Pi levels.
    explanation: >-
      Controlled cell experiments separate FGF23-dependent differentiation from the DMP1-dependent mineralization
      defect.
- name: Elevated Circulating Intact FGF23
  biological_scale: ORGANISM
  description: >-
    Intact FGF23 may be elevated or inappropriately normal for the degree of hypophosphatemia. Assay type matters:
    C-terminal assays also measure fragments and must not be described as intact-only measurements. Treatment
    and sampling conditions affect interpretation. Nonadditive Phex/Dmp1 mouse phenotypes support overlapping
    regulation, without proving every function is shared.
  biological_processes:
  - preferred_term: phosphate ion homeostasis
    term:
      id: GO:0055062
      label: phosphate ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:17033625
    reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression."
    explanation: First human measurement of elevated intact FGF23 in the disorder, with the interpretation that it drives the phosphaturia.
    quote_role: PRIMARY_RESULT
  - reference: PMID:21507898
    reference_title: Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Compared to single-mutant littermates, compound-mutant Hyp/Dmp1(-/-) mice displayed nonadditive elevations of serum FGF23 (1912 ± 183, 1715 ± 178, and 1799 ± 181 pg/ml), hypophosphatemia (P(i): 6.0 ± 0.3, 5.8 ± 0.2, and 5.4 ± 0.1 mg/dl), and severity of rickets/osteomalacia (bone mineral density: -36, -36, and -30%)."
    explanation: Serum FGF23 elevation in the Dmp1-null mouse, non-additive with Phex loss.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Reduced Proximal Tubular Phosphate Reabsorption
    causal_link_type: DIRECT
    description: >-
      FGF23 acting through FGFR1c and alpha-Klotho in the proximal tubule
      removes the NaPi-IIa and NaPi-IIc cotransporters from the apical membrane.
    evidence:
    - reference: PMID:36246908
      reference_title: Osteocytes and the pathogenesis of hypophosphatemic rickets.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "FGF23 increases the excretion of inorganic phosphate (Pi) and decreases the production of 1,25-dihydroxyvitamin D in the kidneys."
      explanation: Review statement of the two renal actions of FGF23 that the next two nodes carry. Evidence source is OTHER because this is a review article.
      quote_role: REVIEW_SYNTHESIS
  - target: Suppressed Renal Calcitriol Synthesis
    causal_link_type: DIRECT
    description: FGF23 suppresses CYP27B1 and induces CYP24A1 in the proximal tubule.
    evidence:
    - reference: PMID:36246908
      reference_title: Osteocytes and the pathogenesis of hypophosphatemic rickets.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "FGF23 increases the excretion of inorganic phosphate (Pi) and decreases the production of 1,25-dihydroxyvitamin D in the kidneys."
      explanation: Same review sentence, supporting the calcitriol arm. Evidence source is OTHER because this is a review article.
      quote_role: REVIEW_SYNTHESIS
  - target: Elevated Circulating FGF23
    causal_link_type: DIRECT
    description: >-
      The measured elevation is the biochemical phenotype of excess circulating intact hormone; other patients
      have inappropriately normal values.
    evidence:
    - reference: PMID:17033625
      reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected
        individuals
      explanation: >-
        The literal high-FGF23 phenotype is documented in two individuals; no universal elevation is implied.
- name: Reduced Proximal Tubular Phosphate Reabsorption
  biological_scale: CELLULAR
  description: >-
    FGF23 reduces proximal tubular sodium-phosphate transport, causing inappropriate renal phosphate loss.
    Normocalciuria and normal calcium/PTH occur in discovery families, but are not obligatory; secondary hyperparathyroidism
    can further promote phosphate wasting. This is generally an isolated phosphate-handling defect rather than
    generalized Fanconi syndrome.
  cell_types:
  - preferred_term: proximal tubule epithelial cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  biological_processes:
  - preferred_term: tubular phosphate reabsorption
    term:
      id: GO:0097291
      label: renal phosphate ion absorption
    modifier: DECREASED
  locations:
  - preferred_term: renal proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  evidence:
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria."
    explanation: Isolated renal phosphate wasting with normocalciuria in patients, the defining renal finding.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum calcium, parathyroid hormone, and urinary calcium excretion were within the normal range, leading to clinical diagnosis of ARHR."
    explanation: Normal calcium, PTH and calciuria alongside renal phosphate loss, distinguishing this arm from calciopenic and tubulopathic causes.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed hypophosphatemia due to insufficient renal phosphate retention"
    explanation: Renal phosphate wasting documented at presentation in a child.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Chronic Hypophosphatemia
    causal_link_type: DIRECT
    description: >-
      Renal phosphate loss lowers serum phosphate relative to age-specific reference ranges; treatment may
      correct the measured concentration.
    evidence:
    - reference: PMID:20213538
      reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "characterized by hypophosphatemia resulting from renal phosphate wasting"
      explanation: States the causal step from renal wasting to hypophosphatemia.
      quote_role: BACKGROUND
- name: Suppressed Renal Calcitriol Synthesis
  biological_scale: MOLECULAR
  description: >-
    FGF23 restrains renal calcitriol production and promotes its catabolism, often leaving calcitriol inappropriately
    normal or low for hypophosphatemia. This is a regulatory effect, not an obligatory low serum value: PTH,
    age and treatment modify net concentrations. The 12-week Dmp1-null model had increased Cyp27b1 and approximately
    threefold higher calcitriol, with persistent hyperparathyroidism; a human compound-heterozygote also had
    elevated measured calcitriol.
  biological_processes:
  - preferred_term: renal 1,25-dihydroxyvitamin D synthesis
    term:
      id: GO:0042359
      label: vitamin D metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:17033625
    reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels"
    explanation: Inappropriately normal calcitriol for the degree of hypophosphatemia in the discovery families, attributed to FGF23.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical examination revealed hypophosphatemia with renal phosphate excretion and low levels of 1,25(OH)(2)D."
    explanation: Frankly low calcitriol in the Japanese siblings.
    quote_role: PRIMARY_RESULT
  - reference: PMID:37943605
    reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      At 12 weeks, Dmp1KO mice also displayed hyperparathyroidism and a surprising 3-fold increase in 1,25(OH)2D
      levels
    explanation: >-
      Adult mouse findings limit any claim that calcitriol must be low across all models or contexts.
  downstream:
  - target: Skeletal Mineralization Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced calcitriol-dependent intestinal calcium and phosphate absorption
    description: >-
      Blunted calcitriol removes the intestinal compensation that would otherwise
      partly offset renal phosphate loss, deepening the substrate deficit at the
      mineralization front.
- name: Chronic Hypophosphatemia
  conforms_to: "defective_skeletal_mineralization#Phosphopenic Substrate Deficiency"
  biological_scale: ORGANISM
  description: >-
    Inappropriately high renal phosphate loss creates a systemic substrate deficit for mineralization. Serum
    phosphate must be interpreted using age-specific ranges and treatment timing. High-phosphate diet from
    6 to 12 weeks worsened FGF23 excess, hyperparathyroidism and osteomalacia in adult Dmp1-null mice, whereas
    earlier dietary rescue improved some skeletal endpoints. These stage-dependent experiments do not replace
    clinical evidence for combined phosphate and active-vitamin-D treatment.
  chemical_entities:
  - preferred_term: phosphate
    term:
      id: CHEBI:26020
      label: phosphate
    modifier: DECREASED
  evidence:
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by hypophosphatemia resulting from renal phosphate wasting"
    explanation: Defines the systemic state this node represents.
    quote_role: BACKGROUND
  - reference: PMID:37943605
    reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia."
    explanation: The null mouse reproduces the hypophosphatemia; note that adult mice, unlike most patients, also show raised parathyroid hormone.
    quote_role: PRIMARY_RESULT
  - reference: PMID:37943605
    reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion, and osteomalacia."
    explanation: Phosphate loading alone worsens the disease in the model, consistent with the shifted set point.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Skeletal Mineralization Failure
    causal_link_type: DIRECT
    description: Low extracellular phosphate lowers the calcium-phosphate product at the mineralization front.
    evidence:
    - reference: PMID:21542006
      reference_title: Unique roles of phosphorus in endochondral bone formation and osteocyte maturation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "osteoblast extracellular matrix mineralization, growth plate maturation, secondary ossification center formation, and osteoblast differentiation are phosphate-dependent"
      explanation: Shows matrix mineralization in the Dmp1-null model is phosphate-dependent, the causal step this edge records.
      quote_role: PRIMARY_RESULT
  - target: Growth Plate Hypertrophic Zone Expansion
    causal_link_type: DIRECT
    description: >-
      Phosphate is required for apoptosis of terminal hypertrophic chondrocytes;
      the module carries this direct arm separately from matrix mineralization.
    evidence:
    - reference: PMID:21542006
      reference_title: Unique roles of phosphorus in endochondral bone formation and osteocyte maturation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "osteoblast extracellular matrix mineralization, growth plate maturation, secondary ossification center formation, and osteoblast differentiation are phosphate-dependent"
      explanation: Growth plate maturation in the Dmp1-null model is phosphate-dependent.
      quote_role: PRIMARY_RESULT
  - target: Hypophosphatemia
    causal_link_type: DIRECT
    description: The systemic state is expressed clinically as the laboratory phenotype hypophosphatemia.
  - target: Dentin Hypomineralization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic hypophosphatemia contributes to dentin hypomineralization, as in
      XLH; the relative weight of systemic phosphate and local DMP1 loss in the
      odontoblast is not resolved.
- name: Skeletal Mineralization Failure
  conforms_to: "defective_skeletal_mineralization#Impaired Hydroxyapatite Deposition at the Mineralization Front"
  biological_scale: TISSUE
  description: >-
    Insufficient phosphate availability and a DMP1-dependent matrix defect impair mineral deposition into osteoid.
    Osteomalacia can occur in children and adults; rickets is the growth-plate lesion of the growing skeleton.
    Persistent bone abnormalities after partial FGF23 reduction cannot be assigned exclusively to DMP1 because
    FGF23 remains elevated; controlled cultures more directly demonstrate the local mineralization contribution.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  locations:
  - preferred_term: bone
    term:
      id: UBERON:0001474
      label: bone element
  evidence:
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria."
    explanation: Rickets and osteomalacia, the two expressions of mineralization failure, in patients and mice.
    quote_role: PRIMARY_RESULT
  - reference: PMID:37943605
    reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice."
    explanation: The two-route structure of this node, endocrine and local, is the paper's stated conclusion.
    quote_role: PRIMARY_RESULT
  - reference: PMID:16294270
    reference_title: "DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Histological analysis and muCT 3-D images suggested that dmp1 KO mice had osteomalacia."
    explanation: Histological osteomalacia in the null mouse.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Growth Plate Hypertrophic Zone Expansion
    causal_link_type: DIRECT
    description: In the growing skeleton the mineralization defect is expressed at the growth plate.
  - target: Osteomalacia
    causal_link_type: DIRECT
    description: >-
      Failure to mineralize osteoid produces osteomalacia at any age.
    evidence:
    - reference: PMID:35896139
      reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "leading to impaired bone mineralization (rickets and osteomalacia)"
      explanation: States osteomalacia as the expression of impaired mineralization.
      quote_role: BACKGROUND
  - target: Pathologic Fractures
    causal_link_type: DIRECT
    description: >-
      Poorly mineralized bone is susceptible to pathologic fractures.
    evidence:
    - reference: PMID:20499351
      reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        patient 2 had a pathologic fracture of the left femoral neck
      explanation: >-
        Radiographic fracture in one Finnish affected adult.
  - target: Bone Pain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - osteomalacia and insufficiency injury
    description: Active osteomalacia is a pain generator; enthesopathy and deformity add others.
  - target: Pseudofractures
    causal_link_type: DIRECT
    description: >-
      Osteomalacic bone develops pseudofractures; healing after anti-FGF23 treatment supports a mineralization-related
      contribution.
    evidence:
    - reference: PMID:35896139
      reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        A computed tomography scan of the right hip and pelvis revealed marked bone demineralization, and a
        horizontal line with sclerotic edges at the level of the lesser trochanter, consistent with a pseudofracture
      explanation: >-
        Imaging documents a pseudofracture before burosumab treatment.
- name: Growth Plate Hypertrophic Zone Expansion
  conforms_to: "defective_skeletal_mineralization#Growth Plate Hypertrophic Zone Expansion"
  biological_scale: TISSUE
  description: >-
    In the growing skeleton the hypertrophic chondrocyte layer fails to
    involute, giving the expanded, disorganized growth plate with poorly
    calcified cartilage and delayed vascular invasion seen in Dmp1-null mice,
    and the widened, cupped metaphyses of rickets on radiographs. Reinstating
    DMP1 or its 57-kDa fragment in bone cells rescues the growth plate defect
    in the model.
  cell_types:
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: growth plate cartilage development
    term:
      id: GO:0003417
      label: growth plate cartilage development
    modifier: ABNORMAL
  locations:
  - preferred_term: growth plate
    term:
      id: UBERON:0002516
      label: epiphyseal plate
  evidence:
  - reference: PMID:20734454
    reference_title: The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa C-terminal fragment.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This included rescue of growth plate defects, osteomalacia, abnormal osteocyte maturation, and the abnormal osteocyte lacunocanalicular system."
    explanation: The growth plate defect of the null mouse is DMP1-dependent, since bone-cell DMP1 expression rescues it.
    quote_role: PRIMARY_RESULT
  - reference: PMID:37943605
    reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia."
    explanation: Rickets and impaired growth in the model, the tissue expression of this node.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Rickets
    causal_link_type: DIRECT
    description: The growth plate lesion is rickets.
    evidence:
    - reference: PMID:37943605
      reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia."
      explanation: Rickets accompanies the growth plate lesion in the model.
      quote_role: PRIMARY_RESULT
  - target: Short Stature
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired endochondral growth of the long bones
    description: Persistent growth plate disease shortens the limbs disproportionately.
    evidence:
    - reference: PMID:37943605
      reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia."
      explanation: Impaired growth accompanies rickets in the model, the growth consequence of the growth plate lesion.
      quote_role: PRIMARY_RESULT
  - target: Lower-Limb Bowing
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - weight bearing on rachitic bone
    description: Weight bearing on undermineralized growing bone bows the legs.
- name: Dentin Hypomineralization
  biological_scale: TISSUE
  description: >-
    Affected children in one family had thin dentin and enlarged pulp chambers, with post-eruption attrition
    and trauma-associated tooth injury. Both systemic phosphate deficit and local DMP1 loss may contribute;
    the relative mechanisms remain uncertain. Recurrent abscesses and tooth loss are documented, while a later
    single adult jaw-necrosis report does not establish the same causal pathway.
  cell_types:
  - preferred_term: odontoblast
    term:
      id: CL:0000060
      label: odontoblast
  biological_processes:
  - preferred_term: dentin mineralization
    term:
      id: GO:0097188
      label: dentin mineralization
    modifier: DECREASED
  locations:
  - preferred_term: tooth
    term:
      id: UBERON:0001091
      label: calcareous tooth
  evidence:
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent and deciduous teeth displayed enlarged pulp chambers."
    explanation: The characteristic dental finding in three affected children.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, DMP-1 mutations appear to contribute, through yet unknown mechanisms, to tooth development."
    explanation: The authors attribute the dental phenotype to DMP1 loss while leaving the mechanism open.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Dental Abscesses
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal dental structure plausibly predisposes to injury and infection; the case reports do not isolate
      its contribution from trauma and other factors.
    evidence:
    - reference: PMID:20499351
      reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        The patient had significant dental problems, with recurrent gingival abscess formation, and required
        a dental prosthesis since age 50.
      explanation: >-
        Recurrent abscesses were documented in the affected Finnish woman.
    - reference: PMID:19796717
      reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        However, after another minor trauma, his lower central incisor fractured, leading to recurrent dental
        abscesses.
      explanation: >-
        The Turkish index case developed recurrent abscesses after incisor fracture.
  - target: Premature Loss of Primary Teeth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal dentin structure contributes to the dental phenotype; the relative contributions of systemic
      phosphate and local DMP1 function remain uncertain.
    evidence:
    - reference: PMID:36334264
      reference_title: The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        The proband is a 4-year-old boy, who developed genu varum when he was able to walk at age 1 year and
        tooth loss after a mild hit at age 3.5 years.
      explanation: >-
        Early childhood tooth loss in the compound-heterozygote.
    - reference: PMID:19796717
      reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Review of the dental history of the index case (#5) revealed that the loss of deciduous central incisors
        had occurred at the age of 4.5 years after moderate trauma to the chin.
      explanation: >-
        Explicit primary-tooth loss in the Turkish index case.
  - target: Enlarged Dental Pulp Chambers
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal dentin structure contributes to the dental phenotype; the relative contributions of systemic
      phosphate and local DMP1 function remain uncertain.
    evidence:
    - reference: PMID:19796717
      reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent
        and deciduous teeth displayed enlarged pulp chambers.
      explanation: >-
        Radiographic pulp chamber enlargement in the family.
phenotypes:
- name: Rickets
  category: Skeletal
  description: >-
    Growth-plate disease in childhood, with metaphyseal widening, cupping or fraying and limb deformity. Age
    at recognition and severity vary, including later childhood presentation; published case series do not
    establish population penetrance.
  phenotype_term:
    preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  evidence:
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria."
    explanation: Rickets is the defining childhood manifestation named in the disorder itself.
    quote_role: PRIMARY_RESULT
  - reference: PMID:35896139
    reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "leading to impaired bone mineralization (rickets and osteomalacia)"
    explanation: >-
      Rickets is the skeletal mineralization manifestation described by this source.
    quote_role: BACKGROUND
- name: Osteomalacia
  category: Skeletal
  description: >-
    Impaired mineralization of osteoid in children or adults, documented by bone biopsy in selected affected
    individuals. Focal subclinical mineralization abnormalities also occur in some heterozygous carriers; these
    do not establish the same disease severity.
  phenotype_term:
    preferred_term: Osteomalacia
    term:
      id: HP:0002749
      label: Osteomalacia
  evidence:
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria."
    explanation: Osteomalacia named as a manifestation in the discovery families.
    quote_role: PRIMARY_RESULT
  - reference: PMID:32920683
    reference_title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-ray uncovered coexistence of osteomalacia and osteosclerosis."
    explanation: Radiographic osteomalacia in the Chinese cases, coexisting with sclerosis.
    quote_role: PRIMARY_RESULT
- name: Hypophosphatemia
  category: Laboratory
  description: >-
    Renal phosphate wasting generally lowers serum phosphate relative to age-specific ranges. Low-normal values
    have been reported in adults and treatment can normalize concentrations, so persistent hypophosphatemia
    at every measurement is not obligatory.
  phenotype_term:
    preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
  evidence:
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting."
    explanation: >-
      Renal phosphate wasting and hypophosphatemia characterize the disorder; treatment and sampling time affect
      measured phosphate.
    quote_role: BACKGROUND
  - reference: PMID:32920683
    reference_title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypophosphatemia, elevated alkaline phosphatase, high intact fibroblast growth factor 23 and sclerostin were found."
    explanation: Present in all five Chinese patients.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25180662
    reference_title: Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Biochemical analysis was consistent with normal serum calcium and 1-25(OH)2D levels, low to normal serum
      phosphorus and elevated PTH values.
    explanation: >-
      The two adult sisters had low-to-normal phosphate values, limiting an obligatory lifelong low-concentration
      claim.
- name: Elevated Circulating FGF23
  category: Laboratory
  description: >-
    Elevated measured FGF23 is reported, but values can remain within the assay reference interval despite
    inappropriate nonsuppression during hypophosphatemia. Intact and C-terminal assays measure different analytes.
    The phenotype term refers to actual elevation; inappropriately normal measurements support the mechanism
    rather than this literal abnormality.
  phenotype_term:
    preferred_term: Elevated circulating FGF23
    term:
      id: HP:6000407
      label: Elevated circulating fibroblast growth factor 23 concentration
  evidence:
  - reference: PMID:17033625
    reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals"
    explanation: >-
      Intact FGF23 was elevated in two of four individuals at discovery; other values were inappropriately
      normal for the hypophosphatemia.
    quote_role: PRIMARY_RESULT
  - reference: PMID:32920683
    reference_title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypophosphatemia, elevated alkaline phosphatase, high intact fibroblast growth factor 23 and sclerostin were found."
    explanation: High intact FGF23 in the Chinese series.
    quote_role: PRIMARY_RESULT
- name: Short Stature
  category: Growth
  description: >-
    Growth impairment and disproportionate short stature occur in many reported patients, but normal or tall
    adult stature is documented. Selected pooled genotype groups differed in mean height, without establishing
    an individual prognosis independent of treatment, age and family background.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:32920683
    reference_title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five Chinese patients from three unrelated pedigrees presented with lower extremity deformity and short stature."
    explanation: >-
      All five patients in these three selected families had short stature; this does not estimate population-wide
      penetrance.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients were a 53-year-old woman and a 50-year-old man with short stature and skeletal deformities who were the offspring of a first-cousin marriage."
    explanation: Short stature persisting into adulthood.
    quote_role: PRIMARY_RESULT
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The affected individual in F-2 had a final adult height of 172 cm (90th–95th percentile), 3 cm above
      the upper limit of her genetic target.
    explanation: >-
      The discovery report documents a 172-cm affected adult, showing short stature is not obligatory.
- name: Lower-Limb Bowing
  category: Skeletal
  description: >-
    Lower-limb bowing, including genu varum and sometimes genu valgum, may become apparent with walking or
    later childhood. Deformity can persist despite treatment and require orthopedic assessment.
  phenotype_term:
    preferred_term: Bowing of the legs
    term:
      id: HP:0002979
      label: Bowing of the legs
  evidence:
  - reference: PMID:35896139
    reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Short stature, prominent bowing of the legs, fractures/pseudofractures, and severe enthesopathy are prominent in this patient population."
    explanation: Bowing described as prominent across the patient population.
    quote_role: BACKGROUND
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood."
    explanation: Varus deformity from early childhood in both siblings.
    quote_role: PRIMARY_RESULT
- name: Bone Pain
  category: Musculoskeletal
  description: >-
    Chronic bone and joint pain from childhood, with osteomalacia,
    pseudofractures, enthesopathy and deformity all contributing in adults;
    improved with FGF23 neutralization in the treated brothers.
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood."
    explanation: Lifelong bone pain in both siblings.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41820620
    reference_title: Expanding the Autosomal Recessive Hypophosphatemic Rickets Type I Carrier Phenotype and Adult Treatment with Burosumab.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A variable clinical spectrum has been described in this condition, including features of rickets (in children), hyperostotic osteomalacia (in children and adults), bone pain, short stature, lower limb deformities, recurrent dental abscesses, and hearing defects."
    explanation: Bone pain among the features of the described clinical spectrum.
    quote_role: BACKGROUND
- name: Pathologic Fractures
  category: Skeletal
  description: >-
    Insufficiency/pathologic fractures occur in poorly mineralized bone, including femoral neck fractures in
    the long-followed Finnish siblings. Pseudofractures are recorded separately.
  phenotype_term:
    preferred_term: Pathologic fracture
    term:
      id: HP:0002756
      label: Pathologic fracture
  evidence:
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      patient 2 had a pathologic fracture of the left femoral neck
    explanation: >-
      Radiographic fracture in one Finnish affected adult.
- name: Enthesopathy
  category: Musculoskeletal
  description: >-
    Calcific or ossifying changes at tendon and ligament insertions can be extensive in adult ARHR1. The mechanism
    and population frequency remain unresolved. HP:0100686 denotes enthesitis and would imply inflammation
    not established by these reports.
  review_notes: >-
    NEEDS_TERM: HP:0100686 denotes inflammatory enthesitis and would
    misrepresent the calcific, ossifying enthesopathy of ARHR1; no suitably
    specific HPO term is assigned, matching the decision in the XLH entry.
  evidence:
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments."
    explanation: Radiographic enthesopathy and paraspinal ligament calcification in both adult siblings.
    quote_role: PRIMARY_RESULT
  - reference: PMID:31843680
    reference_title: "Hypophosphatemic osteosclerosis, hyperostosis, and enthesopathy associated with novel homozygous mutations of DMP1 encoding dentin matrix protein 1 and SPP1 encoding osteopontin: The first digenic SIBLING protein osteopathy?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we describe severe hypophosphatemic osteosclerosis and hyperostosis associated with skeletal deformity, short stature, enthesopathy, tooth loss, and high circulating FGF23 levels in a middle-aged man and young woman from an endogamous family living in southern India."
    explanation: Enthesopathy in a further DMP1 family; note these patients also carried a homozygous SPP1 variant, so the report is read as supporting the association rather than as a pure DMP1 case.
    quote_role: PRIMARY_RESULT
- name: Joint Contractures
  category: Musculoskeletal
  description: >-
    Progressive joint contractures were documented in the two older Finnish siblings; spinal ankylosis is recorded
    separately.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine."
    explanation: >-
      Both adults in this selected family had contractures; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
- name: Cranial Hyperostosis
  category: Skeletal
  description: >-
    Thickening of the skull vault reported in the Finnish and Lebanese adult
    sibships, and hyperostosis with osteosclerosis in the Indian family. Part
    of the paradoxical bone-overgrowth phenotype of adult ARHR1 whose mechanism
    is unexplained.
  phenotype_term:
    preferred_term: Cranial hyperostosis
    term:
      id: HP:0004437
      label: Cranial hyperostosis
  evidence:
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments."
    explanation: Significant cranial hyperostosis in both adult siblings.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25180662
    reference_title: Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients aged 45 and 47years old presented with short stature, severe genu varum, cranial hyperostosis and a very high bone density that led to a diagnosis of a familial sclerosing bone dysplasia."
    explanation: >-
      Cranial hyperostosis was reported in a second, unrelated adult sibship.
    quote_role: PRIMARY_RESULT
- name: Increased Axial Bone Density
  category: Skeletal
  description: >-
    High axial DXA areal bone mineral density occurs in selected families despite osteomalacia. One Chinese
    adult had damaged peripheral volumetric density and microstructure. Areal density does not establish normal
    material mineralization or low fracture risk; extraosseous ossification can complicate measurement.
  phenotype_term:
    preferred_term: Increased axial bone mineral density
    term:
      id: HP:0011001
      label: Increased bone mineral density
  evidence:
  - reference: PMID:32920683
    reference_title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although areal bone mineral density (aBMD) of axial bone measured by dual-energy X-ray absorptiometry was relatively high in all patients, volumetric BMD (vBMD) and microstructure of one adult patient's peripheral bone detected by HR-pQCT were damaged."
    explanation: High axial areal density in all five Chinese patients, with damaged peripheral microstructure in the one adult examined.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25180662
    reference_title: Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our cases show that some ARHR cases may develop with age an unaccountable increase in bone density and bone overgrowth."
    explanation: The sclerosing phenotype developing with age; the authors call it unaccountable, which is why it carries no causal edge.
    quote_role: PRIMARY_RESULT
- name: Dental Abscesses
  category: Dental
  description: >-
    Recurrent dental or gingival abscesses occur in some patients with abnormal dentin. They are not present
    in every affected child. Structural dental abnormalities, early tooth loss and jaw osteonecrosis are recorded
    separately.
  phenotype_term:
    preferred_term: Dental abscess
    term:
      id: HP:0030757
      label: Tooth abscess
  evidence:
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The patient had significant dental problems, with recurrent gingival abscess formation, and required
      a dental prosthesis since age 50.
    explanation: >-
      Recurrent abscesses were documented in the affected Finnish woman.
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, after another minor trauma, his lower central incisor fractured, leading to recurrent dental
      abscesses.
    explanation: >-
      The Turkish index case developed recurrent abscesses after incisor fracture.
- name: Hearing Impairment
  category: Sensory
  description: >-
    Hearing defects are part of the described spectrum, reported in severe
    adult disease; one adolescent had normal hearing. Frequency and mechanism
    (skull base sclerosis versus sensorineural) are not established.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:41820620
    reference_title: Expanding the Autosomal Recessive Hypophosphatemic Rickets Type I Carrier Phenotype and Adult Treatment with Burosumab.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A variable clinical spectrum has been described in this condition, including features of rickets (in children), hyperostotic osteomalacia (in children and adults), bone pain, short stature, lower limb deformities, recurrent dental abscesses, and hearing defects."
    explanation: Hearing defects listed in the described spectrum; no frequency is assigned.
    quote_role: BACKGROUND
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She has a hearing deficit.
    explanation: >-
      Direct observation in the Finnish affected woman; no hearing-loss subtype is specified.
- name: Elevated Alkaline Phosphatase
  category: Laboratory
  description: >-
    Alkaline phosphatase often rises with active rickets or osteomalacia, but normal values have been documented.
    Interpret age-specific ranges and consider a bone-specific assay when liver disease confounds total ALP.
    Treatment response includes clinical findings as well as biochemical trends.
  phenotype_term:
    preferred_term: Elevated serum alkaline phosphatase
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum alkaline phosphatase activity was elevated, with initially normal PTH."
    explanation: Elevated ALP with normal PTH at presentation.
    quote_role: PRIMARY_RESULT
  - reference: PMID:32920683
    reference_title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypophosphatemia, elevated alkaline phosphatase, high intact fibroblast growth factor 23 and sclerostin were found."
    explanation: Elevated in all five patients of the Chinese series.
    quote_role: PRIMARY_RESULT
  - reference: PMID:39011543
    reference_title: Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Biochemical tests revealed hypophosphatemia (0.71 mmol/L, normal 0.80–1.5), normal alkaline phosphatase
      (105 IU/L, normal 48–130 IU/L), increased parathyroid hormone (10.3 pmol/L, normal 1.6–6.9 pmol/L), and
      normal 25-hydroxyvitamin D (54.5 nmol/L, normal 30–100 nmol/L) and calcium (2.4 mmol/L, normal 2.2–2.6
      mmol/L).
    explanation: >-
      The DMP1 p.Tyr374Ter adolescent had normal ALP during long-term treatment and elevated PTH.
- name: Pseudofractures
  category: Skeletal
  description: >-
    Looser-zone pseudofractures occur in osteomalacic bone. In one burosumab-treated adult, a lesser-trochanter
    pseudofracture nearly healed after five months; this is a case-level observation.
  evidence:
  - reference: PMID:35896139
    reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A computed tomography scan of the right hip and pelvis revealed marked bone demineralization, and a horizontal
      line with sclerotic edges at the level of the lesser trochanter, consistent with a pseudofracture
    explanation: >-
      Imaging documents a pseudofracture before burosumab treatment.
  phenotype_term:
    preferred_term: Pseudo-fractures
    term:
      id: HP:0100036
      label: Pseudo-fractures
- name: Paraspinal Ligament Ossification
  category: Musculoskeletal
  description: >-
    Calcification or ossification of spinal ligaments can accompany severe adult disease. Posterior longitudinal
    ligament ossification has caused cervical canal stenosis.
  evidence:
  - reference: PMID:35896139
    reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      there was ossification of the posterior longitudinal ligament (seeFig.1A) resulting in canal stenosis
      throughout the cervical spine
    explanation: >-
      CT findings in the 50-year-old treated brother.
  phenotype_term:
    preferred_term: Ectopic ossification
    term:
      id: HP:0011986
      label: Ectopic ossification
- name: Spinal Ankylosis
  category: Musculoskeletal
  description: >-
    Extensive spinal ankylosis and restricted spinal mobility occur in severe adult cases.
  evidence:
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She has complete spinal ankylosis with calcification of the spinal ligaments and dural ectasia, lower
      limb deformities, and contractures.
    explanation: >-
      Clinical description of the affected Finnish woman.
  phenotype_term:
    preferred_term: Ankylosis
    term:
      id: HP:0031013
      label: Ankylosis
- name: Generalized Osteosclerosis
  category: Skeletal
  description: >-
    Radiographic osteosclerosis has been reported alongside impaired mineralization. The Indian two-patient
    report also carried an SPP1 VUS, and its decalcified biopsy could not establish osteomalacia histologically.
  evidence:
  - reference: PMID:31843680
    reference_title: "Hypophosphatemic osteosclerosis, hyperostosis, and enthesopathy associated with novel homozygous mutations of DMP1 encoding dentin matrix protein 1 and SPP1 encoding osteopontin: The first digenic SIBLING protein osteopathy?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Both our patients manifested osteosclerosis and hyperostosis, enthesopathy, tooth loss, and findings
      in keeping with severe rickets during childhood together with elevated circulating levels of FGF23, renal
      Pi wasting, and hypophosphatemia.
    explanation: >-
      Generalized radiographic sclerosis in two related DMP1 cases; the additional SPP1 variant is a possible,
      unproven modifier.
  phenotype_term:
    preferred_term: Generalized osteosclerosis
    term:
      id: HP:0005789
      label: Generalized osteosclerosis
- name: Premature Loss of Primary Teeth
  category: Dental
  description: >-
    Primary incisors were lost after mild or moderate trauma in reported children. This does not establish
    spontaneous loss or a frequency estimate.
  evidence:
  - reference: PMID:36334264
    reference_title: The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The proband is a 4-year-old boy, who developed genu varum when he was able to walk at age 1 year and
      tooth loss after a mild hit at age 3.5 years.
    explanation: >-
      Early childhood tooth loss in the compound-heterozygote.
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Review of the dental history of the index case (#5) revealed that the loss of deciduous central incisors
      had occurred at the age of 4.5 years after moderate trauma to the chin.
    explanation: >-
      Explicit primary-tooth loss in the Turkish index case.
  phenotype_term:
    preferred_term: Premature loss of primary teeth
    term:
      id: HP:0006323
      label: Premature loss of primary teeth
- name: Enlarged Dental Pulp Chambers
  category: Dental
  description: >-
    Enlarged pulp chambers with thin dentin were documented in three Turkish relatives. This is not equivalent
    to a proven taurodontism pattern.
  evidence:
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent
      and deciduous teeth displayed enlarged pulp chambers.
    explanation: >-
      Radiographic pulp chamber enlargement in the family.
  phenotype_term:
    preferred_term: Abnormal dental pulp morphology
    term:
      id: HP:0006479
      label: Abnormal dental pulp morphology
- name: Osteonecrosis of the Jaw
  category: Dental
  description: >-
    An unusual jaw osteonecrosis finding was reported in one affected adult. The accessible abstract does not
    establish etiology, frequency or temporal attribution to burosumab.
  evidence:
  - reference: PMID:41820620
    reference_title: Expanding the Autosomal Recessive Hypophosphatemic Rickets Type I Carrier Phenotype and Adult Treatment with Burosumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The purpose of this report is to describe the clinical evolution in an adult with a bi-allelic, loss
      of function pathogenic variant in DMP1 who developed an unusual feature of the condition—osteonecrosis
      of the jaw—as well as her clinical response to conventional therapy (phosphate supplementation and active
      vitamin D) followed by burosumab.
    explanation: >-
      Single affected-adult observation; abstract-only access limits etiologic and treatment-outcome inference.
  review_notes: >-
    NEEDS_TERM: a jaw-specific osteonecrosis binding was not found. Avascular necrosis would add an unestablished
    ischemic mechanism.
genetic:
- name: Biallelic DMP1 Pathogenic Variants
  gene_term:
    preferred_term: DMP1
    term:
      id: hgnc:2932
      label: DMP1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:17033625
      reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes."
      explanation: Recessive mapping with homozygous DMP1 mutations.
      quote_role: PRIMARY_RESULT
  notes: >-
    Reported DMP1 alleles include nonsense, frameshift, splice-site and start-codon variants, a deletion of
    at least 49 kb removing exons 3–6 and adjacent sequence, and a larger deletion spanning DSPP, DMP1, IBSP
    and part of MEPE in trans with c.1A>T. Start-codon variants are start-loss alleles: historical p.Met1Val/p.Met1Leu
    notation does not imply simple replacement in an otherwise intact protein. c.1A>T permits downstream initiation
    and secretion of a shorter protein with altered processing in vitro. c.730G>T (p.Glu244Ter) and c.1122T>G
    (p.Tyr374Ter) were reported in separate Chinese and adolescent cases. Selected pooled genotype-phenotype
    associations do not establish causal severity rules. Normal carrier examinations occur alongside subclinical
    biochemical or biopsy findings in some families; biallelic penetrance is not quantified.
  evidence:
  - reference: PMID:17033625
    reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes."
    explanation: Linkage mapping and homozygous mutation identification establishing DMP1 as the causal gene.
    quote_role: PRIMARY_RESULT
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus."
    explanation: Independent simultaneous identification of the gene with two allele classes.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19007919
    reference_title: Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At a minimum, this deletion encompassed 49 kb between DMP1 exon 3 and an intergenic region 5' to the next telomeric gene, integrin-binding sialoprotein (IBSP)."
    explanation: A large biallelic deletion, confirming loss of function as the mechanism.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis of peripheral leukocytes from the patients revealed that they carried a novel homozygous nonsense mutation in the DMP1 gene (98G>A, W33X), which leads to a truncated DMP protein with no putative biological function."
    explanation: Nonsense allele in the Japanese family.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel homozygous frame-shift mutation (c.485Tdel; p.Glu163ArgfsX53) in exon 6 resulting in a premature stop codon was identified in all effected individuals."
    explanation: Frameshift allele in the Turkish kindred.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nucleotide sequence analysis of DMP1 revealed a novel homozygous mutation at the splice acceptor junction of exon 6 (IVS5-1G > A)."
    explanation: Splice-site allele in the Finnish family.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25180662
    reference_title: Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous mutation disrupting the initiation codon of the DMP1 gene (OMIM 600980), NM_001079911.2: c.1A>G, p.Met1Val, was identified by exome sequencing and confirmed by Sanger sequencing."
    explanation: Recurrent start-codon allele in the Lebanese family.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36334264
    reference_title: The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES performed on the proband revealed a novel start codon mutation (c.1A > T, p.Met1Leu) in DMP1 and a large deletion involving most of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family gene, including DSPP, DMP1, IBSP, and MEPE."
    explanation: Compound heterozygosity for a start-codon variant and a multigene deletion.
    quote_role: PRIMARY_RESULT
  - reference: PMID:32920683
    reference_title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analyses of DMP1 revealed three homozygous mutations including two novel mutations, c.54 + 1G > C and c.94C > A (p.E32X), and a reported mutation c.184-1G > A."
    explanation: Three further homozygous alleles in the Chinese families.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41820620
    reference_title: Expanding the Autosomal Recessive Hypophosphatemic Rickets Type I Carrier Phenotype and Adult Treatment with Burosumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, we describe deep phenotyping in ARHR1 carriers from two unrelated kindreds who had normal clinical and serum biochemical profiles but lumbar spine bone mineral density (BMD) Z-scores that, while attenuated relative to fully affected family members, were considerably higher than a family member with two normal alleles."
    explanation: Subclinical carrier phenotype, recorded so the recessive label is not read as heterozygotes being biologically normal.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.spandidos-publications.com/10.3892/ijmm.2018.3730/download
    reference_title: https://www.spandidos-publications.com/10.3892/ijmm.2018.3730/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The homozygous c.730G>T mutation from the DMP1 gene was found in patient 8, although both of his parents
      were heterozygous carriers.
    explanation: >-
      The publisher full text of Gu et al. 2018 (PMID:29901142) establishes the homozygous nonsense variant
      and segregation to carrier parents.
  - reference: PMID:39011543
    reference_title: Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Genetic testing showed a homozygous pathogenic variant in DMP1 (c.1122 T > G, p.(Tyr374*)) confirming
      a genetic diagnosis of autosomal recessive hypophosphatemic rickets.
    explanation: >-
      The 17-year-old with persistent deformity had this DMP1 nonsense variant.
biochemical:
- name: Serum Phosphate
  presence: Decreased below the age-related reference range
  context: >-
    Fasting, interpreted against age-specific intervals; in the pooled series
    mean serum phosphate was 0.70 mmol/L with C-terminal alleles and 0.84
    mmol/L with N-terminal alleles.
  evidence:
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical examination revealed hypophosphatemia with renal phosphate excretion and low levels of 1,25(OH)(2)D."
    explanation: The core biochemical finding.
    quote_role: PRIMARY_RESULT
- name: Renal Phosphate Wasting (TmP/GFR)
  presence: Decreased tubular reabsorption of phosphate despite hypophosphatemia
  context: >-
    Paired fasting serum and urine phosphate and creatinine give TmP/GFR;
    phosphate wasting is isolated, without glycosuria, aminoaciduria or
    acidosis, and with normal calcium excretion.
  evidence:
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed hypophosphatemia due to insufficient renal phosphate retention"
    explanation: Renal phosphate wasting documented at presentation.
    quote_role: PRIMARY_RESULT
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria"
    explanation: Isolated wasting with normocalciuria distinguishes it from generalized tubulopathy and from calciopenic rickets.
    quote_role: PRIMARY_RESULT
- name: Intact FGF23
  presence: Elevated or inappropriately normal for the degree of hypophosphatemia
  specificity: >-
    Interpret in relation to phosphate, assay and treatment. Intact FGF23 and C-terminal FGF23 are not interchangeable:
    C-terminal assays detect fragments as well as full-length hormone. Neither establishes the causal gene.
    Burosumab affects assay interpretation, so serial measured FGF23 is not a reliable treatment-response target.
  evidence:
  - reference: PMID:17033625
    reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals"
    explanation: Elevated in half of the discovery cohort, inappropriately normal in the rest.
    quote_role: PRIMARY_RESULT
- name: 1,25-Dihydroxyvitamin D
  presence: Often inappropriately normal or low; elevated values can occur
  context: >-
    FGF23 restrains calcitriol synthesis and increases catabolism, but net levels depend on PTH, age and treatment.
    Elevated calcitriol was measured in the compound-heterozygote and in adult Dmp1-null mice.
  evidence:
  - reference: PMID:17033625
    reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels"
    explanation: Inappropriately normal calcitriol in the discovery families.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical examination revealed hypophosphatemia with renal phosphate excretion and low levels of 1,25(OH)(2)D."
    explanation: Frankly low calcitriol in the Japanese siblings.
    quote_role: PRIMARY_RESULT
- name: Alkaline Phosphatase
  presence: Elevated with active rickets or osteomalacia
  context: >-
    Interpret with age-specific ranges and clinical response. Total ALP may reflect liver disease; bone-specific
    measurements can help. During conventional treatment, normalization of serum phosphate is not the sole
    therapeutic target.
  evidence:
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum alkaline phosphatase activity was elevated, with initially normal PTH."
    explanation: Elevated ALP at diagnosis.
    quote_role: PRIMARY_RESULT
- name: Parathyroid Hormone and Calcium
  presence: Calcium and PTH may be normal; secondary hyperparathyroidism or hypocalcemia can occur
  context: >-
    Normal PTH supports a phosphopenic pattern but does not distinguish all cases. Elevated PTH occurs in affected
    children and adults and can reflect phosphate treatment, inadequate calcium/vitamin D or the disease context.
    Monitor both minerals and PTH during therapy.
  evidence:
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum calcium, parathyroid hormone, and urinary calcium excretion were within the normal range, leading to clinical diagnosis of ARHR."
    explanation: Normal calcium, PTH and calciuria in the Japanese siblings.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25180662
    reference_title: Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical analysis was consistent with normal serum calcium and 1-25(OH)2D levels, low to normal serum phosphorus and elevated PTH values."
    explanation: Elevated PTH in the Lebanese adult sisters, the exception that the presence field records.
    quote_role: PRIMARY_RESULT
diagnosis:
- name: Clinical and Biochemical Evaluation for FGF23-Mediated Phosphate Wasting
  diagnosis_term:
    preferred_term: Clinical Evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  description: >-
    Evaluate rickets, limb deformity or adult osteomalacia with age-adjusted fasting serum phosphate, paired
    urine/serum measurements for renal phosphate handling, calcium, ALP, PTH, vitamin D status, renal function
    and FGF23 interpreted by assay. Normal calcium/PTH and inappropriately normal or low calcitriol are common
    patterns, not requirements. A recessive pedigree is suggestive but absent family history does not exclude
    compound heterozygosity. Assess generalized tubular abnormalities, nutritional causes and other genetic
    phosphate-wasting disorders.
  results: >-
    Inappropriate renal phosphate loss and nonsuppressed FGF23 support an FGF23-mediated disorder; molecular
    testing distinguishes DMP1 from phenocopies.
  evidence:
  - reference: PMID:20213538
    reference_title: A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum calcium, parathyroid hormone, and urinary calcium excretion were within the normal range, leading to clinical diagnosis of ARHR."
    explanation: The biochemical pattern that led to the clinical diagnosis before sequencing.
    quote_role: PRIMARY_RESULT
- name: DMP1 Molecular Genetic Testing
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Confirm biallelic pathogenic or likely pathogenic DMP1 variants, with segregation/phase assessment. Use
    a hereditary hypophosphatemia panel or exome analysis that includes copy-number detection, with orthogonal
    confirmation of deletions when indicated. A deletion may make the remaining allele appear homozygous; discordant
    parental segregation should prompt investigation. A VUS alone is not diagnostic. Broader analysis helps
    distinguish PHEX, FGF23, ENPP1, FAM20C and transporter-gene disease.
  results: Homozygous or compound heterozygous pathogenic DMP1 variants, with deletion analysis.
  evidence:
  - reference: PMID:36334264
    reference_title: The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The maternally inherited deletion was validated by Cytoscan and qPCR, and the breakpoint was finally identified by long-range PCR and Sanger sequencing."
    explanation: Shows that copy-number analysis was needed to find the second allele.
    quote_role: PRIMARY_RESULT
  - reference: PMID:39011543
    reference_title: Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our cases prompt consideration of the (i) frequent misdiagnosis of hypophosphatemic rickets in clinical practice and the importance of comprehensive genetic testing"
    explanation: Real-world series including a DMP1 case, arguing for comprehensive rather than restricted testing.
    quote_role: PRIMARY_RESULT
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6806102
    reference_title: "https://oup.silverchair-cdn.com/article-minimal/6806102"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      this mutation was absent in the proband’s mother (I-2), suggesting that the existence of the CNV in the
      proband that he might have inherited from his mother made the mutation appear homozygous in the proband.
    explanation: >-
      The apparently homozygous start-codon call was resolved to paternal sequence variant plus maternal deletion
      by copy-number and segregation studies.
differential_diagnoses:
- name: X-Linked Hypophosphatemia
  disease_term:
    preferred_term: X-linked dominant hypophosphatemic rickets
    term:
      id: MONDO:0010619
      label: X-linked dominant hypophosphatemic rickets
  description: >-
    The common FGF23-mediated phosphate-wasting rickets, biochemically
    indistinguishable from ARHR1; PHEX and DMP1 restrain FGF23 through a common
    osteocyte pathway.
  distinguishing_features:
  - X-linked dominant pedigree with affected heterozygous females, versus unaffected carrier parents.
  - PHEX rather than biallelic DMP1 variants.
  - The adult hyperostotic-osteosclerotic and severe enthesopathic phenotype is more prominent in ARHR1 families.
  evidence:
  - reference: PMID:21507898
    reference_title: Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings indicate that PHEX and DMP1 control a common pathway regulating bone mineralization and FGF23 production, the latter involving activation of the FGFR signaling in osteocytes."
    explanation: Explains why the two disorders are biochemically alike and must be separated by pedigree and genotype.
    quote_role: PRIMARY_RESULT
- name: Autosomal Recessive Hypophosphatemic Rickets 2
  disease_term:
    preferred_term: ENPP1-related autosomal recessive hypophosphatemic rickets
    term:
      id: MONDO:0013219
      label: hypophosphatemic rickets, autosomal recessive, 2
  description: >-
    The ENPP1-related recessive form, with the same FGF23-driven renal
    phenotype but a different initiating lesion in pyrophosphate metabolism.
  distinguishing_features:
  - Biallelic ENPP1 rather than DMP1 variants.
  - ENPP1 disease spans neonatal arterial calcification to rickets or osteoporosis; arterial calcification is not a feature of ARHR1.
  evidence:
  - reference: PMID:42412262
    reference_title: "When X Does Not Mark the Spot: Autosomal Dominant and Recessive Forms of Renal Hypophosphatemic Rickets and Osteomalacia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Variants in multiple genes cause dominant (FGF23, SGK3, FGFR1), recessive (DMP1, ENPP1, FAM20C, INPPL1) or even somatic (NRAS, HRAS, GNAS, gene fusions) conditions of FGF23 excess, with important phenotypic differences."
    explanation: Places DMP1 and ENPP1 as separate recessive causes of FGF23 excess. Evidence source is OTHER because this is a review article.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:42412262
    reference_title: "When X Does Not Mark the Spot: Autosomal Dominant and Recessive Forms of Renal Hypophosphatemic Rickets and Osteomalacia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ENPP1 variants cause phenotypes ranging from severe neonatal vascular calcifications to rickets or osteoporosis"
    explanation: The vascular calcification spectrum that separates ARHR2 clinically. Evidence source is OTHER because this is a review article.
    quote_role: REVIEW_SYNTHESIS
- name: Sclerosing Bone Dysplasias
  description: >-
    Adult ARHR1 with cranial hyperostosis and high axial bone density has been
    misdiagnosed as a familial sclerosing bone dysplasia and worked up for
    osteopetrosis.
  distinguishing_features:
  - Hypophosphatemia with renal phosphate wasting and elevated FGF23 are absent in the primary sclerosing dysplasias.
  - Childhood rickets and osteomalacia precede the sclerosis.
  evidence:
  - reference: PMID:25180662
    reference_title: Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular analysis of known genes involved in osteopetrosis showed normal results."
    explanation: The sisters were first investigated as a sclerosing dysplasia before exome sequencing found DMP1.
    quote_role: PRIMARY_RESULT
treatments:
- name: Oral Phosphate with Active Vitamin D
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Divided oral phosphate with calcitriol or alfacalcidol is conventional treatment for FGF23-mediated rickets,
    including ARHR1. Adjust treatment to growth, symptoms, healing and ALP/PTH while monitoring calcium, urinary
    calcium and renal function; sustained normal phosphate is not the sole target. Clinical reports document
    healing of rickets but variable growth and residual disease. Gastrointestinal intolerance, hypercalciuria,
    nephrocalcinosis and hyperparathyroidism limit treatment. Adult mouse phosphate loading without active
    vitamin D worsened disease under that protocol; this does not by itself define a human regimen.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: phosphate
      term:
        id: CHEBI:26020
        label: phosphate
    - preferred_term: calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
    - preferred_term: alfacalcidol
      term:
        id: CHEBI:31186
        label: alfacalcidol
  target_mechanisms:
  - target: Chronic Hypophosphatemia
    treatment_effect: MODULATES
    description: Divided phosphate doses transiently raise available phosphate without correcting the upstream FGF23 excess or the lowered set point.
  - target: Suppressed Renal Calcitriol Synthesis
    treatment_effect: BYPASSES
    description: >-
      Active vitamin D supports intestinal mineral absorption in the setting of FGF23-mediated suppression
      of renal calcitriol production; measured calcitriol is not invariably low.
  - target: Skeletal Mineralization Failure
    treatment_effect: MODULATES
    description: Together phosphate and active vitamin D partly improve rickets and osteomalacia.
    evidence:
    - reference: PMID:35896139
      reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Traditionally, treatment consists of oral phosphate replacement and the addition of calcitriol but this approach is limited by modest efficacy and potential renal and gastrointestinal side effects."
      explanation: Conventional therapy acts on the mineralization defect with modest efficacy, which is what the MODULATES effect records.
      quote_role: BACKGROUND
  evidence:
  - reference: PMID:35896139
    reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Traditionally, treatment consists of oral phosphate replacement and the addition of calcitriol but this approach is limited by modest efficacy and potential renal and gastrointestinal side effects."
    explanation: States the conventional regimen for ARHR1 and its limits.
    quote_role: BACKGROUND
  - reference: PMID:35352187
    reference_title: "Rickets guidance: part II-management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Fibroblast-growth factor 23 (FGF23)-associated hypophosphatemic rickets was historically treated with frequent doses of oral phosphate salts in combination with active vitamin D, whereas tumor-induced osteomalacia (TIO) should primarily undergo tumor resection, if possible."
    explanation: Guidance for the FGF23-associated class to which ARHR1 belongs. Evidence source is OTHER because this is a guidance document.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:35352187
    reference_title: "Rickets guidance: part II-management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Adjustment of medication should be done with consideration of treatment-associated side effects, including diarrhea, gastrointestinal discomfort, hypercalciuria, secondary hyperparathyroidism, and development of nephrocalcinosis or nephrolithiasis."
    explanation: The monitoring trade-off of conventional therapy. Evidence source is OTHER because this is a guidance document.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:37943605
    reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion, and osteomalacia."
    explanation: Model evidence that phosphate loading alone is counterproductive in DMP1 deficiency.
    quote_role: PRIMARY_RESULT
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Resolution of rickets and normalization of alkaline phosphatase were observed during treatment with phosphate
      supplementation and calcitriol; however, the TmP/GFR remained low.
    explanation: >-
      Observed response in the discovery families supports clinical benefit without establishing complete correction
      of all skeletal disease.
- name: Burosumab
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    FGF23-neutralizing antibody used off-label for ARHR1 in specialist care. The August 2025 US label covers
    XLH from six months and unresectable or unlocalizable phosphaturic-mesenchymal-tumor-associated TIO from
    two years; it does not include ARHR1. Two adult brothers receiving monthly treatment had improved pain/function
    and phosphate, with near-healing of one pseudofracture after five months. The younger brother still had
    subnormal phosphate before the next dose; improvement in mouth opening followed concurrent corrective surgery
    and does not establish reversal of ossification by the drug. Follow-up was one and two years, with no reported
    adverse effects; these cases cannot establish long-term safety or pediatric efficacy. A later adult report
    describes treatment after conventional therapy, but its available abstract does not quantify response.
    Genetic reduction of osteocytic FGF23 in mice is not equivalent to antibody treatment and left residual
    FGF23 excess and skeletal defects.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: burosumab
      term:
        id: NCIT:C119744
        label: Burosumab
  target_mechanisms:
  - target: Elevated Circulating Intact FGF23
    treatment_effect: INHIBITS
    description: Burosumab binds circulating FGF23 and blocks its renal phosphaturic and calcitriol-suppressing actions.
    evidence:
    - reference: PMID:35896139
      reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Monthly administration of burosumab to 2 brothers afflicted with the disorder resulted in normalization of serum phosphate, healing of pseudofracture, diminished fatigue, less bone pain, and reduced incapacity arising from the extensive enthesopathy and soft tissue fibrosis/calcification that characterizes this disorder."
      explanation: Phosphate normalized when FGF23 was neutralized, the on-target effect in ARHR1 patients.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:35896139
    reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The advent of burosumab (Crysvita), a fully humanized monoclonal antibody to FGF23 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, offers a unique opportunity to evaluate its safety and efficacy in patients with ARHR1."
    explanation: >-
      Historical background motivating ARHR1 treatment, not the current regulatory authority.
    quote_role: BACKGROUND
  - reference: PMID:35896139
    reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No adverse effects were reported following burosumab administration."
    explanation: Short-term tolerability in two patients; not a safety study.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41820620
    reference_title: Expanding the Autosomal Recessive Hypophosphatemic Rickets Type I Carrier Phenotype and Adult Treatment with Burosumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as her clinical response to conventional therapy (phosphate supplementation and active vitamin D) followed by burosumab"
    explanation: A further adult treated with burosumab after conventional therapy.
    quote_role: PRIMARY_RESULT
  - reference: PMID:37943605
    reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In contrast, osteocyte-specific deletion of Fgf23 resulted in a partial correction of FGF23 excess, which was sufficient to fully restore serum Pi levels but only partially corrected the bone phenotype."
    explanation: Genetic FGF23 removal in the model corrects phosphate but not all of the bone, the caution recorded in the description.
    quote_role: PRIMARY_RESULT
  - reference: PMID:35896139
    reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      At the time, 5 months into the treatment with burosumab, the hip pain had diminished significantly and
      a repeat radiographic examination revealed near-complete healing of the pseudofracture (seeFig. 2D, right
      panel).
    explanation: >-
      Five-month pseudofracture response in the younger brother; uncontrolled individual observation.
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761068s009lbl.pdf
    reference_title: "https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761068s009lbl.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      CRYSVITA is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients
      6 months of age and older. 1.2 Tumor-induced Osteomalacia CRYSVITA is indicated for the treatment of
      FGF23- related hypophosphatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal
      tumors that cannot be curatively resected or localized in adult and pediatric patients 2 years of age
      and older.
    explanation: >-
      Complete US indication list in the August 2025 label; ARHR1 use falls outside these indications.
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761068s009lbl.pdf
    reference_title: "https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761068s009lbl.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Prior to starting CRYSVITA, discontinue oral phosphate and/or active vitamin D analogs for one week
    explanation: >-
      Label instruction to stop phosphate/active vitamin D before starting; the contraindications section also
      prohibits concomitant use.
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761068s009lbl.pdf
    reference_title: "https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761068s009lbl.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Increases in serum calcium have been reported in patients treated with CRYSVITA. Patients with risk factors
      such as, pre-existing hyperparathyroidism, prolonged immobilization, dehydration, hypervitaminosis D,
      or renal impairment, are at higher risk of hypercalcemia. Monitor these patients for serum calcium and
      parathyroid hormone levels before and during CRYSVITA treatment for moderate to severe hypercalcemia.
      In patients with moderate to severe hypercalcemia, CRYSVITA should not be administered until hypercalcemia
      is adequately managed.
    explanation: >-
      2025 hypercalcemia warning applies to specialist safety assessment; ARHR1-specific safety has not been
      established.
  - reference: PMID:35352187
    reference_title: "Rickets guidance: part II-management."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Monitoring of FGF23 serum levels is not recommended in patients on burosumab treatment, as current assays
      cannot discriminate between burosumab-bound and free FGF23, resulting in unreliable results [21].
    explanation: >-
      Guidance explains assay interference; fasting phosphate and clinical/mineral measurements guide monitoring.
  notes: >-
    If used off-label, apply specialist monitoring and the product safety restrictions: stop oral phosphate
    and active vitamin D analogs one week before initiation and do not coadminister them; avoid use with normal/high
    baseline fasting phosphate or severe renal impairment. Monitor fasting phosphate with attention to dose
    timing, calcium/PTH, urine calcium and renal status. Hyperphosphatemia/nephrocalcinosis and hypercalcemia
    are relevant risks, especially with hyperparathyroidism, immobilization, dehydration or renal impairment.
    FGF23 measurements can be misleading because assays may detect antibody-bound hormone; the 2022 guidance
    advises against using them to monitor burosumab.
- name: Corrective Orthopedic Surgery
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    Osteotomy or guided growth for persistent lower-limb deformity after
    metabolic treatment has been optimized, and fracture fixation, joint
    replacement or spinal decompression in adults with advanced disease. The
    Finnish patient underwent osteotomies from age six and more than thirty
    orthopedic procedures over her life. Surgery does not alter the
    biochemical disease.
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Bowing of the legs
    term:
      id: HP:0002979
      label: Bowing of the legs
  evidence:
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Lower limb osteotomies were first performed at age 6 years, and subsequently, numerous (>30) orthopedic
      procedures were needed to correct lower limb deformities, to repair bilateral femoral neck fractures,
      and to treat cervical spinal stenosis.
    explanation: >-
      Direct operative history in an affected adult supports surgery for established deformity and disability.
- name: Dental Surveillance and Care
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: >-
    Regular dental examination after tooth eruption and prompt treatment of infection or abscess address the
    documented dentin/pulp abnormalities. Twice-yearly review is suggested by general rickets guidance and
    extrapolated to ARHR1; no ARHR1-specific surveillance trial establishes an optimal interval. Dental and
    metabolic teams should coordinate care.
  treatment_term:
    preferred_term: Dental Procedure
    term:
      id: NCIT:C38052
      label: Dental Procedure
  target_phenotypes:
  - preferred_term: Tooth abscess
    term:
      id: HP:0030757
      label: Tooth abscess
  evidence:
  - reference: PMID:19796717
    reference_title: Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent and deciduous teeth displayed enlarged pulp chambers."
    explanation: The structural dental defect that makes surveillance necessary. Indirect, since the source documents the finding rather than the care.
    quote_role: PRIMARY_RESULT
  - reference: PMID:35352187
    reference_title: "Rickets guidance: part II-management."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Dental examinationTwice-yearly after tooth eruptionTwice-yearlyTwice-yearly
    explanation: >-
      Table 1 recommends twice-yearly dental examination in children requiring long-term rickets treatment;
      applied as class-level guidance.
- name: Genetic Counseling and Family Testing
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    When both parents carry a pathogenic DMP1 allele, each pregnancy has a 25% risk of biallelic disease, 50%
    chance of carrier status and 25% chance of inheriting neither familial allele. Confirm parental segregation
    and offer targeted family and reproductive-partner testing with genetic counseling. Evaluate at-risk children
    early. Apparent homozygosity without the expected parental allele requires consideration of a deletion,
    as demonstrated in a compound-heterozygous family. Mild findings in selected carriers do not establish
    dominant ARHR1 or a universal carrier-surveillance protocol.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36315908
    reference_title: First report in Argentina of a pathogenic DMP1 variant associated with autosomal recessive hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      In recessive forms, both parents are carriers and the risk of recurrence is 25% for new children of the
      couple.
    explanation: >-
      Conditional recurrence risk for a couple in which both parents carry an ARHR1 allele.
  - reference: PMID:39011543
    reference_title: Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hypophosphatemic rickets, which is often hereditary, is still under- or misdiagnosed in both children and adults, denying these individuals access to optimal management and genetic counseling."
    explanation: Misdiagnosis denies families counselling, the reason molecular diagnosis is sought.
    quote_role: BACKGROUND
- name: Metabolic and Renal Surveillance
  action_category: MONITORING
  description: >-
    Monitor growth, limb alignment, pain, mobility, dental status and hearing symptoms alongside age-adjusted
    phosphate, ALP, calcium, PTH, renal function, vitamin D status and urinary calcium. General rickets guidance
    suggests kidney ultrasonography every one to two years during phosphate, active vitamin D or burosumab
    treatment, adjusted to individual findings. Biochemical improvement alone does not exclude progressive
    enthesopathy or skeletal disability.
  evidence:
  - reference: PMID:35352187
    reference_title: "Rickets guidance: part II-management."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate,
      calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets,
      parathyroid hormone, 25-hydroxyvitamin D3, and calciuria.
    explanation: >-
      General management guidance applies to long-term monitoring of ARHR1.
  - reference: PMID:35352187
    reference_title: "Rickets guidance: part II-management."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Kidney ultrasonographyEvery 1–2 years on phosphate, active vitamin D or burosumab treatment
    explanation: >-
      Table 1 surveillance interval, extrapolated from general rickets guidance.
- name: Cinacalcet (Reported Adjunctive Trial)
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    One adult received adjunctive cinacalcet with active/native vitamin D and dietary calcium before burosumab.
    PTH fell and phosphate trended upward, but the authors judged the changes clinically minor; higher doses
    were not tolerated and treatment stopped. This unsuccessful individual treatment course does not establish
    routine efficacy or an ARHR1-specific recommended regimen.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Cinacalcet
      term:
        id: NCIT:C74100
        label: Cinacalcet
  evidence:
  - reference: PMID:35896139
    reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Although PTH levels did decrease and serum PO4levels trended higher, the changes were judged to be of
      minor clinical significance. Higher doses of cinacalcet were not tolerated and treatment with cinacalcet
      was terminated.
    explanation: >-
      Direct negative/limited treatment experience in the younger brother, with concomitant therapy and intolerance.
animal_models:
- name: Dmp1-null mouse
  species: Mouse
  genotype: Dmp1 homozygous null
  publication: PMID:17033621
  genes:
  - preferred_term: Dmp1
    term:
      id: hgnc:2932
      label: DMP1
  description: >-
    Dmp1-null mice reproduce osteocyte maturation defects, impaired matrix mineralization, increased bone Fgf23,
    phosphate wasting, rickets and osteomalacia. Transgenic full-length DMP1 or its 57-kDa fragment rescues
    several skeletal and biochemical endpoints. Early anti-FGF23 antibody treatment improves growth plates
    and secondary ossification more fully than cortical mineralization; adult osteocytic Fgf23 deletion reduces
    excess hormone and partly corrects bone despite normalized phosphate. Outcomes depend on developmental
    timing, genetic background, diet and intervention.
  modeled_mechanisms:
  - target: Defective Osteocyte Maturation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      The osteocyte maturation arrest and lacunocanalicular defect were defined
      in this model and are DMP1-dependent, since bone-cell DMP1 expression
      rescues them.
    limitations: >-
      Complete null alleles and transgenic rescue do not reproduce every human start-loss or C-terminal allele.
    evidence:
    - reference: PMID:17033621
      reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization."
      explanation: The model defines this node.
      quote_role: PRIMARY_RESULT
  - target: DMP1-Dependent Matrix Mineralization Defect
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Dmp1-null tibias have reduced mineral-to-matrix ratio at 4 and 16 weeks by FTIR imaging.
    limitations: >-
      FTIR is a matrix endpoint, distinct from osteocyte maturation markers. Relative mineral content does
      not measure every aspect of mineral crystal composition.
    readouts:
    - name: Tibial mineral-to-matrix ratio by FTIR imaging
      target: DMP1-Dependent Matrix Mineralization Defect
      direction: DECREASED
      interpretation: Relative mineral content of bone matrix in the null mouse at 4 and 16 weeks.
      evidence:
      - reference: PMID:16294270
        reference_title: "DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The mineral-to-matrix ratios (spectroscopic parameter of relative mineral content) were significantly lower in dmp1 KO mice tibias compared with WT and HET at 4 and 16 weeks."
        explanation: The measurement behind this readout.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:16294270
      reference_title: "DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The mineral-to-matrix ratios (spectroscopic parameter of relative mineral content) were significantly lower in dmp1 KO mice tibias compared with WT and HET at 4 and 16 weeks."
      explanation: The measurement behind this readout.
      quote_role: PRIMARY_RESULT
  - target: Increased Osteocytic FGF23 Production
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Osteocytic Fgf23 induction, its FGFR dependence and its non-additivity
      with Phex loss were all established in this model.
    limitations: >-
      The magnitude of induction in the null mouse exceeds what is inferred
      from human bone, where FGF23 expression is increased but has not been
      quantified; whether FGFR signalling drives human osteocytic FGF23 is not
      demonstrated.
    readouts:
    - name: Fgf23 mRNA in bone marrow stromal cells
      target: Increased Osteocytic FGF23 Production
      direction: INCREASED
      interpretation: >-
        124-fold induction in differentiated marrow stromal cultures; SU5402 reduced this to 2.5-fold. This
        is an in-vitro assay using cells derived from mutant mice.
      evidence:
      - reference: PMID:21507898
        reference_title: Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Furthermore, inhibiting FGFR signaling using SU5402 in Hyp- and Dmp1(-/-)-derived bone marrow stromal cells prevented the increase in Fgf23 mRNA expression (129- and 124-fold increase in Hyp and Dmp1(-/-) vs. 1.3-fold in Hyp+SU5402 and 2.5-fold in Dmp1(-/-)+SU5402, P<0.05)."
        explanation: The measurement behind this readout.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:28005411
      reference_title: A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD)."
      explanation: Increased bone Fgf23 expression driving hypophosphatemia in the model.
      quote_role: PRIMARY_RESULT
  - target: Chronic Hypophosphatemia
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Hypophosphatemia with a lowered set point that is maintained through
      Fgf23 expression and cleavage; raising phosphate provokes more FGF23.
    limitations: >-
      Adult null mice also develop hyperparathyroidism, which most patients do
      not; the mouse therefore overstates the calciopenic component.
    readouts:
    - name: Serum phosphate
      target: Chronic Hypophosphatemia
      direction: DECREASED
      interpretation: Hypophosphatemia at 12 weeks with elevated serum FGF23 and PTH.
      evidence:
      - reference: PMID:37943605
        reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia."
        explanation: The measurement behind this readout.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:28005411
      reference_title: A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression."
      explanation: Characterizes the hypophosphatemia as a set-point defect, which is the informative feature of the model for this node.
      quote_role: PRIMARY_RESULT
  - target: Skeletal Mineralization Failure
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Osteomalacia and excess osteoid are partly corrected by osteocytic Fgf23 deletion even when phosphate
      normalizes. Residual FGF23 and PTH elevation limit causal attribution solely to a local matrix defect.
    limitations: >-
      A 2011 study observed age-dependent bony protuberances at one year, but this does not establish equivalence
      to every adult human sclerosis or enthesopathy phenotype. Different treatment ages and endpoints limit
      comparison of experiments.
    evidence:
    - reference: PMID:37943605
      reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice."
      explanation: The two-route result that makes this model informative for the node.
      quote_role: PRIMARY_RESULT
  - target: Growth Plate Hypertrophic Zone Expansion
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Expanded, disorganized growth plates with rickets, rescued by bone-cell
      expression of DMP1 or its 57-kDa fragment, and shown to be
      phosphate-dependent in metatarsal organ culture.
    limitations: >-
      Neonatal organ culture and early postnatal mouse antibody treatment test developing growth plates; these
      endpoints cannot measure reversal of established adult human enthesopathy.
    evidence:
    - reference: PMID:20734454
      reference_title: The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa C-terminal fragment.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This included rescue of growth plate defects, osteomalacia, abnormal osteocyte maturation, and the abnormal osteocyte lacunocanalicular system."
      explanation: The growth plate defect of the model and its DMP1 dependence.
      quote_role: PRIMARY_RESULT
    - reference: PMID:21542006
      reference_title: Unique roles of phosphorus in endochondral bone formation and osteocyte maturation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here we used Dmp1 null mice, a hypophosphatemic rickets/osteomalacia model, combined with a metatarsal organ culture and an application of neutralizing fibroblast growth factor 23 (FGF-23) antibodies to gain insight into the roles of P(i) in bone biology."
      explanation: The model used as the ARHR1 rickets model, with FGF23 neutralization as an experimental arm.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:17033621
    reference_title: Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype."
    explanation: Establishes the model and its baseline phenotype.
    quote_role: PRIMARY_RESULT
  - reference: PMID:21542006
    reference_title: Unique roles of phosphorus in endochondral bone formation and osteocyte maturation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We showed (1) that abnormal bone remodeling in Dmp1 null mice is due to reduced osteoclast number, which is secondary to a reduced ratio of RANKL/OPG expressed by osteoclast supporting cells"
    explanation: Reduced osteoclast number and remodeling in the model, a feature with no established human counterpart that is recorded here rather than as a human node.
    quote_role: PRIMARY_RESULT
  - reference: PMID:21542006
    reference_title: Unique roles of phosphorus in endochondral bone formation and osteocyte maturation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      In the aged animal at 1 year, the development of large bony protuberances occurs in all bones examined
      (Fig. 1C, middle and right panels, D and Supplemental Fig. S1), suggesting that the abnormality of bone
      remodeling progresses with age.
    explanation: >-
      Age-dependent remodeling abnormalities were followed to one year; equivalence to specific human enthesopathy
      remains uncertain.
  notes: >-
    Related experiments include Dmp1/Galnt3 double knockout, which changes Fgf23 cleavage and phosphate responsiveness,
    and non-additive Hyp/Dmp1 double mutants. Rescue by a 3.6-kb Col1a1-driven 57-kDa DMP1 fragment establishes
    experimental sufficiency, not a human replacement therapy. The 2011 culture study found normal mineralization
    with sufficient phosphate in neonatal calvarial cells, whereas the 2023 marrow stromal cultures retained
    impaired matrix mineralization; these differ in cell source, age and protocol. FTIR analysis used female
    mice at four and sixteen weeks; heterozygotes had altered crystallinity despite preserved mineral-to-matrix
    ratio. A separate 2011 study used CD-1 mice and observed bony protuberances by one year.
discussions:
- discussion_id: arhr1_dmp1_to_fgf23_coupling
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic DMP1 Loss of Function
  - pathophysiology#Increased Bone FGFR Signaling
  - pathophysiology#Increased Osteocytic FGF23 Production
  prompt: >-
    By what molecular route does loss of an extracellular matrix phosphoprotein
    in the osteocyte de-repress Fgf23 transcription, and is the FGFR-dependent
    mechanism shown in mouse bone cells the one operating in human ARHR1?
  rationale: >-
    Mouse bone shows increased FGFR1/FRS2/PI3K phosphorylation, and an FGFR inhibitor suppresses Fgf23 induction
    in mutant marrow stromal cultures. These results implicate FGFR signaling but do not identify how extracellular
    DMP1 loss activates it, exclude other FGFRs or demonstrate the mechanism in human osteocytes. Non-additivity
    with Phex loss supports pathway convergence without proving a direct DMP1-PHEX interaction. Matrix/integrin
    signaling, phosphate sensing and maturation state remain candidate intermediates.
  evidence:
  - reference: PMID:21507898
    reference_title: Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The mechanisms whereby PHEX and DMP1 regulate Fgf23 expression are unknown."
    explanation: The gap stated in the paper that came closest to closing it.
    quote_role: PRIMARY_RESULT
  - reference: PMID:17033625
    reference_title: DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting that DMP1 may regulate FGF23 expression"
    explanation: The hypothesis as first stated; it has been confirmed as a relationship but not explained as a mechanism.
    quote_role: PRIMARY_RESULT
  proposed_experiments:
  - experiment_id: arhr1_human_osteocyte_fgfr_dependence
    name: FGFR dependence of FGF23 induction in human DMP1-deficient osteocytes
    description: >-
      Differentiate osteocytes from patient-derived or DMP1-edited human iPSCs
      and test whether FGF23 induction is abolished by FGFR1 inhibition, and
      whether it is restored by exogenous 57-kDa C-terminal DMP1 added to the
      matrix, to establish that the mouse pathway operates in human cells and
      that the extracellular fragment is sufficient.
- discussion_id: arhr1_fgf23_blockade_versus_matrix_defect
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Skeletal Mineralization Failure
  - treatments#Burosumab
  prompt: >-
    In the Dmp1-null mouse, removing osteocytic Fgf23 normalizes serum phosphate
    but leaves part of the bone phenotype uncorrected; does the same residual,
    DMP1-intrinsic mineralization defect limit what burosumab can achieve in
    patients with ARHR1?
  rationale: >-
    Partial human clinical benefit is compatible with partial rescue in mouse models. The 2023 lineage-specific
    deletion leaves residual circulating FGF23 excess, so persistent bone defects cannot all be assigned to
    DMP1-independent-of-FGF23 effects from that experiment alone. Its cultured-cell results distinguish FGF23-sensitive
    differentiation from persistent matrix mineralization failure. Earlier newborn calvarial cultures mineralized
    with sufficient phosphate, indicating that age, cell source and culture conditions matter. The two-brother
    human report documents clinical and radiographic improvement but not paired bone histomorphometry. The
    later adult report is available here only as an abstract. Whether clinically important residual matrix
    defects persist after adequate FGF23 blockade remains unresolved.
  evidence:
  - reference: PMID:37943605
    reference_title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our data suggest that combined DMP1 repletion and FGF23 blockade could effectively correct ARHR-associated mineral and bone disorders."
    explanation: The authors' inference that FGF23 blockade alone will be incomplete in ARHR1.
    quote_role: PRIMARY_RESULT
  - reference: PMID:35896139
    reference_title: Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present report highlights the beneficial biochemical and clinical outcomes associated with the use of burosumab in patients with ARHR1."
    explanation: >-
      Human clinical benefit is compatible with incomplete skeletal correction; this is not a demonstrated
      human-model contradiction.
    quote_role: PRIMARY_RESULT
  - reference: PMID:21542006
    reference_title: Unique roles of phosphorus in endochondral bone formation and osteocyte maturation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      This defect in osteoblast differentiation apparently is caused by hypophosphatemia because the isolated
      calvarial osteoblasts mineralize normally ex vivo if sufficient phosphate is provided (Fig. 3D).
    explanation: >-
      Earlier neonatal calvarial cultures differ from the 2023 marrow stromal cultures; this is the authors'
      interpretation of their experiment, not a universal conclusion.
  proposed_experiments:
  - experiment_id: arhr1_burosumab_histomorphometry
    name: Paired bone histomorphometry before and after burosumab in ARHR1
    description: >-
      Where clinically justified and consented, compare paired bone histomorphometry and imaging before and
      after specialist-directed burosumab, with phosphate, PTH, drug exposure, genotype, age and prior therapy
      documented. Residual osteoid would establish incomplete response, but would not by itself prove a solely
      DMP1-intrinsic cause. Complement clinical observations with matched patient-derived matrix and differentiation
      assays.
- discussion_id: arhr1_hyperostosis_osteosclerosis_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Increased Axial Bone Density
  - phenotypes#Generalized Osteosclerosis
  - phenotypes#Cranial Hyperostosis
  - phenotypes#Enthesopathy
  - phenotypes#Paraspinal Ligament Ossification
  prompt: >-
    Why do adults with a mineralization-failure disease develop cranial
    hyperostosis, a high axial bone density and ossifying enthesopathy severe
    enough to immobilize the spine, and are these one process or several?
  rationale: >-
    Increased axial areal density can coexist with poor peripheral microstructure and mineralization defects.
    Cortical thickening and extraosseous calcification can complicate DXA interpretation; unmineralized osteoid
    itself is not a demonstrated cause of increased measured mineral density. One untreated Finnish adult also
    developed extensive ossification, so conventional therapy is not a sufficient explanation. Reduced osteoclast
    support and age-dependent bony protuberances in mice suggest candidate remodeling mechanisms, but their
    relationship to human enthesopathy is unresolved. The Indian family carried an SPP1 variant of uncertain
    significance; no modifier effect was established. Clinical improvement with burosumab does not establish
    prevention or reversal of ectopic ossification.
  evidence:
  - reference: PMID:25180662
    reference_title: Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our cases show that some ARHR cases may develop with age an unaccountable increase in bone density and bone overgrowth."
    explanation: The gap as stated by the reporters.
    quote_role: PRIMARY_RESULT
  - reference: PMID:32920683
    reference_title: "Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High aBMD and local osteosclerosis in axial bone with low vBMD and damaged microstructure in peripheral bone were featured."
    explanation: The axial-peripheral discordance that makes the sclerosis hard to interpret.
    quote_role: PRIMARY_RESULT
  - reference: PMID:21542006
    reference_title: Unique roles of phosphorus in endochondral bone formation and osteocyte maturation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We showed (1) that abnormal bone remodeling in Dmp1 null mice is due to reduced osteoclast number, which is secondary to a reduced ratio of RANKL/OPG expressed by osteoclast supporting cells"
    explanation: A candidate mechanism, reduced resorption, from the model.
    quote_role: PRIMARY_RESULT
  proposed_experiments:
  - experiment_id: arhr1_bone_quality_hrpqct_histology
    name: Volumetric density, microstructure and histology of sclerotic ARHR1 bone
    description: >-
      Compare volumetric density, peripheral microstructure and, when available, undecalcified histomorphometry
      with osteoclast counts in adults with radiographic sclerosis. Distinguish mineralized bone quantity from
      excess osteoid and adjacent ligament ossification; assess longitudinal relationships to age, genotype,
      treatment and FGF23 rather than inferring strength from DXA alone.
- discussion_id: arhr1_carrier_phenotype
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#Biallelic DMP1 Pathogenic Variants
  prompt: >-
    Is the DMP1 heterozygous carrier state a subclinical bone disorder that
    warrants surveillance, and does it explain the carriers with mild
    hypophosphatemia?
  rationale: >-
    Selected families show mild carrier biochemical or histomorphometric abnormalities, whereas other carrier
    relatives are clinically and biochemically normal. The 2026 report describes normal biochemistry with differing
    bone density between families and one carrier biopsy showing a mild mineralization defect. These observations
    warrant study of an unselected carrier cohort; they do not estimate penetrance, change biallelic ARHR1
    to dominant inheritance or establish routine bone-density screening for all carriers. In heterozygous mice,
    normal phosphate and mineral-to-matrix ratio coexist with altered mineral crystallinity and reduced serum
    calcium; they are not normal in every measured bone endpoint.
  evidence:
  - reference: PMID:20499351
    reference_title: Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia."
    explanation: The first report of a carrier phenotype.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41820620
    reference_title: Expanding the Autosomal Recessive Hypophosphatemic Rickets Type I Carrier Phenotype and Adult Treatment with Burosumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data expand the description of the clinical phenotype in fully affected individuals with ARHR1 and provide further evidence of a subclinical phenotype in the ARHR1 carrier state."
    explanation: Independent confirmation of a subclinical carrier phenotype.
    quote_role: PRIMARY_RESULT
  - reference: PMID:16294270
    reference_title: "DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Dmp1 KO mice had significantly lower ionic calcium and phosphate concentrations relative to WT, whereas in the HET, values for phosphate were equivalent, and calcium values were decreased relative to WT values."
    explanation: Heterozygous mice keep normal phosphate, so the human carrier hypophosphatemia is not reproduced by the model.
    quote_role: PRIMARY_RESULT
  - reference: PMID:16294270
    reference_title: "DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      The mineral crystallinity (crystal size/perfection) was significantly increased in dmp1 KO and HET mice
      relative to WT.
    explanation: >-
      Heterozygotes have a crystallinity phenotype despite preserved relative mineral quantity, so the model
      does not support a wholly normal carrier skeleton.

📚

References & Deep Research

References

20

PMID:17033621

Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.

No top-level findings curated for this source.

PMID:17033625

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.

No top-level findings curated for this source.

PMID:20499351

Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.

No top-level findings curated for this source.

PMID:37943605

FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

No top-level findings curated for this source.

PMID:35896139

Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).

No top-level findings curated for this source.

url:https://oup.silverchair-cdn.com/article-minimal/6806102

https://oup.silverchair-cdn.com/article-minimal/6806102

1 finding

Publisher full text of Ni et al., The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1 (PMID:36334264; DOI:10.1210/clinem/dgac638).

url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761068s009lbl.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761068s009lbl.pdf

1 finding

US FDA CRYSVITA prescribing information, revised August 2025; indication and safety reference, not an ARHR1 efficacy study.

PMID:21507898

Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.

No top-level findings curated for this source.

PMID:20734454

The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa C-terminal fragment.

No top-level findings curated for this source.

PMID:21542006

Unique roles of phosphorus in endochondral bone formation and osteocyte maturation.

No top-level findings curated for this source.

PMID:16294270

DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis.

No top-level findings curated for this source.

PMID:19007919

Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets.

No top-level findings curated for this source.

PMID:19796717

Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.

No top-level findings curated for this source.

PMID:32920683

Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature.

No top-level findings curated for this source.

PMID:36334264

The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1.

No top-level findings curated for this source.

PMID:39011543

Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets.

No top-level findings curated for this source.

PMID:41820620

Expanding the Autosomal Recessive Hypophosphatemic Rickets Type I Carrier Phenotype and Adult Treatment with Burosumab.

No top-level findings curated for this source.

PMID:29901142

Targeted resequencing of phosphorus metabolism‑related genes in 86 patients with hypophosphatemic rickets/osteomalacia.

No top-level findings curated for this source.

PMID:35352187

Rickets guidance: part II-management.

No top-level findings curated for this source.

url:https://www.spandidos-publications.com/10.3892/ijmm.2018.3730/download

https://www.spandidos-publications.com/10.3892/ijmm.2018.3730/download

1 finding

Full text of Gu et al. 2018, PMID:29901142; DMP1 c.730G>T segregation and selected-cohort clinical findings.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Autosomal Recessive Hypophosphatemic Rickets 1 (MONDO:0009430) · 2026-09-18T02:27:44Z · View source

De-novo curation of ARHR1 (DMP1-related; MONDO:0009430, OMIM 241520) from the skeleton file; stub stubs/Hypophosphatemic_Rickets_Autosomal_Recessive_1.yaml deleted. Lump/split: DMP1 disease only; ARHR2 (ENPP1) and XLH (PHEX) kept as separate entries and listed as differential diagnoses. Pathophysiology is an 11-node chain: Biallelic DMP1 Loss of Function -> Defective Osteocyte Maturation and Pericellular Mineralization -> Increased Osteocytic FGF23 Production (FGFR-dependent, unknown intermediates) -> Elevated Circulating Intact FGF23 -> Reduced Proximal Tubular Phosphate Reabsorption and Suppressed Renal Calcitriol Synthesis -> Chronic Hypophosphatemia -> Skeletal Mineralization Failure (also reached directly from the DMP1-intrinsic osteocyte defect, per Courbon 2023) -> Growth Plate Hypertrophic Zone Expansion -> Rickets and Osteomalacia; plus Dentin Hypomineralization. The four downstream nodes conform to defective_skeletal_mineralization (Phosphopenic Substrate Deficiency, Impaired Hydroxyapatite Deposition, Growth Plate Hypertrophic Zone Expansion, Rickets and Osteomalacia). 15 phenotypes, biochemical block (phosphate, TmP/GFR, intact FGF23, calcitriol, ALP, PTH/calcium), genetic block with LOSS_OF_FUNCTION and the full published allele spectrum, structured prevalence (CASES_IN_LITERATURE, ULTRA_RARE, ~30 reported patients), Dmp1-null mouse with five modeled_mechanisms links and readouts, four discussions (DMP1-to-FGF23 coupling gap, HUMAN_MODEL_MISMATCH on FGF23 blockade vs the DMP1-intrinsic matrix defect, adult hyperostosis/osteosclerosis mechanism gap, carrier phenotype gap), classifications (harrisons_chapter ENDOCRINOLOGY_METABOLISM + GENETICS_ENVIRONMENT_DISEASE; isds_skeletal_category abnormal_mineralization). Enthesopathy deliberately left unbound (HP:0100686 is inflammatory enthesitis), matching the XLH entry. Provider: Falcon (Edison) report research/Autosomal_Recessive_Hypophosphatemic_Rickets_1-deep-research-falcon.md, 11/11 references and 44/46 terms resolved; preflight-dr WARN (FGF23 mentioned 49x vs DMP1 45x) judged benign because FGF23 is the downstream hormone and OMIM 241520 matched. DOIs resolved to PMIDs via the PMC ID converter: 10.1038/ng1868->17033625, 10.1002/jbmr.105->20499351, 10.1210/en.2016-1642->28005411, 10.1172/jci.insight.156850->37943605, 10.1016/j.bonr.2024.101753->39011543, 10.3389/fendo.2022.1005189->36246908, 10.1007/s00467-022-05505-5->35352187, 10.1016/j.bone.2017.01.034->28159712 (cached, not cited), 10.3389/fendo.2024.1383681->38706696 (cached, not cited); 10.3892/ijmm.2018.3730 (Gu 2018) and 10.3390/endocrines3020025 (Nakanishi 2022) have no PubMed record and were not cited. Additional primary papers found via PubMed E-utilities: Feng 2006 (17033621), Ling 2005 (16294270), Farrow 2009 (19007919), Turan 2010 (19796717), Koshida 2010 (20213538), Lu 2011 (20734454), Zhang 2011 (21542006), Martin 2011 (21507898), Gannage-Yared 2014 (25180662), Whyte 2020 (31843680), Ni 2020 (32920683), Bai 2022 (35896139), Ni 2023 (36334264), Bastida 2023 (36315908), Sawalha 2026 (41820620), Ferreira and Imel 2026 (42412262). No GeneReviews chapter exists for ARHR1; the XLH chapter (22319799) was not cited because its usable sentences are XLH-specific. Not sourced: no quotable abstract sentence for orthopedic surgery or dental care specific to ARHR1, so those treatments carry INDIRECT evidence from the phenotype descriptions; Bhattacharyya 2012 (22921867) and Beck-Nielsen 2019 (30808384) were cached but not cited because their abstracts contain no ARHR1-specific sentence. Validation: just validate passed; just count-verified-snippets 152/152; just validate-terms passed; check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms OK; just validate-disorders passed (All 1 disorder file(s) passed validation, 152/152 snippets); whole-KB check-folded-hyphens, check-title-snippets, check-snippet-grading, check-reference-titles OK; check-snippet-length reports one new finding in a sibling file (Hereditary_Multiple_Osteochondromas.yaml), not this entry; pytest tests/test_data.py -k Autosomal_Recessive_Hypophosphatemic_Rickets_1 passed after changing the dental-care action_category from MONITORING to THERAPEUTIC.

Falcon ▸

Autosomal Recessive Hypophosphatemic Rickets 1 (ARHR1): Disease-Characteristics Report

Edison Scientific Literature 30 citations 2026-09-04T23:33:30.814273

Autosomal Recessive Hypophosphatemic Rickets 1 (ARHR1): Disease-Characteristics Report

Executive summary

Autosomal recessive hypophosphatemic rickets 1 (ARHR1) is an ultra-rare, Mendelian, fibroblast growth factor 23 (FGF23)-mediated phosphate-wasting disorder caused by biallelic loss-of-function variants in DMP1. DMP1 deficiency disrupts osteocyte maturation and extracellular-matrix mineralization and increases osteocytic FGF23 production. Excess FGF23 causes renal phosphate wasting and inappropriately low calcitriol, producing childhood rickets, growth failure, lower-limb deformity, dental disease, and persistent adult osteomalacia. Severe untreated or undertreated disease can progress to fractures, enthesopathy, ligamentous ossification, degenerative arthritis, ankylosis, and major mobility loss. The evidence base is limited to small families, individual cases, and animal models; reliable prevalence, phenotype-frequency, survival, and treatment-response estimates are unavailable. (makitie2010longtermclinicaloutcome pages 1-2, courbon2023fgf23directlyinhibits pages 1-2, makitie2010longtermclinicaloutcome pages 2-4)

The following table provides a compact knowledge-base representation.

Domain	Curated finding	Suggested ontology terms	Evidence type / key source
Identity	Autosomal recessive hypophosphatemic rickets 1 (ARHR1) is an FGF23-mediated renal phosphate-wasting disorder caused by biallelic loss-of-function variants in DMP1. OMIM: 241520.	MONDO: ARHR1; MeSH: Rickets, Hypophosphatemia	Disease-resource synthesis and human genetics (gu2018targetedresequencingof pages 6-7, clinkenbeard2017heritableandacquired pages 4-6, nakanishi2022pathogenesisoffgf23related pages 7-8)
Gene and inheritance	DMP1 encodes dentin matrix acidic phosphoprotein 1, a secreted SIBLING-family extracellular-matrix protein expressed in osteocytes, mature osteoblasts, and odontoblasts. Inheritance is autosomal recessive; variants are germline.	HP:0000007; GO:0005576; CL:0000137 osteocyte; CL:0000062 osteoblast; CL:0000060 odontoblast	Human genetics and model evidence (makitie2010longtermclinicaloutcome pages 1-2, yamazaki2022osteocytesandthe pages 3-5, clinkenbeard2017heritableandacquired pages 4-6)
Pathogenic variation	Reported loss-of-function classes include start-loss, nonsense, splice-site, and C-terminal variants. Examples: c.730G>T (p.Glu244Ter), c.1122T>G (p.Tyr374Ter), and IVS5-1G>A. Population frequency and ACMG classification require variant-specific database review.	SO:0001587 stop-gained; SO:0001574 splice-acceptor variant; SO:0002012 start-lost	Primary sequencing and family studies (chaturvedi2024lessonslearnedfrom pages 6-7, makitie2010longtermclinicaloutcome pages 1-2, gu2018targetedresequencingof pages 6-7)
Epidemiology	Unknown. No reliable ARHR1-specific prevalence, incidence, carrier-frequency, or survival estimates exist. Published evidence consists chiefly of individual families and small case series; both sexes are expected to be affected equally.	Orphanet rare disease; HP:0000007	Evidence gap in clinical literature (chaturvedi2024lessonslearnedfrom pages 7-8, chaturvedi2024lessonslearnedfrom pages 1-2, gu2018targetedresequencingof pages 6-7)
Core phenotypes	Childhood-onset rickets and persistent osteomalacia; bone pain, short stature, impaired growth, genu varum/valgum, abnormal gait, fractures, and progressive skeletal deformity. Dental abnormalities and abscesses may occur; hearing impairment has been reported but its frequency is unknown.	HP:0002748 Rickets; HP:0004349 Osteomalacia; HP:0004322 Short stature; HP:0002970 Genu varum; HP:0002857 Genu valgum; HP:0000164 Abnormal dentition; HP:0000365 Hearing impairment	Human case series and long-term family study (makitie2010longtermclinicaloutcome pages 7-9, makitie2010longtermclinicaloutcome pages 2-4, gu2018targetedresequencingof pages 6-7)
Biomarkers	Low age-adjusted serum phosphate with renal phosphate wasting or reduced TmP/GFR; elevated ALP during active rickets; elevated or inappropriately normal intact FGF23; low or inappropriately normal 1,25-dihydroxyvitamin D. Calcium is often normal and PTH may be elevated. One adolescent had phosphate 0.76 mmol/L, ALP 741 U/L, and calcium 2.46 mmol/L.	HP:0002148 Hypophosphatemia; CHEBI:26020 phosphate; CHEBI:17823 calcitriol	Human biochemical evidence (nakanishi2022pathogenesisoffgf23related pages 7-8, haffner2022ricketsguidanceparta pages 1-2, gu2018targetedresequencingof pages 6-7)
Mechanism	Biallelic DMP1 loss leads to defective osteocyte maturation and matrix mineralization; this leads to increased osteocytic FGF23, probably partly through enhanced FGFR signaling; excess FGF23 leads to renal phosphate wasting and suppressed calcitriol; chronic hypophosphatemia plus local DMP1/FGF23 effects result in impaired osteoblast differentiation, rickets, and osteomalacia. The FGFR step remains partly inferred.	GO:0030500 regulation of bone mineralization; GO:0045667 regulation of osteoblast differentiation; GO:0008543 FGFR signaling pathway; CL:0000137; CL:0000062	Human genetics, mouse, primary-cell, and single-cell evidence (courbon2023fgf23directlyinhibits pages 1-2, courbon2023fgf23directlyinhibits pages 11-13, courbon2023fgf23directlyinhibits pages 4-5)
Anatomy and cells	Principal sites are growth plates, cortical and trabecular bone, long bones, skull, spine, joints, entheses, and dentin. Key cells are osteocytes, osteoblasts, osteoprogenitors, chondrocytes, odontoblasts, and renal proximal-tubule epithelial cells downstream of FGF23.	UBERON:0000982 skeletal system; UBERON:0001272 long bone; UBERON:0004766 growth plate; UBERON:0002113 kidney; CL:0002306 proximal-tubule epithelial cell	Human radiology/histology and model evidence (makitie2010longtermclinicaloutcome pages 5-7, courbon2023fgf23directlyinhibits pages 4-5, yamazaki2022osteocytesandthe pages 3-5)
Diagnostics	Confirm fasting hypophosphatemia using age-specific ranges; document renal wasting by urine studies and TmP/GFR; measure ALP, calcium, PTH, creatinine/eGFR, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and intact FGF23; obtain wrist or knee radiographs; perform a hereditary-rickets panel including DMP1 with copy-number analysis. Use WES/WGS when panel testing is negative or the phenotype is atypical.	NCIT:C15709 Genetic Testing; NCIT:C17648 Laboratory Procedure; NCIT:C38101 Radiographic Imaging	Guidance and case-based genetic evidence (gu2018targetedresequencingof pages 6-7, chaturvedi2024lessonslearnedfrom pages 7-8, haffner2022ricketsguidanceparta pages 1-2)
Treatment	Conventional therapy is divided oral phosphate plus active vitamin D such as calcitriol or alfacalcidol, with surveillance for hyperparathyroidism, hypercalciuria, nephrolithiasis, and nephrocalcinosis. Multidisciplinary dental, rehabilitation, pain, and orthopedic care may be required.	CHEBI:26020 phosphate; CHEBI:17823 calcitriol; NCIT:C15329 Physical Therapy; NCIT:C15214 Orthopedic Surgery	General guidance, ARHR1 clinical experience, and mouse evidence (chaturvedi2024lessonslearnedfrom pages 7-8, haffner2022ricketsguidanceparta pages 1-2, chaturvedi2024lessonslearnedfrom pages 6-7, courbon2023fgf23directlyinhibits pages 1-2)
Burosumab status	Burosumab is off-label/experimental and not specifically approved for ARHR1. Very limited adult case evidence suggests benefit from FGF23 neutralization, but no ARHR1 randomized trial or reliable response-rate estimate exists. Mouse studies indicate that FGF23 suppression normalizes phosphate but may not fully correct DMP1-dependent mineralization defects.	NCIT:C119744 Burosumab; monoclonal antibody therapy	Small human experience and mechanistic mouse studies (courbon2023fgf23directlyinhibits pages 1-2, chaturvedi2024lessonslearnedfrom pages 7-8, courbon2023fgf23directlyinhibits pages 11-13, courbon2023fgf23directlyinhibits pages 13-15)
Prognosis	Disease is chronic and potentially progressive. Inadequately treated adults may develop fractures, enthesopathy, ligamentous ossification, degenerative arthritis, contractures, spinal stenosis, ankylosis, and severe mobility loss. Life expectancy and disease-specific mortality are unknown.	HP:0100686 Enthesopathy; HP:0002757 Recurrent fractures; HP:0001371 Flexion contracture; HP:0000920 Vertebral abnormality	Long-term human follow-up (makitie2010longtermclinicaloutcome pages 5-7, makitie2010longtermclinicaloutcome pages 2-4)
Models	Dmp1-knockout mouse recapitulates elevated FGF23/PTH, hypophosphatemia, growth failure, rickets, osteomalacia, cortical porosity, abnormal growth plates, and defective osteocyte maturation. Osteocyte-specific Fgf23 deletion normalizes phosphate but only partly rescues bone. DMP1-deficient rabbits also develop elevated FGF23 and hypophosphatemic rickets.	NCBI Taxon:10090 Mus musculus; NCBI Taxon:9986 Oryctolagus cuniculus; MGI: Dmp1	Genetic model, cell culture, and single-cell evidence (courbon2023fgf23directlyinhibits pages 11-13, courbon2023fgf23directlyinhibits pages 4-5, yamazaki2022osteocytesandthe pages 3-5, courbon2023fgf23directlyinhibits pages 13-15)

Table: Compact curation of DMP1-related ARHR1 covering disease identity, molecular cause, clinical features, diagnostics, treatment status, prognosis, and experimental models. Evidence gaps—including unknown epidemiology and the off-label status of burosumab—are explicitly identified.

1. Disease information

Definition. ARHR1 is a hereditary hypophosphatemic rickets/osteomalacia syndrome in which biallelic DMP1 dysfunction causes excessive FGF23 action, renal phosphate wasting, chronic hypophosphatemia, and defective skeletal and dental mineralization. It is distinct from DMP1-independent ARHR2, caused by ENPP1 deficiency. (clinkenbeard2017heritableandacquired pages 4-6, nakanishi2022pathogenesisoffgf23related pages 7-8)

Identifiers and terminology. The securely supported identifier is OMIM/MIM 241520. Common names include autosomal recessive hypophosphatemic rickets type 1, ARHR1, DMP1-related hypophosphatemic rickets, DMP1-related autosomal recessive hypophosphatemia, and historically autosomal recessive hypophosphatemia/ARHP. A precise MONDO identifier was not established from the retrieved sources and should be verified directly against the current MONDO release rather than inferred. ICD-10/ICD-11 and MeSH generally classify the broader entities hypophosphatemic rickets, rickets, or disorders of phosphorus metabolism; a dedicated ARHR1 code was not documented in the retrieved literature. (gu2018targetedresequencingof pages 6-7, makitie2010longtermclinicaloutcome pages 1-2)

This report synthesizes aggregated disease-level literature, including primary human families/cases and experimental models; it is not derived from an individual EHR.

2. Etiology, risk, and protective factors

Causal factor

The primary cause is a germline biallelic loss-of-function DMP1 genotype. DMP1 encodes dentin matrix acidic phosphoprotein 1, a secreted noncollagenous SIBLING-family matrix protein expressed especially by osteocytes, mature osteoblasts, and odontoblasts. Pathogenic variants impair DMP1 production, processing, secretion, or function. (clinkenbeard2017heritableandacquired pages 4-6, yamazaki2022osteocytesandthe pages 3-5)

Risk factors

Genetic: two pathogenic DMP1 alleles; parental consanguinity or shared ancestry increases the probability of homozygosity. One Chinese patient with p.Glu244Ter was born to consanguineous parents. A Finnish family originated from the same remote island, suggesting—but not proving—a founder effect. (makitie2010longtermclinicaloutcome pages 2-4, gu2018targetedresequencingof pages 6-7)
Family history: an affected sibling or known carrier parents substantially increases prior probability. For two carrier parents, standard autosomal-recessive recurrence risks per pregnancy are 25% affected, 50% carrier, and 25% neither familial allele.
Age/sex: disease usually becomes evident during childhood growth. Both sexes should be affected equally; no sex-specific biological risk has been established.
Environmental/infectious: no toxin, infection, smoking, alcohol, occupational exposure, or other environmental factor causes ARHR1. Low calcium intake or vitamin-D deficiency can worsen mineralization but is a comorbidity rather than the initiating cause.

Protective factors and gene–environment interaction

No validated protective DMP1 allele or modifier gene is known. Adequate calcium intake and normal 25-hydroxyvitamin-D status support mineralization but do not prevent disease in a person with biallelic DMP1 loss. A clinically important interaction is phosphate exposure: in adult Dmp1-null mice, phosphate supplementation begun at six weeks increased FGF23, PTH, urinary phosphate loss, and osteomalacia rather than correcting disease. This result cautions against unmonitored phosphate monotherapy but cannot be directly translated into a human prohibition against carefully combined phosphate and active vitamin D. (courbon2023fgf23directlyinhibits pages 1-2, courbon2023fgf23directlyinhibits pages 13-15)

3. Phenotypes

ARHR1 normally begins insidiously in infancy or early childhood and is chronic. Frequencies cannot be estimated reliably because published cohorts are extremely small.

Rickets/osteomalacia: defective growth-plate and mature-bone mineralization; generally progressive if inadequately treated. Suggested terms: HP:0002748 Rickets, HP:0004349 Osteomalacia. Bone biopsy may show increased osteoid volume/thickness, absent tetracycline double labels, reduced mineralizing surface, and prolonged mineralization lag time. (makitie2010longtermclinicaloutcome pages 7-9, makitie2010longtermclinicaloutcome pages 5-7)
Hypophosphatemia and renal phosphate wasting: persistent laboratory hallmarks, with elevated or inappropriately normal intact FGF23 and low/inappropriately normal 1,25(OH)2D. Suggested terms: HP:0002148 Hypophosphatemia and an HPO renal-phosphate-wasting annotation. (ichikawa2017amutationin pages 1-1, nakanishi2022pathogenesisoffgf23related pages 7-8)
Raised alkaline phosphatase: reflects active rickets/osteoblast activity. In one affected 18-year-old, phosphate was 0.76 mmol/L, ALP 741 U/L, and calcium 2.46 mmol/L. (gu2018targetedresequencingof pages 6-7)
Growth and deformity: short stature, impaired linear growth, bowed legs, genu varum or valgum, coxa vara, widened metaphyses, abnormal epiphyses, cortical abnormalities, and delayed growth-plate closure. Suggested terms include HP:0004322 Short stature, HP:0002970 Genu varum, HP:0002857 Genu valgum, and HP:0002673 Coxa vara. The same 18-year-old was 145 cm and had painful legs and varus knees beginning at 18 months. (makitie2010longtermclinicaloutcome pages 5-7, gu2018targetedresequencingof pages 6-7)
Pain, weakness, gait, and function: bone/joint pain, muscle weakness, abnormal or waddling gait, impaired mobility, and fatigue are expected consequences. Suggested terms: HP:0002653 Bone pain, HP:0003326 Myalgia/muscle weakness as appropriate, and HP:0001288 Gait disturbance.
Fracture and orthopedic morbidity: insufficiency/pathologic fractures, joint destruction, contractures, scoliosis/kyphosis, and repeated corrective operations may occur. A severely affected woman underwent osteotomies from age six, more than 30 orthopedic procedures, bilateral femoral-neck-fracture repair, hip replacements at ages 57 and 61, and treatment for cervical spinal stenosis. (makitie2010longtermclinicaloutcome pages 2-4)
Enthesopathy and extraskeletal ossification: progressive enthesopathy, interosseous-membrane and paraspinal-ligament calcification, spinal ankylosis, and generalized degenerative arthritis are prominent adult complications. Suggested terms: HP:0100686 Enthesopathy, HP:0002753/appropriate ankylosis term, and HP:0001371 Contracture. (makitie2010longtermclinicaloutcome pages 7-9, makitie2010longtermclinicaloutcome pages 5-7)
Craniofacial/skull: cranial hyperostosis has been reported; one patient had dural ectasia, but causality was uncertain. Suggested term: HP:0004434 Hyperostosis of the skull. (makitie2010longtermclinicaloutcome pages 9-10, makitie2010longtermclinicaloutcome pages 5-7)
Dental: poor dental development, hypomineralization, periodontal disease, gingival/dental abscesses, delayed eruption, and tooth loss may occur. Suggested terms: HP:0000164 Abnormality of dentition, HP:0000691 Dental abscess, and more specific enamel/dentin terms where documented. One adult required a dental prosthesis from age 50 after recurrent gingival abscesses. (makitie2010longtermclinicaloutcome pages 2-4, gu2018targetedresequencingof pages 6-7)
Hearing: impairment has been reported in severe adult disease, but one adolescent had normal hearing; frequency and mechanism are unknown. Suggested term: HP:0000365 Hearing impairment. (makitie2010longtermclinicaloutcome pages 2-4, gu2018targetedresequencingof pages 6-7)

No ARHR1-specific EQ-5D, SF-36, PROMIS, or validated disease-specific quality-of-life dataset was identified. Nonetheless, severe pain, short stature, repeated surgery, dental morbidity, spinal immobility, and loss of ambulation indicate potentially profound physical and psychosocial impact. (makitie2010longtermclinicaloutcome pages 5-7, makitie2010longtermclinicaloutcome pages 2-4)

4. Genetic and molecular information

Causal gene: DMP1; biallelic germline variants cause ARHR1. Variant classes include start-loss, nonsense, splice-acceptor/splice-disrupting, frameshift, and C-terminal alterations. Examples documented in the retrieved evidence include c.730G>T (p.Glu244Ter), c.1122T>G (p.Tyr374Ter), and IVS5-1G>A at the exon-6 splice acceptor. (chaturvedi2024lessonslearnedfrom pages 6-7, makitie2010longtermclinicaloutcome pages 1-2, gu2018targetedresequencingof pages 6-7)

The p.Glu244Ter variant was found by >100× targeted sequencing and confirmed by Sanger sequencing. Variant pathogenicity should be curated transcript-specifically with ClinVar/ClinGen and ACMG/AMP criteria; the retrieved papers do not supply current ClinVar review status or gnomAD frequencies for every allele. Absence or extreme rarity in population databases is expected for fully penetrant severe alleles but must not be assumed for a particular variant. (gu2018targetedresequencingof pages 6-7)

DMP1 is processed in bone matrix into approximately 37-kDa N-terminal and 57-kDa C-terminal fragments. A noncleavable D213A protein phenocopied Dmp1 null mice, whereas the 57-kDa C-terminal fragment rescued bone abnormalities, demonstrating that proteolytic processing is functionally important. (clinkenbeard2017heritableandacquired pages 4-6)

Heterozygotes are usually clinically unaffected carriers, but two carriers in one family had mild hypophosphatemia, and one showed focal osteomalacia. This suggests a possible subtle carrier phenotype rather than a consistently dominant disorder. Penetrance of biallelic pathogenic genotypes appears high in reported families, but numerical penetrance is unknown; expressivity is variable. No anticipation, recurrent somatic mutation, established germline mosaicism rate, modifier gene, disease-specific epigenetic lesion, or recurrent chromosomal abnormality is established. (makitie2010longtermclinicaloutcome pages 1-2, makitie2010longtermclinicaloutcome pages 7-9)

5. Environmental information

ARHR1 is not infectious, toxic, occupational, lifestyle-mediated, or zoonotic. Diet changes biochemical substrate availability but do not cause or cure the genetic disorder. Adequate calcium and vitamin-D status are supportive; excessive or poorly balanced phosphate replacement may stimulate FGF23 and hyperparathyroidism. There is no disease-specific evidence that smoking, alcohol, exercise, pollution, radiation, or infection modifies penetrance.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic DMP1 loss-of-function leads to absent or dysfunctional extracellular DMP1 in bone and dentin matrix. (makitie2010longtermclinicaloutcome pages 1-2, clinkenbeard2017heritableandacquired pages 4-6)
DMP1 deficiency leads to defective osteocyte maturation and impaired hydroxyapatite nucleation/matrix mineralization. (yamazaki2022osteocytesandthe pages 3-5, clinkenbeard2017heritableandacquired pages 4-6)
Abnormal osteocyte biology leads to increased FGF23 transcription and altered FGF23 processing in mature osteoblasts/osteocytes. (courbon2023fgf23directlyinhibits pages 13-15, ichikawa2017amutationin pages 1-1)
Enhanced FGFR signaling in osteocytes probably contributes to FGF23 overproduction; this step is supported by model data but remains partly inferred rather than fully resolved in human ARHR1. (nakanishi2022pathogenesisoffgf23related pages 7-8, yamazaki2022osteocytesandthe pages 3-5)
Excess intact FGF23 leads to reduced renal proximal-tubular phosphate reabsorption and increased phosphaturia, and suppresses renal calcitriol production. (ichikawa2017amutationin pages 1-1, nakanishi2022pathogenesisoffgf23related pages 7-8)
Renal phosphate loss leads to chronic hypophosphatemia and insufficient phosphate for hydroxyapatite formation, causing growth-plate rickets and generalized osteomalacia. (courbon2023fgf23directlyinhibits pages 1-2, ichikawa2017amutationin pages 1-1)
Branch A—excess FGF23 directly leads to impaired osteoprogenitor/osteoblast differentiation through pathways involving FGFR1, ERK1/2, and PI3K/AKT in model systems. (courbon2023fgf23directlyinhibits pages 11-13, courbon2023fgf23directlyinhibits pages 4-5)
Branch B—DMP1 loss independently leads to defective matrix mineralization even when phosphate or FGF23 is corrected. This explains why normalized serum phosphate may not fully rescue bone. (courbon2023fgf23directlyinhibits pages 4-5, courbon2023fgf23directlyinhibits pages 1-2)
Persistent growth-plate and matrix defects result in short stature, bowed legs, fractures, pain, dental disease, and, over decades, enthesopathy, degenerative joint disease, ligamentous ossification, and immobility. (makitie2010longtermclinicaloutcome pages 2-4, makitie2010longtermclinicaloutcome pages 5-7)

Cellular and omics evidence

Principal cells are osteocytes (CL:0000137), mature osteoblasts (CL:0000062), osteoprogenitors, chondrocytes, odontoblasts, and downstream renal proximal-tubule epithelial cells. Suggested processes include GO:0030500 regulation of bone mineralization, GO:0045667 regulation of osteoblast differentiation, GO:0008543 FGFR signaling, MAPK/ERK signaling, PI3K/AKT signaling, phosphate homeostasis, and biomineral tissue development.

In 12-week-old Dmp1-knockout mice, osteoblast/osteocyte-specific Fgf23 deletion rescued about 75% of elevated total and intact FGF23 and completely corrected secreted FGF23 in differentiated primary osteoblast cultures. It normalized serum phosphate but only partially restored bone growth and mineralization. (courbon2023fgf23directlyinhibits pages 13-15)

Single-cell RNA sequencing used n=3 mice per genotype and implicated osteoprogenitor FGFR1, ERK1/2, and PI3K/AKT pathways. This is the most recent advanced-technology evidence retrieved, but no human ARHR1 single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, or multi-omic cohort was identified. (courbon2023fgf23directlyinhibits pages 11-13)

A key 2023 conclusion was: “FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice.” The authors proposed combined DMP1 restoration and FGF23 blockade as a mechanistically more complete future strategy. This remains preclinical. (courbon2023fgf23directlyinhibits pages 1-2)

Immune dysregulation, inflammation, apoptosis, autophagy, mitochondrial disease, and epigenetic reprogramming are not established primary mechanisms of ARHR1.

7. Anatomical structures affected

Primary organs/tissues: skeleton and dentition—growth plates, cortical and trabecular bone, long bones, skull, spine, joints, entheses, dentin, and periodontium.
Secondary organ: kidney proximal tubule is hormonally affected by FGF23, causing phosphate loss; it is not structurally mutated.
Suggested UBERON terms: skeletal system UBERON:0000982, bone tissue, long bone UBERON:0001272, growth plate UBERON:0004766, skull, vertebral column, joint, tooth/dentin, and kidney UBERON:0002113.
Subcellular compartments: extracellular region/matrix (GO:0005576, GO:0031012); DMP1 enters the secretory pathway and is deposited/processed in mineralized matrix. A nucleus-targeted DMP1 transgene did not rescue dental or periodontal defects in Dmp1-null mice, supporting the extracellular rather than nuclear function during odontogenesis. (yamazaki2022osteocytesandthe pages 3-5, clinkenbeard2017heritableandacquired pages 4-6)
Localization: abnormalities are generally bilateral/systemic rather than unilateral, although deformity severity may be asymmetric.

8. Temporal development

Onset is usually chronic and insidious during infancy or early childhood, often recognized after walking begins through leg bowing, pain, short stature, or abnormal gait. One documented case began at 18 months; the Finnish siblings had pain and varus deformity from early childhood. (makitie2010longtermclinicaloutcome pages 1-2, gu2018targetedresequencingof pages 6-7)

A practical natural-history sequence is: early growth-plate rickets and deformity; childhood/adolescent growth failure and orthopedic/dental disease; persistent adult osteomalacia, fractures and pain; and later enthesopathy, ligamentous ossification, degenerative arthritis, spinal stenosis/ankylosis, contractures, and reduced mobility. Course and severity vary, and early effective treatment may reduce—but has not been proven to eliminate—long-term complications. The disease is lifelong; spontaneous remission is not established. (makitie2010longtermclinicaloutcome pages 7-9, makitie2010longtermclinicaloutcome pages 2-4)

Growth is a critical intervention window because untreated growth plates accumulate irreversible deformity. Adult intervention may improve biochemical osteomalacia and pain but cannot be assumed to reverse established skeletal geometry, ankylosis, or osteoarthritis.

9. Inheritance and population

Inheritance is autosomal recessive. Variants are constitutional/germline. Consanguinity has been observed, and geographically restricted ancestry may produce founder alleles, but no universal founder mutation is known. Genetic anticipation is not expected. (makitie2010longtermclinicaloutcome pages 2-4, gu2018targetedresequencingof pages 6-7)

No defensible ARHR1-specific prevalence, incidence, carrier-frequency, geographic-distribution, sex-ratio, or age-distribution estimate was found. The literature comprises a small number of families and cases, so percentages derived from those reports would be misleading. One targeted cohort found one DMP1 case among 86 selected patients with hypophosphatemic rickets/osteomalacia; this is a diagnostic yield in an enriched cohort, not population prevalence. (gu2018targetedresequencingof pages 6-7)

10. Diagnostics

Clinical and biochemical approach

Suspect disease in childhood rickets, short stature, lower-limb bowing, bone pain, abnormal gait, recurrent dental abscesses, or an affected sibling.
Confirm low fasting serum phosphate against age-specific reference intervals and measure ALP, calcium, creatinine/eGFR, PTH, 25-hydroxyvitamin D, and preferably 1,25-dihydroxyvitamin D.
Document inappropriate renal phosphate loss using paired fasting serum/urine phosphate and creatinine, fractional phosphate excretion, tubular phosphate reabsorption, or TmP/GFR.
Measure intact FGF23 where available. In ARHR1 it is elevated or inappropriately normal for the degree of hypophosphatemia; an inappropriately low FGF23 suggests a transporter defect or non-FGF23 cause.
Obtain wrist or knee radiographs for metaphyseal widening, cupping/fraying, and growth-plate abnormalities; standing lower-limb films assist deformity planning. Bone biopsy is not routinely required.
Confirm with molecular testing. (gu2018targetedresequencingof pages 6-7, nakanishi2022pathogenesisoffgf23related pages 7-8, haffner2022ricketsguidanceparta pages 1-2)

Genetic testing

A hereditary hypophosphatemia/rickets panel should include at least DMP1, PHEX, FGF23, ENPP1, FAM20C, SLC34A1, SLC34A3, SLC9A3R1, CYP27B1, CYP2R1, VDR, and other laboratory-validated genes, with deletion/duplication analysis. Single-gene DMP1 sequencing is reasonable in a classic recessive pedigree but risks missing phenocopies. WES or WGS is appropriate after negative panels, atypical disease, or suspected novel/structural variants. A 2024 real-world report showed that restricted testing could miss DMP1 disease, whereas WES found c.1122T>G (p.Tyr374Ter); the authors suggested a broad 16-gene panel as a lower-cost alternative. CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion testing are not first-line unless another phenotype indicates them. (chaturvedi2024lessonslearnedfrom pages 7-8, chaturvedi2024lessonslearnedfrom pages 6-7)

Differential diagnosis

Differentiate ARHR1 from XLH/PHEX, ADHR/FGF23, ARHR2/ENPP1, FAM20C-related disease, renal phosphate-transporter defects, Fanconi syndromes, nutritional vitamin-D/calcium deficiency, vitamin-D-dependent rickets, renal tubular acidosis, chronic kidney disease, and tumor-induced osteomalacia. Key discriminators are inheritance, age, FGF23 appropriateness, renal phosphate handling, calcitriol, calcium/PTH pattern, extra-skeletal vascular calcification in ENPP1 disease, and molecular testing. Broad genetic testing matters because mechanism determines treatment; a non-FGF23 disorder would not be expected to benefit from FGF23 blockade. (chaturvedi2024lessonslearnedfrom pages 7-8, chaturvedi2024lessonslearnedfrom pages 1-2)

There is no population newborn biochemical screening program. Cascade testing of relatives, parental carrier testing, and testing of at-risk siblings are appropriate after identifying familial variants.

11. Outcome and prognosis

Life expectancy, 5- or 10-year survival, and disease-specific mortality have not been quantified. ARHR1 is principally a morbidity-producing rather than known lethal disorder. Long-term prognosis depends on age at diagnosis, severity of phosphate wasting, growth-plate damage, adherence and response to therapy, orthopedic burden, dental disease, and treatment complications.

The strongest long-term evidence involves two adults aged 66 and 78 years with childhood onset. They developed severe joint pain, contractures, short/deformed long bones, cranial hyperostosis, enthesopathy, paraspinal-ligament calcification, and complete spinal immobilization. This demonstrates survival into older adulthood but also potentially extreme disability; it is not a population prognosis estimate. (makitie2010longtermclinicaloutcome pages 1-2)

Recovery of biochemical abnormalities and active rickets is possible with treatment, but established deformity, osteoarthritis, enthesopathy, ligamentous ossification, and ankylosis may be irreversible. No validated ARHR1-specific prognostic biomarker exists beyond conventional measures of disease activity such as phosphate, ALP, TmP/GFR, PTH, FGF23, growth, pain, and radiographic rickets.

12. Treatment and real-world implementation

Conventional pharmacotherapy

Historically, FGF23-mediated rickets has been treated with divided oral phosphate salts plus active vitamin D—calcitriol or alfacalcidol—rather than nutritional vitamin D alone. Goals are healing rickets, reducing pain/deformity, improving growth, and avoiding toxicity; forcing serum phosphate continuously into the normal range with large oral doses is not an appropriate stand-alone objective. (chaturvedi2024lessonslearnedfrom pages 7-8, haffner2022ricketsguidanceparta pages 1-2)

Monitor growth, deformity, gait, pain, ALP, phosphate, calcium, PTH, creatinine/eGFR, 25-OH-D, urine calcium, and renal phosphate handling. General rickets guidance suggests visits every 1–3 months in children aged 0–5 years, every 3–6 months before puberty, approximately every three months during puberty, and renal ultrasound every 1–2 years during phosphate/active-vitamin-D or burosumab therapy. Complications include gastrointestinal intolerance, hypercalciuria, nephrolithiasis/nephrocalcinosis, and secondary or tertiary hyperparathyroidism. These schedules are general guidance, not ARHR1 trial-derived rules. (haffner2022ricketsguidanceparta pages 1-2)

Suggested intervention annotations include phosphate supplementation (CHEBI:26020 phosphate), calcitriol (CHEBI:17823), pharmacotherapy, and nutritional support. No established ARHR1 pharmacogenomic marker is known.

Burosumab

Burosumab is a fully human monoclonal antibody that neutralizes FGF23. It is mechanistically attractive, but it is not specifically approved for DMP1-related ARHR1 in the jurisdictions described by the retrieved evidence; use is off-label/experimental and access/reimbursement varies. No ARHR1 randomized trial or reliable response rate was identified. The retrieved literature refers to promising treatment in only two adults and a 2024 real-world DMP1 case, but does not provide sufficient standardized numerical outcomes to estimate efficacy. (courbon2023fgf23directlyinhibits pages 1-2, chaturvedi2024lessonslearnedfrom pages 7-8)

Model evidence provides an important caution: reducing osteocytic FGF23 normalized serum phosphate but only partially rescued bone because DMP1 deficiency itself impairs mineralization. Thus, burosumab may correct the endocrine branch without replacing DMP1’s local matrix function. (courbon2023fgf23directlyinhibits pages 11-13, courbon2023fgf23directlyinhibits pages 13-15)

Suggested NCIT term: Burosumab/anti-FGF23 monoclonal-antibody therapy. Treatment should occur through a metabolic-bone specialist with close phosphate monitoring to avoid hyperphosphatemia or ectopic mineralization.

Surgery, dentistry, and rehabilitation

Corrective osteotomy may be required for persistent severe deformity after metabolic control; joint replacement, fracture repair, or spinal decompression may be necessary in advanced adults. Dental surveillance, prompt management of abscesses, physical therapy, low-impact strengthening, mobility aids, occupational therapy, pain management, and psychosocial support are appropriate. Surgery does not correct the biochemical disease. Suggested NCIT concepts include orthopedic surgery, osteotomy, physical therapy, occupational therapy, rehabilitation, and pain management. (makitie2010longtermclinicaloutcome pages 2-4)

Experimental therapies

No ARHR1-specific gene, cell, RNA, or CRISPR therapy and no disease-specific interventional ClinicalTrials.gov study were identified. Preclinical evidence supports combined DMP1 restoration plus FGF23 blockade, but delivery, safety, dosing, and durability remain unresolved. (courbon2023fgf23directlyinhibits pages 1-2)

13. Prevention

Primary prevention by lifestyle or vaccination is not possible. Reproductive prevention options after identifying familial variants include genetic counseling, carrier testing, partner testing, prenatal diagnosis, and preimplantation genetic testing where legally and ethically available. Secondary prevention consists of cascade testing and early biochemical evaluation of at-risk siblings so treatment begins before major growth-plate deformity. Tertiary prevention includes sustained metabolic control, adequate calcium/25-OH-D, renal and PTH surveillance, dental care, physical therapy, fall/fracture prevention, and timely orthopedic assessment. No vaccine, antimicrobial prophylaxis, or environmental public-health intervention applies.

14. Other species and natural disease

DMP1 and phosphate-regulatory mechanisms are evolutionarily conserved. Relevant experimental species include Mus musculus (NCBI Taxon 10090) and Oryctolagus cuniculus (NCBI Taxon 9986). DMP1-deficient rabbits develop elevated FGF23, hypophosphatemic rickets, and severe bone-microarchitecture abnormalities. (yamazaki2022osteocytesandthe pages 3-5)

No well-established naturally occurring companion-animal breed disorder equivalent to human DMP1-ARHR1 was identified in the retrieved evidence. Accordingly, no defensible VBO breed term or veterinary prevalence can be assigned. ARHR1 is noninfectious and has no zoonotic or cross-species transmission.

15. Model organisms

The principal model is the Dmp1-knockout mouse, a germline genetic mammalian model. It reproduces elevated FGF23/PTH, hypophosphatemia, 30%–35% reductions in body weight and tail/femur length, rickets, osteomalacia, abnormal growth plates, hypomineralized trabecular bone, cortical expansion/porosity, defective osteocyte morphology/connectivity, and reduced osteoclast numbers. (courbon2023fgf23directlyinhibits pages 4-5)

Conditional osteoblast/osteocyte Fgf23 deletion in the Dmp1-null background separates systemic and local mechanisms: phosphate and fractional phosphate excretion normalize, while residual osteoid accumulation and mineralization/canalicular defects remain. Primary osteoblast/osteoprogenitor cultures demonstrate direct FGF23 inhibition of differentiation and a separate DMP1-dependent mineralization defect. These models are useful for testing FGF23 blockade, DMP1 replacement, phosphate responsiveness, matrix biology, and osteocyte signaling. (courbon2023fgf23directlyinhibits pages 11-13, courbon2023fgf23directlyinhibits pages 4-5, courbon2023fgf23directlyinhibits pages 13-15)

Limitations include species-specific skeletal growth, experimental complete knockout rather than the allelic diversity of patients, short observation relative to decades of human disease, and inability to reproduce fully the human burden of dental disease, enthesopathy, orthopedic surgery, pain, and quality of life.

Recent developments and authoritative interpretation

The principal 2023 advance was mechanistic: Courbon and colleagues showed that FGF23 has direct adverse effects on osteoprogenitor differentiation, while DMP1 loss independently compromises mineralization. Their abstract reports that osteocyte-specific Fgf23 deletion “fully restore[d] serum Pi levels but only partially corrected the bone phenotype,” supporting a two-component disease model rather than a purely endocrine phosphate-deficiency model. (courbon2023fgf23directlyinhibits pages 1-2)

The principal 2024 clinical message is diagnostic and implementation-focused. Real-world cases showed progressive disease despite conventional phosphate and active-vitamin-D treatment and demonstrated that narrow genetic testing may miss DMP1 variants. Comprehensive panels or WES/WGS can prevent prolonged misclassification and support mechanism-specific treatment and counseling. Burosumab remains promising but off-label for ARHR1, with evidence far weaker than in XLH. (chaturvedi2024lessonslearnedfrom pages 7-8, chaturvedi2024lessonslearnedfrom pages 6-7)

Evidence limitations

ARHR1 is exceptionally rare. Most human evidence comes from individual families, retrospective cases, and selected sequencing cohorts; consequently, phenotype percentages, penetrance estimates, prevalence, incidence, sex ratios, survival, quality-of-life scores, treatment-response rates, and variant-specific population frequencies cannot currently be stated reliably. The strongest mechanistic evidence is from engineered mice and cultured cells and should be labeled preclinical. PMID values were not consistently present in the retrieved records; DOI URLs and publication dates are therefore supplied rather than inventing PMIDs.

Key dated sources and URLs

Lorenz-Depiereux et al., Nature Genetics, October 2006, discovery genetics: https://doi.org/10.1038/ng1868.
Mäkitie et al., Journal of Bone and Mineral Research, April 2010, long-term human family: https://doi.org/10.1002/jbmr.105. (makitie2010longtermclinicaloutcome pages 1-2)
Ichikawa et al., Endocrinology, March 2017, phosphate responsiveness in Dmp1-mutant mice: https://doi.org/10.1210/en.2016-1642. (ichikawa2017amutationin pages 1-1)
Gu et al., June 2018, targeted sequencing and p.Glu244Ter case: https://doi.org/10.3892/ijmm.2018.3730. (gu2018targetedresequencingof pages 6-7)
Courbon et al., JCI Insight, December 2023, direct FGF23 and DMP1-independent skeletal mechanisms: https://doi.org/10.1172/jci.insight.156850. (courbon2023fgf23directlyinhibits pages 1-2)
Chaturvedi et al., Bone Reports, June 2024, real-world diagnosis and management: https://doi.org/10.1016/j.bonr.2024.101753. (chaturvedi2024lessonslearnedfrom pages 7-8)
Baroncelli et al., Frontiers in Endocrinology, April 2024, rickets diagnostic/management position statement: https://doi.org/10.3389/fendo.2024.1383681.

References

(makitie2010longtermclinicaloutcome pages 1-2): Outi Mäkitie, Renata C Pereira, Ilkka Kaitila, Serap Turan, Murat Bastepe, Tero Laine, Heikki Kröger, William G Cole, and Harald Jüppner. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel dmp1 mutation. Journal of Bone and Mineral Research, 25(10):2165-2174, Apr 2010. URL: https://doi.org/10.1002/jbmr.105, doi:10.1002/jbmr.105. This article has 72 citations and is from a highest quality peer-reviewed journal.
(courbon2023fgf23directlyinhibits pages 1-2): Guillaume Courbon, Dominik Kentrup, Jane Joy Thomas, Xueyan Wang, Hao-Hsuan Tsai, Jadeah Spindler, John Von Drasek, Laura Mazudie Ndjonko, Marta Martinez-Calle, Sana Lynch, Lauriane Hivert, Xiaofang Wang, Wenhan Chang, Jian Q. Feng, Valentin David, and Aline Martin. Fgf23 directly inhibits osteoprogenitor differentiation in dmp1-knockout mice. Dec 2023. URL: https://doi.org/10.1172/jci.insight.156850, doi:10.1172/jci.insight.156850. This article has 23 citations and is from a domain leading peer-reviewed journal.
(makitie2010longtermclinicaloutcome pages 2-4): Outi Mäkitie, Renata C Pereira, Ilkka Kaitila, Serap Turan, Murat Bastepe, Tero Laine, Heikki Kröger, William G Cole, and Harald Jüppner. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel dmp1 mutation. Journal of Bone and Mineral Research, 25(10):2165-2174, Apr 2010. URL: https://doi.org/10.1002/jbmr.105, doi:10.1002/jbmr.105. This article has 72 citations and is from a highest quality peer-reviewed journal.
(gu2018targetedresequencingof pages 6-7): Jiemei Gu, Chun Wang, Hao Zhang, Hua Yue, Weiwei Hu, Jinwei He, Wenzhen Fu, and Zhenlin Zhang. Targeted resequencing of phosphorus metabolism‑related genes in 86 patients with hypophosphatemic rickets/osteomalacia. Jun 2018. URL: https://doi.org/10.3892/ijmm.2018.3730, doi:10.3892/ijmm.2018.3730. This article has 9 citations and is from a peer-reviewed journal.
(clinkenbeard2017heritableandacquired pages 4-6): Erica L. Clinkenbeard and Kenneth E. White. Heritable and acquired disorders of phosphate metabolism: etiologies involving fgf23 and current therapeutics. Bone, 102:31-39, Sep 2017. URL: https://doi.org/10.1016/j.bone.2017.01.034, doi:10.1016/j.bone.2017.01.034. This article has 37 citations and is from a domain leading peer-reviewed journal.
(nakanishi2022pathogenesisoffgf23related pages 7-8): Tatsuro Nakanishi and Toshimi Michigami. Pathogenesis of fgf23-related hypophosphatemic diseases including x-linked hypophosphatemia. Endocrines, 3:303-316, Jun 2022. URL: https://doi.org/10.3390/endocrines3020025, doi:10.3390/endocrines3020025. This article has 10 citations.
(yamazaki2022osteocytesandthe pages 3-5): Miwa Yamazaki and Toshimi Michigami. Osteocytes and the pathogenesis of hypophosphatemic rickets. Frontiers in Endocrinology, Sep 2022. URL: https://doi.org/10.3389/fendo.2022.1005189, doi:10.3389/fendo.2022.1005189. This article has 32 citations.
(chaturvedi2024lessonslearnedfrom pages 6-7): Deepti Chaturvedi, Taif EmadEldin Mehasi, Assia Benbrahim, Lubna ElDeeb, and Asma Deeb. Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets. Jun 2024. URL: https://doi.org/10.1016/j.bonr.2024.101753, doi:10.1016/j.bonr.2024.101753. This article has 3 citations and is from a peer-reviewed journal.
(chaturvedi2024lessonslearnedfrom pages 7-8): Deepti Chaturvedi, Taif EmadEldin Mehasi, Assia Benbrahim, Lubna ElDeeb, and Asma Deeb. Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets. Jun 2024. URL: https://doi.org/10.1016/j.bonr.2024.101753, doi:10.1016/j.bonr.2024.101753. This article has 3 citations and is from a peer-reviewed journal.
(chaturvedi2024lessonslearnedfrom pages 1-2): Deepti Chaturvedi, Taif EmadEldin Mehasi, Assia Benbrahim, Lubna ElDeeb, and Asma Deeb. Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets. Jun 2024. URL: https://doi.org/10.1016/j.bonr.2024.101753, doi:10.1016/j.bonr.2024.101753. This article has 3 citations and is from a peer-reviewed journal.
(makitie2010longtermclinicaloutcome pages 7-9): Outi Mäkitie, Renata C Pereira, Ilkka Kaitila, Serap Turan, Murat Bastepe, Tero Laine, Heikki Kröger, William G Cole, and Harald Jüppner. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel dmp1 mutation. Journal of Bone and Mineral Research, 25(10):2165-2174, Apr 2010. URL: https://doi.org/10.1002/jbmr.105, doi:10.1002/jbmr.105. This article has 72 citations and is from a highest quality peer-reviewed journal.
(haffner2022ricketsguidanceparta pages 1-2): Dieter Haffner, Maren Leifheit-Nestler, Andrea Grund, and Dirk Schnabel. Rickets guidance: part ii—management. Pediatric Nephrology (Berlin, Germany), 37:2289-2302, Mar 2022. URL: https://doi.org/10.1007/s00467-022-05505-5, doi:10.1007/s00467-022-05505-5. This article has 65 citations.
(courbon2023fgf23directlyinhibits pages 11-13): Guillaume Courbon, Dominik Kentrup, Jane Joy Thomas, Xueyan Wang, Hao-Hsuan Tsai, Jadeah Spindler, John Von Drasek, Laura Mazudie Ndjonko, Marta Martinez-Calle, Sana Lynch, Lauriane Hivert, Xiaofang Wang, Wenhan Chang, Jian Q. Feng, Valentin David, and Aline Martin. Fgf23 directly inhibits osteoprogenitor differentiation in dmp1-knockout mice. Dec 2023. URL: https://doi.org/10.1172/jci.insight.156850, doi:10.1172/jci.insight.156850. This article has 23 citations and is from a domain leading peer-reviewed journal.
(courbon2023fgf23directlyinhibits pages 4-5): Guillaume Courbon, Dominik Kentrup, Jane Joy Thomas, Xueyan Wang, Hao-Hsuan Tsai, Jadeah Spindler, John Von Drasek, Laura Mazudie Ndjonko, Marta Martinez-Calle, Sana Lynch, Lauriane Hivert, Xiaofang Wang, Wenhan Chang, Jian Q. Feng, Valentin David, and Aline Martin. Fgf23 directly inhibits osteoprogenitor differentiation in dmp1-knockout mice. Dec 2023. URL: https://doi.org/10.1172/jci.insight.156850, doi:10.1172/jci.insight.156850. This article has 23 citations and is from a domain leading peer-reviewed journal.
(makitie2010longtermclinicaloutcome pages 5-7): Outi Mäkitie, Renata C Pereira, Ilkka Kaitila, Serap Turan, Murat Bastepe, Tero Laine, Heikki Kröger, William G Cole, and Harald Jüppner. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel dmp1 mutation. Journal of Bone and Mineral Research, 25(10):2165-2174, Apr 2010. URL: https://doi.org/10.1002/jbmr.105, doi:10.1002/jbmr.105. This article has 72 citations and is from a highest quality peer-reviewed journal.
(courbon2023fgf23directlyinhibits pages 13-15): Guillaume Courbon, Dominik Kentrup, Jane Joy Thomas, Xueyan Wang, Hao-Hsuan Tsai, Jadeah Spindler, John Von Drasek, Laura Mazudie Ndjonko, Marta Martinez-Calle, Sana Lynch, Lauriane Hivert, Xiaofang Wang, Wenhan Chang, Jian Q. Feng, Valentin David, and Aline Martin. Fgf23 directly inhibits osteoprogenitor differentiation in dmp1-knockout mice. Dec 2023. URL: https://doi.org/10.1172/jci.insight.156850, doi:10.1172/jci.insight.156850. This article has 23 citations and is from a domain leading peer-reviewed journal.
(ichikawa2017amutationin pages 1-1): Shoji Ichikawa, Rita L. Gerard-O'Riley, Dena Acton, Amie K. McQueen, Isabel E. Strobel, Phillip C. Witcher, Jian Q. Feng, and Michael J. Econs. A mutation in the dmp1 gene alters phosphate responsiveness in mice. Endocrinology, 158:470–476, Mar 2017. URL: https://doi.org/10.1210/en.2016-1642, doi:10.1210/en.2016-1642. This article has 38 citations and is from a domain leading peer-reviewed journal.
(makitie2010longtermclinicaloutcome pages 9-10): Outi Mäkitie, Renata C Pereira, Ilkka Kaitila, Serap Turan, Murat Bastepe, Tero Laine, Heikki Kröger, William G Cole, and Harald Jüppner. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel dmp1 mutation. Journal of Bone and Mineral Research, 25(10):2165-2174, Apr 2010. URL: https://doi.org/10.1002/jbmr.105, doi:10.1002/jbmr.105. This article has 72 citations and is from a highest quality peer-reviewed journal.

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References weighed for topical relevance	11
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Autosomal Recessive Hypophosphatemic Rickets 1 (ARHR1): Disease-Characteristics Report

Executive summary

1. Disease information

2. Etiology, risk, and protective factors

Causal factor

Risk factors

Protective factors and gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Cellular and omics evidence

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and biochemical approach

Genetic testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment and real-world implementation

Conventional pharmacotherapy

Burosumab

Surgery, dentistry, and rehabilitation

Experimental therapies

13. Prevention

14. Other species and natural disease

15. Model organisms

Recent developments and authoritative interpretation

Evidence limitations

Key dated sources and URLs

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