| 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 (pqac-00000003, pqac-00000004, pqac-00000007) |
| 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 (pqac-00000012, pqac-00000020, pqac-00000023) |
| 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 (pqac-00000011, pqac-00000012, pqac-00000017) |
| 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 (pqac-00000008, pqac-00000009, pqac-00000017) |
| 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 (pqac-00000005, pqac-00000013, pqac-00000017) |
| 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 (pqac-00000007, pqac-00000010, pqac-00000017) |
| 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 (pqac-00000002, pqac-00000018, pqac-00000019, pqac-00000021) |
| 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 (pqac-00000016, pqac-00000019, pqac-00000020) |
| 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 (pqac-00000003, pqac-00000008, pqac-00000010) |
| 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 (pqac-00000008, pqac-00000010, pqac-00000011, pqac-00000021) |
| 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 (pqac-00000002, pqac-00000008, pqac-00000018, pqac-00000022) |
| 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 (pqac-00000000, pqac-00000013, pqac-00000016) |
| 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 (pqac-00000018, pqac-00000019, pqac-00000020, pqac-00000022) |


*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.*