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PubMed This is a summary of 55 peer-reviewed journal articles Updated
Endocrinology

Autosomal Recessive Hypophosphatemic Rickets (ARHR): A Patient Guide

At a Glance

Autosomal recessive hypophosphatemic rickets causes the kidneys to lose too much phosphate, weakening bones. Genetic testing identifies the subtype and helps clinicians tailor phosphate and vitamin D treatment and monitor kidney, dental, hearing, and cardiovascular health.

Autosomal Recessive Hypophosphatemic Rickets (ARHR) is a group of rare genetic disorders that disrupt the delicate balance of minerals needed to build and maintain healthy bones [1]. At the heart of this condition is a hormone called Fibroblast Growth Factor 23 (FGF23). In a healthy body, FGF23 acts as a regulator to ensure the kidneys keep the right amount of phosphate in the bloodstream. In people with ARHR, the body has excess FGF23 activity (which may appear high or inappropriately normal on lab tests), causing the kidneys to flush out essential phosphate into the urine—a process known as renal phosphate wasting [2][3]. Without enough phosphate, the skeleton cannot properly harden, leading to the bone softening and bowing characteristic of rickets in children and osteomalacia in adults [4].

While all forms of ARHR lead to low phosphate, the condition is actually a collection of several different genetic subtypes, each with its own unique biological “signature.” ARHR1 is caused by mutations in the DMP1 gene, while ARHR3 is linked to the FAM20C gene [2][5]. Perhaps the most complex subtype is ARHR2, caused by mutations in the ENPP1 gene. In ARHR2, the body faces a dual challenge: it has reduced pyrophosphate, a natural substance that helps prevent calcium from hardening in soft tissues, while simultaneously dealing with the excess FGF23 that causes bone softening [3][6]. Because of this, individuals with the ENPP1 subtype require specialized monitoring for ectopic calcification—the buildup of calcium in the heart valves, arteries, and joints [7][8].

Because these subtypes can look identical on standard blood tests, identifying the specific gene mutation through genetic testing is the cornerstone of effective management [9]. Knowing the subtype allows your medical team to look beyond the bones and monitor for other potential complications, such as progressive hearing loss, dental abscesses, or cardiovascular changes [10][4]. This precision is vital because the risks and needs of a patient with ARHR1 can differ significantly from those with ARHR2, particularly when it comes to screening for heart and vascular health [11][12].

Living with ARHR involves a lifelong commitment to a multidisciplinary care team, often led by a metabolic bone specialist or endocrinologist working alongside nephrologists, dentists, and sometimes cardiologists [13][14]. The conventional specialist-directed care typically involves a combination of oral phosphate supplements to “refill” the body’s mineral stores and active vitamin D to help the body absorb that phosphate [15][16]. While this treatment can effectively heal rickets and reduce bone pain, it requires careful, regular monitoring to ensure that mineral levels do not rise too high and cause secondary issues like kidney stones or overactive parathyroid glands [17][18].

Important Safety Note: Phosphate, calcitriol, and alfacalcidol should not be started, stopped, or dose-adjusted without the treating clinician. Monitoring goals differ by age, kidney status, and genotype. With consistent care and a tailored monitoring plan, the goal of treatment is to protect the skeleton and support overall health throughout every stage of life.

In this guide

5 chapters

01

Understanding the Genetic Subtypes of ARHR

Learn how autosomal recessive hypophosphatemic rickets subtypes involve DMP1, ENPP1, and FAM20C, affecting bones, phosphate balance, and long-term monitoring.

02

Symptoms and the Path to Diagnosis

Learn how autosomal recessive hypophosphatemic rickets is diagnosed, including phosphate-wasting labs, FGF23, imaging, symptoms, and genetic test results.

03

Standard Treatment Strategies and Precautions

Learn how autosomal recessive hypophosphatemic rickets is treated with phosphate, calcitriol, monitoring, calcification precautions, and burosumab guidance.

04

Long-Term Monitoring and Managing Complications

Learn how long-term monitoring helps manage autosomal recessive hypophosphatemic rickets, including kidney, heart, hormone, hearing, dental, and bone risks.

05

Building Your Care Team and Preparing for Visits

Learn how to prepare for autosomal recessive hypophosphatemic rickets visits, organize records, and coordinate kidney, heart, hearing, dental, and bone care.

Common questions in this guide

What gene changes cause autosomal recessive hypophosphatemic rickets?
ARHR is caused by inherited changes in genes involved in phosphate regulation. The page discusses DMP1, ENPP1, and FAM20C; these subtypes can increase FGF23 activity or, in ENPP1-related disease, also reduce pyrophosphate, a substance that helps keep calcium from hardening in soft tissues.
Why is genetic testing important for ARHR?
Routine blood tests may look similar across ARHR subtypes, while genetic testing identifies the affected gene. This helps clinicians tailor follow-up, including monitoring for cardiovascular, hearing, dental, and other complications.
What treatment is commonly used for ARHR?
Specialist-directed care often combines oral phosphate supplements with active vitamin D, such as calcitriol or alfacalcidol. The goal is to improve phosphate availability, heal rickets, and reduce bone pain; treatment should not be started or changed without clinician guidance.
Why are blood and urine tests needed during ARHR treatment?
Regular tests help clinicians check whether phosphate and other minerals are in a safe range and whether treatment is working. Monitoring is important because treatment can contribute to kidney stones or overactive parathyroid glands, and goals vary with age, kidney function, and genetic subtype.
Does ARHR2 have health risks beyond low phosphate?
Yes. ENPP1-related ARHR2 can cause reduced pyrophosphate as well as excess FGF23 activity, so calcium may build up in soft tissues such as heart valves, arteries, and joints. This subtype may need specialized heart and blood-vessel monitoring.
Who should be part of an ARHR care team?
Care is often coordinated by a metabolic bone specialist or endocrinologist with a nephrologist, dentist, and, when needed, cardiologist. The team may also monitor bone pain and mobility along with hearing, dental, kidney, and cardiovascular health.

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Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which specific genetic subtype (DMP1, ENPP1, or FAM20C) was identified, and how does it change our long-term monitoring plan?
  2. 2.How do we balance the need for phosphate to heal bones against the potential risks to the kidneys or blood vessels?
  3. 3.What specialists should we add to our team to monitor for symptoms like hearing loss or cardiovascular issues?
  4. 4.How often will we need to repeat blood and urine tests to ensure the treatment is effective and safe?

References

References (18)
  1. 1

    Osteocytes and the pathogenesis of hypophosphatemic rickets.

    Yamazaki M, Michigami T

    Frontiers in endocrinology 2022; (13()):1005189 doi:10.3389/fendo.2022.1005189.

    PMID: 36246908
  2. 2

    A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice.

    Ichikawa S, Gerard-O'Riley RL, Acton D, et al.

    Endocrinology 2017; (158(3)):470-476 doi:10.1210/en.2016-1642.

    PMID: 28005411
  3. 3

    Phenotypic diversity in autosomal recessive hypophosphatemic rickets type 2.

    Al Qanoobi M, Al Badi M, Al Sinani A, Mughal MZ

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2026; (41(7)):705-709 doi:10.1093/jbmr/zjag029.

    PMID: 41665285
  4. 4

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

    Sawalha NA, Sampaio ML, Liu D, et al.

    Calcified tissue international 2026; (117(1)).

    PMID: 41820620
  5. 5

    Fibroblast growth factor 23 (FGF23): From synthesis to cleavage.

    Yuan S, Wang Q, Meng C, et al.

    Molecular and cellular endocrinology 2026; (623()):112909 doi:10.1016/j.mce.2026.112909.

    PMID: 42697502
  6. 6

    INZ-701 Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in ENPP1-Deficient Mice.

    Cheng Z, O'Brien K, Howe J, et al.

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2021; (36(8)):1594-1604 doi:10.1002/jbmr.4315.

    PMID: 33900645
  7. 7

    Phenotypic characterization of ENPP1 deficiency: generalized arterial calcification of infancy and autosomal recessive hypophosphatemic rickets type 2.

    Ferreira CR, Hackbarth ME, Nitschke Y, et al.

    JBMR plus 2025; (9(5)):ziaf019 doi:10.1093/jbmrpl/ziaf019.

    PMID: 40176950
  8. 8

    Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies.

    Ferreira CR, Kintzinger K, Hackbarth ME, et al.

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2021; (36(11)):2193-2202 doi:10.1002/jbmr.4418.

    PMID: 34355424
  9. 9

    Genetic and clinical profile of patients with hypophosphatemic rickets.

    Marik B, Bagga A, Sinha A, et al.

    European journal of medical genetics 2022; (65(8)):104540 doi:10.1016/j.ejmg.2022.104540.

    PMID: 35738466
  10. 10

    Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).

    Ferreira CR, Hackbarth ME, Ziegler SG, et al.

    Genetics in medicine : official journal of the American College of Medical Genetics 2021; (23(2)):396-407 doi:10.1038/s41436-020-00983-0.

    PMID: 33005041
  11. 11

    Autosomal recessive hypophosphatemic rickets type 2 due to ENPP1 deficiency (ARHR2).

    Edouard T, Linglart A

    Archives de pediatrie : organe officiel de la Societe francaise de pediatrie 2024; (31(4S1)):4S27-4S32 doi:10.1016/S0929-693X(24)00154-4.

    PMID: 39343470
  12. 12

    Autosomal recessive hypophosphatemic rickets type 2 (ARHR2): Is phosphate supplementation safe?

    Munteanu M, Rutsch F, Nitschke Y, et al.

    Bone 2026; (202()):117698 doi:10.1016/j.bone.2025.117698.

    PMID: 41176198
  13. 13

    Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia.

    Haffner D, Emma F, Eastwood DM, et al.

    Nature reviews. Nephrology 2019; (15(7)):435-455 doi:10.1038/s41581-019-0152-5.

    PMID: 31068690
  14. 14

    Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium.

    Laurent MR, De Schepper J, Trouet D, et al.

    Frontiers in endocrinology 2021; (12()):641543 doi:10.3389/fendo.2021.641543.

    PMID: 33815294
  15. 15

    FGF23 and Associated Disorders of Phosphate Wasting.

    Gohil A, Imel EA

    Pediatric endocrinology reviews : PER 2019; (17(1)):17-34 doi:10.17458/per.vol17.2019.gi.fgf23anddisordersphosphate.

    PMID: 31599133
  16. 16

    Rickets guidance: part II-management.

    Haffner D, Leifheit-Nestler M, Grund A, Schnabel D

    Pediatric nephrology (Berlin, Germany) 2022; (37(10)):2289-2302 doi:10.1007/s00467-022-05505-5.

    PMID: 35352187
  17. 17

    Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice.

    Ferreira CR, Kavanagh D, Oheim R, et al.

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2021; (36(5)):942-955 doi:10.1002/jbmr.4254.

    PMID: 33465815
  18. 18

    Phosphatonins: From Discovery to Therapeutics.

    Kritmetapak K, Kumar R

    Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 2023; (29(1)):69-79 doi:10.1016/j.eprac.2022.09.007.

    PMID: 36210014

This page is for informational purposes only and does not constitute medical advice. Do not start, stop, or adjust phosphate, calcitriol, or alfacalcidol without guidance from your treating clinician.