Skip to content
How It Works
Explore
Ask a Question Resources Pricing
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Sign Up
PubMed This is a summary of 29 peer-reviewed journal articles Updated
Endocrinology

Symptoms and the Path to Diagnosis

At a Glance

ARHR is suspected when low blood phosphate is paired with kidney phosphate wasting and high or inappropriately normal FGF23. Doctors use age-based labs, urine testing, imaging, symptoms, and genetic testing to confirm the diagnosis and identify subtype-specific risks.

When Autosomal Recessive Hypophosphatemic Rickets (ARHR) is suspected, the diagnostic process focuses on proving two things: that the body is losing too much phosphate through the urine, and that this loss is being driven by the hormone FGF23 [1][2]. Because ARHR can look identical to other forms of rickets on the surface, a precise “workup” of labs and imaging is essential to confirm the diagnosis [3].

Common Symptoms and Physical Signs

Age at onset varies by gene and phenotype. Some children with ARHR begin showing signs around the time they start walking (roughly age one), while ENPP1-related disease can present as infantile GACI, and FAM20C disease can be apparent at birth [4]. In adults, the condition may manifest as unexplained bone pain or frequent fractures.

  • Skeletal Changes: Notable bowing of the legs (genu varum) or knock-knees, a “waddling” gait, and shorter-than-average stature [5][6].
  • Bone and Joint Pain: Deep, persistent aching in the long bones or joints [7].
  • Dental Issues: Recurrent dental abscesses (infections at the tooth root) even without significant cavities, and occasionally weak tooth enamel (amelogenesis imperfecta) [8][9].
  • Head and Neck: In some types, specific facial features or a narrowing at the base of the skull may occur in selected patients, which can occasionally cause headaches or vision changes [10][11].

Warning Signs of ENPP1 (ARHR2)

While all forms of ARHR cause bone issues, mutations in the ENPP1 gene (ARHR2) can affect other parts of the body due to low levels of pyrophosphate, a natural mineral-blocker [12]. These complications are reported in some patients:

  • Hearing Loss: Progressive hearing loss has been reported in ENPP1 deficiency, with some children requiring hearing aids early in life [13][14].
  • Ectopic Calcification: This is the hardening of soft tissues. It can occur in the heart valves, large arteries, or around joints, causing stiffness or “crunchy” joint pain [15][16].
  • Spinal Stiffness: Adults may develop Ossification of the Posterior Longitudinal Ligament (OPLL), where a ligament in the spine turns to bone, potentially leading to neck stiffness or nerve compression [16][14].

The Diagnostic Laboratory Profile

To diagnose ARHR, doctors look for a specific “biochemical signature” in the blood and urine. Important: While baseline samples are preferable when clinically feasible, do NOT stop or delay prescribed treatments just to get “clean” lab results [17]. Specialists can interpret treated results and genetic testing remains useful [3].

Test Typical Finding in ARHR What it Means
Serum Phosphate Low The primary marker; must be compared to age-specific ranges [18].
TmP/GFR Low A calculated value showing the kidneys are failing to reabsorb phosphate [17].
Intact FGF23 High or “Inappropriately Normal” In the presence of low phosphate, FGF23 should be very low. A “normal” or high result supports it is driving the disease, though it does not by itself confirm ARHR [19][20].
Alkaline Phosphatase High An enzyme that increases when bone is actively soft or trying to heal [21].
1,25(OH)₂ Vitamin D Low or “Inappropriately Normal” High FGF23 prevents the body from activating vitamin D properly [22].
Serum Calcium Normal Usually stays within the normal range in these disorders [23].

Distinguishing ARHR from Other Conditions

While the symptoms of ARHR overlap heavily with X-Linked Hypophosphatemia (XLH) and Autosomal Dominant Hypophosphatemic Rickets (ADHR), there are key differences:

  • Inheritance: ARHR is recessive, whereas family history in XLH and ADHR can vary. An unremarkable family history does not reliably favor ARHR, as XLH can arise de novo and ADHR has variable penetrance [24].
  • Other Phenocopies: Conditions like Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) feature high active vitamin D and hypercalciuria, meaning they require different treatment.
  • ADHR and Iron: Patients with ADHR may see their symptoms fluctuate or worsen specifically when they have an iron deficiency [25].
  • Imaging: While all show rickets, ARHR1 (DMP1) may uniquely show some bones—like the spine—appearing unusually dense (osteosclerosis) even while other bones are soft [5][6].

The Role of Genetic Testing

Genetic testing helps establish the molecular cause. A phenotype-guided panel will look for mutations in the PHEX (XLH), FGF23 (ADHR), DMP1 (ARHR1), ENPP1 (ARHR2), FAM20C (ARHR3), and other relevant genes [5]. Identifying the specific gene mutation is vital not just for the diagnosis, but for screening for subtype-specific risks [26][14]. However, a negative genetic test or a “Variant of Uncertain Significance” does not completely exclude a clinical diagnosis.

Diagnostic Checklist for Patients

When reviewing your lab results, ensure the following have been considered:

  1. Paired Samples: Blood and urine samples were taken correctly (ideally fasting or first thing in the morning) to calculate the TmP/GFR [17].
  2. Age-Appropriate Ranges: Your phosphate and alkaline phosphatase levels were compared to ranges for your specific age, not adult ranges [18].
  3. Complete Vitamin D Panel: Both 25-hydroxy (storage) and 1,25-dihydroxy (active) vitamin D were measured [27].
  4. Baseline Imaging: X-rays of the wrists or knees (to check for rickets) and potentially a renal ultrasound (to check for kidney stones or calcium deposits) [28][29].

Common questions in this guide

What symptoms can suggest autosomal recessive hypophosphatemic rickets?
ARHR may cause bowed legs or knock-knees, a waddling gait, short stature, bone or joint pain, and frequent fractures. Recurrent dental abscesses can occur even without major cavities. Some ENPP1-related cases also involve hearing loss, soft-tissue calcification, or spinal stiffness.
Which blood and urine tests are used to diagnose ARHR?
Typical findings include low age-adjusted blood phosphate and a low TmP/GFR, a calculation showing that the kidneys are not reabsorbing enough phosphate. FGF23 is high or inappropriately normal when it should be very low in response to low phosphate. Alkaline phosphatase is often high, active vitamin D may be low or inappropriately normal, and calcium is usually normal. The overall pattern is used because no single test confirms ARHR.
What does an inappropriately normal FGF23 result mean?
When blood phosphate is low, FGF23 should normally be suppressed to a very low level. A result in the normal range may therefore be abnormal in context and can support FGF23-driven kidney phosphate loss. It does not by itself prove ARHR, so clinicians also use urine studies, imaging, and genetic testing.
How is ARHR distinguished from XLH, ADHR, and HHRH?
Doctors compare inheritance patterns, lab results, imaging, and genetic findings. HHRH typically has high active vitamin D and excess calcium in the urine, while ADHR symptoms may change with iron deficiency. Genetic testing can help separate ARHR subtypes from XLH and ADHR, but an unremarkable family history does not rule out the other disorders.
What genes are tested when ARHR is suspected?
A phenotype-guided panel may include DMP1, ENPP1, and FAM20C, along with genes associated with XLH, ADHR, and other similar disorders. ARHR is typically associated with mutations in both copies of a relevant gene. A negative result or a variant of uncertain significance does not completely exclude a clinical diagnosis.
Does ENPP1-related ARHR require extra screening?
ENPP1 deficiency can be associated with progressive hearing loss, calcification in soft tissues such as heart valves or arteries, and spinal ligament ossification. Depending on the patient's age, symptoms, and genetic results, a clinician may consider hearing evaluation, an echocardiogram, and other imaging. The appropriate screening plan should be individualized.
Should I stop treatment before ARHR testing?
No. Baseline samples may be preferred when clinically feasible, but prescribed treatment should not be stopped or delayed just to obtain untreated results. Specialists can interpret results obtained during treatment, and genetic testing may still help.

Questions For You

Answer a question to get research tailored to you. Your answers are private.

Get notified when new evidence is published on Autosomal recessive hypophosphatemic rickets.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What was my (or my child's) age-specific serum phosphate level, and how does it compare to the normal range for that age?
  2. 2.Is my intact FGF23 level 'inappropriately normal' or high, and does that confirm this is a phosphate-wasting disorder?
  3. 3.Has a TmP/GFR calculation been performed using a paired blood and urine sample to measure exactly how much phosphate my kidneys are losing?
  4. 4.Given the risk of ENPP1-related issues, should we perform a baseline hearing test or a heart ultrasound (echocardiogram) to look for calcification?
  5. 5.Does my genetic report show 'biallelic' mutations, and which specific gene (DMP1, ENPP1, or FAM20C) is affected?

References

References (29)
  1. 1

    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
  2. 2

    X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management.

    Baroncelli GI, Mora S

    Frontiers in endocrinology 2021; (12()):688309 doi:10.3389/fendo.2021.688309.

    PMID: 34421819
  3. 3

    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
  4. 4

    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.

    Ni X, Li X, Zhang Q, et al.

    Calcified tissue international 2020; (107(6)):636-648 doi:10.1007/s00223-020-00755-7.

    PMID: 32920683
  5. 5

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

    Ni X, Gong Y, Jiang Y, et al.

    The Journal of clinical endocrinology and metabolism 2023; (108(4)):791-801 doi:10.1210/clinem/dgac640.

    PMID: 36334264
  6. 6

    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
  7. 7

    First report in Argentina of a pathogenic DMP1 variant associated with autosomal recessive hypophosphatemic rickets.

    Bastida G, Ramírez F, Exeni G, et al.

    Archivos argentinos de pediatria 2023; (121(2)):e202202682 doi:10.5546/aap.2022-02682.eng.

    PMID: 36315908
  8. 8

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

    Bai X, Levental M, Karaplis AC

    The Journal of clinical endocrinology and metabolism 2022; (107(10)):2777-2783 doi:10.1210/clinem/dgac433.

    PMID: 35896139
  9. 9

    Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications.

    Rafaelsen S, Johansson S, Ræder H, Bjerknes R

    European journal of endocrinology 2016; (174(2)):125-36 doi:10.1530/EJE-15-0515.

    PMID: 26543054
  10. 10

    Mutant Fam20c knock-in mice recapitulate both lethal and non-lethal human Raine Syndrome.

    Chen M, Sun D, Yee SP, et al.

    BMC molecular and cell biology 2025; (26(1)):1 doi:10.1186/s12860-024-00526-4.

    PMID: 39748245
  11. 11

    Base of Skull & Spinal Canal Narrowing in an Adolescent with Autosomal Recessive Hypophosphatemic Rickets Type 2.

    Gokul PR, Jarvis C, Kassab G, et al.

    Calcified tissue international 2025; (116(1)):20 doi:10.1007/s00223-024-01324-y.

    PMID: 39751914
  12. 12

    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
  13. 13

    Early onset hearing loss in autosomal recessive hypophosphatemic rickets caused by loss of function mutation in ENPP1.

    Steichen-Gersdorf E, Lorenz-Depiereux B, Strom TM, Shaw NJ

    Journal of pediatric endocrinology & metabolism : JPEM 2015; (28(7-8)):967-70.

    PMID: 25741938
  14. 14

    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
  15. 15

    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
  16. 16

    Chronic hypophosphatemia leading to the diagnosis of autosomal recessive hypophosphatemic rickets type 2 caused by a novel pathogenic variant in ENPP1.

    Tsai P, Maalouf NM

    Bone 2026; (213()):118086 doi:10.1016/j.bone.2026.118086.

    PMID: 42735739
  17. 17

    Tubular phosphate transport: a comparison between different methods of urine sample collection in FGF23-dependent hypophosphatemic syndromes.

    Arcidiacono GP, Camozzi V, Zaninotto M, et al.

    Clinical chemistry and laboratory medicine 2024; (62(6)):1126-1132 doi:10.1515/cclm-2023-1292.

    PMID: 38295343
  18. 18

    Congenital Conditions of Hypophosphatemia Expressed in Adults.

    Marcucci G, Brandi ML

    Calcified tissue international 2021; (108(1)):91-103 doi:10.1007/s00223-020-00695-2.

    PMID: 32409880
  19. 19

    Determination of FGF23 Levels for the Diagnosis of FGF23-Mediated Hypophosphatemia.

    Hartley IR, Gafni RI, Roszko KL, et al.

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2022; (37(11)):2174-2185 doi:10.1002/jbmr.4702.

    PMID: 36093861
  20. 20

    Clinical performance of a novel chemiluminescent enzyme immunoassay for FGF23.

    Ito N, Kubota T, Kitanaka S, et al.

    Journal of bone and mineral metabolism 2021; (39(6)):1066-1075 doi:10.1007/s00774-021-01250-1.

    PMID: 34255195
  21. 21

    Unveiling the biochemical signature of tumor-induced osteomalacia: implications for distinguishing it from primary osteoporosis.

    Chai Y, Wang X, Li S, et al.

    Frontiers in endocrinology 2026; (17()):1899331 doi:10.3389/fendo.2026.1899331.

    PMID: 42568369
  22. 22

    Tumor-induced osteomalacia.

    Florenzano P, Gafni RI, Collins MT

    Bone reports 2017; (7()):90-97 doi:10.1016/j.bonr.2017.09.002.

    PMID: 29021995
  23. 23

    Concordant X-linked hypophosphatemic rickets in monozygotic twins: diagnostic challenges and a novel genetic insight.

    Ribeiro S, Moreno T, Varela A, et al.

    Endocrinology, diabetes & metabolism case reports 2025; (2025(3)).

    PMID: 40980824
  24. 24

    Iron replacement ameliorates hypophosphatemia in autosomal dominant hypophosphatemic rickets: A review of the role of iron.

    Menon LP, Weinstein RS

    Bone 2020; (131()):115137 doi:10.1016/j.bone.2019.115137.

    PMID: 31756522
  25. 25

    Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets.

    Kapelari K, Köhle J, Kotzot D, Högler W

    The Journal of clinical endocrinology and metabolism 2015; (100(9)):3388-92 doi:10.1210/jc.2015-2391.

    PMID: 26186302
  26. 26

    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
  27. 27

    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
  28. 28

    FGF23-Mediated Hypophosphatemic Rickets: Phenotype, Genotype, and Comparison to Non-FGF23-Mediated Forms.

    Karlekar MP, Dodamani MH, Lila A, et al.

    Indian pediatrics 2025; (62(3)):211-216 doi:10.1007/s13312-025-00024-6.

    PMID: 40126839
  29. 29

    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

This page explains symptoms and diagnostic testing for ARHR for informational purposes only and does not constitute medical advice. Do not stop or delay prescribed treatment to prepare for testing; ask your healthcare professional how to interpret your results.