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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Medical Genetics

The Diagnostic Path: Labs, Genetics, and Differentials

At a Glance

XLH is diagnosed by combining age-adjusted low blood phosphate with evidence that the kidneys are wasting phosphate, often measured by TmP/GFR. FGF23, vitamin D, genetic testing, and tests for look-alike conditions complete the evaluation; a negative PHEX test does not always rule out XLH.

Confirming a diagnosis of X-Linked Hypophosphatemia (XLH) requires a precise series of blood and urine tests. Because XLH is a rare disease, the goal of this diagnostic workup is to prove that your kidneys are inappropriately wasting phosphate and to rule out other conditions that can look similar [1][2].

The Biochemical Profile

To diagnose XLH, doctors look for a specific “signature” in your bloodwork. It is important to note that for children, phosphate levels must be compared to pediatric reference ranges, which are naturally higher than adult ranges [3][4].

A typical untreated XLH lab profile includes:

  • Low Serum Phosphate: This is the hallmark of the disease [3].
  • High Alkaline Phosphatase (ALP): This enzyme is an indicator of bone activity and is often elevated in children with active rickets [5][4].
  • Often Normal Calcium and PTH: While calcium is often normal, parathyroid hormone (PTH) can sometimes be elevated in untreated XLH or during conventional therapy. Normal calcium/PTH is not unique to XLH, but it helps complete the picture [5][6].
  • Inappropriate FGF23: Because the PHEX gene isn’t working, the body produces too much Fibroblast Growth Factor 23 (FGF23) [7]. Even a “normal” FGF23 level can be considered abnormal if your phosphate is low; it should be suppressed when phosphate is lacking [8].
  • Inappropriate Vitamin D: Your body’s “active” vitamin D (1,25-dihydroxyvitamin D) level will be low or “inappropriately normal” given how low your phosphate is [5][4].

Measuring Phosphate Wasting (TmP/GFR)

Simply knowing your blood phosphate is low isn’t enough; the doctor must determine if it is being lost in the urine. They often calculate the TmP/GFR, which measures the threshold at which your kidneys begin to dump phosphate [9].

A low TmP/GFR provides evidence of inappropriate renal phosphate wasting [4][9]. However, it does not by itself confirm XLH, and must be interpreted with simultaneous serum phosphate, age, kidney function, and diet. To get an accurate measurement, laboratory protocols commonly involve a fasting blood sample and a “second-morning-void” urine collection [9].

The Role of Genetic Testing

Testing the PHEX gene provides very useful molecular confirmation for XLH, but a clinical diagnosis can still be made if testing is negative or unavailable.

  • Diagnostic Yield: Routine sequencing finds a mutation in many, but not all, people with a clinical diagnosis of XLH [10][11].
  • Negative Results: If a standard test is negative, you may still have inherited XLH. Some mutations involve large missing chunks of DNA (deletions) or are hidden in parts of the gene standard tests don’t check [11][12].
  • Advanced Testing: If suspicion remains high, doctors may order MLPA (to find deletions) or broader gene panels with genetic-counseling input [13][12].

Rule-Out: The “Look-Alike” Conditions

Your doctor must ensure your symptoms aren’t caused by other conditions that require very different treatments:

  1. Nutritional Rickets: Caused by dietary deficiency in vitamin D or calcium. Unlike XLH, this usually shows appropriately low FGF23 [14][15].
  2. Fanconi Syndrome: A general failure of the kidney’s “filter.” While it also causes phosphate wasting, it usually also results in sugar (glucose) spilling into the urine despite normal blood sugar, alongside protein or amino acids [7][16].
  3. Tumor-Induced Osteomalacia (TIO): This is an acquired condition where a small tumor produces excess FGF23. It is most often considered when symptoms start suddenly in adulthood [17][8].
  4. Other Genetic Disorders: Other inherited FGF23-mediated and non-FGF23-mediated hypophosphatemias must also be considered.

Tests Your Clinical Team May Choose

Based on your presentation, your specialist may select from the following to build a complete diagnostic picture. Not every patient will need every test.

Test Category Tests Your Specialist May Select
Blood (Fasting) Phosphate (age-adjusted), Calcium, ALP, PTH, Creatinine, 25-OH Vitamin D, 1,25-OH Vitamin D
Urine (Paired) Phosphate and Creatinine (to calculate TmP/GFR), Glucose, Amino Acids (to check for Fanconi)
Specialized Intact FGF23 [8]
Genetics PHEX sequencing + Deletion/Duplication analysis (MLPA) [13]
Imaging X-rays of wrists/knees (children) or symptomatic joints (adults) [18]

Common questions in this guide

What blood tests are used to diagnose XLH?
Doctors usually check phosphate, alkaline phosphatase, calcium, parathyroid hormone, kidney function, and vitamin D. They may also measure FGF23, a hormone that affects phosphate handling. In children, phosphate must be compared with age-specific ranges because normal levels are higher than in adults.
What does a low TmP/GFR result mean?
TmP/GFR estimates how well the kidneys retain phosphate. A low result supports inappropriate phosphate loss in the urine, but it does not prove XLH by itself; clinicians interpret it alongside serum phosphate, age, kidney function, diet, and other results. It is commonly calculated from fasting blood and a second-morning urine sample.
Can I still have XLH if my PHEX genetic test is negative?
Yes. Standard PHEX sequencing does not detect every disease-causing change, including some large deletions or changes in regions the test does not examine. If clinical suspicion remains high, a clinician may consider deletion or duplication testing such as MLPA or a broader gene panel, often with genetic-counseling support.
Can FGF23 be normal in someone with XLH?
Yes. When blood phosphate is low, FGF23 should normally be suppressed, so a laboratory result in the usual range may be inappropriately high for that situation. Doctors interpret FGF23 together with phosphate and the rest of the biochemical profile rather than using the number alone.
What conditions can look like XLH?
The evaluation may consider nutritional rickets, Fanconi syndrome, tumor-induced osteomalacia, and other inherited phosphate disorders. Nutritional rickets generally has low FGF23, whereas Fanconi syndrome often causes urine glucose, protein, or amino acids despite normal blood sugar. Tumor-induced osteomalacia is acquired and is more often suspected when symptoms begin suddenly in adulthood.
What other tests might be part of an XLH diagnostic workup?
Depending on the presentation, clinicians may order paired blood and urine tests, PHEX sequencing with deletion or duplication analysis, and X-rays of affected bones or joints. Not everyone needs every test. The choice depends on age, symptoms, kidney function, and initial results.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Are my (or my child's) phosphate levels being compared to age-specific reference ranges rather than adult standards?
  2. 2.Was my TmP/GFR calculated to assess kidney phosphate wasting, and how does it fit with my other lab results?
  3. 3.Since my initial PHEX test was negative, can we order deletion/duplication testing (MLPA) or a broader gene panel to look for other rare causes?
  4. 4.My FGF23 was in the 'normal' range—how do you interpret that in the context of my low blood phosphate?
  5. 5.Have we ruled out Fanconi syndrome by checking for glucose or amino acids in my urine?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (18)
  1. 1

    Effects of Burosumab Treatment on Mineral Metabolism in Children and Adolescents With X-linked Hypophosphatemia.

    Ewert A, Rehberg M, Schlingmann KP, et al.

    The Journal of clinical endocrinology and metabolism 2023; (108(10)):e998-e1006 doi:10.1210/clinem/dgad223.

    PMID: 37097907
  2. 2

    Diagnosis and management of X-linked hypophosphatemia in children and adolescent in the Gulf Cooperation Council countries.

    Al Juraibah F, Al Amiri E, Al Dubayee M, et al.

    Archives of osteoporosis 2021; (16(1)):52 doi:10.1007/s11657-021-00879-9.

    PMID: 33660084
  3. 3

    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
  4. 4

    The Metabolic Bone Disease X-linked Hypophosphatemia: Case Presentation, Pathophysiology and Pharmacology.

    Vincze J, Skinner BW, Tucker KA, et al.

    Life (Basel, Switzerland) 2021; (11(6)) doi:10.3390/life11060563.

    PMID: 34203792
  5. 5

    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
  6. 6

    Safety and efficacy of burosumab in improving phosphate metabolism, bone health, and quality of life in adolescents with X-linked hypophosphatemic rickets.

    Baroncelli GI, Grandone A, Aversa A, et al.

    European journal of medical genetics 2024; (70()):104958 doi:10.1016/j.ejmg.2024.104958.

    PMID: 38950880
  7. 7

    Plasma intact fibroblast growth factor 23 level is a useful tool for diagnostic approach of renal hypophosphatemia.

    Giralt M, Chocron S, Ferrer R, Ariceta G

    Pediatric nephrology (Berlin, Germany) 2021; (36(4)):1025-1028 doi:10.1007/s00467-020-04906-8.

    PMID: 33492457
  8. 8

    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
  9. 9

    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
  10. 10

    Molecular Diagnoses of X-Linked and Other Genetic Hypophosphatemias: Results From a Sponsored Genetic Testing Program.

    Rush ET, Johnson B, Aradhya S, et al.

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2022; (37(2)):202-214 doi:10.1002/jbmr.4454.

    PMID: 34633109
  11. 11

    RNA-first Approach Identifies Deep Intronic PHEX Variants in X-linked Hypophosphatemic Rickets.

    Ludwig K, Wu Z, Bardai G, et al.

    The Journal of clinical endocrinology and metabolism 2025; (110(8)):2288-2298 doi:10.1210/clinem/dgae785.

    PMID: 39512182
  12. 12

    Case Report: Deep intronic PHEX variant causing aberrant splicing identified by whole genome and targeted RNA sequencing in X-linked hypophosphatemia.

    Spranger S, Faust H, Duffek P, et al.

    Frontiers in endocrinology 2026; (17()):1847219 doi:10.3389/fendo.2026.1847219.

    PMID: 42494860
  13. 13

    Clinical and Molecular Genetic Characteristics of Patients with Hereditary Hypophosphatemia.

    Eltan M, Alavanda C, Yavas Abali Z, et al.

    The Journal of clinical endocrinology and metabolism 2025; (110(9)):e3021-e3030 doi:10.1210/clinem/dgae868.

    PMID: 39700445
  14. 14

    An Overview of Rickets in Children.

    Chanchlani R, Nemer P, Sinha R, et al.

    Kidney international reports 2020; (5(7)):980-990 doi:10.1016/j.ekir.2020.03.025.

    PMID: 32647755
  15. 15

    FGF23-related hypophosphatemic rickets/osteomalacia: diagnosis and new treatment.

    Fukumoto S

    Journal of molecular endocrinology 2021; (66(2)):R57-R65.

    PMID: 33295878
  16. 16

    Hypophosphatemic rickets: diagnosis and treatment.

    Bruneau H, Bergwitz C

    Archives of endocrinology and metabolism 2026; (70(3)) doi:10.20945/2359-4292-2026-0044.

    PMID: 42138629
  17. 17

    Tumor-induced osteomalacia.

    Yin Z, Du J, Yu F, Xia W

    Osteoporosis and sarcopenia 2018; (4(4)):119-127 doi:10.1016/j.afos.2018.12.001.

    PMID: 30775554
  18. 18

    Genetic analysis of three families with X-linked dominant hypophosphatemic rickets.

    Lin X, Zhu Y, Luo J, Huang J

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    PMID: 29858904

This page explains XLH diagnostic testing for informational purposes only and does not constitute medical advice. Your clinician or genetic counselor should interpret your results in the context of your medical history.

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