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symptoms & Diagnosis

symptoms & Diagnosis

XLH is commonly misdiagnosed

The symptoms of XLH are chronic and progressive, and can worsen throughout adulthood.1 Additionally, misdiagnosis of XLH may lead to inappropriate disease management.

XLH can be misdiagnosed as nutritional rickets, osteomalacia, hypophosphatasia, Pyle disease, or physiologic bowing. Clinical/radiographic findings, family history, and biochemical tests can help establish a diagnosis of XLH. XLH can be confirmed through genetic testing for variants of the PHEX gene, and checking for elevated levels of FGF23 can help to further establish a diagnosis.2-4

Clinical and radiographic findings

Bowed legs
X-ray image representing bowed legs in a child with XLH
X-ray image representing rickets in a child with XLH
Knock knees
X-ray image representing knock knees in a child with XLH

Predominant clinical findings in children include2,5-7:

  • Rickets
  • Lower extremity bowing
  • Leg abnormalities
  • Pain
  • Short stature
  • Gait disturbances

Evaluate skeletal symptoms through radiography.

Other signs and symptoms may also include8:

  • Dental abscesses
  • Craniosynostosis
  • Chiari malformations
Micrograph image of osteomalacia in the bones
X-ray image representing enthesopathy in the foot
X-ray image of a pseudofracture

Adults with XLH may present with8-10:

  • Osteomalacia manifesting as bone pain
  • Enthesopathy
  • Fractures
  • Pseudofractures

Other signs and symptoms may also include8,11:

  • Lateral trunk lean (waddling gait)
  • Dental abscesses
  • Hearing loss

Family history

With known family history of XLH

XLH is inherited in an X-linked dominant pattern, so a positive family history of the disease supports the diagnosis. In a family with a history of XLH, screen other first-generation family members for XLH. This can help identify previously undiagnosed individuals.12

Without known family history of XLH

Since approximately 20% to 30% of XLH cases are spontaneous, it’s important to ask your patient if they have a medical history of short stature, rickets, osteomalacia, osteoarthritis, and dental abscesses, all of which may indicate XLH.13

Biochemical findings

The following are predominant clinical findings in children and adults.

Evaluate age-normalized levels of fasting serum phosphorus for an accurate diagnosis. Low phosphorus levels and a low TmP/GFR ratio are the most relevant biochemical findings for XLH.2,12,13

Key biochemical findings for XLH2,12,14,15
Biochemical Test XLH
Fasting serum phosphorus
Down or inappropriately normal
25(OH)D Normal
Serum calcium Normal
Urinary calcium
Normal to decreased
PTH Normal to slightly up
1,25(OH)2D=1,25-dihydroxyvitamin D (calcitriol); 25(OH)D=25-hydroxyvitamin D (calcifediol); ALP=alkaline phosphatase; PTH=parathyroid hormone; TmP/GFR=ratio of tubular maximum reabsorption of phosphorus to glomerular filtration rate.

Confirmatory testing

In both children and adults, evaluating PHEX genetic variant status and FGF23 levels can help establish an accurate diagnosis for XLH.2,12
Confirm XLH4,9:
Through a genetic analysis of the PHEX gene By checking for elevated intact FGF23 levels in untreated patients
Learn more about sponsored genetic testing Request a sponsored FGF23 testing kit*
*FGF23 test cannot be billed to insurance (including without limitation federal healthcare programs) and there is no obligation to prescribe or use Kyowa Kirin products as a condition of participation.
The letter i within a diamond denoting a callout specific to the XLH disease-monitoring program

Prioritize testing your patient’s fasting serum phosphorus levels in addition to clinical/radiographic, family history, biochemical, and genetic findings in order to help diagnose XLH.2,12

Interested in learning more about real life case studies or resources for XLH?

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Patient case studies of XLH

See sample case studies of adults and children.

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Learn more about XLH

Watch videos to get more information about how XLH affects the body.

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XLH resources and community

From case studies to brochures, find resources for you and your patients to understand more about this rare condition.

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1. Hamilton AA, Faitos S, Jones G, Kinsley A, Gupta RN, Lewiecki EM. Whole body, whole life, whole family: patients' perspectives on X-linked hypophosphatemia. J Endocr Soc. 2022;6(8):bvac086. doi:10.1210/jendso/bvac086 2. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician's guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381-1388. doi:10.1002/jbmr.340 3. Rush ET, Johnson B, Aradhya S, et al. Molecular diagnoses of X-linked and other genetic hypophosphatemias: results from a sponsored genetic testing program. J Bone Miner Res. 2022;37(2):202-214. doi:10.1002/jbmr.4454 4. Haffner D, Emma F, Eastwood DM, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019;15(7):435-455. doi:10.1038/s41581-019-0152-5 5. Carpenter TO. Primary disorders of phosphate metabolism. Endotext. Accessed February 3, 2023. 6. Linglart A, Dvorak-Ewell M, Marshall A, San Martin J, Skrinar A. Impaired mobility and pain significantly impact the quality of life of children with X-linked hypophosphatemia. Bone Abstracts. 2015;4(P198). doi:10.1530/boneabs.4.P198 7. Skrinar A, Dvorak-Ewell M, Evins A, et al. The lifelong impact of X-linked hypophosphatemia: results from a burden of disease survey. J Endocr Soc. 2019;3(7):1321-1334. doi:10.1210/js.2018-00365 8. Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3(1):R13-R30. doi:10.1530/EC-13-0103 9. Trombetti A, Al-Daghri N, Brandi ML, et al. Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia. Nat Rev Endocrinol. 2022;18(6):366-384. doi:10.1038/s41574-022-00662-x 10. Giannini S, Bianchi ML, Rendina D, Massoletti P, Lazzerini D, Brandi ML. Burden of disease and clinical targets in adult patients with X-linked hypophosphatemia. A comprehensive review. Osteoporos Int. 2021;32(10):1937-1949. doi:10.1007/s00198-021-05997-1 11. Mindler GT, Kranzl A, Stauffer A, et al. Lower limb deformity and gait deviations among adolescents and adults with X-linked hypophosphatemia. Front Endocrinol (Lausanne). 2021;12:754084. doi:10.3389/fendo.2021.754084 12. Ruppe MD. X-linked hypophosphatemia. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; February 9, 2012. Updated April 13, 2017. 13. Dahir K, Roberts MS, Krolczyk S, Simmons JH. X-linked hypophosphatemia: a new era in management. J Endocr Soc. 2020;4(12):bvaa151. doi:10.1210/jendso/bvaa151 14. Santos F, Fuente R, Mejia N, Mantecon L, Gil-Peña H, Ordoñez FA. Hypophosphatemia and growth. Pediatr Nephrol. 2013;28(4):595-603. doi:10.1007/s00467-012-2364-9 15. Florenzano P, Cipriani C, Roszko KL, et al. Approach to patients with hypophosphataemia. 2020;8(2):163-174. Lancet Diabetes Endocrinol doi:10.1016/S2213-8587(19)30426-7