A diagnosis of XLH is typically based on clinical and biochemical findings in combination with family history; however, variations in disease presentation can lead to delayed diagnosis or misdiagnosis.1,2

Molecular genetics can be used to establish a diagnosis, determine if XLH is inherited, and what risk there is to family members.1


In children:

Children with XLH typically present with lower-extremity bowing, impaired growth, and gait abnormalities during the first 1 to 2 years of life. However, diagnosis may occur after the age of 2 or even in adulthood.1,3

In adults:

Adult patients present with joint and bone pain, along with stiffness associated with osteoarthritis and enthesopathy. Nearly half report having had a fracture. The majority of adults with XLH exhibit short stature and lower-extremity deformity.2,4,5


If a patient presents with clinical characteristics that resemble rickets, 
a diagnosis of XLH can be made via biochemical assessment

The main biochemical features of XLH are low serum phosphate levels, decreased 1,25-dihydroxyvitamin D levels relative to the serum phosphate concentration, a reduced ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR), and elevated serum FGF23 levels.1,6,8

  • Additional biochemical features of XLH include normal 25-hydroxyvitamin D levels, elevated urinary phosphorus levels, elevated alkaline phosphatase levels, and elevated or normal parathyroid hormone levels1,7,8
Phosphate reabsorption9-13

The TmP/GFR is the ratio of renal tubular maximum reabsorption of phosphate (TmP) to glomerular filtration rate (GFR)

Biochemical assessment: Continually assess ongoing disease in children 
and adults

Family History

Key points:

  • Evaluation of at-risk infants and children is warranted to ensure early diagnosis and treatment, which has been shown to improve clinical outcomes3
  • Screening of family members of XLH patients may help to identify previously undiagnosed individuals14
Pedigree Analysis

However, 20% to 30% of cases are spontaneous, and therefore have no family history.15-17

Learn about inheritance and the prevalence of XLH

1. Ruppe MD. X-linked hypophosphatemia. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. Gene Reviews. https://www.ncbi.nlm.nih.gov/books/NBK83985/. Accessed October 20, 2017. 2. Econs MJ, Samsa GP, Monger M, Drezner MK, Feussner JR. X-linked hypophosphatemic rickets: a disease often unknown to affected patients. Bone Miner. 1994;24(1):17-24. 3. 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. 4. Skrinar A, Dvorak-Ewell M, Evins A, et al. The lifelong impact of X-linked hypophosphataemia: results from a burden of disease survey. J Endocr Soc. 2019;3(7):1321-1334. 5. Hardy DC, Murphy WA, Siegel BA, Reid IR, Whyte MP. X-linked hypophosphatemia in adults: prevalence of skeletal radiographic and scintigraphic features. Radiology. 1989;171(2):403-414. 6. 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. 7. Santos F, Fuente R, Mejia N, Mantecon L, Gil-Peña H, Ordoñez FA. Hypophosphatemia and growth. Pediatr Nephrol. 2013;28(4):595-603. 8. 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. 9. Payne RB. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Ann Clin Biochem. 1998;35(pt. 2):201-206. 10. Goldsweig BK, Carpenter TO. Hypophosphatemic rickets: lessons from disrupted FGF23 control of phosphorus homeostasis. Curr Osteoporos Rep. 2015;13(2):88-97. 11. Imel EA, Carpenter TO. A practical clinical approach to paediatric phosphate disorders. Endocr Dev. 2015;28:134-161. 12. Özkan B. Nutritional rickets. J Clin Res Pediatr Endocrinol. 2010;2(4):137-143. 13. Nield LS, Mahajan P, Joshi A, Kamat D. Rickets: not a disease of the past. Am Fam Physician. 2006;74(4):619-626. 14. Beck-Nielsen SS, Brusgaard K, Rasmussen LM, et al. Phenotype presentation of hypophosphatemic rickets in adults. Calcif Tissue Int. 2010;87(2):108-119. 15. Beck-Nielsen SS, Brixen K, Gram J, Brusgaard K. Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets. J Hum Genet. 2012;57(7):453-458. 16. Gaucher C, Walrant-Debray O, Nguyen T-M, Esterle L, Garabédian M, Jehan F. PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. Hum Genet. 2009;125(4):401-411. 17. Whyte MP, Schranck FW, Armamento-Villareal R. X-linked hypophosphatemia: a search for gender, race, anticipation, or parent of origin effects on disease expression in children. J Clin Endocrinol Metab. 1996;81(11):4075-4080.

XLH Link

You are about to leave a Kyowa Kirin website

You are leaving the XLH Link website to a site that is not under the control of Kyowa Kirin. Kyowa Kirin is not responsible for the content of any such site or any further link from such site. Are you sure you want to continue?