A diagnosis of XLH is typically based on clinical and biochemical findings in combination with family history

Misdiagnosis can lead to inappropriate disease management, which can lead to worsening of symptoms of XLH. XLH can be misdiagnosed as nutritional rickets, osteomalacia, hypophosphatasia, Pyle’s disease, and physiologic bowing.1


XLH is a hereditary disorder. A detailed family history may help identify undiagnosed individuals.

 

Family is considered as part of XLH diagnosis

WITH KNOWN FAMILY HISTORY OF XLH

XLH is inherited in an X-linked dominant pattern.2 In a family with a history of XLH, screen for other family members. This can help you identify previously undiagnosed individuals.

WITHOUT A KNOWN FAMILY HISTORY OF XLH

About 20% to 30% of XLH cases are spontaneous.3 Ask about his/her medical history of short stature, rickets, osteomalacia, osteoarthritis, and dental abscesses, which may indicate XLH.

GENETIC TESTING IS IMPORTANT TO CONFIRM A DIAGNOSIS OF XLH.

Learn more about a program offering no-charge genetic testing to eligible patients suspected of having hypophosphatemia.

The following are predominant clinical findings in children and adults.

Children

Common XLH symptoms in children include bowed legs, rickets, and knock-knees

Rickets, lower extremity bowing, leg abnormalities, pain, short stature, and gait disturbances.1,2,4 Confirm skeletal findings through radiography.1 Other signs and symptoms may also include dental abscesses, craniosynostosis, and Chiari malformations.2,4

Adults

Common XLH symptoms in adults include osteomalacia, hardened ligaments, and low-trauma fractures

Adults with XLH may present with osteomalacia manifesting as bone and muscle pain, enthesopathy, fractures, and pseudofractures. Other signs and symptoms may also include waddling gait, dental abscesses, and hearing loss.1,2,4-6

SYMPTOMS OF XLH WILL CONTINUE TO PROGRESS IF UNTREATED.

It is critical to begin management of XLH early to prevent further damage caused by underlying osteomalacia.

Include age- and gender-normalized levels of serum phosphorus in metabolic panels for an accurate diagnosis. Low phosphate levels and a low TmP/GFR ratio are the most relevant biochemical findings for XLH.1,2

Key biochemical findings for xlh

Biochemical tests used to confirm XLH diagnosis

Other biochemical findings that may be useful for establishing the diagnosis of XLH include serum alkaline phosphatase (ALP) levels and FGF23 levels.

Alkaline phosphatase can be a good marker of skeletal health in children but not necessarily for adults.2

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 phosphate to glomerular filtration rate; XLH = X-linked hypophosphatemia.

ELEVATED FGF23 IS THE UNDERLYING CAUSE OF XLH.

Testing serum FGF23 may help to confirm a diagnosis of XLH. Learn more about FGF23 testing.

—Dr. Thomas Carpenter, XLH expert

References:

1. 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. 2. Ruppe MD. X-Linked Hypophosphatemia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 3. Gaucher C, Walrant-Debray O, Nguyen TM, Esterle L, Garabedian M, Jehan F. PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. Hum Genet. 2009;125(4):401-411. 4. Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3(1):R13-30. 5. 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. 6. X-linked hypophosphatemia. Genetic and Rare Diseases Information Center (GARD) Website. https://rarediseases.info.nih.gov/diseases/12943/x-linked-hypophosphatemia. Updated 2018. Accessed January 3, 2019. 7. Santos F, Fuente R, Mejia N, Mantecon L, Gil-Peña H, Ordoñez FA. Hypophosphatemia and growth. Pediatr Nephrol. 2013;28(4):595-603.