X-Linked Hypophosphatemia Diagnosis

X-linked hypophosphatemia (XLH) is the most common cause of hereditary rickets in children. Its early recognition is crucial to appropriate pediatric management and surveillance for complications related to the disease as well as to its treatment.


The clinical features of rickets is the bowing of the lower extremity bones following the initiation of weight bearing in early childhood, with evidence of biochemical abnormalities consistent with this condition. Radiographic evidence of defective bone mineralization is also a diagnostic factor.  

Clinical Findings

Clinically, XLH is suspected when there is progressive leg bone bowing, either varus or valgum in type (bowing of the legs outwards or inwards respectively), and the height is shorter than expected for age once the child becomes ambulant. Growth rate is also slower than normal. Sitting height is disproportionately less affected than the total height. Growth velocity is slowed.

Other typical rachitic signs include:

  • Rachitic rosary due to enlargement of the costal cartilage
  • Craniotabes
  • Harrison’s groove caused by the powerful pull of the diaphragm on the subcostal margin or lower end of the rib cage leading to a horizontal groove and due to osteomalacia or defectively mineralized bone
  • Swollen and sometimes painful epiphyses

In adults, the presence of XLH is signaled by the presence of stress fractures, dental abscesses, or musculoskeletal pain.

Radiographic Findings

Children with XLH typically have widening and fraying of the femoral and upper tibial metaphyses, or of any metaphysis in the body. These are sometimes cupped over the joint surface. Rachitic rosary may be present.

Biochemical Findings

The characteristic findings of XLH include a low serum phosphate level for the child’s age, with reduced renal threshold for the resorption of phosphate when corrected for the glomerular filtration rate known as TmP/GFR. In addition, there is absence of the normally expected rise in the concentration of 1,25-dihydroxy vitamin D in response to the low serum phosphate supports the diagnosis.

Serum calcium levels are typically normal, as is the 25-hydroxy vitamin D concentration. The parathyroid hormone is either normal or only a little higher than expected. However, low vitamin D levels should be normalized before any treatment could be applied. A lack of rise in serum phosphate levels associated with intervention strengthens the diagnosis for XLH.

Another characteristic finding is the elevation of serum alkaline phosphatase in childhood, most evidently during the periods of rapid growth. This usually normalizes once skeletal growth is complete, irrespective of treatment.

Genetic Testing

To be diagnosed with XLH, genetic testing should also show a defect in the PHEX gene, which is hemizygous in males and heterozygous in females. Both genders are equally affected because the disease is transmitted through the dominant X-linked chromosome. This may be by single-gene, multi-gene panels, or genomic testing, but is not mandatory for diagnosis; however, it may help greatly in genetic counseling and in detecting the condition early in infants with a positive family history or in siblings of an affected patient.


  • Ruppe, M.D. (2012). X-Linked Hypophosphatemia. In Adam et al. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK83985/.
  • Carpenter, T. O., Imel, E. A., Holm, I. A., Jan de Beur, S. M., & Insogna, K. L. (2011). A CLINICIAN’S GUIDE TO X-LINKED HYPOPHOSPHATEMIA. Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research, 26(7), 1381–1388. http://doi.org/10.1002/jbmr.340.
  • X-linked hypophosphatemia. Retrieved from rarediseases.info.nih.gov/diseases/12943/x-linked-hypophosphatemia.

Further Reading

  • All Hypophosphatemia Content
  • What is X-Linked Hypophosphatemia?
  • X-Linked Hypophosphatemia Symptoms
  • X-Linked Hypophosphatemia Management
  • All X-Linked Hypophosphatemia Content

Last Updated: Aug 23, 2018

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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