X-Linked Hypophosphatemia Diagnosis

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

X-linked Hypophosphatemia


The clinical features of rickets include 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 valgus in type, which indicates bowing of the legs outwards or inwards, respectively.

Additionally, the height is shorter than expected for the patient's age once the child becomes ambulant; thus, the growth rate is also slower than normal in XLH. 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, which leads to a horizontal groove 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.

Image Credit: Double Brain / Shutterstock.com

Radiographic findings

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

Biochemical findings

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

Serum calcium levels are typically normal in XLH, 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 is initiated. 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 levels 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.

Genetic testing for XLH may be acheived by single-gene, multi-gene panels, or genomic testing, but is not mandatory for diagnosis. However, genetic testing for a defect in PHEX 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.


Further Reading

Last Updated: Apr 26, 2021

Dr. Liji Thomas

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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