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.
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.
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
- 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.
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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.
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.
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.
- 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 https://rarediseases.info.nih.gov/diseases/12943/x-linked-hypophosphatemia.