X-Linked Hypophosphatemia (XLH) is characterized by short stature, bony deformities and rickets in children, and was previously called Vitamin D Resistant Rickets (VDRR). XLH is the most frequent form of heritable rickets today. Blood phosphorus is usually low (hypophosphatemia) since phosphorus is lost in the urine and the low phosphorus is the main cause of the bony changes. While rickets is a childhood disease that resolves as the growth plates close, the low phosphate and soft bones persist in adulthood if not treated. In adults, osteoarthritis and joint pain are common, along with muscle weakness and gait abnormalities. In some cases, calcification of tendons and ligaments may occur, causing pain on movement. Later in life, narrowing of the spinal canal (spinal stenosis) may occur, sometimes requiring surgery.

What causes X-linked hypophosphatemia?

XLH is caused by mutations in the PHEX gene, which is important for keeping normal levels of fibroblast growth factor 23 (FGF23), a hormone that decreases phosphorus levels in the blood by causing the kidneys to spill phosphorus into the urine. PHEX mutations result in excessively high FGF23 levels and low blood phosphorus. The PHEX gene is found on the X chromosome (hence, the name of this disease), and cannot be directly transmitted from male to male, but skeletal problems can occur in both males and females. There are other forms of hereditary hypophosphatemia and rickets caused by mutations in other genes present on different chromosomes. These other disorders are even rarer and only a few cases have been reported around the world.

Are genetic tests available?

XLH is first diagnosed based on the clinical features noted above. However, a genetic test will confirm the diagnosis when the clinical features are not clear. Genetic tests are now widely available, they are accurate and have become easier to afford. Sometimes they are offered for free (sponsored by drug companies). Knowing about the genetic causes also helps with family planning, and in some cases, helps physicians determine the best therapy.

Are treatments for X-linked hypophosphatemia available?

Until recently, oral phosphorus and vitamin D in different forms were used to increase blood phosphorus in subjects with XLH. Although helpful, this approach treated the symptoms but was not effective in eliminating rickets in most cases. The doses of vitamin D necessary to improve phosphorus levels may cause excessive calcium levels in the urine and cause kidney damage. Furthermore, oral phosphorus tastes bad and can cause diarrhea. Fortunately, a new medication, burosumab-twza (Crysvita®) became available in 2018. Burosumab reduces FGF23 in the bloodstream, leading to improvement of the serum phosphorus levels, often to the normal range. The related bone disease heals over time. The doses of burosumab, which is given by under the skin injections every 2 – 4 weeks, must be tailored for each patient. Doses are based on weight, serum phosphorus, urine calcium, and urine phosphorus levels. Therefore, treatment requires close supervision by a doctor with experience with this new medication.

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