Image of chromosome in body related to X-linked hypophosphatemia.
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X-Linked Hypophosphatemia (XLH)

January 23, 2022

A rare disorder affecting 1 in 20,000 individuals, XLH occurs when levels of the mineral phosphorus are low in the blood and phosphorus is excreted in urine. This “wasting” can cause low phosphorus levels in blood called hypophosphatemia. XLH may lead to bone abnormalities and defects that may impair mobility, including bone fractures, hearing loss, ligament and bone pains, and increased risk of infections such as spontaneous dental abscesses. 

XLH may affect individuals at any age. Adults may develop calcification of the tendons, ligaments, and joint capsules, also known as enthesopathies. In the past, XLH was called “hypophosphatemic rickets" or “vitamin D-resistant rickets,” because it resembles the bone problems of vitamin D deficiency but doesn’t respond to vitamin D supplementation. However, there is now a different disorder with this name, caused by problems of vitamin D action. XLH also has been referred to as “phosphate diabetes,” due to the urinary wasting of phosphorus. 

XLH and Endocrine Connection 

Phosphorus is a mineral found in bones that is responsible for building and repairing bones and teeth, making muscles contract, and supplying the cells with energy. Phosphorus is essential for normal growth and development. Bones release stored phosphorus to try to keep blood levels normal, but the loss of phosphorus from bones leads to soft weak bones, also called rickets, where mineral deficiency deforms the growth plate, and osteomalacia, where poor mineralization weakens the bone structure.

XLH is caused by a defect (a mutation) in a gene called PHEX [pronounced “Feks”] gene on the X chromosome. This gene is responsible for regulating phosphates in the body. The genetic change prevents the kidneys from processing phosphorus correctly. Problems with PHEX lead to increased production of fibroblast growth factor 23 (FGF 23), which blocks the kidney’s ability to hold on to phosphorus. As a result, too much phosphorus leaves the body in the urine, which is also known as “phosphate wasting”.

Although there can be other reasons for rickets, such as vitamin D deficiency, XLH is one of the few causes that is inherited, meaning it is passed down from parent to child on a mutated gene. In about 20% of cases, a person develops XLH without any family history.

Hypophosphatemia: low blood phosphate 
Enthesopathy: calcification of tendons, ligaments, and joint capsules 
ALP: alkaline phosphatase

The diagnosis of XLH is established with hypophosphatemia (low serum phosphate concentration), a reduced re-absorption of phosphate from the kidneys through specific calculations, elevated alkaline phosphatase, and/or by identification of a PHEX genetic change.  

XLH is most often passed on through families by inheriting a PHEX mutation on the X chromosome. A new genetic change can occur spontaneously in an individual, however, and then be passed on to future family members. A female with XLH has a 50% chance of passing XLH to her children and a male with XLH will pass the condition down it his daughters but none of his sons. 

Symptoms of XLH often first appear in early childhood, but because phosphorus is important for normal growth and development, children with XLH may grow slowly and not grow very tall. When they start to walk, their legs may become bowed outward or bent inward. Symptoms will vary from person to person and will vary in severity. 

Bone pain, tenderness at major joints, or undiagnosed fractures incidentally found on x-ray are often the first symptoms or signs of XLH. Once children begin standing, bowing of the legs may be noted. Over time, a slow growth rate for height may develop and often leads to short stature as an adult. Other signs include: 

  • Chronic fractures 
  • Bone pain and muscle weakness 
  • Tooth problems or abnormal tooth development 
  • Chronic pain from early osteoarthritis 
  • Calcium in tendons 
  • Bone spurs, or, rarely, narrowing of the spine around the spinal cord 

Adults may also have muscle weakness, fatigue, hearing loss, and abnormal patterns of walking. 

Nutritional rickets due to inadequate dietary vitamin D, which causes low calcium levels, can mimic XLH. Other rarer low calcium disorders can cause rickets, such as problems of vitamin D absorption, metabolism, or action. Low phosphorus disorders besides XLH include autosomal recessive and autosomal dominant hypophosphatemic rickets (very rare), tumor-induced osteomalacia, and Fanconi syndrome, which all cause bone problems. Poor kidney function can also lead to bone disease, including rickets. Skeletal dysplasia (like achondroplasia) is another cause of bowed legs. Hypophosphatasia is another rare genetic disorder of low alkaline phosphatase activity that causes low bone mineral density and early loss of teeth. Blount disease can cause leg bowing due to damage of knee cartilage, sometimes related to obesity. 

Addressing a life-long condition like XLH requires a multidisciplinary approach. Getting the right diagnosis and starting treatment as soon as possible is vital to preventing problems, stopping existing problems from getting worse, and helping to provide a more comfortable, more functional life. 

The main goal with treatment is to increase the level of phosphate to allow the body to develop and function more normally. This helps ease symptoms and stop them from getting worse. 

Prevention of dental abscesses requires regular oral hygiene with flossing/brushing and dental care. 

Pain and lower extremity bowing may improve with oral phosphate and active vitamin D supplements. 

Surgery may help lower limb bowing and/or torsion. The Food and Drug Administration has approved the first and only specific therapy for XLH, Burosumab, in adults and children at least 6 months old. 

If your signs and symptoms are consistent with XLH, reach out to a health care provider with expertise in the diagnosis and management of this condition. 

  • What are the options for treatment for my child (or for me)? 
  • What are the risks and benefits of the treatment options? 
  • Should I (or my child) have genetic testing for carrier identification of XLH? 
  • Should I see a pediatric endocrinologist (or an endocrinologist)? 

Infographic on understanding X-Linked Hypophosphatemia (XLH).

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