X-linked Hypophosphataemia

What else is it called?

  • XLH 
  • Hypophosphatemic rickets, X-linked dominant 
  • Hypophosphatemia, X-linked 
  • Vitamin D-Resistant Rickets, X-linked 
  • Hypophosphatemic vitamin D-resistant rickets 
  • HPDR 

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What causes it?

X-linked Hypophosphataemia is caused by mutations (changes) in the PHEX gene. This causes an imbalance of phosphate in the body. Phosphate has many functions in the body, one of which being an important role in the formation and growth of bones in childhood and bone strength in adults. Phosphate levels in the body are controlled mainly by the kidneys.  

Normally, the kidneys excrete (release) excess phosphate in the urine and reabsorb the phosphate into the bloodstream when more is needed. In individuals with XLH on the other hand, the kidneys cannot reabsorb phosphate effectively which causes too much phosphate to be excreted from the body through the urine. Due to this, not enough phosphate is available in the bloodstream for normal bone development.  

The PHEX gene linked to this condition is responsible for maintaining the right balance of phosphate. This gene plays a role in regulating (controlling) a protein called fibroblast growth factor 23. This protein prevents the kidneys’ ability to reabsorb phosphate into the bloodstream. Mutations (changes) in this gene increase the production or reduce the breakdown of fibroblast growth factor 23. This causes an overactivity of this protein, reducing phosphate reabsorption by the kidneys which leads to the symptoms associated with x-linked hypophosphatemic rickets.  

How common is it?

X-linked Hypophosphataemia is reported to affects roughly 1 in 20,000 new-borns.  

What are the signs and symptoms?

The signs and symptoms of XLH usually begin in early childhood. The signs and symptoms can vary greatly even within patients of the same family.  

Individuals who are mildly affected may have low levels of phosphate without any other signs or symptoms. More severely affected individuals may experience slower growth causing them to be shorter than their peers (short stature), a waddling gait (manner of walking), craniosynostosis (premature fusion of the skull bones) and dental abnormalities. Other symptoms include bone abnormalities that may affect movement and cause bone pain, rickets (bone disease) and muscle pain. The most obvious symptoms of the condition are bowed legs or knock knees (a condition in which the knees angle in and touch each other when the legs are straightened). Most of these symptoms become apparent in the first 18 months of life when a child begins to bear weight on the legs and starts walking. The symptoms usually worsen with time if they are left untreated.  

These symptoms may continue into adulthood. Other symptoms present in adulthood may include: 

  • Muscle pain or muscle weakness  
  • Enthesopathy (calcification of joints and tendons)  
  • Early onset osteoarthritis (when protective cartilage that cushions the ends of your bones wears down) 
  • Spinal stenosis (a condition where your spinal canal starts to narrow)  
  • Hearing loss  
  • Fatigue  
  • Non-traumatic fractures and delayed fracture healing  
  • Osteomalacia (softening of the bones in adults)  

How is it diagnosed?

This condition is diagnosed based on a physical examination, blood tests, X-rays and a full family history. Specific signs and symptoms looked for during the diagnosis include:  

  • Slow growth rate and bowing of the legs or other bone abnormalities 
  • Low levels of phosphate and high levels of FGF23 in the blood  
  • Lack of response to phosphate levels when treated with vitamin D 
  • Phosphate wasting in the kidneys  

Diagnosis of the condition can be confirmed through molecular genetic testing if a mutation is identified, however this is not necessary for the diagnosis.  

Can it be treated?

This condition is different from normal types of rickets because it cannot be treated by only increasing the amount of vitamin D.  

 Phosphate supplements and a high dose of calcitriol are usually given to individuals with XLH in the form of a drink. Calcitriol will increase levels of calcium through increasing the amount of calcium absorbed in the intestines and the amount of calcium kept in the kidneys.  

In children, treatment will start when the individual is diagnosed and will continue until the bones stop growing.  

In adults, the main treatments aim at pain relief.  

Other treatments of this condition are specific to treating symptoms and may include:  

  • Growth hormones to improve growth in children 
  • Corrective surgery to correct bowed or bent legs 
  • Treatment to repair skull abnormalities  
  • Dental procedures treating pain in teeth and gums 

Do my family need to be tested?

XLH is an inherited condition. Humans have chromosomes made up of DNA. Genes are pieces of DNA that carry the genetic information. Each chromosome may have several thousand genes. We inherit chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents. 

 The pattern of inheritance in this condition is an X-linked dominant pattern. This is because the PHEX gene in located on the X chromosome (one of the two sex chromosomes). In females (who have two X chromosomes) a mutation in ne of the two copies of the gene in each cell is enough to cause the disorder. In males (who have only on X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. Therefore, a female with XLH has a 50% chance of passing XLH to each of her children. A male with XLH will pass the condition to all his daughters but to none of his sons.  

 Genetic counselling can be requested to get a full explanation.  

Relevant Organisations

XLH UK: https://xlhuk.org/


References are available on request. Please contact Helen Morris by phoning 0845 241 2173 or emailing helen@metabolicsupportuk.org [Resource Library No: AAP002]. 

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