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Shining a Light on a rare bone disease XLH

On 2 March, people living with XLH, a rare genetic bone disease, as well as scientists, staff and students from across the Institute and wider university heard about exciting new developments in research into XLH from Professor Stuart Ralston and Ryan Frew, who has XLH, described how his life has been transformed by a new treatment: March 2021

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This is our Institute’s third event for Rare Disease Day that takes place annually on 28 February. Rare Disease Day has been taking place internationally for 14 years, to raise awareness of rare diseases that affect 3.5% - 5.9% of the worldwide population. There are over 300 million people living with one or more of over 6,000 identified rare diseases around the world. 72% of rare diseases are genetic and in Europe a disease defined as rare when it affects fewer than 1 in 2,000 people.

XLH is a rare genetic bone disease. Professor Stuart Ralston provided an overview of XLH and current research. X-linked hypophosphatemia is an inherited condition, caused by mutations in the PHEX or PEX gene that leads to low levels of phosphate in the blood and this affects bones, muscles and teeth. Globally XLH affects approximately 1 in 90,000 babies born each year. The symptoms of XLH can vary in severity, ranging from no apparent bone-related symptoms and only hypophosphatemia, while others have severe symptoms. This condition is usually diagnosed in early childhood (~18 month) and is a lifelong condition that may require ongoing treatment and monitoring.

XLH is an X-Linked dominant disorder, because the PHEX gene is located on the X chromosome. People with one PHEX gene mutation will have XLH, even if there are no mutations in the PHEX gene from the other parent. Women with XLH have a 50% chance of passing XLH on to their children. Men with XLH will pass the condition on to all of their daughters, but not to their sons. Sometimes, people with XLH are the first ones in a family to have the condition. In these very rare cases, they did not receive the mutated PHEX gene from a parent but due to a random mutation. However, they can still pass the condition on to their children.

Mutations in the PHEX gene on the X chromosome cause too much Fibroblast Growth Factor 23 (FGF23) to be made in bone cells. FGF23 blocks phosphate re-absorption by the kidney and suppresses the vitamin D dependent phosphate absorption by the intestine, resulting in abnormally low levels of phosphate in the blood. Low phosphate levels in children will lead to poor bone health and a variety of clinical symptoms that may include abnormal bone formation, bone pain, lower bone density, fractures, tooth abscesses and deformities in the legs, muscle pain and weakness.

Stuart shared clips from interviews that he had videoed with his patient Ryan Frew. Ryan then shared his own experiences of living with XLH through a lengthy Q&A session.

Stuart concluded the event by describing the XLH Clinical Trial that Ryan participated in. XLH cannot be treated by increasing vitamin D alone and phosphate supplements are typically combined with high dose Calcitriol. In 2018, the medication Burosumab was found to help XLH in the USA, In the UK, it’s currently in Clinical Trial with adults in the UK but is routinely used in treating children. Burosumab deals directly with the raised levels of FGF23 as it is a monoclonal antibody to FGF23, so it neutralises it and this increases the blood phosphate levels. This is given as a subcutaneous injection once a month and no other medication is needed. Ryan described how being on Stuart’s Clinical Trial has transformed his life – he is now pain-free and living life to the full.

The XLHUK Support Group are encouraging dropping the term "Rickets" associated with XHL because Rickets implies a nutritional condition but XHL is a genetic condition. Rickets describes a nutritional condition with a single childhood symptom of bendy legs bones.

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