Indiana University School of Medicine is a world leader in research related to hypophosphatemic rickets, a group of rare bone conditions caused by low phosphate levels in the blood.
Phosphate is a mineral critical for proper bone formation in children and bone strength in adults. When blood phosphate levels are inadequate, patients can suffer debilitating complications, including bent or bowed legs, bone pain and dental abscesses.
Decades of research led by IU School of Medicine faculty Michael Econs, MD, and Kenneth White, PhD, have led to the discovery of genes linked to hypophosphatemic rickets, elucidated the effects of mutations on these genes, and played a critical role in the development of promising new treatments.
Notably, their research provided the basis for the development of a burosumab, a new drug that was approved by the European Medicines Agency and then the US Food and Drug Administration in April 2018 for use in the treatment of X-linked hypophosphatemia (XLH). Clinical trials to test the efficacy of burosumab are led by Erik Imel, MD, and Munro Peacock, MD, DSC.
Research Offers New Hope for Patients
About Hereditary Hypophosphatemic Rickets
Rickets is a skeletal disorder that involves the softening and weakening of bones. Hypophosphatemic rickets is a form of rickets caused by changes, or mutations, in genes. It is usually inherited and is the most common form of rickets in the Western world.
Hypophosphatemic rickets is an umbrella term that covers several forms of the disease. The most common type of hereditary hypophosphatemic rickets is called X-linked hypophosphatemia (XLH). It is also referred to as X-linked dominant hypophosphatemic rickets and X-linked vitamin d-resistant rickets.
IU School of Medicine is also deeply involved with research and treatment related to autosomal dominant hypophosphatemic rickets (ADHR), a related disease that follows a different inheritance pattern.
XLH is a rare disease and occurs in approximately one in every 20,000 individuals. ADHR is far less common, affecting only about 100 people worldwide; it is considered an ultra-rare disease.
XLH and ADHR have nearly identical symptoms, including bent or bowed legs, short stature, bone pain, stiffness, fractures, limited mobility and tooth abscesses.
Patients are typically diagnosed with XLH as children, whereas ADHR has a variable age of onset. The severity of symptoms for both diseases varies from patient to patient and ranges from mild to severe.
Both XLH and ADHR are caused by inherited genetic mutations, or mistakes in the DNA sequence in a patient’s genes.
Dr. Econs was part of a team that discovered that XLH is caused by a mutation in the PHEX gene. Though much is still unknown about the PHEX gene, Drs. Econs and White and their scientific collaborators later played a role in determining that the “genetic typos” in PHEX somehow signaled the body to make too much of a hormone called fibroblast growth factor-23 (FGF23).
High levels of FGF23 cause the body to excrete excessive amounts of phosphate in the urine. Without enough blood phosphate to maintain bone strength and support bone growth, patients develop rickets and other debilitating symptoms of XLH.
Though caused by a different genetic mutation, ADHR involves similar processes. Dr. Econs, Dr. White and others discovered that ADHR is the result of a mutation on the FGF23 gene, so-named because it is the gene that produces the FGF23 hormone. As with XLH, patients with ADHR have high blood concentrations of FGF23 and suffer from low levels of blood phosphate and therefore develop weak, soft bones.
XLH is caused by a mutation in the PHEX gene, which is located on the X chromosome. Women have two X chromosomes, whereas men have one X and one Y chromosome, these are referred to as the ‘sex chromosomes’. Women with a single PHEX mutation get the disease, making XLH one of the few X-linked dominant disorders in human genetics. Therefore:
If a mother has the mutation, her children all have a 50 percent chance of inheriting the mutation. Children of either gender will inherit one of the mother’s two X chromosomes. If they inherit the chromosome with the mutation, they will develop the disorder.
If a father has the mutation, all of his daughters will develop the disease, because the daughter inherits one X chromosome from her father and one from her mother. None of his sons will inherit the disorder, because the son inherits the Y chromosome from his father and the X chromosome from his mother.
ADHR is an autosomal dominant disorder, meaning the mutation is located in a gene on an ‘autosome’ (a nonsex chromosome). As a result, gender does not affect inheritance patterns. A child of either gender has a 50 percent chance of inheriting the mutant gene from an affected parent.
Patients have typically been treated with oral high-dose vitamin D and phosphorous several times a day, but this does not address the root cause of the disease.
A new drug based in large part on Drs. Econs and White’s discoveries was approved by the FDA in April 2018. The drug, burosumab (an antibody to neutralize FGF23 in the blood), is being brought to market by Ultragenyx Pharmaceuticals in collaboration with Kyowa Hakko Kirin Co., Ltd. under the brand name Crysvita. Clinical trials, led in part by Erik Imel, MD, an associate professor of medicine and pediatrics at IU School of Medicine, Munro Peacock, MD, DCC, a professor of medicine at IU, and Dr. Thomas Carpenter of the Yale School of Medicine, have demonstrated that burosumab normalizes blood phosphate thereby improving rickets and lower-limb deformity of the legs in children, and bone healing, fracture resolution, and osteomalacia in adults.
Recent research by Drs. Econs and White revealed that low iron levels correlate with high levels of FGF23 in patients with ADHR. Dr. Econs is conducting a study to see if administering oral iron can restore FGF23 to normal levels and therefore prevent excess discharge of phosphate. In some cases, low dose oral iron has allowed for a complete remission of the disease.