Skip to main content
Expertise in Musculoskeletal Health

Hypophosphatemic Rickets

International leader in rare bone disease research

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

Participate in clinical research

Research studies are always seeking participants, and many are never completed because they cannot find enough volunteers. Thanks to research volunteers, new treatments and drugs can be discovered which improve health care for you, your family, and people throughout the world.

Learn More

Video

Research offers new hope for XLH patients

Debbie Moore knows firsthand the debilitating effects of XLH. Diagnosed with the disease at 18 months, she spent much of her childhood wearing leg braces. She also underwent surgeries to remove pieces of bone from her femurs and tibias in an effort to straighten her legs.

About Hereditary Hypophosphatemic Rickets

  • What is 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.

  • How common is hereditary hypophosphatemic rickets
    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.
  • What are the symptoms of XLH and ADHR
    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.

  • What causes XLH
    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.

  • What causes ADHR
    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.
  • Who gets XLH
    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.

  • Who gets ADHR
    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.
  • What is the treatment for XLH
    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.

  • What is the treatment for ADHR
    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.

Meet the Investigators

4904-Econs, Michael

Michael J. Econs, MD

Distinguished Professor

The research of Mike Econs, MD, is in the area of genetic aspects of metabolic bone disease. His research has led to the development of an FDA-approved drug to treat children and adolescents with X-linked hypophoshatemic rickets.

Read Bio

5039-Imel, Erik

Erik A. Imel, MD

Associate Professor of Medicine

The research focus of Erik Imel, MD, is on pediatric metabolic bone and mineral disorders, especially hypophosphatemic disorders, calcium disorders and disorders of low bone density.

Read Bio

1931-White, Kenneth

Kenneth E. White, PHD

Chancellor's Professor

Ken White, PhD, played an instrumental role in discovering the novel hormone FGF23. His laboratory has since received funding to study this hormone and its co-receptor Klotho.

Read Bio

4894-Peacock, Munro

Munro Peacock, MBCHB

Professor Emeritus of Medicine

Munro Peacock, MD, DSC, specializes in endocrinology and internal medicine. His research interests include endocrine disorders of mineral metabolism.

Read Bio