Frequently Asked Questions
QUESTION: What is XLH?
ANSWER: X-chromosome Linked Hypophosphatemia is a genetic metabolic disorder that usually results in bowed or bent legs in growing children. In XLH, the body's mechanisms to make and maintain bones and teeth do not work correctly. One of the things needed for good bone growth is the mineral phosphorus.
The key characteristic of XLH -- low phosphorus in the blood, also known as hypophosphatemia -- is the result of a mutation that essentially inactivates one of the genes on the X chromosome. When this gene, called the PHEX gene, has the XLH mutation, a protein circulating in the bloodstream called FGF23 increases, causing the kidneys to waste phosphorus and suppresses complete activation of vitamin D to a form the body can use. The loss of phosphate from the kidneys prevents the body from maintaining the proper level of phosphorus in the blood.
Q: Is there a single mutation responsible for XLH?
A: So far, approximately 260 different mutations in a particular section of the X chromosome have been identified for XLH. An XLH patient might have one of these mutations, or a new one that has not yet been described. Everyone in the world has about 10 genetic mutations. Often these mutations have no apparent effect, but sometimes, as in the case of XLH, their effects can be significant. Here is a database of XLH mutations.
Q: Does XLH affect everyone the same?
A: Everyone with XLH has low phosphorus in the blood; but the severity of bone symptoms can vary widely. Some show phosphorus levels that are not below normal, but at the lower end of normal so it's important in those cases to test in the morning before eating or drinking anything, in order to find that patient's lowest phosphorus level. Phosphorus rises normally throughout the day, and foods eaten can affect phosphorus levels in the blood as well. At least 5 percent of people with XLH do not show any bone symptoms, and have only low levels of phosphorus in their blood. A 1994 study by Dr. Michael Econs showed people with mild to moderate symptoms may go undiagnosed.
Q. How do people get XLH?
A: XLH is a genetic disorder. About one-third of our mailing list subscribers have XLH without any apparent family history, and are considered to be spontaneous cases. The rest inherited XLH from a parent. The condition is X-Linked and dominant. This means that the gene responsible for XLH is on the X chromosome and people with the mutated gene will have XLH.
Men have one X and one Y chromosome, whereas women have two X chromosomes. Daughters receive the father’s X chromosome and one of their mother's X chromosomes. Sons get their father’s Y chromosome and one of their mother’s X chromosomes.
Therefore, if a man has XLH, all his daughters will have it, but none of his sons. Every child of an affected mother has a 50-50 chance of inheriting XLH, depending on which X chromosome is passed on.
If the syndrome is present, regardless of whether it is a spontaneous case or inherited from an individual's parents, that individual will have the same likelihood of passing on the condition to their children.
Q. Is XLH curable?
A: No. But it is treatable, and research is ongoing. The gene that carries the XLH mutation was identified in 1995 but it’s still not clear what that gene does. Current research is focusing on processes and proteins involved in the control of phosphorus levels in the blood. The XLH Network Inc. keeps in contact with the world’s leading researchers and stays up to date on the latest developments, but a cure remains years away.
Q. Is XLH treatable?
A: Available treatments can help in many, but isn’t equally helpful in all cases. Often, a combination of a particularly active Vitamin D, together with phosphorus supplements, can help achieve a better balance of phosphate, calcium and crucial hormones.
This treatment may have limited effect and may have side effects requiring periodic monitoring throughout the patient's life. Because of the variability of symptoms, each case is unique and must be treated individually.
In general, however, the earlier the diagnosis can be confirmed and therapy started, the better the results may be. The crucial time for treatment is during a child's growth years to help the legs grow straight. Many children who begin treatment with very bowed or bent legs, mature into adults with straight lower limbs.
Sometimes orthopedic surgery is required to correct badly deformed legs, but often specialists expect to see good progress with medication, minimizing the need for surgery.
Whether treatment should continue after adulthood is a matter of debate, balancing whether drug therapy is needed once an adult’s bones are straight against the potential of premature wear in the knees and joints, osteoarthritis and calcification in the membranes around the joints and between bones.
Q. How is XLH rickets different from other forms of rickets?
A: At the end of the 19th century, many children had rickets because they didn't get enough Vitamin D in their diet or have sufficient exposure to sunshine, which helps the body make Vitamin D. Today this kind of rickets is much less common, but is still found when sunlight exposure or dietary sources of Vitamin D are in short supply.
For people affected by XLH, rickets does not improve no matter how much Vitamin D they get. This is the reason for one of the early names for XLH: Vitamin D-Resistant Rickets.
Different kinds of genetic rickets have been discovered, but XLH is still the most common form of rickets that can be inherited. Each of the different forms of rickets provides a unique insight into the linkages between genes and bones, and each condition has been invaluable in improving our basic understanding of bone formation and maintenance.
Q: How common is XLH?
A: About one person in 20,000 has XLH. It is a rare disorder, but that’s unimportant if you or someone you love is that one person. That's why The XLH Network, Inc. is here. We try to link people so they can share experiences, information and support.
Q: How is XLH diagnosed?
A: XLH patients have low phosphorus in the blood, or hypophosphatemia, which can be detected with a simple blood test typically performed in a clinical chemistry laboratory, or in a doctor's office. However, clinical chemistry laboratories do not always report age-matched phosphorus normals, leading to a misdiagnosis.
Especially if there is no family history, more exhaustive tests wil be needed to rule out other causes of hypophosphatemia and of rickets symptoms. Generally serum (blood) phosphorus is low, serum calcium is normal, and serum alkaline phosphatase is quite elevated. Vitamin D levels are also normal, although the activated form is lower than would be expected with a low phosphorus level.
Rickets can often be identified using X-rays, but that alone doesn't tell the physician what caused the rickets. Lower leg bowing can be obvious. Additionally, to a trained eye, X-rays can provide clear evidence of what are called rickets lesions, even before the leg begins to bow. Parents may notice early bowing problems when their child begins to walk. Increasingly, dental problems, especially numerous spontaneous tooth abscesses and enlarged pulp chambers, are recognized as a common ailment of XLH. Other possible symptoms are bone pain, as well as muscle pain and weakness although this isn't as common in XLH as in some other causes of rickets.
Q: Is there a genetic test for XLH?
A: Yes. A genetic test for XLH and two other forms of genetic rickets became available in March 2001. A detailed analysis of the issues involved with genetic testing with specific reference to this genetic test, is available in the Members section.
Q: How do I find a specialist who has experience with XLH?
A: Most often an endocrinologist or nephrologist with a special interest in metabolic bone diseases will be the specialist to see. These specialists are found in major medical centers and teaching hospitals because they will generally be the ones keeping most up-to-date on rare conditions such as XLH. The XLH Network maintains a limited database of XLH-experienced medical specialists and is always looking for references to others with that specific experience.
Q: Can XLH patients participate in athletic activities?
A: Healthy bones and exercise go together. However, it is important for XLH patients, especially children, to be under the care of a medical professional who can monitor bone growth, maintain medication, and advise on the appropriateness of any particular exercise.
Q: Are there dental problems associated with XLH?
A: Problems with the formation of teeth can result in dental abscesses, not because of poor dental hygiene, but because of improper formation of dentin and other tooth structures. Like bone problems, dental problems also vary from patient to patient. Information on dental issues associated with XLH is available in the Members section.
Q: Has research been done using Human Growth Hormone for XLH patients?
A: Medical researchers have studied Human Growth Hormone as a way to increase stature of XLH patients during their growth years, and some of the reports are linked in our listing of XLH Research Citations. While there have been encouraging results with some patients, there does not yet exist a medical consensus for this treatment option for XLH. Details are available in the Members section.
Q: Has hearing loss been associated with XLH?
A: Some XLH patients have hearing loss that progressively increases over time. The severity and frequency of hearing problems vary from patient to patient. Because so many variables can play a part, it is often difficult to attribute specific hearing loss to XLH.
© 2011, The XLH Network Inc.
The authors of this web site are not medical professionals, and this information does not substitute for medical care. Information on these pages is based on biomedical research, published in peer-reviewed journals, and international research conferences. Additionally, in some cases anecdotal information is provided by subscribers of the F-HYPDRR group, a mailing list for The XLH Network Inc. A listing of XLH research is available. Please read our full disclaimer.
- XLH Network Survey
- The XLH Network is currently in a year-long process of working to grow our organization and better meet the needs of the XLH community. As part of our initiatives, we have designed a survey in hopes of getting feedback from our members. Your feedback…
- 2013 Rare Disease Day Symposium
- In February the 2013 Rare Disease Day Symposium was held in California at the Sanford-Burnham Medical Research Institute. This year's topic was "Calcification Disorders - from Hardened Arteries to Soft Bones". Amo…
- New National Institutes of Health Research Study
- NIH Research Study: Open-label Dose-titration Study of the Tolerability and Efficacy of Cinacalcet to Treat Fibroblast Growth Factor 23 (FGF23)-mediated HypophosphatemiaPrincipal Investigator: Dr. Rachel Gafni, MDSponsoring Institute: Craniofacial and Ske…
- Scientific Advisory Board member wins award at ASBMR
- Michael Econs, XLH Network Scientific Advisory Board Member (SAB), was awarded the Frederic C. Bartter Award for outstanding clinical investigation in disorders of bone and mineral metabolism at the American Society for Bone and Mineral Research…