Wednesday, August 16, 2017

The experts behind the Natural History Study

We are excited to let our members know that the XLH Patient Registry and Natural History Study is coming together! A project like this is essential for providing researchers with the information they need both to ask and to answer questions about hypophosphatemic disorders.

From big picture snapshots of the XLH population of patients to more narrow questions that consider whether or not there are actual links between hypophosphatemia and other system disorders such as Chiari malformations, the Natural History Study will provide qualified researchers with instant access to the data necessary to begin their research.

In order to create a study that will be valuable to researchers, we are working with experts across the world to ensure that our questions capture the correct content and are accurately worded (no easy task!).

Dr. Yves Sabbagh (creator of the PHEX database, which contains the known genetic mutations responsible for XLH) provided insight for our genetics survey. Dr. Tom Carpenter weighed in on enthesopathy. Dr. Carolyn Macica reviewed the questions related to pregnancy and nursing.

In all, we have nine experts from four different countries providing their expertise and insight to help ensure that this project is as productive for members and their families as it can possibly be. It has been a true team effort, and we are so grateful to these doctors for donating their time and experience to this project.

The Network’s Registry and Data are part of the National Organization for Rare Disorders’(NORD) Natural History Program.We are thankful for NORD’s investment in the health and wellbeing of all rare disorder communities, including ours.

Wednesday, August 9, 2017

XLH: it's not just for kids any more!

Last year, when Network board members had a booth at the Endocrine Society's annual conference, the most frequent statement they heard from passing doctors was "Oh, I don't need to know about XLH because I only treat kids."

The board members jumped up and down, pulled their hair out and dragged the doctors back to the booth (slight exaggeration there; professional demeanors were maintained, despite all temptation to the contrary) to say, "It's not just for kids any more!"

Of course, we know it's never been a kids-only disorder. It's just that the adult symptoms weren't well known before the Network connected patients who could share their experiences and get confirmation that there was a pattern to the symptoms, that they weren't alone in developing calcifications and arthritis much earlier than the general population, or in needing joint replacement well ahead of the usual timeframe. At the same time, a few doctors like Karl Insogna at Yale University, Michael Econs at Indianopolis University and Suzanne Jan deBeur at Johns Hopkins University began treating larger numbers of adult XLH patients and noticing the pattern of adult symptoms.

The problem now is that the facts about adult issues, well known to patients and the few experts, haven't been absorbed by the broader medical community. There's an often-quoted statistic that it takes seventeen years from the time medical research establishes something definitively until the findings from that research are used by the clinicians treating patients, and it wouldn't be surprising to find that it can take even longer for rare diseases.

Even pediatric endocrinologists who treat a lot of XLH kids may know a lot about the childhood issues, but since they don't see the later progression of the condition after the patients leave the practice, they may be unaware of the adult issues. It's often assumed that the successful straightening of legs with childhood treatment will take care of all the problems, but we're seeing now that that is not the case. Patients who were treated after Phos/calcitriol first became available shortly before 1980 are now in their twenties and thirties and are still reporting a recurrence of bone pain and a variety of more significant joint issues than others their age.

Destroying the myth that adults have no symptoms is a major undertaking, but one that the Network will pursue with our community's support. We're confident that someday, board members will go to a medical conference and no longer have to explain, "It's not just for kids any more!"

Wednesday, August 2, 2017

The basics of XLH genetics

Technically, XLH refers to hypophosphatemia that is "X-linked" (i.e., the relevant genetic defect is on the X chromosome), and the genetic transmission is explained below. Note, however, that the "autosomal dominant" version (where the relevant genetic defect is not on the X chromosome) is informally referred to as XLH, since the symptoms and treatment are the same, but the genetic transmission is slightly different. The only way to know for sure which version a patient has is through genetic testing. Whether the defect is on the X chromosome or elsewhere does not appear to affect the symptomatology, although there is no scientific research on the topic.

There's a good explanation of the genetic transmission of x-linked conditions (both dominant and recessive; keep in mind that XLH is a DOMINANT condition, while there are both dominant and recessive versions of the autosomal hypophosphatemias) here (and click on the illustrations if you're a visual learner): http://ghr.nlm.nih.gov/handbook/inheritance/inheritancepatterns

You can find information about autosomal transmission there as well. Again, it is believed that in MOST autosomal cases, the condition is DOMINANT, although a vanishingly small number of recessive cases have been identified.

The simple version (for true X-linked hypophosphatemia) is:

A woman has a 50/50 chance of transmitting the defective gene to each of her children, who will then have XLH. If she has four children, regardless of their gender, the odds are that two would have XLH and two would not. (Of course, that's just a statistical average, and actual outcomes may be different.)

A man will transmit the defective gene to ALL of his DAUGHTERS ONLY (and none of his sons). Thus, statistically, if he has four children, and two are girls and two are boys, then both girls will have XLH and neither boy will have XLH.

One frequently repeated myth is that someone can be a "carrier" for XLH without having the condition him/herself. That is only true of recessive conditions, and X-linked hypophosphatemia (including most autosomal versions) are DOMINANT. That means that if the person has the genetic defect, and is capable of passing it on to the next generation, he/she will also have hypophosphatemia.

This misconception arises from three common situations with XLH: 1. the symptoms are variable, so a mildly affected parent (especially women who tend to have less severe symptoms at least during childhood and early adulthood) may not be aware he/she has it until his/her child is diagnosed with XLH and doctors then check the parents' blood levels for phosphorus wasting. If the parent is never properly diagnosed, it may appear as if he/she was a carrier.  2. There can be some confusion even by genetic counselors, since most x-linked conditions are recessive, rather than dominant, so the counselor may assume that XLH is recessive, and therefore has carriers. 3. Finally, a substantial number of XLH patients are "spontaneous" cases. This just means that the defect first occurred in that patient's DNA during conception, much like any birth defect happens.

There's a natural, human tendency to want to explain away the spontaneous mutation, to look for someone in the family who might have had been a carrier. Unless that person was one of the patient's parents (see the first example of an undiagnosed case) who simply hadn't been diagnosed, there won't be an answer in the family tree. The mutation is simply a random event. Neither parent has XLH and neither parent is a carrier. The child simply has a new, or "spontaneous" mutation, and the children of the spontaneous XLH patient will inherit in the pattern described above.

Wednesday, July 26, 2017

Unanswered questions

As we were starting to construct the first-ever comprehensive natural history study of XLH, we realized it was a huge challenge, because, unlike some conditions, XLH affects pretty much every system of the body.

Scientists divide the human body into ten systems: 1) cardiovascular, 2) digestive, 3) endocrine, 4) integumentary/exocrine, 5) lymphatic/immune, 6) musculo-skeletal, 7) nervous, 8) renal/urinary, 9) reproductive, 10) respiratory.

It's immediately obvious that the endocrine, musculo-skeletal and renal (kidney) systems are relevant to XLH. The endocrine system regulates phosphorus and FGF23, muscle function and skeleton structure are adversely affected by elevated FGF23 and low phosphorus, and the kidneys are where the phosphate wasting occurs. Some digestive issues have been reported with phosphorus supplements. Some XLHers have nerve involvement as a secondary effect, when calcification impinges on nerves or when the patient has a Chiari malformation or syringomyelia (both of which may or may not be related to XLH).

What about the other, less obviously affected body systems? Wouldn't it be good to know if there's any correlation between XLH and an increased (or decreased!) risk of heart disease or elevated blood pressure? Between XLH and lung conditions? Between XLH and infertility? Or, more generally, and crossing a variety of systems: is there any correlation between XLH and an increased/decreased incidence in various forms of cancer? And what about pain and its treatment: what's the nature/extent of the pain, what's being prescribed and what, if anything, is most likely to be effective?

No one has those answers, in part because the questions have never been asked in a rigorously scientific manner. But we're hoping to change that soon!

The Network’s Registry and Data are part of the National Organization for Rare Disorders’(NORD) Natural History Program.We are thankful for NORD’s investment in the health and wellbeing of all rare disorder communities, including ours.


Wednesday, July 19, 2017

School's back .... Well, almost

It may only be mid-July but in just a few short weeks, school will be back in session! It can be a hectic time of the year, from shopping for clothing to making sure everything on the supply list is in the backpack before the first day.

Did you know there’s an easy way to shop for back to school AND support the Network at the same time? That’s right…and you can do it all from the comfort of your own home. No trips to the mall, no worrying about parking, no hustle and bustle. A few short clicks of the mouse and you will have everything you need and benefit those living with XLH.

When you shop on Amazon Smile or IGive and choose The XLH Network, Inc. as your charity, a portion of your purchases benefits us! It’s really that simple. If Amazon is your retailer of choice, visit smile.amazon.com and indicate The XLH Network, Inc. as your charity and you’ll be well on your way to taking advantage of all the great deals that Amazon offers. There’s a reason it’s the world largest marketplace, and now you can shop from the comfort of your own home and help those living with XLH.

IGive offers a similar option. You can choose from over 1700 online stores at the IGive Marketplace and a portion of your purchases will benefit The XLH Network, Inc. All you have to do is set up an account at IGive, select The XLH Network, Inc., as your charity, and you’re shopping, and helping, with one click of the mouse. Go here to set up an IGive Account: https://www.igive.com/welcome/lp16/cr64a.cfm

And remember, you don’t have to limit your online shopping to just back to school time. These programs are available throughout the year so keep it in mind for birthdays, Christmas, Father’s Day, Mother’s Day, anniversaries or "just because" days!

Wednesday, July 12, 2017

XLH Day Registration is Open!

XLH Day Registration is open at XLHDay.org. We think you'll be as excited as we are with everything we've got planned, from panel discussions to interactive discussions, a children's program, and even a picnic dinner at a local state park. You can see the list of speakers and the preliminary agenda here: http://xlhday.com/?page_id=1071

Before registering, please read the information about hotel accommodations here http://xlhday.com/?page_id=220  We don't have a grant to cover hotel costs for everyone this year, so the stipends will be granted on the basis of need. We understand the financial burdens of living with a rare disease, and we will do our best to accommodate everyone who could not attend without the financial assistance. For your own planning purposes and for ours, we encourage anyone who does need the help to apply for the stipend as early as possible in the registration period by contacting our Executive Director, Carol LaFleur at ExecutiveDirector@xlhnetwork.org

If you know anyone else with an XLHer in the family, please make sure they know about XLH Day. We don't want anyone to miss out on such a great experience!


Tuesday, July 4, 2017

Happy Independence Day!

We're all on vacation, but want to wish everyone in the U.S. a great Independence Day, and to everyone else we wish the best of your July holidays, including but not limited to:

Bastille Day Canada Day
Constitution Day
Day of the Sea
Emancipation Day
Family Day
Freedom Day
Heroes' Day
Liberation Day
National Day
Orangeman's Day
Republic Day
Revolution Day
Somers' Day
St. Peter's and St. Paul's Day
Union Day
United States Friendship Day
Unity Day