Four siblings with same disease help Montreal scientists make medical discovery

Scientists in Montreal have discovered a new genetic mutationlinked to "bone death" or osteonecrosis of the hip, with the helpof four young siblings who suffered from the debilitating disease.

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Dr. Chantal Seguin, a hematologist-oncologist at the ResearchInstitute at McGill University Health Centre, said three sisters anda brother were diagnosed in their 20s and 30s with osteonecrosis atthe top of the femur.

"Four siblings out of six in the same family, and all of themhad advanced disease on both hips," she said, adding patients canbe as young as 10, and that the entire bone beneath the cartilagecan "die" in some cases.

Early diagnosis

Seguin's path toward the discovery began about three and a halfyears ago when she saw a patient in her 30s at the OsteonecrosisClinic at Montreal General Hospital.

She was diagnosed at age 21, but the disease had progressed tothe point of extreme pain by the time Seguin intervened and laterlearned that three of the patient's siblings also had trouble withtheir hips.

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Orthopedic surgeon Dr. Ed Harvey, who had worked at the clinicwith Seguin for 18 years, helped diagnose the disease through X-raysand MRIs, eventually leading to identification of a gene calledTRPV4.

Research on the gene, which plays a critical role in blood flowand bone development, has been published in the Journal of MedicalGenetics.

Seguin said an intriguing aspect of the research is that thefamily is of European descent and that up to now, only one othersuch gene mutation had been identified in five Asian families.

However, the findings from the Asian families in 2005 have notled to early diagnosis or new treatments, she said, adding she iscollaborating with two American experts on TRPV4 in hopes ofdeveloping early detection and targeted therapies for osteonecrosispatients.

'There's got to be a connection here'

Dimitra, who did not want her surname used, said her sister Eleniwas the patient who saw Seguin three and a half years ago, settingoff a study that led to the genetic mutation discovery.

She said Eleni suffered acute pain in her hips, starting at aboutage 19, and could sometimes barely stand.

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About a decade later, Dimitra, now 43, also started having painin her hips.

"I didn't think anything of it at the time but after I gavebirth at 35, within a two- or three-year period I had pain all the
time and I could barely make it through the day," she said.

"That's when I said to my sister, when I was actually having alot of difficulty, I said, 'There's got to be a connection here.'My other siblings were also having a bit of trouble and that's howwe all got involved with (the study)."

Dimitra had both hips replaced about three years ago.

"It was impossible to care for a five-year-old (daughter) at thetime and be in constant pain," she said.

Dimitra said a treatmentcalled core decompression wasused to slow the progression of Eleni's disease.

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Her brother, now 40, is managing his pain and has not yet had ahip replacement, and neither has another sister. She does not knowif her parents, who are deceased and of Greek origin, had hipproblems.

Dimitra said she's hoping further research could one day help herdaughter and her children.

Seguin said she may take more DNA samples from Dimitra and hersiblings to further her research.

"The next step is to try and find other families also in theworld, of European descent and try to see if this mutation is seenworldwide."

A better understanding

Seguin said the discovery could help to better understand a muchmore common form of osteonecrosis that is induced by medicationscalled glucocorticoids, or steroids, used as anti-inflammatories orin chemotherapy to treat blood cancer.

Seguin said she treated a 24-year-old patient who developedosteonecrosis after being prescribed the medication for leukemia.

The young woman, who is half Greek, has had both of her hipsreplaced.