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Legg Calve Perthes Disease- The hunt for genetic associations by 51S3X66w

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									         Legg Calve Perthes Disease-
        The hunt for genetic associations



           S Hayek; E Ezra; S Wientroub; D Steinberg *;
             N Rosenberg *; D Waldman *; G Kenet *

Pediatric Orthopedic Department
Tel-Aviv Sourasky Medical Center
*Pediatric Coagulation Service, National Hemophilia Center,
Sheba Medical Center, Tel Hashomer
Introduction


 LCPD is a disease of unknown origin and may be
  attributed to genetic as well as environmental
  risk factors
 Our aim was to evaluate the potential role of
  genetic factors in LCPD patients.
 We studied mutations causing thrombophilia,
  Gaucher disease and inherited osteonecrosis
Thrombophilia

   Intravascular thrombosis may be the
    causative mechanism of LCPD
   The role of heritable thrombophilic risk
    factors in pathogenesis of LCPD is
    controversial
Glueck CJ. et al Clin Orthop 1997
Gallistl SJ et al Pediatr Orthop 1999
Hayek S et al J Bone Joint Surg 1999
Sirvbent N et al. J Pediatr Orthop B2000
Hresko T. et al J Bone Joint Surg 2002
Elbridge J. et al Pediatrics 2001
Hresko T. et al J Bone Joint Surg 2002
Gaucher disease

 Clinical and radiological findings of
  avascular hip necrosis due to LCPD may be
  indistinguishable from Gaucher disease
 We previously studied Gaucher mutations
  among LCPD patients and found an increase in
  their prevalence.
      Horwitz M et al Hum Mut 1998
      Kenet G et al .Blood Cells Molec Dis   2003
Inherited osteonecrosis

   Inherited osteonecrosis of the femoral head
    has recently been found to be associated
    with variant mutations of collagen type II.

                 Liu YF, Chen WM, Lin YF et al .Type II collagen gene
                 variants and inherited osteonecrosis of the femoral head.
                 N Engl J Med. 2005.
Methods

   Genomic DNA of confirmed LCPD patients was
    analysed for the following:

  Thrombophilic polymorphisms:
• • Factor-Vmutations (COL2A1) ofand Factor-II
• Enzyme assays were performed for
     Gaucher mutations:
  Collagen Lieden, 677T-MTHFR 12q13 gene
   G20210A. of Gaucher disease status
  confirmation insertion (84GG), L444P, .
     N370S, G
    – Results were compared with 276 pediatric
     Intron 2(IVS2+1G>A) and R496H
       controls referred for elective surgery.
Results

                                    females
 119 LCPD patients were          HERRING CLASSIFICATION
                                 CATTERALLCLASSIFICATION
                                    , 23.20%
  studied                                   I
                                                          II
                                          4%
                                                        10%
 Male to female ratio was
  3.3 to 1                                      Amales,
                                                 76.80%
                                              5.80%
 Mean age at diagnosis       C
                           38.40%                         , III
  was -6 y                                               29%
                        IV                                      B
 (range 1y to 14.9y) 57%                                     40.40%


                                    B-C
                                  15.40%
Thrombophilic markers in LCPD vs
controls

Marker             )%( #-LCPD      )%( #-Controls   P value



Factor V Lieden   )5.9%( 7/119     )4.7%( 13/276     0.81



Factror II        )3.4%( 4/119      )4%( 11/276      0.99
G20210A


MTHFR 677T        )15.1%( 18/119   )14.9%( 41/276    0.93



   Patients and controls were not statistically
                    different
Gaucher mutations in LCPD patients


    The prevalence of N370S mutation was 2.5%
    (6/238 alleles)
     –   4 patients were heterozygous and one was homozygous
 No positive cases for the other mutations.
 26/55 patients had a low threshold (< 1.0) for
 -Glucosidase enzyme activity,

These findings are lower than the Israeli population carriership data
(5.8% of Ashkenazi Jews)

The association with LCPD found in a smaller previous study was
not confirmed
Horwitz M et al Hum Mut 1998; Kenet G et al Blood Cells Molec Dis 2003
            Conclusion
Familial osteonecrosis mutations


 All LCPD patients were negative for
We found no evidence that LCPD is
  COLA21 mutations
associated with any of the genetic
factors causing thrombophilia,
Gaucher disease or familial
osteonecrosis

								
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