Winchester-Torg syndrome

  • Winchester syndrome (OMIM phenotype number #277950)
  • Torg syndrome, Nodulosis-Arthropathy-Osteolysis Syndrome (OMIM phenotype number #259600)

The inherited osteolysis syndromes are a heterogeneous group of diseases characterized by bone destruction and resorption. There are several forms of osteolysis described under a variety of designations with often overlapping clinical findings, and their classification is still a matter of debate. Torg syndrome, Winchester syndrome and Nodulosis Arthropathy Osteolysis syndrome (NAO) are three autosomal recessive inheritance osteolysis syndromes with multicentric involvement. Recently, it has been hypothesized that these three syndromes may be allelic disorders of a continuous clinical spectrum. Indeed, mutations in the MMP2 (matrix metalloproteinase 2) gene have been identified in affected individuals with a clinical diagnosis of NAO and Winchester syndrome. Mutations in the MMP2 gene has been identified also in a patient with Torg syndrome with a complete loss of MMP2 activity. MMP2 is a key enzyme involved in connective tissue turnover, degrading type IV collagen, the major component of basement membranes, and denaturing collagen (gelatin). Winchester syndrome is also caused by homozygous mutation in the MMP14 gene. It has a similar phenotype to NOA, but the subcutaneous nodules are absent.

Gene

MMP2 gene, 16q12.2 (OMIM gene/locus number #120360).

Phenotype

Torg syndrome (includes NAO syndrome): multiple, painless, subcutaneous nodules (interphalangeal joints, knees, feet, elbows, pretibial), mild to moderate osteoporosis and osteolysis usually limited to the hands and feet, widening of the metacarpal and metatarsal bones. Winchester syndrome: subcutaneous nodules are characteristically absent, severe osteolysis in the hands and feet, and various additional features including coarse face, corneal opacities, gum hypertrophy, and EKG coarse face

Main biochemical alterations

High ANA, high IL-6, and high IL-1β.

References

  1. Rouzier C, Vanatka R, Bannwarth S, et al.  A novel homozygous MMP2 mutation in a family with Winchester syndrome. Clin Genet. 2006 Mar;69(3):271-6.
  2. Zankl A, Bonafé L, Calcaterra V, et al. Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2. Clin Genet. 2005 Mar;67(3):261-6.
  3. Zankl A, Pachman L, Poznanski A, et al.  Torg syndrome is caused by inactivating mutations in MMP2 and is allelic to NAO and Winchester syndrome. J Bone Miner Res. 2007 Feb;22(2):329-33.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  5. http://www.omim.org