In the 1960s, two young sisters, an 8-year old and a 2-and-a-half-year old, came to New York City to see a well-known radiologist. The bones in their hands and feet were rapidly deteriorating, causing severe arthritis in their fingers. The girls couldn’t move parts of their shoulders, elbows, hips and knees.
The girls’ doctors bequeathed an official name on the condition: Winchester syndrome. In their 1969 paper announcing the disease, the doctors wrote, “There were progressive grotesque deformities of trunk anti limbs, coarse facial features, and peripheral corneal opacities.” They noted that both girls had normal births, though their parents were first cousins. The doctors guessed that the mother and father were recessive carriers of the mysterious disease and had unwittingly passed on two bad genes to their children.
Years passed, and the girls’ conditions worsened. “By age 8 years, despite intensive rehabilitative measures she exhibited extensive contractures and grotesque deformities,” the doctors wrote of one of the sisters. “Her facial features were coarse with gargoyle-like thick lips, hypertrophied gums, fleshy nose witha flat bridge and a prominent forehead. No gross mental deficiency is present.”
At a loss, the doctor took a few samples from their young patients, storing the cells in the hopes that future knowledge or technologies would shed light on the sisters’ disease. Eventually, the two girls’ bones became so brittle and worn that they could no longer move. The doctors watched helplessly as their patients slowly deteriorated and the mysterious disease proved fatal.
Fast forward 50 years. A couple of post-doctoral students at Mount Sinai School of Medicine came across the sisters’ cellular remnants, still awaiting investigation in the hospital freezer. They began sniffing around a gene called MT1-MMP. The gene codes for an enzyme that ensures cell membranes function correctly.
“What we discovered is that these girls had a gene mutation which resulted in incorrect shuttling of the protein,” the lead authors said in a statement. While the protein normally would have travelled to a cell surface, where it could interact with the outside environment, the mutant protein would lose its way. Instead, it “remained trapped in the cell’s cytoplasm,” the authors found, where it “lost its ability to function and the children developed severe arthritis.” The post-docs and their supervisors had identified similar mutations as the cause of other bone disorders affecting children.
Winchester syndrome is extremely rare and almost always fatal. The genetic discovery arrives too late to help the sisters. But the researches hope the gene will assist in making a diagnosis for future cases and eventually lend itself to possible treatment for children suffering from the brutal condition.
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