Overgrowth with increased proliferation of fibroblast and matrix metalloproteinase activity related to reduced TIMP1: a new syndrome?

Poster Presentation: program no. 930/FWe report on a child with prenatal onset overgrowth associated with facial dysmorphism, thick, excessive wrinkled skin, cleft palate, Chiari malformation and polymicrogyria. His clinical features do not resemble any reported overgrowth syndromes. Genetic investigations tests including testing the possibility of epigenetic alterations of 11p15 region and mutations of the CDKN1C gene (Beckwith-Wiedemann syndrome), mutations and dosage changes of GPC3 gene (Simpson-Golabi-Behmel syndrome), mutations of HRAS gene (Costello syndrome) and chromosomal rearrangement by karyotype and oligo-array. Using immunohistochemistry, we found that cultured skin fibroblasts obtained from this patient demonstrated normally assembled elastic fibers and normal pattern of chondroitin sulfate-deposition with defective deposition of Collagen I fibers. In addition, the fibroblasts revealed high levels of immuno-detectable metalloproteinase (MMP) and undetectable tissue-inhibitors of metalloproteinase (TIMPs). The defective collagen deposition in the fibroblast culture can be reversed by broad spectrum MMP inhibitor - doxycycline. The fibroblasts of this patient also had an increased rate of cellular proliferation. We propose that this is a previously unreported syndrome with overgrowth associated with increased cellular proliferation and defective collagen I deposition due to an imbalance between MMP and TIMP in fibroblasts.The 60th Annual Meeting of the American Society of Human Genetics (ASHG 2010), Washington, DC., 2-6 November 2010