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Overgrowth with increased proliferation of fibroblast and matrix metalloproteinase activity related to reduced TIMP1: A newly recognized syndrome?
Author(s) -
Chung Brian,
Hinek Aleksander,
Keating Sarah,
Weksberg Rosanna,
Shah Vibhuti,
Blaser Susan,
Hawkins Cynthia,
Chitayat David
Publication year - 2012
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.35570
Subject(s) - fibroblast , timp1 , tissue inhibitor of metalloproteinase , biology , matrix metalloproteinase , multiplex ligation dependent probe amplification , pathology , microbiology and biotechnology , medicine , genetics , cell culture , exon , gene , gene expression
We report on a child with prenatal onset of overgrowth associated with thick, excessive wrinkled skin and other abnormalities including cleft palate, Chiari malformation and polymicrogyria. His clinical features do not resemble any of the known reported overgrowth syndromes. Genetic evaluations, including karyotype, oligoarray, methylation‐sensitive multiplex ligation‐dependent probe amplification (MLPA) for 11p11.2 region, CDKN1C sequencing, GPC3 sequencing and dosage analysis, and HRAS sequencing, have been un‐revealing. Immunohistochemistry done on the patient's cultured skin fibroblasts showed normally assembled elastic fibers and normal pattern of chondroitin sulfate deposition with defective deposition of Collagen I fibers. In addition, there were high levels of immuno‐detectable metalloproteinase 3 (MMP3) and undetectable tissue inhibitor of metalloproteinase 1 (TIMP1). The defective collagen deposition in the fibroblast culture could be reversed by the broad spectrum MMP inhibitor, doxycycline. We also present evidence that the fibroblasts of this patient have an increased rate of cellular proliferation. We propose that this is a previously unrecognized overgrowth syndrome associated with increased cellular proliferation and defective collagen I deposition due to an imbalance between MMP and TIMP in fibroblasts. © 2012 Wiley Periodicals, Inc.