title: Overgrowth with increased proliferation of fibroblast and matrix metalloproteinase activity related to reduced TIMP1: a newly recognized syndrome?
abstract: 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.
authors.affiliation: The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Ontario, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Chung
authors.forename: Aleksander
authors.initials: A
authors.lastname: Hinek
authors.forename: Sarah
authors.initials: S
authors.lastname: Keating
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Shah
authors.forename: Susan
authors.initials: S
authors.lastname: Blaser
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000328:Adult; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D013577:Syndrome; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D024042:Collagen Type I; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3