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Myocardial Storage of Chondroitin Sulfate-Containing Moieties in Costello Syndrome Patients With Severe Hypertrophic Cardiomyopathy

Aleksander Hinek,1 * Michael A. Teitell,2 Lisa Schoyer,3 William Allen,4 Karen W. Gripp,5 Robert Hamilton,6 Rosanna Weksberg,7 Michael Klu¨ ppel,8 and Angela E. Lin9

1  Division of Cardiovascular Research, The Hospital for Sick Children, Toronto, Canada

2  Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, USA

3  President, United States Costello Syndrome Family Network; Chief, Family Support at County of Los Angeles Children’s Medical Services, Los Angeles, California, USA

4  Fullerton Genetics Center, Asheville, North Carolina, USA

5  Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware, USA

6  Division of Cardiology, The Hospital for Sick Children, Toronto, Canada

7  Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada 8 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada 9 Genetics and Teratology Service, MassGeneral Hospital for Children, Boston, Massachusetts, USA

Costello syndrome is a distinctive multiple congenital anomaly syndrome, characterized by loose soft skin with deep palmar and plantar creases, loose joints, distinctive coarse facial features, skeletal abnormalities, cardiac abnormalities (cardiovascular malformation (CVM), hypertrophic cardiomyopathy, tachycardia), predisposition to malignancy, developmental delays, andmentalretardation.Previousstudieswithcultured fibroblasts from individuals with Costello syndrome demonstrate excessive accumulation of chondroitin sulfate-bearing proteoglycans, associated with both impaired formation of elastic fibers and an unusually high rate of cellular proliferation. Despite multiple clinical reports of cardiac abnormalities, there has been only one previously published report describing post-mortem findings in hearts from Costello syndrome patients. Here we provide a detailed description of the post-mortem findings of the hearts of three children with Costello syndrome. Routine histological examination and results of targeted histochemical and immunohistochemical studies revealed that in addition to cardiomyocyte hypertrophy, these hearts also demonstrated massive pericellular and intracellular accumulation of chondroitin sulfate-bearing proteoglycans and a marked reduction of elastic fibers. Normal stroma was replaced by multifocal collagenous fibrosis. Most peculiar was the finding that the bulk of the chondroitin sulfate accumulated in these Costello syndrome hearts is a chondroitin-6-sulfate. In contrast, deposition of chondroitin-4 sulfate was below the level detected in normal hearts. We propose that an imbalance in sulfation of chondroitin sulfate molecules and subsequent accumulation of chondroitin-6-sulfate in cardiomyocytes contribute to the development of the hypertrophic cardiomyopathy of Costello syndrome