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, and
mental retardation. Previous studies with cultured 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.