Studies on the pathogenesis of Costello syndrome.

Costello syndrome is characterised by high birth weight, early psychomotor and growth retardation, cardiomyopathy, relative macrocephaly, coarse face, and laxity of the small joints. Skin abnormalities include nasal and perianal papillomata, acanthosis nigricans, cutis laxa, and curly and sparse scalp hair. 2 Increased paternal age and sporadic occurrence have suggested autosomal dominant de novo mutations. Recently, several solid tumours have been described in patients with Costello syndrome, such as bladder carcinoma (2), rhabdomyosarcomas (10), neuroblastomas (3), vestibular schwannoma (1), and epithelioma (1). The estimated frequency of tumours is about 17%. Whereas rhabdomyosarcomas and neuroblastomas are relatively frequent in childhood, our attention was drawn to bladder carcinoma because it is extremely rare in childhood. Its occurrence has been suggested to be specific for this syndrome. FGFR3 is the oncogene most often mutated in bladder cancer, with mutations shown in more than 40% of carcinomas. Activating mutations have been found in “hot spots” of exons 7, 10, and 1. Also FGFR3 somatic mutations are found in 3–25% of cervical carcinomas and 14% of multiple myelomas. 12 FGFR3 dominant germline mutations can cause different types of chondrodysplasia (achondrodysplasia and hypochondroplasia, thanatophoric dysplasia, and SADDAN) or some craniosynostosis syndromes (reviewed by Vajo et al). Among these, the variant of Crouzon syndrome and SADDAN are associated with acanthosis nigricans and hyperpigmentation which are also found in patients with Costello syndrome. Recent biochemical studies showed that cutis laxa is caused by impaired assembly of elastin fibres, owing to a functional deficiency of the 67 kDa elastin binding protein. This protein is inactivated by abnormal binding to excessive mucopolysaccharides, in particular chondroitin sulphate, which accumulate in cultured fibroblasts of patients with Costello syndrome. The observation of chondroitin sulphate storage in the lysosomal compartment suggests a defect in mucopolysaccharide degradation. Also a high rate of cellular proliferation in fibroblast cultures was found, suggesting a constitutive activation of the fibroblast growth factor pathway. We studied the pathogenesis of this disorder in five patients by a molecular and a biochemical approach. Considering the heterogeneity of syndromes caused by FGFR3 germline mutations, we searched for FGFR3 gene mutations. Activation of the FGF signal transduction pathway also depends on extracellular heparan sulphate mucopolysaccharides. Consequently we studied mucopolysaccharide turnover by the sulphate incorporation test and by measuring the activity of a novel lysosomal sulfatase involved in heparan sulphate metabolism. Finally we checked whether the sialuria found earlier depends on an intracellular sialic acid abnormality, by measuring the sialic acid content of cultured fibroblasts.