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Studies on the pathogenesis of Costello syndrome
  1. G M S Mancini1,
  2. O P van Diggelen1,
  3. W J Kleijer1,
  4. M Di Rocco2,
  5. V Farina3,
  6. M Yuksel-Apak4,
  7. H Kayserili4,
  8. D J J Halley1
  1. 1Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands
  2. 22nd Department of Paediatrics, Hospital Gaslini, Genova, Italy
  3. 3Clinical Department of General Paediatrics, Federico II University, Napoli, Italy
  4. 4Child Health Institute, Division of Medical Genetics, University of Istanbul, Turkey
  1. Correspondence to:
 Dr G M S Mancini, Department of Clinical Genetics, Erasmus University Medical Centre, PO Box 1738, 3000 DR Rotterdam, The Netherlands; 
 g.mancini{at}erasmusmc.nl

https://doi.org/10.1136/jmg.40.4.e37

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    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.1,2

    Increased paternal age and sporadic occurrence have suggested autosomal dominant de novo mutations.3

    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%.4 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.5

    FGFR3 is the oncogene most often mutated in bladder cancer, with mutations shown in more than 40% of carcinomas.6–8 Activating mutations have been found in “hot spots” of exons 7, 10, and 1.9 Also FGFR3 somatic mutations are found in 3–25% of cervical carcinomas10 and 14% of multiple myelomas.11,12

    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 al13). 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.14 The observation of chondroitin sulphate storage in the lysosomal compartment suggests a defect …

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