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Is the locus for Costello syndrome on 11p?
  1. B Kerr1,
  2. M L Mucchielli2,
  3. S Sigaudy2,
  4. M Fabre3,
  5. P Saunier4,
  6. M A Voelckel2,
  7. E Howard1,
  8. R Elles1,
  9. T O B Eden5,
  10. G C Black1,
  11. N Philip2
  1. 1Academic Unit of Medical Genetics and Regional Genetic Service, Central Manchester and Manchester Children’s University Hospitals NHS Trust, Manchester, UK
  2. 2Department of Medical Genetics, Hôpital d’Enfants de la Timone, Marseille, France
  3. 3Department of Pathology, Hôpital Bicetre, Paris, France
  4. 4Department of Paediatrics, Centre Hospitalier, Fontainebleau, France
  5. 5Academic Unit of Paediatric Oncology, Christie Hospital and Central Manchester and Manchester Children’s University Hospitals NHS Trust, Manchester, UK
  1. Correspondence to:
 Dr B Kerr, Academic Unit of Medical Genetics and Regional Genetic Service, Central Manchester and Manchester Children’s University Hospitals NHS Trust, Royal Manchester Children’s Hospital, Hospital Road, Manchester M27 4HA, UK;
 bronwyn.kerr{at}cmmc.nhs.uk

https://doi.org/10.1136/jmg.40.6.469

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    Costello syndrome (CS) is characterised by postnatal growth retardation, relative macrocephaly, distinctive facies, loose, hyperpigmented skin with deep palmar and plantar creases, and developmental delay.1–4 Cutaneous papillomata, which when present are the hallmark of this syndrome, develop in childhood. Cardiac anomalies, either structural defects, hypertrophic cardiomyopathy, or tachyarrhythmia, are present in 60% of cases.5

    The cause of CS is unknown. Segregation analysis and recognition of advanced paternal age support autosomal dominant inheritance, with most cases being the result of de novo mutations.6 For uncommon conditions such as CS, which are generally sporadic, gene identification often relies upon clinical observation or rare cases with chromosomal rearrangements. A single translocation has been described in CS, t(1;22)(q25;q11).7 Recently, malignant tumours have been reported in a significant number of patients with CS, suggesting that a predisposition to malignancy is part of the condition. Bladder carcinoma has been reported twice.8,9 Three patients developed ganglioneuroblastomas.10,11 There have been single reports of epithelioma12 and vestibular schwannoma.13 However, rhabdomyosarcoma (RMS) has been reported in 10 patients.14–18 In seven of these cases, the tumour histology was embryonal; one was pleomorphic, one of unknown subtype,18 and the other alveolar.15 Based on the published cases of CS, with and without tumours, a tumour frequency as high as 17% has been suggested.18

    We hypothesise that the increased malignancy risk in CS is the result of involvement of a tumour suppressor gene in the causation of CS, either by deletion or mutation. We suggest that the predisposition to malignancy occurs when a second mutation in the tumour suppressor gene occurs. Demonstration of loss of heterozygosity (LOH) is a proven technique for localisation of tumour suppressor genes.

    We report here the outcome of LOH and candidate gene studies …

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