Cerebro-oculo-facio-skeletal syndrome: three additional cases with CSB mutations, new diagnostic criteria and an approach to investigation
- V Laugel1,
- C Dalloz1,
- E S Tobias2,
- J L Tolmie2,
- D Martin-Coignard3,
- V Drouin-Garraud4,
- V Valayannopoulos5,
- A Sarasin6,
- H Dollfus1
- 1Laboratory of Medical Genetics, Faculte de Medecine, Strasbourg, France
- 2Division of Developmental Medicine, The Royal Hospital for Sick Children, University of Glasgow, UK
- 3Department of Medical Genetics, University Hospital, Le Mans, France
- 4Department of Medical Genetics, University Hospital, Rouen, France
- 5Department of Metabolic Disorders, Necker Hospital, Paris, France
- 6FRE2939, Institut Gustave Roussy, Villejuif, France
- Dr V Laugel, Laboratory of Medical Genetics, Faculte de Medecine, 11 rue Humann, F-67000 Strasbourg, France;
- Received 26 January 2008
- Revised 12 May 2008
- Accepted 16 May 2008
- Published Online First 15 July 2008
Background: The cerebro-oculo-facio-skeletal syndrome (COFS syndrome) is an autosomal recessive disorder which was initially described in a specific aboriginal population from Manitoba. In recent years, COFS syndrome has been linked in this original population to a defective DNA repair pathway and to a homozygous mutation in the major gene underlying Cockayne syndrome (CSB). However, most reports of suspected COFS syndrome outside this population have not been confirmed at the molecular level, leading to considerable heterogeneity within the syndrome and confusing overlaps between COFS syndrome and other eye and brain disorders.
Objective: To refine the delineation of the syndrome on genetically proven COFS cases.
Methods: We report the exhaustive clinical, cellular and molecular data of three unrelated COFS patients with mutations in the CSB gene.
Results: All three patients present the cardinal features of COFS syndrome including extreme microcephaly, congenital cataracts, facial dysmorphism and arthrogryposis. They also exhibit a predominantly postnatal growth failure, a severe psychomotor retardation, with axial hypotonia and peripheral hypertonia and neonatal feeding difficulties. Fibroblasts from the patients show the same DNA repair defect which can be complemented by transfection of the CSB wild-type cDNA. Five new mutations in the CSB gene have been identified in these patients.
Conclusions: Our data indicate that COFS syndrome represents the most severe end of the Cockayne spectrum. New diagnostic criteria for COFS syndrome are proposed, based on our findings and on the few genetically proven COFS cases from the literature.
Competing interests: None declared.
Patient consent: Parental/guardian consent obtained.