Brueton, Louise A.; (1996) Craniodigital syndromes and chromosome 7p. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Craniosynostosis or premature closure of the cranial sutures is a common abnormality occuring in about 1 m 2000 children. There is evidence of Mendelian inheritance in some 20% of cases. A number of autosomal dominant craniosynostosis syndromes exist in which craniosynostosis occurs in association with various limb anomalies. Although relatively rare, this group of monogenic craniodigital syndromes provides a way of mapping, by molecular genetic methods, genes important in craniofacial and limb development. The aims of the present work were to determine the chromosomal location of the mutations responsible for some of the human craniodigital syndromes. Chromosome 7 was chosen as a suitable starting point as premature sutural fusion is a relatively uncommon finding in patients with chromosome anomalies but has been reported in at least 10 patients with a variety of structural alterations of 7p. Craniosynostosis appears to be consistently associated with deletion of one of two specific and separate regions, either deletion of part of band 7p21/proximal 7p22 or deletion of 7p13-p14. Many of the patients with deletions of the more proximal region 7p13-7p14 have features of the Greig cephalopolysyndactyly syndrome (GCPS), whereas those with more distal deletions have features reminiscent of the non-Apert acrocephalosyndactylies. The karyotypic findings in these cases suggest that two or more genes responsible for craniosynostosis and limb anomalies may be situated on chromosome 7p. The localisation, identification and characterisation of one or more of the genes responsible for such autosomal dominant craniodigital syndromes will help lead to determination of the genetic elements involved in the complex process of normal craniofacial and limb formation and the consequences of mutation in these developmental genes. The results of clinical and molecular genetic studies undertaken to investigate the possible localisation of GCPS and the non-Apert acrocephalosyndactyly syndromes to chromosome 7p are reported. It is demonstrated that GCPS maps to 7p13 whilst the gene responsible for Saethre-Chotzen syndrome is localised to 7p21-22. Evidence to show that GCPS and the acrocallosal syndrome are not allelic disorders is also provided. The outcome of a clinical study of the non-Apert acrocephalosyndactylies is presented in detail. This helps to define the degree of variability within and between families and the question of genetic heterogeneity in this group of conditions is addressed.

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