1. ¹South East Scotland Genetic Service, Western General Hospital, Edinburgh, UK
2. ²Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
3. ³Paediatric Radiology Department, Royal Hospital for Sick Children, Edinburgh, UK
4. ⁴The Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, UK
5. ⁵Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK

Correspondence: Prof AOM Wilkie, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK. Tel: +44 1865 222 619; Fax: +44 1865 222 500; E-mail: awilkie@molbiol.ox.ac.uk

⁶The first two authors contributed equally to this work

Received 14 February 2003; Revised 26 May 2003.

Abstract

The combination of skull defects in the form of enlarged parietal foramina (PFM) and deficient ossification of the clavicles is known as parietal foramina with cleidocranial dysplasia (PFMCCD). It is considered to be distinct from classical cleidocranial dysplasia (CCD) and is listed as a separate OMIM entry (168550). So far, only two families have been reported and the molecular basis of the disorder is unknown. We present a third family with PFMCCD, comprising four affected individuals in three generations, and demonstrate that a heterozygous tetranucleotide duplication in the MSX2 homeobox gene (505_508dupATTG) segregates with the phenotype. PFMCCD is indeed aetiologically distinct from CCD, which is caused by mutations in the RUNX2 gene, but allelic with isolated PFM, in which MSX2 mutations were previously identified. Our observations highlight the role of MSX2 in clavicular development and the importance of radiological examination of the clavicles in subjects with PFM.