1. ¹Department of Clinical Genetics, Sheffield Children's Hospital, Sheffield, South Yorkshire, UK
2. ²Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
3. ³Craniofacial Centre, Children's Hospital, Boston, MA, USA

Correspondence: Dr PC Vasudevan, Department of Clinical Genetics, Sheffield Childrens Hospital, Western Bank, Sheffield, SouthYorkshire, S10 2 TH, UK. Tel: +44 114 2717025 or +44 114 2260570; Fax: +44 114 2737467; E-mail: pradeepcv@yahoo.com

⁴These authors contributed equally to this work

Received 5 January 2006; Revised 1 March 2006; Accepted 1 March 2006; Published online 26 April 2006.

Abstract

Craniofrontonasal syndrome (CFNS, MIM 304110) is an X-linked craniofacial disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Mutations have been identified in the EFNB1 gene that encodes a member of the ephrin-B family of transmembrane ligands for Eph receptor tyrosine kinases. Here, we describe two unrelated families, in both of which a mother and her son have proven mutations in EFNB1. The mothers have classical features of CFNS; although the sons have no major craniofacial features other than telecanthus, both had a congenital diaphragmatic hernia (CDH). Our cases represent the first in which CDH has been confirmed in males with mutations in EFNB1, highlighting an important role for signalling by ephrin-B1 in the development of the diaphragm.