1. ¹Molecular Ophthalmic Genetics Laboratory, Department of Surgery, University of Connecticut Health Center, Farmington, CT, USA
2. ²Department of Medical Genetics, St George's University of London, London, UK
3. ³Department of Cardiac and Vascular Sciences, St George's University of London, London, UK
4. ⁴Department of Vascular Surgery, Guy's and St Thomas' NHS Hospital Trust, London, UK
5. ⁵Department of Ophthalmology, University Hospital, Queen's Medical Center, Nottingham, UK

Correspondence: Professor M Sarfarazi, Molecular Ophthalmic Genetics Laboratory, Department of Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06032-1110, USA. Tel: +1 860 679 3629; Fax: +1 860 679 7524; E-mail: Mansoor@Neuron.uchc.edu

Received 24 July 2007; Revised 23 October 2007; Accepted 24 October 2007; Published online 16 January 2008.

Abstract

Primary lymphoedema is a genetic disorder with numerous phenotypic subgroups. The most common form is the non-syndromic Meige disease, which is primarily of pubertal or later onset, with oedema clinically indistinguishable from that found in the lymphoedema–distichiasis syndrome. There are also other very rare forms of lymphoedema such as yellow nail syndrome and lymphoedema with ptosis, which are clinically similar to Meige disease. The only causative genes so far identified for the non-congenital primary lymphoedemas are the transcription factor FOXC2, where mutations are known to produce lymphoedema with distichiasis, and SOX18 in the very rare condition hypotrichosis–lymphoedema–telangiectasia. This study has examined FOXC2 gene by sequence analysis in 23 affected individuals with Meige disease. A novel truncating mutation (c.563–584del) was identified in one family and found to segregate with the disease in eight affected relatives over three generations. This deletion creates a frameshift that predicts a premature stop at nucleotide 599 and truncating the normal protein by 38%. Although the affected patient initially selected for mutation screening from this family had lymphoedema without distichiasis, all but one of his affected relatives who carried the FOXC2 mutation did have accessory eyelashes originating from their meibomian glands. This is further confirmation that of the primary lymphoedemas, only lymphoedema with distichiasis is caused by FOXC2 mutations. All forms of post-pubertal lymphoedema need careful phenotyping for distichiasis, which may prove difficult to confirm unless several family members are examined, and cannot ever be assumed to be absent from self-report.