Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations

Abstract

Background-Hereditary lymphoedemadistichiasis (LD) is an autosomal dominant disorder that classically presents as lymphoedema of the limbs, with variable age of onset, and extra aberrant growth of eyelashes from the Meibomian gland (distichiasis). Other major reported complications include cardiac defects, cleft palate, and extradural cysts. Photophobia, exotropia, ptosis, congenital ectropion, and congenital cataracts are additional eye findings. Recently, we reported that truncating mutations in the forkhead transcription family member FOXC2 resulted in LD in two families. Methods-The clinical findings in seven additional families with LD, including the original family described by Falls and Kertesz, were determined and mutational analyses were performed. Results-Distichiasis was the most common clinical feature followed by age dependent lymphoedema. There is a wide variation of associated secondary features including tetralogy of Fallot and cleft palate. The mutational analyses identified truncating mutations in all of the families studied (two nonsense, one deletion, three insertion, and one insertion-deletion), which most likely result in haploinsuYciency of FOXC2. Conclusions-FOXC2mutations are highly penetrant with variable expressivity which is not explicable by the pattern of mutations. (J Med Genet 2001;38:761-766)

Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24

“…The third was a missense mutation, and is only the second in FOXC2 so far identified as likely to give rise to LD, all the remainder being nonsense or frameshifts. [9][10][11][12] As the G362A (R121H) change is found in an isolated case of LD, it is impossible to prove that this is the causative mutation in this person. However, this is a highly conserved amino acid, being one of only 11 that are identical in 24 members of the forkhead family in the 100 amino acid DNA binding domain.…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…FOXC2, a Forkhead family transcription factor, is one of the few causative genes associated with human lymphatic disorder and malformation to date and is found to be responsible for lymphedema -distichiasis (double row of eye lashes) syndrome by multiple groups (Fang et al 2000;Erickson 2001;Erickson et al 2001;Finegold et al 2001;Bahuau et al 2002;Brice et al 2002;Traboulsi et al 2002;Kriederman et al 2003;Fabretto et al 2010). Foxc2 is expressed in both arterial and lymphatic endothelial cells and, along with Foxc1, is required for arterial specification and normal lymphatic sprouting from the vein during development (Dagenais et al 2004;Seo et al 2006;Kume 2009).…”

Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia

“…In humans, only three causative genes have been identified for disorders where lymphoedema is the primary phenotype; VEGFR3 in Milroy disease (Ferrell et al 1998, Irrthum et al 2000, FOXC2 for Lymphoedema distichiasis (Fang et al 2000, Bell et al 2001, Erickson et al 2001, Brice et al 2002) and mutations in SOX18 are responsible for causing the rare syndrome, hypotrichosislymphoedema-telangiectasia (Irrthum et al 2003). There are many other forms of primary lymphoedema where the genetic cause is unknown and the phenotype not well delineated.…”