FOXC2 truncating mutation in distichiasis, lymphedema, and cleft palate

Abstract

We report a family showing autosomal-dominant segregation of upper- and lower-eyelid distichiasis (double row of eyelashes) in seven affected relatives over three generations, in addition to below-knee lymphedema of pubertal onset (lymphoedema proecox) in three. Two children had cleft palate in addition to distichiasis, but without the previously reported association with the Pierre-Robin sequence. Other ophthalmologic anomalies included divergent strabismus and early-onset myopia. This family was found to be completely linked to markers mapped to 16q24.3 and thereby proposed to be allelic to the distichiasis-lymphedema syndrome (DL, MIM 153400), although pterygium colli, congenital heart disease, or facial dysmorphism were not features found here. As FOXC2/FKLH14 mutations were found to underlie DL and diverse hereditary lymphedema conditions, this gene was examined by sequence analysis. An out-of-frame deletion (914-921del) was identified and found to segregate with the disease, further highlighting the phenotypic heterogeneity of lymphedema conditions linked to FOXC2 truncating mutations. Whether such heterogeneity is related to genotype-phenotype correlation, a hypothesis not primarily supported by the apparent loss-of-function mechanism of the mutations, or governed by modifying genes, remains to be determined.

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

“…27 Cleft palate occurred in three of our patients from different families. All three had novel FOXC2 mutations and were in different domains to the mutation described by Bahau et al 27 Ptosis occurred frequently in this group of patients. This suggests another developmental role for FOXC2.…”

Orofacial clefting: recent insights into a complex trait

“…Interestingly, the distribution of mutations over the different p63 protein domains shows a clear pattern of genotype-phenotype correlation. Other notable examples of clefting syndromes that might include phenocopies of isolated clefts are X-linked cleft palate with ankyloglossia, caused by mutations in TBX22 [14,25], cleft lip and palate-ectodermal dysplasia syndrome (PVRL1) [13,26], and lymphedema-distichiasis syndrome (FOXC2) [27,28]. Other genes underlying additional clefting syndromes that are also excellent candidates for investigating the causes of isolated clefts include FOXE1 in Bamforth-Lazarus syndrome [29] and FLNA in otopalatodigital syndromes types 1 and 2 [30].…”

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).…”