FOXC2 truncating mutation in distichiasis, lymphedema, and cleft palate

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.