• cleft palate;
  • distichiasis;
  • FOXC2;
  • lymphedema

Bahuau M, Houdayer C, Tredano M, Soupre V, Couderc R, Vazquez M-P. FOXC2 truncating mutation in distichiasis, lymphedema, and cleft palate. Clin Genet 2002: 62: 470–473. © Blackwell Munksgaard, 2002

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 (lymphœdema prœcox) 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.