Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations

Background-Hereditary lymphoedema-distichiasis (LD) is an autosomal dominan t disorder that classically presents as lymphoedema of the limbs, with vari able age of onset, and extra aberrant growth of eyelashes from the Meibomia n 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 finding s. Recently, we reported that truncating mutations in the forkhead transcri ption family member FOXC2 resulted in LD in two families. Methods-The clinical findings in seven additional families with LD, includi ng 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 d ependent lymphoedema. There is a wide variation of associated secondary fea tures including tetralogy of Fallot and cleft palate. The mutational analys es identified truncating mutations in all of the families studied (two nons ense, one deletion, three insertion, and one insertion-deletion), which mos t likely result in haploinsufficiency of FOXC2. Conclusions-FOXC2 mutations are highly penetrant with variable expressivity which is not explicable by the pattern of mutations.