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.
Bahuau
M
M
Service de Biochimie et Biologie Moléculaire, Hôpital d'Enfants Armand-Trousseau, AP-HP Paris, France. assistants.bm@trs.ap-hop-paris.fr
Houdayer
C
C
Tredano
M
M
Soupre
V
V
Couderc
R
R
Vazquez
M-P
MP
D000015:Abnormalities, Multiple / Q000235:genetics*; D001483:Base Sequence; D002885:Chromosomes, Human, Pair 16; D002972:Cleft Palate / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005140:Eyelashes / Q000002:abnormalities; D005192:Family Health; D005260:Female; D051858:Forkhead Transcription Factors; D016368:Frameshift Mutation; D006801:Humans; D008209:Lymphedema / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein