Age of onset in hereditary lymphedema.
OBJECTIVE
To characterize age of onset patterns and penetrance in hereditary lymphedema, including differences caused by sex and genetic heterogeneity.


METHODS
Kaplan-Meier analysis of three family cohorts with autosomal dominant lymphedema: (1) five families with unique mutations in FLT4, (2) 16 families with unique mutations in FOXC2, and (3) 77 families with no mutations yet identified in any gene (the heterogeneous group).


RESULTS
Age of onset was typically congenital among FLT4 mutation families and pubertal among FOXC2 mutation families, with similar male and female penetrance in both groups. Age of onset was highly variable in the families with no identified mutation, with substantially higher penetrance among female patients than male patients. In addition, male patients and female patients in the heterogeneous group had very different overall age of onset profiles.


CONCLUSIONS
The two genes identified to date that cause hereditary lymphedema have equal male and female effects, but each displays a different pattern of onset age and penetrance. The heterogeneous group represents a genetically heterogeneous population and has phenotypic overlaps with the FLT4 and FOXC2 mutation families.
Levinson
Kara L
KL
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Feingold
Eleanor
E
Ferrell
Robert E
RE
Glover
Thomas W
TW
Traboulsi
Elias I
EI
Finegold
David N
DN
D017668:Age of Onset; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors; D006801:Humans; D008209:Lymphedema / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D019683:Penetrance; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein; D040321:Vascular Endothelial Growth Factor Receptor-3