Objective: To characterize age of onset patterns and penetrance in hereditary lymphedema, including differences caused by sex and genetic heterogeneity.
Study design: 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.