Ferrell et al. (2010) reported 2 unrelated families with autosomal dominant inheritance of lymphedema. In 1 family, age at onset ranged from before 1 year to 15 years. Affected individuals had onset of uncomplicated lymphedema of the lower ... Ferrell et al. (2010) reported 2 unrelated families with autosomal dominant inheritance of lymphedema. In 1 family, age at onset ranged from before 1 year to 15 years. Affected individuals had onset of uncomplicated lymphedema of the lower limbs, and some later developed upper limb involvement. Four had recurrent skin infections. In the second family, age at onset was between 10 and 21 years, and 2 patients developed cellulitis. Ostergaard et al. (2011) reported 5 unrelated families with primary lymphedema. The age of initial presentation ranged from birth to 40 years, but most had onset in the first or second decade. Severity ranged from mild swelling below the knees to severe swelling of all 4 limbs. Severely affected individuals had multiple episodes of cellulitis. Lymph scans, when performed, showed impaired lymphatic drainage consistent with distal hypoplasia of the lymphatics and variable incompetence of the great saphenous vein.
In affected members of 2 large families with autosomal dominant hereditary lymphedema type IC, Ferrell et al. (2010) identified 2 different heterozygous mutations in the GJC2 gene (608803.0009 and 608803.0010, respectively). Both mutations affected the extracellular domain. Incomplete ... In affected members of 2 large families with autosomal dominant hereditary lymphedema type IC, Ferrell et al. (2010) identified 2 different heterozygous mutations in the GJC2 gene (608803.0009 and 608803.0010, respectively). Both mutations affected the extracellular domain. Incomplete penetrance was observed. Ferrell et al. (2010) hypothesized that the mutations may result in impaired channel activity, which may cause impaired coordination of pulsatile lymphatic flow. Four additional putative mutations in the GJC2 gene were identified in 4 smaller families with lymphedema; no functional studies were performed. By linkage analysis followed by whole-exome sequencing, Ostergaard et al. (2011) identified a heterozygous mutation in the GJC2 gene (S48L; 608803.0011) in 8 affected members of a family with autosomal dominant primary lymphedema. Genetic analysis of another affected family identified the same pathogenic mutation. Further sequencing of this gene in 19 unrelated individuals with lymphedema identified 3 with mutations in the GJC2 gene, 2 of whom also carried the S48L substitution. Ostergaard et al. (2011) concluded that mutations in GJC2 are a significant cause of autosomal dominant primary lymphedema.