Lymphatic Malformation 2

Description

Hereditary primary lymphedema is caused by anatomic or functional defects in the lymphatic system, resulting in chronic swelling of body parts. There may be accompanying nail and skin changes, such as nail dysplasia or papillomatosis. Onset is usually at birth or in early childhood but can occur later, and the severity is variable (summary by Gordon et al., 2013 and Balboa-Beltran et al., 2014).

For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.

Clinical Features

Malik and Grzeschik (2008) reported a large consanguineous Pakistani family in which 25 individuals spanning 5 generations had lymphedema confined to the lower limbs. Despite consanguinity, detailed pedigree analysis indicated autosomal dominant inheritance with reduced penetrance. Onset occurred in early childhood and showed maximum manifestations at puberty. The phenotype was variable, ranging from swelling of a foot to severe bilateral lymphedema of the lower legs below the knee. Some, but not all, patients had papillomatosis over the affected areas. Swelling began to subside by age 30 years and became unremarkable in the following 12 to 15 years. The phenotype was similar to that seen in hereditary lymphedema type 1 (LMPHM1; 153100).

Mapping

By genomewide linkage analysis of a large Pakistani family with lymphedema, Malik and Grzeschik (2008) identified a candidate locus on chromosome 6q16.2-q22.1 (maximum 2-point lod score of 3.19 at D6S1671; multipoint lod score of 3.75 at 108 cM). Haplotype analysis delineated a 17.26-cM interval between D6S1716 and D6S303. Genetic analysis excluded mutations in the FOXO3A gene (602681).