Lymphatic Malformation 4

A number sign (#) is used with this entry because of evidence that lymphatic malformation-4 (LMPHM4) is caused by heterozygous mutation in the VEGFC gene (601528) on chromosome 4q34.

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

Clinical Features

Gordon et al. (2013) reported a 3-generation Caucasian family in which 7 individuals had lymphedema affecting the lower limbs. The adult proband and his adult sister had congenital lymphedema of the feet and ankles, which in the sister alternately improved and deteriorated over time. Both had below-the-knee lymphedema; the sister also had prominent veins around the ankles and on the dorsa of the feet. Other affected family members had variable expression of congenital or early-onset leg swelling, and/or prominent veins in the lower limbs. One patient had a hydrocele. Four affected adults who underwent lymphoscintigraphy were found to have reduced lymphatic uptake and tortuous lymphatic routes, with evidence of rerouting that corresponded to the affected areas on clinical examination. Skin changes over the affected areas included hyperkeratosis, papillomatosis, and fibrosis, with occasional cellulitis.

Balboa-Beltran et al. (2014) reported a Caucasian family in which a girl, her father, and her paternal grandmother all had primary lymphedema. The proband presented at birth with asymmetric lymphedema affecting the lower limbs. Other features included upslanting and dysplastic toenails, deep toes creases, papillomas over the affected area, and cellulitis. The father and paternal grandmother had similar features, although the onset in the grandmother occurred later, in adulthood. Lymphoscintigraphy in the father showed asymmetric impaired lymph drainage in the affected area. The grandmother reported history of the disorder in prior generations.

Inheritance

The transmission pattern of LMPHM4 in the family reported by Gordon et al. (2013) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of a family with primary lymphedema, Gordon et al. (2013) identified a heterozygous truncating mutation in the VEGFC gene (c.571insTT; 601528.0001). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. In vitro functional cellular expression assays and studies in zebrafish showed that the mutation resulted in a loss of function without a dominant-negative effect, consistent with haploinsufficiency. Screening the VEGFC gene in 16 additional patients with a similar phenotype did not identify any mutations.

In 3 members of a 3-generation Caucasian family with LMPHM4, Balboa-Beltran et al. (2014) identified a heterozygous truncating mutation in the VEGFC gene (R210X; 601528.0002). The mutation, which was found by exome sequencing, segregated with the disorder in the family. Functional studies were not performed.