Lymphatic Malformation 5

Description

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 the genetic heterogeneity of lymphocytic malformation, see 153100.

Nomenclature

An early classification of primary lymphedema was based on age of onset. The first descriptions of familial lymphedema were published by Milroy (1892), who described early onset of the disorder, and Meige (1898), who described onset around the time of puberty. Lymphedema of early onset became classified as Milroy disease (type I; see 153100), and lymphedema after puberty as Meige disease or lymphedema praecox (type II). However, later reports showed that lymphedema could occur with early and late onset within the same family and that the features of the disorder could vary within a family. Primary lymphedema is here classified by molecular defect and mode of inheritance.

Clinical Features

Edema, particularly severe below the waist, develops about the time of puberty. Meige (1898) described 8 cases in 4 generations without male-to-male transmission. Goodman (1962) reported the condition in 2 sisters and a brother with presumed normal parents who were not known to be related.

Herbert and Bowen (1983) described a kindred with many cases of lymphedema of postpubertal onset. Involvement of the upper limbs (as well as the lower limbs), face, and larynx and, in one, a persistent pleural effusion were notable features. Scintilymphangiography indicated paucity or absence of lymph nodes in the axillae and above the inguinal ligaments. Chronic facial swelling resulted in a characteristic appearance of affected members including puffiness, shiny skin, deep creases, and, in some, excessive wrinkling. Emerson (1966) noted similar facial features and remarked on the possible erroneous diagnosis of myxedema.

Herbert and Bowen (1983) noted the difficulties of nosology. For example, because lymphedema and yellow nail syndrome has yellow or dystrophic nails as a variable feature, this could be the same disorder. They pointed also to the association of late-onset lymphedema with deafness (Emberger et al., 1979) and with primary pulmonary hypertension and cerebrovascular malformations (152900; Avasthey and Roy, 1968).

Figueroa et al. (1983) reported the association of cleft palate. In their family, the mother, with only lymphedema praecox of the legs, gave birth to 5 sons, 3 of whom had both lymphedema of the legs and cleft palate. A mild form of lymphedema affecting mainly the medial aspect of both ankles in a 21-year-old son was pictured.

Andersson et al. (1995) described a family in which 3 individuals, a grandmother, her son and her grandson, had onset of lymphedema in their mid-twenties or thirties. The grandson was 23 years old when he had his first episode of lymphedema, which was thought to be due to thrombophlebitis. During the ensuing decade, he had episodic waxing and waning of lymphedema of both lower limbs and was treated with anticoagulant therapy. At the age of 35, he developed lymphangiosarcoma on the inner right thigh and died of metastases some months later. Lymphangiosarcoma, usually associated with postmastectomy lymphedema, had not been described previously in late-onset hereditary lymphedema. Andersson et al. (1995) raised the question of whether a genetic predisposition to malignancy combined with the lymphedema was etiologically significant. There seemed to be an unusually high frequency of cancer (uterine, colon, lung, prostate, breast, and bone) in the proband's family.

Molecular Genetics

Exclusion Studies

Finegold et al. (2001) reported a mutation in the FOXC2 gene (589insC; 602402.0007) in a family with supposed Meige lymphedema. Rezaie et al. (2008) disputed the clinical diagnosis of the family reported by Finegold et al. (2001). The family included patients with distichiasis, consistent with lymphedema-distichiasis syndrome (153400). Rezaie et al. (2008) did not identify mutations in the FOXC2 gene in 22 unrelated probands with Meige disease, i.e., lymphedema without distichiasis. One additional proband was found to carry a FOXC2 mutation, but further detailed ophthalmologic examination revealed accessory eyelashes in him and his affected family members, thus confirming the diagnosis of lymphedema-distichiasis. Rezaie et al. (2008) concluded that Meige disease is not caused by FOXC2 mutations. The authors also emphasized that the detection of distichiasis may be difficult to confirm and cannot be assumed to be absent from patient self-reports.