Lymphatic Malformation 1

A number sign (#) is used with this entry because of evidence that lymphatic malformation-1 (LMPHM1) is caused by heterozygous mutation in the FLT4 gene (136352) on chromosome 5q35. One patient with homozygous mutation in the FLT4 gene has been reported.

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).

Genetic Heterogeneity of Lymphatic Malformation

Primary lymphedema is genetically heterogeneous: see also LMPHM2 (611944), which maps to chromosome 6q16.2-q22.1; LMPHM3 (613480), caused by mutation in the GJC2 gene (608803) on chromosome 1q42; LMPHM4 (615907), caused by mutation in the VEGFC gene (601528) on chromosome 4q34; LMPHM5 (153200); LMPHM6 (616843), caused by mutation in the PIEZO1 gene (611184) on chromosome 16q24; and LMPHM7 (617300), caused by mutation in the EPHB4 gene (600011) on chromosome 7q22.

Lymphedema can also be a feature of syndromic disorders such as lymphedema-distichiasis syndrome (153400), which is caused by mutation in the FOXC2 gene (602402).

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), and lymphedema after puberty as Meige disease or lymphedema praecox (type II; see 153200). 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

Milroy (1892), a physician in Omaha, Nebraska, described the lymphedema in 6 generations of a family. Also see Milroy (1928).

Rosen et al. (1962) observed congenital chylous ascites in an affected infant whose father had recurrent swelling of the scrotum beginning at the age of 20 years. Marked loss of albumin into the intestinal tract with consequent hypoproteinemia was demonstrated.

In 2 patients, Hurwitz and Pinals (1964) observed persistent bilateral pleural effusion in which the protein content of the pleural fluid was high. Esterly (1965) described a family with 15 affected members of 3 generations. One child had striking congenital edema of the hands as a main feature and a second had similar swelling of the hands, as well as bilateral involvement of the legs and feet. A sib of the proposita had no apparent lymphedema, although 2 of his 4 children had bilateral swelling of the legs and feet. He was regarded at first as a 'skipped' generation similar to those noted in previous pedigrees of Milroy disease. Closer examination, however, demonstrated a definite 3 x 5 cm area of slight edema on the medial aspect of the left lower leg. This area was warm to the touch and could be pitted against the underlying tibia. High blood flow in the leg affected by congenital lymphedema has been thought to be due to accumulation of vasodilatory metabolites. Lymphedematous legs generally feel warm and the patients have warm feet. The proposita in the family reported by Esterly (1965) could recover the newspaper from her front walk in her bare feet in winter without discomfort. Esterly (1965) reviewed 22 previously documented pedigrees which, with his own family, gave a total of 152 affected persons.

Ferrell et al. (1998) studied 13 lymphedema families from the U.S. and Canada. All members of these families were of western European ancestry. In the 13 families, 105 individuals were classified as affected, with a male:female ratio of 1:2.3. The age of onset of lymphedema ranged from prenatal (diagnosed by ultrasound) to age 55 years. When affected x normal matings were analyzed, 76 of 191 children were affected, yielding a penetrance of 80%.

Brice et al. (2005) examined 211 individuals from 10 families with a history of congenital lymphedema and mutations in FLT4. Mutations were confirmed in 64 clinically affected individuals, and 7 clinically unaffected individuals were also found to have mutations. In all but 2 patients onset of swelling was from birth. Lymphedema was confined to the lower extremities in all patients and was associated with secondary changes including deep creases over the toes, small dysplastic ('ski jump') toenails, and papillomas. Brice et al. (2005) noted that these patients also had prominent, wide-caliber leg and foot veins not seen in other forms of congenital lymphedema. Apart from hydroceles and some urethral abnormalities, there were no major structural abnormalities or consistent dysmorphic features.

Ghalamkarpour et al. (2006) reported 3 unrelated families with autosomal dominant lymphedema confirmed by genetic analysis (see, e.g., 136352.0008-136352.0009). In 1 family, the proband had severe elephantiasis up to the inguinal ligaments bilaterally associated with chronic venous ulcerations, cellulitis, and papillomatosis. In another family, a 22-week-old fetus was found to have fetal hydrops with bilateral leg edema, pleural effusions, hydrothorax, and pulmonary hypoplasia on ultrasound. The pregnancy was terminated. Other affected family members had congenital lymphedema of the legs with variable severity. One affected member from a third family had spontaneous resolution of the edema.

Liu et al. (2012) examined 378 patients with primary lymphedema of the lower extremities using magnetic resonance lymphangiography. Defects of the inguinal lymph nodes were detected in 63 (17%) of the patients, with mild or moderate dilation of the afferent lymph vessels. Lymphatic abnormalities were present in 123 (32%) of the patients, including aplasia, hypoplasia, or hyperplasia, with no obvious defects of the drainage lymph nodes. Abnormalities of both lymph vessels and lymph nodes were observed in 192 (51%) of the patients. There was no significant difference in age at onset or severity of disease between the groups, including between patients exhibiting hypoplasia or hyperplasia.

Inheritance

Holberg et al. (2001) performed a complex segregation analysis and a genomewide search for linkage in 6 previously described families with Milroy congenital lymphedema. Results confirmed that Milroy lymphedema is generally inherited as a dominant condition, but this mode of inheritance did not account for all observed familial correlations. The authors suggested that shared environmental or additional genetic factors may also be important in explaining the observed familial aggregation.

The possibility of an autosomal recessive form of congenital lymphedema was raised by Kajii and Tsukahara (1985), who described brother and sister. The parents were not known to be related but came from an island with a population of 1,500 in the Sea of Japan. Kajii and Tsukahara (1986) cited a similar experience of brother and sister with congenital lymphedema of the lower extremities and no associated malformations.

Mapping

In linkage studies of 3 multigeneration families demonstrating hereditary lymphedema segregating as an autosomal dominant with incomplete penetrance, Ferrell et al. (1998) demonstrated a 2-point lod score of 6.1 at theta = 0.0 for marker D5S1354 and a maximum multipoint lod score of 8.8 at marker D5S1354 located at 5q34-q35. Linkage analysis in 2 additional families using markers from the linked region showed 1 family consistent with linkage to distal chromosome 5; in the second family, linkage to 5q was excluded for all markers in the region.

Evans et al. (1999) carried out a genomewide search in a 4-generation North American family with what they termed 'dominantly inherited primary congenital lymphedema.' They established linkage to markers from the 5q35.3 region in this family and in 4 additional British families. The locus appeared to be situated in the most telomeric region of 5q35.3. No recombination was observed with D5S408 (lod = 10.03) and D5S2006 (lod = 8.46), with a combined multipoint score of 16.55. Four unaffected subjects were identified as gene carriers and provided an estimated penetrance ratio of 0.84 for this disorder.

Molecular Genetics

In a family with hereditary lymphedema, Ferrell et al. (1998) identified a mutation in the FLT4 gene (136352.0005). In several families with autosomal dominant hereditary lymphedema, Karkkainen et al. (2000) identified different mutations in the FLT4 gene (see, e.g., 136352.0002).

Evans et al. (2003) identified 8 different heterozygous mutations in the FLT4 gene (see, e.g., 136352.0011) in affected members of 12 different Caucasian families with hereditary lymphedema. All the mutations occurred in the tyrosine kinase domains. Several families showed incomplete penetrance of the phenotype.

In 14 affected and 2 unaffected members of a 3-generation consanguineous Israeli family of Muslim Arab origin with hereditary lymphedema, Spiegel et al. (2006) identified heterozygosity for a missense mutation in the FLT4 gene (136352.0010). The mutation was not found in 110 control individuals. There was wide intrafamilial phenotypic variability including 2 asymptomatic individuals, a case of prenatal hydrothorax evolving to hydrops fetalis, and a late-onset complication of chronic degenerative joint disease of the knees.

Connell et al. (2009) identified mutations in the FLT4 gene, including 14 novel mutations, in 22 (42%) of 52 patients with primary lymphedema. Mutation prevalence was 75% in patients with a typical Milroy phenotype and a positive family history, and 68% if positive family history was not a diagnostic criterion. No mutations were found outside the kinase domains, showing that analysis of nonkinase domains of FLT4 is not useful for Milroy disease patients. No mutations were identified in the VEGFC gene (601528), which encodes the FLT4 ligand. The findings indicated that a positive family history is not essential in Milroy disease, and that the likelihood of detecting FLT4 mutations in patients with a phenotype not typical for Milroy disease is less than 5%.

Recessive Inheritance

Ghalamkarpour et al. (2009) studied a Hispanic female, born of first-cousin parents, who had lymphedema at birth that extended below the knees bilaterally and was accompanied by a hypoplastic fourth toe. Her parents were unaffected, and there was no family history of lymphedema. The authors identified homozygosity for a missense mutation in the ATP-binding domain of the FLT4 gene (136352.0012) in the proband; her parents were heterozygous for the hypomorphic mutation, which was not found in 110 controls. Ghalamkarpour et al. (2009) suggested that there should be large-scale screening of the FLT4 gene in all primary lymphedema patients.

Animal Model

Congenital lymphedema is autosomal dominant in the pig (Van der Putte (1978, 1978)).