Milroy (1892), a physician in Omaha, Nebraska, described the disorder 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 ... Milroy (1892), a physician in Omaha, Nebraska, described the disorder 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.
In a family with hereditary lymphedema, Ferrell et al. (1998) identified a mutation in the FLT4 gene (136352.0001). In several families with autosomal dominant hereditary lymphedema, Karkkainen et al. (2000) identified different mutations in the FLT4 gene (see, ... In a family with hereditary lymphedema, Ferrell et al. (1998) identified a mutation in the FLT4 gene (136352.0001). 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.