A new classification system for primary lymphatic dysplasias based on phenotype

Abstract

Traditional classification systems for lymphoedema are of limited use for the diagnosis of specific forms of primary lymphoedema. The understanding of primary lymphoedema has been impeded by confusing terminology and a tendency to simply divide patients into three categories based on the age of onset: lymphoedema congenita manifests at or shortly after birth, lymphoedema praecox is apparent before the age of 35 years and lymphoedema tarda manifests thereafter. The clinical presentation in the spectrum of primary lymphoedema disorders is very variable; the phenotypes of primary lymphoedema conditions vary in the age of onset, site of the oedema, inheritance patterns, associated features and genetic causes. Different inheritance patterns are recognised and there are numerous associated anomalies. Some subgroups, such as Milroy disease and Lymphoedema distichiasis, are well characterised, but others are not. A new clinical classification for primary lymphoedema has been developed as a diagnostic algorithm. Its use is demonstrated on 333 probands referred to our lymphoedema clinic. Grouping patients by accurate phenotyping facilitates molecular investigations, understanding of inheritance patterns, and the natural history of different types of primary lymphoedema. Descriptions of the diagnostic categories, some of which have not been previously clearly defined as distinct clinical entities, are illustrated by clinical cases.

Primary Lymphedema: Clinical Features and Management in 138 Pediatric Patients

“…51,52 A mutation in VEGFR3 is found in 75 percent of children with familial lower extremity lymphedema at birth, compared with 68 percent of infants with a similar presentation without a family history. 20,53 Consequently, the term "Milroy disease" should be restricted to infants with lower extremity lymphedema (unilateral or bilateral) present at birth with either (1) a positive family history or (2) a mutation in VEGFR3 (regardless of family history). 20,52,53 Because our patients did not undergo genetic screening for VEGFR3 mutations, Milroy disease may have been underdiagnosed.…”

“…20,53 Consequently, the term "Milroy disease" should be restricted to infants with lower extremity lymphedema (unilateral or bilateral) present at birth with either (1) a positive family history or (2) a mutation in VEGFR3 (regardless of family history). 20,52,53 Because our patients did not undergo genetic screening for VEGFR3 mutations, Milroy disease may have been underdiagnosed. Children with nonfamilial lower extremity swelling at birth whose test results for a VEGFR3 mutation are negative should not be labeled as having Milroy disease.…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…Luckily, several attempts have been made to establish new classifications and categorizations of primary lymphedema based on clinical phenotypes, familiar history, onset age, associated abnormalities, local and systemic involvement, and underlying genetics (Szuba and Rockson 1998;Miller et al 1999;Board and Harlow 2002;Northup et al 2003;Honnor 2008;Connell et al 2010). …”

Congenital multisegmental lymphatic dysplasia with systemic involvement: a case report

“…Data on the prevalence of PLD are limited; it has an estimated prevalence of one in 6000 individuals in the general population based on Dale's report in 1985(Dale, 1985. To our knowledge, there are only 15 cases of MLDSI in the literature (Connell et al, 2010;Ozyurt et al, 2014).…”