Update and audit of the St George’s classification algorithm of primary lymphatic anomalies: a clinical and molecular approach to diagnosis

Abstract

<jats:p>Primary lymphatic anomalies may present in a myriad of ways and are highly heterogenous. Careful consideration of the presentation can lead to an accurate clinical and/or molecular diagnosis which will assist with management. The most common presentation is lymphoedema, swelling resulting from failure of the peripheral lymphatic system. However, there may be internal lymphatic dysfunction, for example, chylous reflux, or lymphatic malformations, including the thorax or abdomen. A number of causal germline or postzygotic gene mutations have been discovered. Some through careful phenotyping and categorisation of the patients based on the St George’s classification pathway/algorithm. The St George’s classification algorithm is aimed at providing an accurate diagnosis for patients with lymphoedema based on age of onset, areas affected by swelling and associated clinical features. This has enabled the identification of new causative genes. This update brings the classification of primary lymphatic disorders in line with the International Society for the Study of Vascular Anomalies 2018 classification for vascular anomalies. The St George’s algorithm considers combined vascular malformations and primary lymphatic anomalies. It divides the types of primary lymphatic anomalies into lymphatic malformations and primary lymphoedema. It further divides the primary lymphoedema into syndromic, generalised lymphatic dysplasia with internal/systemic involvement, congenital-onset lymphoedema and late-onset lymphoedema. An audit and update of the algorithm has revealed where new genes have been discovered and that a molecular diagnosis was possible in 26% of all patients overall and 41% of those tested.</jats:p>

Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs

“…The latter makes them more challenging to identify since the genetic lesion might be present only in a subset of cells or organs [ 129 ]. For roughly 40% of primary lymphedema cases, the underlying genetic lesion can be identified, and a clinical guide for this process has been established [ 130 ]. However, secondary lymphedema also has a genetic component [ 131 , 132 , 133 ], and thus, primary and secondary lymphedema should be considered the endpoints of a continuous spectrum.…”

Sex Hormones in Lymphedema

“…Recently, the St George’s classification algorithm has provided an accurate diagnosis for patients with lymphoedema based on age of onset, areas affected by swelling, and associated clinical features. Therefore, primary lymphedema can be divided in two subgroups including congenital onset (<1 year) and late onset (>1 year) [ 58 ]. Congenital onset is characterized by congenital unisegmental edema, lower limb lymphedema, and lower limb/genital edema.…”

“…The late onset lymphedema is mainly associated with distichiasis syndrome (FOXC2 mutation). If not, it has to be classified into four-limbs or lower limbs only lymphedema [ 58 ]. Sexual differences are sharp in this pathology as primary lymphedema, and particularly late onset ones, develop preferentially in women with an average women to men ratio of 3:1 [ 59 ].…”

Genetik und Diagnostik des primären Lymphödems

“…Ist diese gestört, kommt es durch Fehlbildung oder Fehlfunktion der Lymphgefäße oder -klappen zum Lymphödem [3]. Entsprechende Krankheitsbilder lassen sich einer der verbliebenen 4 Kategorien zuteilen [11]. Zur ersten Kategorie des primären Lymphödems, den syndromalen Erkrankungen, zählen vorrangig Erkrankungen, bei denen das primäre Lymphödem zwar typischerweise auftritt, aber nicht dominierendes Merkmal ist [10].…”