Klippel-Trénaunay syndrome (KTS) is characterized by the combination of capillary, venous, and lymphatic malformations (the latter predominantly as lymphedema, more rarely microcystic or macrocystic) with an ipsilateral circumscribed overgrowth usually of a lower extremity. Unfortunately, this syndrome designation is often used very vaguely for all other possible combinations of vascular malformations and circumscribed overgrowth. If there is uncertainty regarding the classification, it is better to describe the exact malformations that are present in the patient (e.g., combined capillary-venous malformation with limb hyperplasia).
Klippel-Trénaunay syndrome occurs sporadically (not familial). It is based on a genetic mosaic. In at least some patients, somatic (present only in affected tissues) gain-of-function mutations have been detected in the PIK3CA oncogene, which encodes the catalytic alpha subunit of phosphatidylinositol 3-kinase (PI3K). PI3K activation causes overactivation of the PI3K (phosphatidylinositol 3-kinase)/AKT/mTOR pathway (with the consequences of enhanced cell growth and anti-apoptosis). In addition, sequence variants of the gene AGGF1, which encodes an angiogenic factor, have been identified as a predisposing factor.
Regional overgrowth, especially of adipose tissue and bone, usually affects one limb or parts of it. The legs are much more commonly affected than the arms. There is bilateral occurrence in approximately 15%.
Capillary malformations (CM) appear on the skin as nevi flammei. These are light red to dark purple in color, highly variable in size, and irregularly contoured. They often appear on the lateral aspect of the leg.
Venous malformations (VM) often present as varicose tubular subcutaneous venous convolutes. The characteristic picture is of an atypical “marginal vein” localized to the outside of the leg (because of persistence of the embryonic marginal fibular vein), often combined with hypoplasia or aplasia of the deep conducting venous system of the affected limb.
Lymphatic malformation (LM) manifests predominantly as circumscribed lymphedema of the affected limb. Circumscribed microcystic and/or macrocystic lymphatic malformations also occur. A very typical appearance in KTS is a large combined capillary-veno-lymphatic malformation located laterally on the limb with multiple stipple-like lymphatic vesicles forming on it in the manner of small petechiae. Lymph (also admixed with some blood) can ooze from these lymphatic vesicles.