Malformations of vessels (veins, arteries, lymphatics) occur either singly, affecting one type of vessel (“simple” or singular malformations), or as a combination of malformations of different types of vessels (combined malformations). In addition to a vascular malformation, other anomalies may be present that are not secondary sequelae or complications of the malformation.
The diseases in which vascular malformations are regularly combined with other anomalies are grouped together as “vascular malformations associated with other anomalies”. Localized overgrowth is a typical anomaly. Therefore, these diseases belong to the group of “syndromes with localized (or: circumscribed or regional) overgrowth”.
In contrast to syndromes with generalized overgrowth, localized overgrowth never affects the entire body. Frequently, individual limbs or limb segments show increased growth, resulting in asymmetric limb overgrowth.
The reason for this is hyperplasia of supporting tissue (bones and tendons), connective tissue and/or adipose tissue. However, localized hyperplasia of the aforementioned tissues may also occur outside the extremities, for example, on the trunk. Finally, hyperplasia phenomena of the skin may be present (e.g., epidermal nevi).
The nature of the vascular malformations, characteristics of the overgrowth, and the presence of certain other abnormalities are the basis for assignment to one of the following syndromes with localized overgrowth.
From the genetic point of view, syndromes with regional overgrowth (with or without vascular involvement) are typically known as “mosaic diseases”; they are based on gene mutations that occurred only after fertilization (postzygotic) during embryonic development. As a result, the individuals concerned possess not only mutation-bearing cells but also an individually varying proportion of cells without the mutation. The mixture of cells with and without mutation is called a “genetic mosaic”. The existence of two genetically different cell clones explains the appearance of the disease in certain body regions, while other body regions are not affected. The clinical picture is essentially determined firstly by the time of the onset of the mutation in embryonic development (the earlier, the more extensive) and secondly by the cell type and the degree of differentiation of the cell in which the mutation occurred (from this follows the type of tissues involved).
A mosaic event results in enormous clinical diversity. Thus, mutations of the gene PIK3CA alone cause a whole spectrum of clinically very different phenotypes. These diseases are grouped under the umbrella term “PIK3CA-related overgrowth spectrum” (PROS). They include the overgrowth syndromes with vascular anomalies (Klippel-Trénaunay syndrome, CLOVES syndrome, CLAPO syndrome, megalencephaly-capillary malformations), but also diseases in which vascular malformations play a minor or no role (fibroadipose gigantism, hemihyperplasia-lipomatosis, isolated muscular hyperplasia, isolated macrodactyly).
The cell mosaic results in an important diagnostic feature: If one wants to detect the mutation (e.g., to confirm the diagnosis), clinically affected tissue must undergo native examination (without formalin fixation) if possible. Attempts to detect the mutation in blood are usually unsuccessful. With a few exceptions, syndromes with regional overgrowth are not hereditary, so there is no likelihood of recurrence in siblings of the patient or their offspring.
The mutations detected in affected tissues in syndromes with regional overgrowth involve genes whose proteins play a role in either the phosphatidylinositol (PI)3-kinase (PIK3)/AKT/mTOR signaling pathway, or the RAS/MAP kinase (MAPK) signaling pathway. Both signaling cascades are involved in the formation and maturation of blood vessels, among other pathways. Dysregulation, typically activating overregulation of these signaling pathways, leads to enhanced cell growth and anti-apoptosis. Overactivation can occur on the one hand by activation of the agonists (AKT1, PIK3CA, GNAQ, GNA11, RAS, RAF, MAP2K1) or, on the other hand, by inactivation of the antagonists (PTEN, RASA1).
Specific vascular malformations are characteristic of each of the syndromes with regional overgrowth. Nevertheless, there are overlaps, which is why an exact syndrome assignment is often not possible based on the vascular malformations alone.