The emerging genetic mosaic of lymphatic and vascular malformations

somatic mosaic mutations vascular anomalies vascular malformations CLOVES Klippel-Trenaunay KTS fibroadipose FAVA lymphatic malformation

Our genes can mutate at any point in our lives. In rare cases, a mutation randomly occurs in a single cell of an embryo and gets carried forward only in the descendants of that particular cell, leaving its mark in some tissues, but not in others. This pattern of mutation, called somatic mosaicsm, can have complicated consequences down the road.

Take CLOVES, a rare syndrome combining vascular, skin, spinal and bone or joint abnormalities described by Ahmad Alomari, MD, co-director of Boston Children’s Hospital Vascular Anomalies Center (VAC). Four years ago, a research team including Alomari and Matthew Warman, MD, discovered that the growths in CLOVES patients had mutations in a growth-regulating gene called PIK3CA. Those mutations, they found, were spread through the affected tissues in a somatic mosaic pattern.

Now it turns out that CLOVES is not alone. In a recent paper in the Journal of Pediatrics, VAC researchers led by Warman proved that three other rare lymphatic and vascular anomalies and overgrowth syndromes often share the same somatic mosaic PIK3CA mutations: Klippel-Trenaunay syndrome (KTS), fibroadipose vascular anomaly (FAVA) and isolated lymphatic malformations.

Together, CLOVES, KTS, FAVA and isolated lymphatic malformations form a kind of gradient of vascular malformations, with CLOVES having the most widespread effects. To see whether the four conditions share a common biological backbone, Warman’s team—including Alomari; VAC co-directors Steven Fishman, MD, and John Mulliken, MD; and surgical research fellow Rudy Murillo, MD—looked for PIK3CA mutations in tissues removed from patients with each condition during surgery, finding them in most of the patients studied.

“Finding somatic PIK3CA mutations in patients with KTS was less of a surprise, since this condition resembles CLOVES syndrome,” says Warman, who heads Boston Children’s Orthopedic Research Laboratories. “However, we did not expect that most lymphatic malformations would be due to mutations in PIK3CA.

“The PIK3CA signaling pathway is complex, and we thought mutations affecting other pathway members would also cause lymphatic disease,” he continues. “Yet we found that nearly all patients with isolated lymphatic malformations have the exact same PIK3CA mutations as we saw in CLOVES and KTS.”

Importantly, each condition also displayed a somatic mosaic pattern of PIK3CA mutation. The percentage of mutated cells in each patient’s tissues ranged from as little as 2 percent to as high as 60 percent.

Timing is everything

Warman thinks that the timing of when and where during embryonic development PIK3CA gets mutated may play a part in determining how it presents itself as a child develops, and how broad its effects turn out to be.

“If a mutation occurs very early on, it’s more likely to cause CLOVES syndrome,” he says. “If it occurs a little bit later, it’s more likely to be KTS. Later still, isolated lymphatic malformations or FAVA.

“This gene is remarkable in that it can create a myriad of phenotypes,” he adds.

A little could go a long way

But if only a few cells in an affected tissue are mutated, how do we explain the varying magnitude of those cells’ effects?

Warman puts forward a few possibilities, such as:

  • the interplay between the mutation and the person’s genetic background affects how the mutation’s expressed
  • the mutation is only active in the affected tissues early in development
  • the mutated cells somehow signal unmutated cells to grow abnormally as well

The key to understanding the chain from mutation to malformation—and to testing potential drug treatments capable of breaking it—will be mouse modeling, something Warman and his colleague are already working on.

Warman notes that he and his colleagues want to expand their strategy to study other conditions that might arise from somatic mosaic mutations in PIK3CA or other genes.

“For diseases we think might be caused by this mechanism, we’re continuing to sequence, looking for the causative mutations, he says. “We’ve had some success, but there’s plenty more that we’re trying to better understand.”