Capillary malformations, from genotype to phenotype: a focus on endothelial function

Capillary malformations, also known as port wine stains (PWSs), are vascular
lesions affecting the dermis and are present at birth. They are characterized
by hyperdilated capillaries and post-capillary venules. These congenital
lesions occur in 0.04-2.1% of newborns and frequently appear as flat, pink
macules that slowly evolve into more hypertrophic, red-to purple lesions. About
two-thirds of the patients develop nodular or papular-like elements as a result
of soft tissue overgrowth, leading to asymmetry, dysmorphosis, and possibly
sporadic spontaneous bleeding. The stigma of a disfiguring capillary
malformation can cause significant psychological burden and a decreased quality
of life, especially when located in the face. PWSs can be part of a syndrome,
such as the Sturge Weber syndrome and Klippel Trenaunay syndrome. Affected
patients show solitary PWSs, or PWSs together with various symptoms, ranging
from bone and soft tissue overgrowth to glaucoma and epilepsy due to
leptomeningeal angiomatosis.

Up till now, the exact pathogenesis of PWSs is still unclear. Though, they have
been linked to somatic mosaic mutations in specific G-proteins and the P110
alpha protein. Recurrent somatic variants have been uncovered in the Guanine
nucleotide-binding protein G(q) subunit alpha (GNAQ) gene, the Guanine
nucleotide-binding protein subunit alpha-11 (GNA11) gene and the
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)
gene of patients with PWSs. These proteins can be found in endothelial cells
and due to the abovementioned mutations, the proteins do not function properly.
The genetic changes lead directly to altered endothelial cell proliferation,
differentiation, and survival. Uncontrolled angiogenesis because of increased
endothelial cell proliferation results in PWSs, with tangling of the
capillaries in the dermis of the skin and in the brain.

When looking at a cellular level, PWSs seem to demonstrate hyperactive and
hyperproliferative endothelial cells, enlarged vessel lumens and disorganized
perivascular cells. But, it is still unclear how the genetic mutation relates
to differences in endothelial function and characteristics of the PWS, such as
hypertrophy.

Currently, no cure has been found yet for PWSs and treatment outcomes are still
far from optimal.Treatment is hence mostly focused on refraining symptoms.
Also, there is a large variation in treatment response that is difficult for
physicians to predict. Theoretically, this variation in response could be the
due to abovementioned genetic mosaic mutations. Over the last years, there has
been an increased interest in the complex interactions between the genetic
alterations and the phenotypic characteristics of PWSs. Unravelling the role of
the genetic mutations will not only lead to new insights on the origin of PWSs,
but may possibly also lead to a better understanding on why certain PWSs do not
respond properly to modern therapies. In this way, new therapeutic strategies
could be designed, mostly based on molecular analysis. Identifying the effector
pathways of the genes that underlie PWS formation will allow for the
development of more specific targeted therapies to approach their treatment. It
may be a new path towards personalized medicine.

We aim to provide preliminary information on the presence of GNAQ, GNA11, RASA1
or PIK3CA gene mutations, assess the endothelial cell properties and compare it
to the phenotypic characteristics of the PWSs of affected patients. This will
lead to a more comprehensive framework by which PWSs can be classified and
managed.

The study design will be a prospective case series. It will be a mono-center
study, carried out at the department of dermatology at the Amsterdam UMC
location AMC. The study is expected to take 6-12 months as we intend to include
20 participants.
Approximately 8 patients with port wine stains visit the outpatient clinic per
week at the department of Dermatology in the Amsterdam UMC.

The study subjects will undergo two skin biopsies during their regular laser
treatment. These skin biopsies are <4 mm, therefore the skin is likely to cure
on its own. If the skin biopsy wound keeps bleeding after applying firm
pressure during 10 minutes, the wound will be closed with Dermabond skin glue
or one non-resorbable suture. There are relatively small risks with
participation: a small risk on prolonged bleeding of the wound and a small risk
on skin infection.