Hello All,
Thanks for all your replies. I’ve had a busy week so I’m just now able to respond to all of you.
Thank you both for the kind welcome.
I’ve been researching vascular malformations for a few years now. I’ve read pretty much every relevant published paper on the topic and I have a science background which has helped in digesting and making sense of the information. I’m not a doctor, but I think I have a fairly good understanding of the underpinnings of these groups of genetic diseases.
Phleboliths are calcified blood clots. They are typical in low-flow vascular malformations called venous malformations (which are purely venous, as opposed to arteriovenous). They occur due to stagnant blood pooling in the malformed venous channels which results in thrombosis. Symptoms are more typical in winter months when blood circulation slows at the extremities due to higher blood viscosity from lower external temperatures. Since AVM’s are high-flow malformations, this is less of a concern.
Thanks for your reply. I am being seen by an interdisciplinary team which specializes in interventional radiology for venous and arterialvenous malformations. My condition is the former, purely venous. It presents as a focal bluish superficial lesion on the skin and extends into my butt cheek, however it is not particularly diffuse but more well-defined with large venous channels. It’s more localized and does not involve any of the major veins in my circulatory system. In MRI, it’s shown as having well defined boundaries with a small diffused section running down my buttcheeck near my sphincter, which causes my bowel problems. It has not been formerly classified, however I believe it’s close to a Grade 2A which is well defined, >5cm diameter.
With regards to inhibitors, I have read extensively about the pathways associated with malformations. The proper umbrella term for our conditions is congenital overgrowth syndromes. There are two genetic pathways primarily associated with overgrowth syndromes. The mTOR pathway and the MAPK1 pathway. You can see these pathways here https://imgur.com/orIJCXY. Both of these pathways regulate cell transcription. In purely venous malformations (VMs), the genetic pathway is associated with the mTOR (mechanistic target of rapamycin) complex. People with VMs (like myself) can have one of two mutations:
- A somatic mutation in the TEK gene which encodes the tyrosine kinase receptor TIE2 which affects the PI3K/AKT signaling pathway (this is the most common mutation in unifocal malformations);
- A somatic mutation in PIK3CA itself (which is more downstream from TEK). Some people with a mutation in PIK3CA can be grouped into a disease spectrum called PIK3CA-related overgrowth spectrum (PROS). There are many disorders under PROS which include: CLOVES, Klippel-Trenaunay syndrome (KTS), and Lymphatic Malformations (LM).
In both cases, the underlying mechanism of overgrowth is due to a high gain feedback-loop in the PI3K/AKT pathway which is associated with mTOR. This pathway is very interesting. mTOR is called a growth signalling molecule. It sits in the lysosome of cells and waits for signals from the body to begin the growth process. When people eat: proteins, nutrients and hormones (like insulin) pass into the cells and ‘turn on’ mTOR which tells the body to begin using energy for growth. When people fast (long periods of time without food) the body shuts down mTOR and begins the process of autophagy (cell death) in order to consume itself for energy. In venous malformations, this process is always turned on in the malformed cells. This is why malformations have growth spurts during periods of development (such as puberty or during pregnancy) because the body is flooded with growth signaling hormones.
Rapamycin (sirolimus) can prevent the growth during these stages, however it has a smaller effect on malformations that have already grown. It does provide some relief here, but not nearly as much as in these growth stages. However it’s being shown that Rapamycin + Ponatinib can cause regression in already developed venous malformations, so there is some hope that in the future people will be able to take these drugs and reduce the size of their malformations without sclerotherapy. The nice thing about these drugs is that a small amount can have a profound impact on the signaling pathway while leaving healthy cells mostly untouched.
As for arteriovenous malformations (AVM) they involve a different genetic pathway. AVM’s typically have one of two mutations:
- somatic mutation in the Mitogen Activated Protein Kinase (MAP2K1) gene which encodes extracellular signal-regulated kinase 1 (MEK1). This gene, MAP2K1, is also associated with growth factor signaling in the cells. It is part of the MAPK/ERK pathway, which acts as an on/off switch in protein signaling during growth. Similarly to mTOR, this gene is associated with cell transcription and regulation of cells. When this gene malfunctions due to a mutation, it causes overgrowth, particularly in the connections between arteries and veins.
- Somatic mutation in HRAS, KRAS or BRAF. These genes are found downstream in the MAPK/ERK pathway. This is analogous to PI3KCA mutations in venous malformations. It’s located more downstream from MAP2K1, but in both cases you have the same general phenotype of overgrowth (physical appearance).
Sometimes VMs have mutations in MAP2K1, and sometimes AVMs have them in TEK, so it’s not a hard rule. Although, all congenital non-familial malformations have the same characteristics. They have a somatic (single) mutation in a gene pathway associated with growth that causes the pathway to be always turned ‘on’, despite a lack of signals from the body.
You’re born with these mutations, so they don’t just arise from chance later in life (as far as I know). When they arise later in life, we call them cancer. This is why cancer drugs are also effective on malformations; because they are both caused by the same pathway. So people with AVMs have always had them, they just present with symptoms at different times, or not at all if it’s minor. If you have one mutation somewhere in your tissue (brain, or elsewhere), it’s not likely that you have any more unless you’re very unlucky, or you have a familial gene mutation which is associated with a broader disorder. In both of our cases, it sounds like we just got unlucky with one mutation in one part of our bodies. Since you have an AVM/VM, it’s very likely that you have a mutation in MAP2K1 rather than in TEK (mTOR).
I’ve done a lot of research so I just wanted to share, especially to the people lurking these forums looking for answers. hope that sheds some light on how this destructive disease is caused. The good news is that both mTOR and MEK inhibitors will work at reducing the size of the malformation. I don’t know about MEK inhibitors, but mTOR inhibitors generally don’t cause too many side-effects and if they do, they are totally reversible when you stop taking them. Luckily for me, my VM is smaller therefore using inhibitors is probably overkill.
Unforunately, I cant wear compressive stockings because of the location of my VM. Whenever I sit, it kind of acts like a compressive stocking because it compresses the VM. Once I stand, the blood begins to pool in the VM and it enlarges. However I have decided to go ahead with sclerotherapy, so I’ll update this post post-treatment to let you know how it went.