Vascular Ehlers-Danlos syndrome: From rupture to rapture?

By Warren R. Heymann, MD, FAAD
February 16, 2022
Vol. 4, No. 7

If there was a statistic for a dermatological diagnostic impact factor, vascular Ehlers-Danlos syndrome (vEDS) would be at the top. Often undiagnosed until tragedy strikes, astute dermatologists who consider the diagnosis prior to an acute event may save a life if that patient is proven to have the disease.

vEDS (formerly “type IV” EDS, OMIM 130050) is characterized by the major complications of arterial and bowel rupture, uterine rupture during pregnancy, and the clinical features of easy bruising, thin skin, and visible veins. Joint hypermobility is largely limited to the digits, and skin hyperextensibility is minimal or absent. (1) Two phenotypes have been described — the acrogeric type and the ecchymotic type. Characteristic facies with an emaciated appearance displaying prominent cheek bones and sunken cheeks, sunken or bulging eyes, eyelid telangiectasias, a pinched and thin nose, and thin lips (particularly the upper lip whose edges are undefined) is the hallmark of acrogeric variant of vEDS. One-fourth of individuals with vEDS experience a significant complication by the age of 20 years and 80% by the age of 40 years. (2) vEDS remains a rare subtype of EDS, with an estimated prevalence of 1:90,000. Life expectancy is estimated to be 51 years of age (range 6–80 years), with the diagnosis occurring around 28 years. The median life expectancy of patients with vEDS is less for men at 46 years compared to women at 54 years. (3)

vEDS is inherited in an autosomal dominant pattern. (4) According to Benrashid and Ohman: “Most frequently, heterozygous mutations in the COL3A1 allele are responsible for vEDS, the gene responsible for type III collagen synthesis. These mutations are typically glycine substitutions (point mutations), which alter the triple helical structure of collagen and prevent its secretion to the extracellular environment, as it is degraded in the endoplasmic reticulum. Type III collagen has also been shown to have a regulatory role in the secretion of fibrils containing type I collagen, along with decreases in expression of the essential extracellular matrix (ECM) component, fibrillin. Infrequently, a heterozygous defect resulting in an arginine-cysteine substitution in the COL1A1 gene (type I collagen; most commonly responsible for the arthrochalastic variant of EDS) can result in vEDS-type phenotypes. There is marked heterogeneity among disease causing mutations, and a corresponding difference in natural history and clinical outcomes. This holds true for variants with haploinsufficiency, who present a decade older, with higher rates of aortic pathology and lower rates of visceral arterial pathology. Downstream phenotypic effects of mutations in COL3A1 result in abnormal protein folding, perturbations in "normal" ECM remodeling, lack of tensile strength in affected tissues, fibroblast malfunction, and early apoptosis.” (3)

Understanding the pathogenesis of vEDS should ultimately lead to targeted therapy. Currently, a multidisciplinary approach involving dermatologists, cardiologists, obstetricians, orthopedists, vascular surgeons, geneticists, and others is most appropriate. (4) General principles of avoiding trauma (such as contact sports) and anticoagulation are important. Maintaining normal blood pressure is essential. Beta-blockade is used off-label; although patients treated with celiprolol had better survival in a retrospective study (5), the FDA denied an NDA, calling for an “adequate and well-controlled” trial to determine whether celiprolol reduces the risk of clinical events in patients with vEDS. (6) Endovascular surgery (angioplasty, stents, stent-assisted coiling) may be indicated in some cases. (7)

Bowen et al created 2 mouse models of vEDS carrying heterozygous mutations in Col3a1 encoding glycine substitutions analogous to those found in patients. The authors demonstrated that signaling abnormalities in the PLC/IP3/PKC/ERK pathway (phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal-regulated kinase) are major mediators of vascular pathology. Treatment with pharmacologic inhibitors of ERK1/2 or PKCβ prevented death due to spontaneous aortic rupture. They also found that pregnancy- and puberty-associated accentuation of vascular risk, also seen in vEDS patients, was rescued by attenuation of oxytocin and androgen signaling, respectively. This suggests that drugs like spironolactone may be of value in vEDS. The authors concluded that these results provide evidence that targetable signaling abnormalities contribute to the pathogenesis of vEDS, highlighting unanticipated therapeutic opportunities. (8) Enzastaurin is an orally administered drug initially developed as an isozyme-specific inhibitor of protein kinase Cβ (PKCβ), which is involved in both the AKT and MAPK signaling pathways that are active in many malignancies. The drug may also prevent angiogenesis, inhibit proliferation, and induce apoptosis. (9) Aytu Biopharma currently has an exclusive worldwide license to investigate enzastaurin for vEDS. (10)

In conclusion, although rare, dermatologists should be familiar with the cutaneous features of vEDS and refer suspect patients and their families for appropriate evaluation and management. Although no specific anti-vEDS therapy currently exists, early recognition and careful surveillance and management can prolong life. Should novel molecular findings and targeted therapies prove beneficial, vEDS patients could shift from rupture to rapture.

Point to Remember: Vascular Ehlers-Danlos syndrome is a life-threatening disease that mandates early recognition and multidisciplinary management. Research exploring abnormalities in the PLC/IP3/PKC/ERK pathway suggests that novel treatments such as the protein kinase Cβ inhibitor enzastaurin could potentially be therapeutic.

Our expert’s viewpoint

Jonathan A. Dyer, MD, FAAD
Professor, Dermatology
Director, Pediatric Dermatology
Chair, Department of Dermatology
University of Missouri School of Medicine

The recent announcement of a clinical trial for a potential treatment for vascular Ehlers-Danlos syndrome (vEDS) was incredibly exciting. Such pathomechanistic-based therapies are very promising — whether this agent is genuinely effective, or another medication proves to be superior in the future, I have no doubt that we will soon see therapeutic interventions that alter the outcomes of these devastating and unpredictable diseases.

vEDS is an autosomal dominant disorder caused by mutations in COL3A1 which produces type III collagen, a critical component of the connective tissue of large vessels and hollow organs. The incidence of vEDS is 1:50,000 to 1:200,000 live births, although there are many people unaware if they have the condition. About 50% of cases are de novo, so there is no family history to raise concern. Defective type III collagen leads to weakening of these tissues over time which can lead to catastrophic vascular or organ rupture causing significant morbidity or sudden death. Affected patients may develop arterial aneurysms, dissections, or ruptures which can happen without warning. Ruptures of the bowel, or of the uterus in pregnant vEDS patients, are additional complications, and the delicate tissues of these patients present greater surgical challenges. There is a 5% mortality risk for female patients with each pregnancy. Patients with vEDS have shortened life spans, with median life span currently ~50 years (somewhat determined by the specific COL3A1 mutation).

The clinical findings of vEDS can be subtle and patients are often not diagnosed until a major health event occurs. The announcement by Aytu BioPharma beginning trials of a new drug for vEDS highlights the powerful interventions that can result from a better pathomechanistic understanding of genetic conditions. For many years it was believed that the defects in type III collagen created a simple structural weakness in the connective tissues of vessels and organs of affected patients. However, this did not explain why patients typically do not exhibit disease-related complications until young adulthood. With further investigation it has become clear that the type III collagen mutations initiate a much more complex cascade of events that lead to gradual structural weakening of large vessels and organs. Mouse models of vEDS showed abnormal signaling through the PLC/IP3/PKC/ERK pathway (phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal-regulated kinase). These changes directly triggered the progression of the vascular changes. Importantly, blocking these impacts with ERK1/2 or PKCb inhibitors such as enzastaurin prevented death from spontaneous aortic rupture in the animal models. The authors also noted that pregnancy- and puberty-associated increases in risk of vascular complications could be modified through modulating oxytocin and androgen signaling, identifying yet more therapeutic targets for vEDS. (8)

Fortunately, PKC inhibitors have been utilized in oncology for some time, for thousands of patients with many different malignancies. The current trial is investigating the impact of enzastaurin in vEDS patients. Enzastaurin is an orally available inhibitor of PKC beta, PI3K, and AKT pathways. Results from animal studies have been encouraging and a trial in humans was a logical next step.

As a dermatologist with an interest in these conditions, trials such as this confirm the promise and power of understanding the pathomechanistic underpinnings of genetic conditions. Many years ago, when I was starting in the field, we were excited as the genetic causes of different conditions were being elucidated. However just knowing the gene and the mutation did not lead to interventions that impacted our patients. It has taken much more investigation to understand that these genetic changes do not occur in a vacuum. They often lead to an enormous number of downstream effects which are often the arbiter of the subsequent disease pathology. One of the early studies demonstrating the power of this pathomechanistic approach was the discovery that topical Lovastatin/cholesterol could reverse the previously untreatable skin findings in CHILD syndrome by Paller et al. (11)

Often the involved downstream pathways are targetable and molecules targeting these pathways already exist, having been developed in oncology. In many cases they may have already been tested, or even approved, for use in humans. We are finally seeing the promise of greater understanding of these conditions lead to clinical improvements. It is a very exciting time in inherited skin and connective tissue diseases.

What is our role in all of this? Being aware of vEDS and thinking about it is paramount. There are many patients with variants of vEDS who are unaware that they have it. Affected patients may have characteristic facies (thin vermilion of lips, micrognathia, narrow nose, prominent eyes), thin translucent skin, and easy bruising. Acrogeria, an aged appearance of the extremities (especially the hands) can be another early finding. Prior to a major vascular event, the clinical findings in children are subtle and include distal joint hypermobility, easy bruising, thin skin, and clubfeet.

It is getting easier to obtain genetic testing on suspected or at-risk patients. If you have patients with vEDS, recommending patient support groups such as The Ehlers-Danlos Society can connect them with a community of patients and families dealing with similar conditions, provide them with information, or connect them with trials. For vEDS patients it is also important to help them create a team of providers with understanding and expertise (or willingness to learn about) vEDS. It is essential that care be coordinated, so that in the event of an emergency, patients can rapidly get to a center with experience dealing with vEDS.

1. https://omim.org/entry/130050 (accessed May 1, 2021).

2. Sharma NL, Mahajan VK, Gupta N, Ranjan N, Lath A. Ehlers-Danlos syndrome--vascular type (ecchymotic variant): cutaneous and dermatopathologic features. J Cutan Pathol. 2009 Apr;36(4):486-92.

3. Benrashid E, Ohman JW. Current management of the vascular subtype of Ehlers-Danlos syndrome. Curr Opin Cardiol. 2020 Nov;35(6):603-609.

4. Miklovic T, Sieg VC. Ehlers Danlos Syndrome. 2020 Jul 10. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 31747221.

5. Frank M, Adham S, Seigle S, Legrand A, Mirault T, Henneton P, Albuisson J, Denarié N, Mazzella JM, Mousseaux E, Messas E, Boutouyrie P, Jeunemaitre X. Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study. J Am Coll Cardiol. 2019 Apr 23;73(15):1948-1957.

6. https://www.hcplive.com/view/fda-denies-nda-for-celiprolol (accessed May 1, 2021).

7. Li X, Chen G. Successful endovascular treatment of multiple systemic aneurysms in a patient with vascular Ehlers-Danlos syndrome. Clin Res Cardiol. 2020 Nov;109(11):1434-1437.

8. Bowen CJ, Calderón Giadrosic JF, Burger Z, Rykiel G, Davis EC, Helmers MR, Benke K, Gallo MacFarlane E, Dietz HC. Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome. J Clin Invest. 2020 Feb 3;130(2):686-698.

9. Bourhill T, Narendran A, Johnston RN. Enzastaurin: A lesson in drug development. Crit Rev Oncol Hematol. 2017 Apr;112:72-79.

10. https://www.prnewswire.com/news-releases/denovos-licenses-db102-enzastaurin-for-rare-genetic-pediatric-onset-disorders-to-aytu-biopharma-301267471.html (accessed May 1, 2021).

11. Paller AS, van Steensel MA, Rodriguez-Martín M, Sorrell J, Heath C, Crumrine D, van Geel M, Cabrera AN, Elias PM. Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism. J Invest Dermatol. 2011 Nov;131(11):2242-8. doi: 10.1038/jid.2011.189. Epub 2011 Jul 14. PMID: 21753784; PMCID: PMC3193573.

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