Knowledge on rare diseases and orphan drugs

The true prevalence of vascular Ehlers-Danlos syndrome (vEDS) is unknown, due to underdiagnosis of both symptomatic and milder forms of the disease. Prevalence estimates range between 1/50 000 and 1/200 000.

Typical physical signs associated with vEDS are predominantly cutaneous, as easy bruising unrelated to trauma, thin translucent skin predominantly on the upper torso and abdomen, with abnormally visible veins. Wound healing may be delayed and may result in widened, papyraceous scars, particularly over prominent bony pressure points (knee). Extremities, particularly hands may appear prematurely aged (acrogeria). Characteristic facial features are prominent eyes, thin lips, sunken cheeks and a pinched nose. Hair loss, particularly notable in women may also be present. Clinical complications of vEDS typically start to occur in the late teenage years, more rarely during childhood, and may repeat at unpredictable time intervals through the entire adult life. Most common complications are arterial accidents involving medium size arteries, including dissections, aneurysms, arterial rupture and arteriovenous fistulas. Spontaneous carotid-cavernous fistula is almost pathognomic of vEDS. Digestive complications are dominated by spontaneous perforations of the sigmoid colon. Solid organ rupture as liver or spleen, may also occur. Other complications are gravid uterine rupture or arterial rupture in the peripartum period. Spontaneous, often recurrent hemo/pneumothoraces are not uncommon. Varicose veins are also commonly present in vEDS patients at a young age.

The disorder is caused by mutations in the COL3A1 gene (2q32.2), which encodes for the pro-alpha1-chains of type III procollagen.

Diagnosis is suspected on the base of physical signs and clinical complications in probands, and requires the identification of a pathogenic variant within the COL3A1 gene by molecular genetic testing (single gene testing or multigene panel including COL3A1).

Main differential diagnosis are other forms of Ehlers-Danlos syndromes, notably classical EDS (including COL1A1 variants leading to substitutions of arginine to cysteine residues in the triple helical domain), kyphoscoliotic EDS and periodontal EDS. Other rare connective tissue disorders are: Loeys-Dietz syndromes, polycystic kidney disease, and Marfan syndrome. In children with marked bruising, coagulation disorders and child abuse are sometimes considered.

Preimplantation and prenatal genetic diagnosis can be considered in families where the mutation is known.

Half of vEDS patients have inherited the pathogenic variant from an affected parent. The other half of patients have a de novo pathogenic variant, except for rare cases of parental COL3A1 somatic mosaicism. The pattern of inheritance is typically autosomal dominant, and thus there is a 50% risk of transmitting the disease to offspring. Rare cases of biallelic mutations have been reported. Therefore, genetic counseling should be offered to affected families.

Patient management requires a multidisciplinary care team, ideally in dedicated centers for vEDS patients. These centers coordinate follow-up of clinically silent patients and implement prophylactic measures. Acute onset, unexplained pain require emergency imaging by appropriate means to exclude arterial rupture. Acute arterial complications commonly require hospitalization with a conservative approach in most cases. Life-saving procedures (arterial rupture, bowel perforation, etc.) may require interventional radiology, vascular or bowel surgery. Medical management includes optimal blood pressure control to minimize arterial stress. Betablockers may be of interest in reducing arterial complications, but only one has been investigated in that indication (celiprolol). Angiotensin receptor blockers might also be beneficial and are currently being investigated.

Prognosis is variable and depends in part on the type of pathogenic COL3A1 variant. There is also an important intra- and interfamilial heterogeneity in the age of onset of complications and life expectancy for the same variant. Overall, patients with vEDS are exposed to recurrent organ complications, estimated at a rate of 1.6 events/5 years, 1.3 events/5 years for arterial complications. Overall life-expectancy is reduced to a median 51 years of age, but with an important range in age of survival for individual patients.

Last update: April 2020 - Expert reviewer(s): Dr Michael FRANK