Ehlers-Danlos syndrome refers to a group of inherited conditions that affect the structure and function of connective tissues. Ehlers-Danlos syndrome type 4 (EDS4) accounts for about 5% of all cases and is characterized by anomalies of collagen type III, which predispose to spontaneous arterial rupture. It's due to this life-threatening complication that EDS4 is also referred to as malignant Ehlers-Danlos syndrome. Another designation is vascular Ehlers-Danlos syndrome, but the clinical presentation is not limited to arterial disease: EDS4 is also associated with an increased risk of hollow organ perforation as well as mildly hyperextensible, very thin skin and focal hypermobility of the joints.
The most severe manifestations of EDS4 involve the arteries and hollow organs. Unfortunately though, they tend to pass unnoticed until spontaneous arterial rupture, dissection, aneurysm, or intestinal perforation occurs, so EDS4 isn't usually diagnosed before the onset of life-threatening hemorrhages or peritonitis  .
Hyperextensible skin, joint hypermobility, and tissue fragility are the clinical hallmarks of classical Ehlers-Danlos syndrome. In EDS4 patients, though, they are usually subtle. The patients' skin is very thin, even translucent and reminiscent of cigarette paper. Subcutaneous veins are visible. Anomalies of the skin render EDS4 patients prone to ecchymosis. Wound healing is delayed. Hyperextensibility may or may not be observed; it is not an exclusion criterion for this type of Ehlers-Danlos syndrome. The hypermobility of joints is often restricted to the small joints of the fingers. Still, aging patients are prone to subluxations, sprains, and chronic arthralgia .
Besides the aforementioned symptoms of Ehlers-Danlos syndrome, a characteristic facial appearance may give rise to a suspicion of EDS4. Affected individuals may have prominent eyes, a slender, pinched nose, and narrow lips, but these features may be very subtle or even absent .
In women, the increased fragility of fibrillar connective tissue in the urogenital tract predisposes to gynecological and obstetric complications. Female patients may present with vaginal tears and lacerations, cervical insufficiency or uterine rupture in advanced pregnancy, and premature rupture of membranes .
Major and minor criteria have been defined for the clinical diagnosis of EDS4 .
The following are major criteria of EDS4:
Additionally, these minor criteria should be considered:
In any case, the clinical diagnosis of EDS4 has to be confirmed by means of molecular biological studies. These are indispensable due to clinical overlaps between distinct types of Ehlers-Danlos syndrome and similarities to other hereditary connective tissue disorders. In this context, the presence of major criteria of EDS4 may warrant a direct approach to identify mutations of COL3A1, and if such mutations cannot be identified, the diagnostic spectrum should be broadened to include genes COL1A1 and COL5A1  . By contrast, gene panels are initially preferred to assess for classical Ehlers-Danlos syndrome and mutations in genes COL5A1 and COL5A2, among others, if the patient shows non-specific symptoms listed here as minor criteria .
Causal therapies are not available. In general, it is important to know about the increased fragility of a patient's vessels and hollow organs to limit invasive procedures to those required to save the patient's life  . Severe hemorrhages surely warrant such interventions, but data regarding the success of distinct therapeutic approaches are scarce. Patients may undergo open surgery for vascular reconstruction, ligature, clip, or suture and extirpation of organs with ruptured arteries, or they may be treated with endovascular techniques. Bergqvist and colleagues compared mortality rates of patients with vascular Ehlers-Danlos syndrome pertaining to either group, and didn't find significant differences. In both scenarios, about a quarter of affected individuals died .
The question has been raised whether catastrophic arterial rupture may be predicted, but that's not always possible. Arterial rupture may occur where aneurysms or pseudoaneurysms exist, and these may eventually be visualized applying diagnostic imaging techniques, although arteriography should be avoided due to high complication rates  . Both rapid aneurysm expansion and large aneurysm size may justify preventive surgery, but high rates of operative mortality argue against invasive measures . To date, no criteria have been established to this end. Furthermore, the rupture of non-aneurysmatic vessels has been described. It may occur after minor trauma or spontaneously, i.e., in the absence of trauma .
Another approach to EDS4 treatment comprises the prevention of vascular events. In this context, celiprolol has recently been demonstrated to reduce vascular complications in EDS4. Celiprolol is a β1-sympatholytic with β2-agonist vasodilatory effects. Possibly, its protective effect is mediated by a decrease of hemodynamic stress , although heart rate, systolic and diastolic blood pressure remain unaltered .
Survivors of bowel perforation and emergency operations tend to relapse with intestinal rupture occurring elsewhere in the digestive tract. In order to avoid the latter, total colectomy with permanent ileostomy may be performed .
EDS4 has the worst prognosis of all types of Ehlers-Danlos syndrome. The low severity of otherwise striking anomalies of the skin and joints results in diagnostic delays of several years, and EDS4 isn't usually considered as a differential diagnosis until life-threatening complications such as arterial rupture or bowel perforation occur. They often arise during the third decade of life and may require the implantation of grafts, with graft-related complications being the second most common cause of early death  . The overall life expectancy of EDS4 patients doesn't exceed 50 years  .
EDS4 is inherited in an autosomal dominant manner, and accordingly, the majority of patients has a family history of EDS4 or unspecified arterial disease. But the penetrance of the causal mutations is incomplete, so genealogical analyses may not allow for reliable conclusions as to the mode of inheritance . With regards to mutations underlying EDS4 and vascular Ehlers-Danlos syndrome, the following statements shall be made:
The occurrence of vascular Ehlers-Danlos syndrome due to mutations of genes COL1A1 and COL5A1 stresses the need for the genetic confirmation of any clinical diagnosis and highlights the differences between the molecular biological classification and the descriptive scheme.
The overall incidence of Ehlers-Danlos syndrome may be as high as 1 in 5,000 live births. EDS4 accounts for about 5% of all cases and its incidence is <1 in 100,000 neonates. Despite EDS4 being a congenital condition, the disease isn't usually diagnosed until the end of the third decade of life .
Mutations of the COL3A1 gene interfere with the stability of the pro-α1 chain of type III collagen, with its secretion into the extracellular medium and further processing. Consequently, only small quantities of functional type III collagen are produced. Under physiological conditions, significant amounts of type III collagen are found in arterial walls, so their mechanical properties are altered in EDS4 patients. Furthermore, lack of type III collagen has been suggested to disturb fetal skin development. Therefore, EDS4 patients have very thin skin, despite the fact that healthy adult skin has a low content of type III collagen .
Affected families may benefit from genetic counseling . The prenatal diagnosis of EDS4 is feasible .
Ehlers-Danlos syndrome refers to a heterogeneous group of connective tissue disorders. According to the Villefranche classification, which has been proposed in 1998, there are six different types of the syndrome, with EDS4 being one of them. However, a broad spectrum of novel types of Ehlers-Danlos syndrome has been described in the meantime, and experts proposed a revised classification considering 13 types of Ehlers-Danlos syndrome . The new classification abandons the old numbering system and prefers descriptive designations, with EDS4 being listed as vascular Ehlers-Danlos syndrome.
Both classification systems have their right to exist. EDS4 has been defined as a type of Ehlers-Danlos syndrome with predominant vascular fragility and has been associated with mutations of the COL3A1 gene. However, vascular symptoms have also been reported in patients carrying mutations of genes conventionally related to Ehlers-Danlos syndrome types 1 and 7A. Accordingly, any clinical diagnosis of EDS4 needs to be supported by the results of molecular biological analyses.
Treatment options are very limited. Knowledge regarding the increased fragility of tissues is indispensable when planning surgical interventions, which should be restricted to the absolute minimum. Beyond that, EDS4 patients may benefit from the administration of β-sympatholytics, although long-term results are still pending. Affected individuals rarely reach the age of 50.
Ehlers-Danlos syndrome is a general term referring to a heterogeneous group of hereditary connective tissue disorders. Collagen is an essential component of connective tissues, and there are distinct types of collagen that confer different properties to more or less taut and elastic variants of connective tissues. Type III collagen is mainly found in elastic connective tissue, i.e., in arteries, hollow organs, and skin. Patients suffering from Ehlers-Danlos syndrome type 4 (EDS4) carry mutations of the COL3A1 gene, which encodes for type III collagen. Thus, the structure and function of connective tissues in the aforementioned organs are disturbed.
EDS4 predisposes to spontaneous arterial rupture and intestinal perforation, which are life-threatening events that tend to occur during the third or fourth decade of life. Due to the inherited weakness of arterial and intestinal walls, surgical interventions are high-risk procedures and shouldn't be carried out unless they are absolutely necessary to save the patient's life. Besides the predisposition to arterial disease and bowel rupture, EDS4 is associated with very thin, almost translucent skin and hypermobility of the finger joints. Patients may also have characteristic facial features, such as prominent eyes, a thin, pinched nose, and narrow lips. Gynecological and obstetric complications may occur in women, who may be unable to carry a pregnancy to term. Cervical insufficiency or uterine rupture in advanced pregnancy put mother and child at risk.
Causal treatment is not available, and those suffering from EDS4 have a poor prognosis. To date, their life expectancy doesn't exceed 50 years, but new therapeutic approaches are currently tested in clinical trials. In fact, treatment with β-blocker celiprolol has recently been demonstrated to reduce vascular complications in EDS4 patients. Beyond that, affected individuals should take preventive measures to avoid trauma. Families known to harbor mutations of the COL3A1 gene may benefit from genetic counseling and prenatal diagnostics.