Edit concept Create issue ticket

Ehlers-Danlos Syndrome Type 4

EDS Type 4

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.


Presentation

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 [1] [2].

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 [3].

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 [4].

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 [5].

Easy Bruising
  • In addition to loose joints and very stretchy skin, common symptoms include thin, translucent skin, characteristic facial features (large eyes, small chin, sunken cheeks, thin nose and lips, lobeless ears), small, slim build, easy bruising, bruising without[diseaseinfosearch.org]
  • The surgeons chose a total colectomy because recurrent perforation is frequent in patients treated with resection and diversion. 11 The association of ‘spontaneous’ colonic perforation, haemostatic disorders with tendency to easy bruise should raise a[academic.oup.com]
  • On taking a detailed history regarding the same, the patient reported easy bruising, delay in wound healing, and excessive gaping of wounds since childhood.[ijdvl.com]
  • bruising, and characteristic facial features.[acgcasereports.gi.org]
  • Patients have a lifelong history of easy bruising. Keratoconus [ Kuming et al 1977 ], periodontal disease, and venous varicosities have been reported [ Tsipouras et al 1986 ].[reumatologia-dr-bravo.cl]
Short Stature
  • A few reports have described some unusual phenotypic manifestations, including large eyes with a thin nose, hollow cheeks, small lips, lobeless ears, short stature, and thin scalp hair.[path.upmc.edu]
  • 0012733 Melanocytic nevus Beauty mark 0000995 Mitral valve prolapse 0001634 Pectus excavatum Funnel chest 0000767 Peripheral arteriovenous fistula 0100784 Pneumothorax Collapsed lung 0002107 Protruding ear Prominent ear Prominent ears [ more ] 0000411 Short[rarediseases.info.nih.gov]
  • stature Mitral valve prolapse Vitiligo Cyanosis of the lips, fingernails and toenails in response to cold temperatures Gastrointestinal complications Postural orthostatic tachycardia syndrome Recessed gums Hypermobility of small joints Congenital clubfoot[blog.crowdmed.com]
  • The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs.[icdlist.com]
  • These manifestations include large eyes, thin nose, lobeless ears, short stature and thin scalp hair. Also evident is a decrease in subcutaneous tissue, particularly in the face and extremities. Minor trauma can lead to extensive bruising.[blog.donnawilliams.net]
Ecchymosis
  • Figure 1: Preoperative photograph of the patientâ s arm, showing large tense swelling and ecchymosis just proximal to the antecubital fossa-medial view. Plain radiographs of the elbow were negative.[omicsonline.org]
  • 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.[symptoma.com]
  • Recurrent temporomandibular joint subluxation and facial ecchymosis leading to diagnosis of Ehlers-Danlos syndrome . J Oral Maxillofac Surg 1990; 48(6):641-7. 24. Jones ML. Orthodontic treatment in Ehlers-Danlos syndrome.[cda-adc.ca]
Intestinal Perforation
  • 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.[symptoma.com]
  • The patient’s clinical features (panels D and E) together with his family history (his father died from a distended abdomen after cholecystectomy, a spontaneous intestinal perforation caused his brother’s death, and his sister died suddenly of a ruptured[heart.bmj.com]
Mitral Valve Prolapse
  • No findings indicated mitral valve prolapse.[heart.bmj.com]
  • valve prolapse An increased frequency of mitral valve prolapse (MVP) has been reported in patients with EDS type IV [ 36 ].[ojrd.biomedcentral.com]
  • Results of consultations in ophthalmology and cardiology eliminated the possibility of detached retina or mitral valve prolapse. The genetics and rheumatology consults confirmed a diagnosis of EDS type II or III.[cda-adc.ca]
  • Other fatal complications of EDS 4 include hollow viscera rupture, mitral valve prolapse, and spontaneous pneumothorax (4, 5) . There are currently nine types of EDS. EDS 4 comprises 4% of all EDS cases.[ajnr.org]
  • I also have a mitral valve prolapse. I did a 23 and Me genetic test for fun really to look into my ancestry. I’ve had the results for months. But recently I found out you can look up your genes. So I looked up the genes ...[inspire.com]
Acrogeria
  • There are cases of patients without facial acrogeria. Symptoms associated with skin – the skin is abnormally thin and pale. It is also smooth, soft and velvety to the touch. The skin is translucent with visible veins.[journals.viamedica.pl]
  • The skin on the extremities appears prematurely aged, hence the term acrogeria, and the subcutaneous veins are highly visible.[ojrd.biomedcentral.com]
  • Patients may also have acrogeria, which is a prematurely aged appearance of the extremities (see photo below). Some patients with VEDS have a distinctive facial appearance (see photos at top right and below).[forgottendiseases.org]
  • […] pregnant women, uterine rupture during the third trimester without a previous Caesarean section and/or severe peripartum perineum tears Additionally, these minor criteria should be considered: Thin, translucent skin Easy bruising Early-onset varicose veins Acrogeria[symptoma.com]
  • Other skin manifestations are elastosis serpiginosa (scar formation after trauma with serpiginous keloid formation), keloid formation, Raynaud phenomenon, and acrogeria that refer to excessive wrinkling and thinness of the skin over hands and feet, which[path.upmc.edu]
Thin Skin
  • 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.[symptoma.com]
  • The clinical diagnosis of Ehlers-Danlos syndrome type IV, the vascular type, is made on the basis of four clinical criteria: easy bruising, thin skin with visible veins, characteristic facial features, and rupture of arteries, uterus, or intestines.[ehlersdanlos.ca]
  • Introduction The clinical diagnosis of Ehlers–Danlos syndrome type IV, the vascular type, is made on the basis of four clinical criteria: easy bruising, thin skin with visible veins, characteristic facial features, and rupture of arteries, uterus, or[nejm.org]
  • skin Dominant C1S, C1R Peridontal, Type VIII Musculocontractural Type Craniofacial dysmorphism, congenital contractures of thumbs and fingers, clubfeet, severe kyphoscoliosis, hypotonia, thin skin, easy bruising, atrophic scarring, joint hypermobility[uwcpdx.org]
Delayed Wound Healing
  • The oral manifestations include increased mucosal fragility, delayed wound healing, early onset generalized periodontitis and temporomandibular joint hypermobility.[jdrr.org]
  • wound healing Kyphoscoliotic EDS Kyphoscoliotic EDS (kEDS) is rare.[nhs.uk]
  • Abstract Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility[nature.com]
  • wound healing, atrophic scarring, easy tendon, ligament, vessel rupture) Minor diagnostic criteria typically includes: [2] [4] Positive family history Recurring joint subluxations/dislocations Chronic joint, limb, or back pain Altered blood pressure[physio-pedia.com]
Arthralgia
  • 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.[symptoma.com]
  • Oral score Three oral characteristics remained significantly associated to vEDS after logistic regression: increased root length, modified dental pulp shape and arthralgia/arthrosis (TMJ disorder group 3).[bmjopen.bmj.com]
  • SYMPTOMS EDS can commonly go with dysautonomic issues and the arthralgia.[blog.donnawilliams.net]
  • […] for 3/12 in four or more joints Minor criteria Current/historic Brighton score of 1, 2 or 3/9 (0, 1, 2, 3/9 if 50 years old) Arthralgia for minimum of 3 months in 1-3 joints, or back pain for minimum of 3 months, or spondylosis/spondylolysis/spondylolisthesis[medical-dictionary.thefreedictionary.com]
Hyperlaxity
  • Several stigmata of connective tissue disorder were also noted on exam, including joint hyperlaxity. Extensive questioning of the patient and his parents revealed a history of easy bruising, but no other notable factors.[omicsonline.org]
  • In contrast, we recently reported a syndrome of joint hyperlaxity, easy bruising, pelvic organs prolapses, premature rupture of the membranes and rectal bleeding associated with a non-glycine sequence variant of the COL3A1 gene (P435T) [ 54 ].[ojrd.biomedcentral.com]
  • National Library of Medicine - PubMed Health Ehlers-Danlos Support UK Ehlers-Danlos Foundation of New Zealand References [ edit ] Cashin-Garbutt, A; 2014 'Double-Jointed - Joint Hyperlaxity/Hypermobility'; Zweers, M.C. et al (2005) 'Tenascin-X: a candidate[en.wikibooks.org]
  • […] caused by mutations in the SLC39A13 gene, encoding the membrane-bound zinc transporter SLC39A13. 37 The RIN2-syndrome is characterized by severe progressive scoliosis, progressive facial coarsening, gingival hypertrophy, sparse hair, and skin and joint hyperlaxity[nature.com]
Thin Lips
  • Other significant findings included a characteristic facies with thin lips and philtrum, a small chin, and a pinched nose. The patient also had a large hairy melanocytic nevus extending over his right arm and forearm.[ijdvl.com]
  • These feature include large eyes, thin lips, a thin or pinched nose, blue sclera, and underdeveloped earlobes.[forgottendiseases.org]
  • lips sunken cheeks small chin collapsed lung heart valve problems Doctors may use a series of tests to diagnose EDS (except for hEDS), or rule out other similar conditions.[healthline.com]
  • lips [ more ] 0000233 Varicose veins 0002619 5%-29% of people have these symptoms Abnormal intestine morphology Abnormality of the intestine 0002242 Abnormal pupil morphology Abnormality of the pupil Pupillary abnormalities Pupillary abnormality [ more[rarediseases.info.nih.gov]
  • Very loose small joints (fingers), but most often not the large joints (knees, elbows, hips, shoulders) Distinct facial look with a thin nose, thin lips and hollow-looking cheeks Thin “see-through” skin where blood vessels are seen just under the skin[cincinnatichildrens.org]

Workup

Major and minor criteria have been defined for the clinical diagnosis of EDS4 [6].

The following are major criteria of EDS4:

  • Positive family history of EDS4 with pathogenic mutations of the COL3A1 gene having been identified in at least one of the patient's relatives
  • Spontaneous arterial rupture or dissection diagnosed in individuals aged <40 years
  • Carotid‐cavernous sinus fistula in the absence of identifiable causes
  • Spontaneous sigmoid colon perforation in the absence of other bowel conditions or identifiable causes
  • In pregnant women, uterine rupture during the third trimester without a previous Caesarean section and/or severe peripartum perineum tears

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 [4] [6]. 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 [6].

Treatment

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 [1] [7]. 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 [1].

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 [8] [9]. Both rapid aneurysm expansion and large aneurysm size may justify preventive surgery, but high rates of operative mortality argue against invasive measures [8]. 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 [1].

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 [10], although heart rate, systolic and diastolic blood pressure remain unaltered [11].

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 [2].

Prognosis

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 [1] [8]. The overall life expectancy of EDS4 patients doesn't exceed 50 years [3] [11].

Etiology

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 [1]. With regards to mutations underlying EDS4 and vascular Ehlers-Danlos syndrome, the following statements shall be made:

  • In the vast majority of cases, EDS4 is caused by mutations of the COL3A1 gene, which is located on the long arm of chromosome 2. COL3A1 encodes for the pro-α1 chain of type III collagen. Type III collagen consists of three α1 chains and is mainly found in elastic and reticular connective tissue, i.e., in arteries, skin, hollow organs, and lymphatic tissues. To date, >700 mutations of the COL3A1 gene have been identified [3].
  • Vascular Ehlers-Danlos syndrome has also been related to mutations of the COL1A1 gene. COL1A1 is to be found on the long arm of chromosome 17 and encodes for the pro-α1 chain of type I collagen. Mutations of this gene are generally associated with arthrochalasic-type Ehlers-Danlos syndrome or Ehlers-Danlos syndrome type 7A. Occasionally though, arterial rupture has been observed in patients carrying pathogenic COL1A1 variants [6].
  • Furthermore, mutations of the COL5A1 gene, which generally induce classical Ehlers-Danlos syndrome, have been detected in patients who sustained lethal arterial events due to hereditary connective tissue disorders [4]. The product of this gene, which is located on the long arm of chromosome 9, is the pro-α1 chain of type 5 collagen.

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.

Epidemiology

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 [8].

Sex distribution
Age distribution

Pathophysiology

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 [11].

Prevention

Affected families may benefit from genetic counseling [12]. The prenatal diagnosis of EDS4 is feasible [7].

Summary

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 [6]. 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.

Patient Information

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.

References

Article

  1. Bergqvist D, Björck M, Wanhainen A. Treatment of vascular Ehlers-Danlos syndrome: a systematic review. Ann Surg. 2013; 258(2):257-261.
  2. Demirogullari B, Karabulut R, Demirtola A, et al. A novel mutation in the vascular Ehlers-Danlos syndrome: a case presenting with colonic perforations. J Pediatr Surg. 2006; 41(8):e27-30.
  3. Eagleton MJ. Arterial complications of vascular Ehlers-Danlos syndrome. J Vasc Surg. 2016; 64(6):1869-1880.
  4. Monroe GR, Harakalova M, van der Crabben SN, et al. Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1. Am J Med Genet A. 2015; 167(6):1196-1203.
  5. Malfait F, De Paepe A. The Ehlers-Danlos syndrome. Adv Exp Med Biol. 2014; 802:129-143.
  6. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017; 175(1):8-26.
  7. Germain DP. The vascular Ehlers-Danlos syndrome. Curr Treat Options Cardiovasc Med. 2006; 8(2):121-127.
  8. Oderich GS, Panneton JM, Bower TC, et al. The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience. J Vasc Surg. 2005; 42(1):98-106.
  9. Zilocchi M, Macedo TA, Oderich GS, Vrtiska TJ, Biondetti PR, Stanson AW. Vascular Ehlers-Danlos syndrome: imaging findings. AJR Am J Roentgenol. 2007; 189(3):712-719.
  10. Beridze N, Frishman WH. Vascular Ehlers-Danlos syndrome: pathophysiology, diagnosis, and prevention and treatment of its complications. Cardiol Rev. 2012; 20(1):4-7.
  11. Lum YW, Brooke BS, Black JH, 3rd. Contemporary management of vascular Ehlers-Danlos syndrome. Curr Opin Cardiol. 2011; 26(6):494-501.
  12. Pepin MG, Schwarze U, Rice KM, Liu M, Leistritz D, Byers PH. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genet Med. 2014; 16(12):881-888.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2018-06-21 19:47