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Ehlers-Danlos syndrome, type 4(EDSVASC)

MedGen UID:
82790
Concept ID:
C0268338
Disease or Syndrome
Synonyms: EDSVASC; Ehlers Danlos syndrome, arterial type; Ehlers Danlos syndrome, ecchymotic type; Ehlers Danlos syndrome, Sack-Barabas type; Ehlers-Danlos Syndrome Type IV; Ehlers-Danlos syndrome vascular type
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Ehlers-Danlos syndrome ecchymotic type E-D (17025000); Ehlers-Danlos syndrome arterial type E-D (17025000); Ehlers-Danlos syndrome type IV (17025000); Ehlers-Danlos syndrome, type 4 (17025000); Sack syndrome (17025000); Sack-Barabas syndrome (17025000)
 
Gene (location): COL3A1 (2q32.2)
OMIM®: 130050
Orphanet: ORPHA286

Definition

Vascular Ehlers-Danlos Syndrome (vEDS) is characterized by thin, translucent skin; easy bruising; characteristic facial appearance (in some individuals); and arterial, intestinal, and/or uterine fragility. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in the majority of adults identified to have vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. Neonates may present with clubfoot and/or congenital dislocation of the hips. In childhood, inguinal hernia, pneumothorax, recurrent joint subluxation or dislocation, and bruising can occur. Pregnancy for women with vEDS has an estimated 5.3% risk for death from peripartum arterial rupture or uterine rupture. One fourth of individuals with vEDS, confirmed by laboratory testing, experienced a major complication by age 20 years and more than 80% by age 40 years. The median age of death in this reviewed population was 50 years. [from GTR]

Additional descriptions

From GeneReviews
Vascular Ehlers-Danlos Syndrome (vEDS) is characterized by thin, translucent skin; easy bruising; characteristic facial appearance (in some individuals); and arterial, intestinal, and/or uterine fragility. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in the majority of adults identified to have vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. Neonates may present with clubfoot and/or congenital dislocation of the hips. In childhood, inguinal hernia, pneumothorax, recurrent joint subluxation or dislocation, and bruising can occur. Pregnancy for women with vEDS has an estimated 5.3% risk for death from peripartum arterial rupture or uterine rupture. One fourth of individuals with vEDS, confirmed by laboratory testing, experienced a major complication by age 20 years and more than 80% by age 40 years. The median age of death in this reviewed population was 50 years.  https://www.ncbi.nlm.nih.gov/books/NBK1494
From OMIM
The vascular type of Ehlers-Danlos syndrome is characterized by the joint and dermal manifestations as in other forms of the syndrome but also by proneness to spontaneous rupture of bowel and large arteries.  http://www.omim.org/entry/130050
From GHR
Ehlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.The various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were discovered more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.An unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.Many people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.Some forms of Ehlers-Danlos syndrome, notably the vascular type and to a lesser extent the kyphoscoliotic, classical, and classical-like types, can cause unpredictable tearing (rupture) of blood vessels, leading to internal bleeding and other potentially life-threatening complications. The vascular type of Ehlers-Danlos syndrome is also associated with an increased risk of organ rupture, including tearing of the intestine and rupture of the uterus during pregnancy.Other types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums.  https://ghr.nlm.nih.gov/condition/ehlers-danlos-syndrome

Clinical features

Talipes equinovarus
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Periodontitis
MedGen UID:
42217
Concept ID:
C0017563
Disease or Syndrome
Diseases involving the GINGIVA.
Hemoptysis
MedGen UID:
5502
Concept ID:
C0019079
Sign or Symptom
Coughing up (expectoration) of blood or blood-streaked sputum from the larynx, trachea, bronchi, or lungs.
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
An abdominal hernia with an external bulge in the GROIN region. It can be classified by the location of herniation. Indirect inguinal hernias occur through the internal inguinal ring. Direct inguinal hernias occur through defects in the ABDOMINAL WALL (transversalis fascia) in Hesselbach's triangle. The former type is commonly seen in children and young adults; the latter in adults.
Keratoconus
MedGen UID:
44015
Concept ID:
C0022578
Disease or Syndrome
Keratoconus is an eye condition that affects the shape of the cornea, which is the clear outer covering of the eye. In this condition, the cornea thins and bulges outward, eventually resembling a cone shape. These corneal abnormalities, which worsen over time, can lead to nearsightedness (myopia), blurred vision that cannot be improved with corrective lenses (irregular astigmatism), and vision loss.Other corneal changes typical of keratoconus that can be seen during an eye exam include iron deposits in the cornea that form a yellow-to-brownish ring, called the Fleischer ring, surrounding the colored part of the eye (iris). Affected individuals may also develop Vogt's striae, which are thin, vertical, white lines in the tissue at the back of the cornea.Keratoconus may affect only one eye at first, but eventually the corneas of both eyes become misshapen, although they might not be affected with the same severity. As keratoconus worsens, people with this condition can develop corneal scarring, often caused by exposure of the abnormally thin cornea to prolonged contact lens use or excessive eye rubbing.The eye changes characteristic of keratoconus typically begin in adolescence and slowly worsen until mid-adulthood at which point the shape of the cornea remains stable.
Mitral valve prolapse
MedGen UID:
7671
Concept ID:
C0026267
Disease or Syndrome
A fairly common and often benign valvular heart disorder characterized by redundancy or hooding of mitral valve leaflets so that they prolapse into the left atrium, often causing mitral regurgitation. It is often a symptomless condition but may be marked by varied symptoms (e.g. chest pain, fatigue, dizziness, dyspnea, or palpitations) leading in some cases to endocarditis or ventricular tachycardia.
Uterine prolapse
MedGen UID:
22591
Concept ID:
C0042140
Finding
Downward displacement of the UTERUS. It is classified in various degrees: in the first degree the UTERINE CERVIX is within the vaginal orifice; in the second degree the cervix is outside the orifice; in the third degree the entire uterus is outside the orifice.
Spontaneous pneumothorax
MedGen UID:
57701
Concept ID:
C0149781
Disease or Syndrome
Pneumothorax occurring without traumatic injury to the chest or lung.
Premature loss of teeth
MedGen UID:
66678
Concept ID:
C0232513
Finding
Premature loss of teeth not related to trauma or neglect.
Fragile skin
MedGen UID:
66826
Concept ID:
C0241181
Finding
Skin that splits easily with minimal injury.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to \
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.
Thin vermilion border
MedGen UID:
108294
Concept ID:
C0578038
Finding
Reduced width of the \
Brain aneurysm
MedGen UID:
196706
Concept ID:
C0751003
Disease or Syndrome
The presence of a localized dilatation or ballooning of a cerebral artery.
Acroosteolysis
MedGen UID:
183017
Concept ID:
C0917990
Disease or Syndrome
A condition that is characterized by degeneration of the distal phalanges.
Molluscoid pseudotumors
MedGen UID:
375465
Concept ID:
C1844597
Disease or Syndrome
Bluish-grey, spongy nodules associated with scars over pressure points and easily traumatized areas like the elbows and knees.
Absent earlobe
MedGen UID:
341440
Concept ID:
C1849364
Congenital Abnormality
Absence of fleshy non-cartilaginous tissue inferior to the tragus and incisura.
Premature delivery because of cervical insufficiency or membrane fragility
MedGen UID:
377529
Concept ID:
C1851808
Finding
Hypermobility of distal interphalangeal joints
MedGen UID:
338783
Concept ID:
C1851811
Finding
Cigarette-paper scars
MedGen UID:
342099
Concept ID:
C1851828
Finding
Thin (atrophic) and wide scars.
Alopecia of scalp
MedGen UID:
348030
Concept ID:
C1860137
Abnormality of the urinary system
MedGen UID:
867444
Concept ID:
C4021821
Disease or Syndrome
An abnormality of the urinary system.
MedGen UID:
504972
Concept ID:
CN001667

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Ehlers-Danlos syndrome, type 4 in Orphanet.

Professional guidelines

PubMed

ACMG Board of Directors.
Genet Med 2015 Jan;17(1):68-9. Epub 2014 Nov 13 doi: 10.1038/gim.2014.151. PMID: 25356965
Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, Creager MA, Eckel RH, Elkind MS, Fornage M, Goldstein LB, Greenberg SM, Horvath SE, Iadecola C, Jauch EC, Moore WS, Wilson JA; American Heart Association Stroke Council.; Council on Cardiovascular and Stroke Nursing.; Council on Clinical Cardiology.; Council on Functional Genomics and Translational Biology.; Council on Hypertension.
Stroke 2014 Dec;45(12):3754-832. Epub 2014 Oct 28 doi: 10.1161/STR.0000000000000046. PMID: 25355838Free PMC Article
Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, Evangelista A, Falk V, Frank H, Gaemperli O, Grabenwöger M, Haverich A, Iung B, Manolis AJ, Meijboom F, Nienaber CA, Roffi M, Rousseau H, Sechtem U, Sirnes PA, Allmen RS, Vrints CJ; ESC Committee for Practice Guidelines.
Eur Heart J 2014 Nov 1;35(41):2873-926. Epub 2014 Aug 29 doi: 10.1093/eurheartj/ehu281. PMID: 25173340
Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, Siu SC; Canadian Cardiovascular Society.
Can J Cardiol 2014 Jun;30(6):577-89. Epub 2014 Feb 28 doi: 10.1016/j.cjca.2014.02.018. PMID: 24882528
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics.
Genet Med 2013 Jul;15(7):565-74. Epub 2013 Jun 20 doi: 10.1038/gim.2013.73. PMID: 23788249Free PMC Article
Mayer K, Kennerknecht I, Steinmann B
Eur J Hum Genet 2010 Sep;18(9) Epub 2010 Feb 10 doi: 10.1038/ejhg.2009.227. PMID: 20145674Free PMC Article

External

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

Orphanet Emergency Guidelines: Type IV Ehlers-Danlos Syndrome

Recent clinical studies

Etiology

Kim ST, Cloft H, Flemming KD, Kallmes DF, Lanzino G, Brinjikji W
J Stroke Cerebrovasc Dis 2017 Aug;26(8):1678-1682. Epub 2017 Jun 21 doi: 10.1016/j.jstrokecerebrovasdis.2017.03.025. PMID: 28647420
Ritter A, Atzinger C, Hays B, James J, Shikany A, Neilson D, Martin L, Weaver KN
Am J Med Genet A 2017 Jun;173(6):1467-1472. Epub 2017 Apr 24 doi: 10.1002/ajmg.a.38243. PMID: 28436618
Engelbert RH, Juul-Kristensen B, Pacey V, de Wandele I, Smeenk S, Woinarosky N, Sabo S, Scheper MC, Russek L, Simmonds JV
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):158-167. doi: 10.1002/ajmg.c.31545. PMID: 28306230
Sundelin HE, Stephansson O, Johansson K, Ludvigsson JF
Acta Obstet Gynecol Scand 2017 Jan;96(1):114-119. Epub 2016 Nov 22 doi: 10.1111/aogs.13043. PMID: 27743500
Cederlöf M, Larsson H, Lichtenstein P, Almqvist C, Serlachius E, Ludvigsson JF
BMC Psychiatry 2016 Jul 4;16:207. doi: 10.1186/s12888-016-0922-6. PMID: 27377649Free PMC Article

Diagnosis

Engelbert RH, Juul-Kristensen B, Pacey V, de Wandele I, Smeenk S, Woinarosky N, Sabo S, Scheper MC, Russek L, Simmonds JV
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):158-167. doi: 10.1002/ajmg.c.31545. PMID: 28306230
Mizumoto S, Kosho T, Hatamochi A, Honda T, Yamaguchi T, Okamoto N, Miyake N, Yamada S, Sugahara K
Clin Biochem 2017 Aug;50(12):670-677. Epub 2017 Feb 24 doi: 10.1016/j.clinbiochem.2017.02.018. PMID: 28238810
Cortini F, Marinelli B, Romi S, Seresini A, Pesatori AC, Seia M, Montano N, Bassotti A
Vasc Endovascular Surg 2017 Apr;51(3):141-145. Epub 2017 Feb 9 doi: 10.1177/1538574417692114. PMID: 28183226
Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H, Levy H
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):48-69. Epub 2017 Feb 1 doi: 10.1002/ajmg.c.31538. PMID: 28145611
Cortini F, Marinelli B, Seia M, De Giorgio B, Pesatori AC, Montano N, Bassotti A
J Med Case Rep 2016 Oct 31;10(1):303. doi: 10.1186/s13256-016-1087-0. PMID: 27799058Free PMC Article

Therapy

Engelbert RH, Juul-Kristensen B, Pacey V, de Wandele I, Smeenk S, Woinarosky N, Sabo S, Scheper MC, Russek L, Simmonds JV
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):158-167. doi: 10.1002/ajmg.c.31545. PMID: 28306230
Tewari S, Madabushi R, Agarwal A, Gautam SK, Khuba S
J Bodyw Mov Ther 2017 Jan;21(1):194-196. Epub 2016 Jul 5 doi: 10.1016/j.jbmt.2016.06.017. PMID: 28167178
Neice AE, Stubblefield EE, Woodworth GE, Aziz MF
J Clin Anesth 2016 Sep;33:26-30. Epub 2016 Apr 6 doi: 10.1016/j.jclinane.2016.01.005. PMID: 27555128
Chen W, Perritt AF, Morissette R, Dreiling JL, Bohn MF, Mallappa A, Xu Z, Quezado M, Merke DP
Hum Mutat 2016 Sep;37(9):893-7. Epub 2016 Jul 8 doi: 10.1002/humu.23028. PMID: 27297501Free PMC Article
Vavken P, Tepolt FA, Kocher MS
J Shoulder Elbow Surg 2016 Jun;25(6):907-12. Epub 2016 Jan 14 doi: 10.1016/j.jse.2015.10.010. PMID: 26775746

Prognosis

Ritelli M, Morlino S, Giacopuzzi E, Carini G, Cinquina V, Chiarelli N, Majore S, Colombi M, Castori M
Am J Med Genet A 2017 Jan;173(1):169-176. Epub 2016 Oct 14 doi: 10.1002/ajmg.a.38004. PMID: 27739212
Scheper MC, Pacey V, Rombaut L, Adams RD, Tofts L, Calders P, Nicholson LL, Engelbert RH
Arthritis Care Res (Hoboken) 2017 Mar;69(3):421-429. doi: 10.1002/acr.22998. PMID: 27483212
Eagleton MJ
J Vasc Surg 2016 Dec;64(6):1869-1880. Epub 2016 Sep 26 doi: 10.1016/j.jvs.2016.06.120. PMID: 27687326
De Wandele I, Rombaut L, De Backer T, Peersman W, Da Silva H, De Mits S, De Paepe A, Calders P, Malfait F
Rheumatology (Oxford) 2016 Aug;55(8):1412-20. Epub 2016 Apr 18 doi: 10.1093/rheumatology/kew032. PMID: 27094596
Vavken P, Tepolt FA, Kocher MS
J Shoulder Elbow Surg 2016 Jun;25(6):907-12. Epub 2016 Jan 14 doi: 10.1016/j.jse.2015.10.010. PMID: 26775746

Clinical prediction guides

Ritter A, Atzinger C, Hays B, James J, Shikany A, Neilson D, Martin L, Weaver KN
Am J Med Genet A 2017 Jun;173(6):1467-1472. Epub 2017 Apr 24 doi: 10.1002/ajmg.a.38243. PMID: 28436618
Morlino S, Dordoni C, Sperduti I, Venturini M, Celletti C, Camerota F, Colombi M, Castori M
Am J Med Genet A 2017 Apr;173(4):914-929. Epub 2017 Mar 7 doi: 10.1002/ajmg.a.38106. PMID: 28266107
Sundelin HE, Stephansson O, Johansson K, Ludvigsson JF
Acta Obstet Gynecol Scand 2017 Jan;96(1):114-119. Epub 2016 Nov 22 doi: 10.1111/aogs.13043. PMID: 27743500
Demirdas S, Dulfer E, Robert L, Kempers M, van Beek D, Micha D, van Engelen BG, Hamel B, Schalkwijk J, Loeys B, Maugeri A, Voermans NC
Clin Genet 2017 Mar;91(3):411-425. Epub 2016 Nov 4 doi: 10.1111/cge.12853. PMID: 27582382
Cederlöf M, Larsson H, Lichtenstein P, Almqvist C, Serlachius E, Ludvigsson JF
BMC Psychiatry 2016 Jul 4;16:207. doi: 10.1186/s12888-016-0922-6. PMID: 27377649Free PMC Article

Recent systematic reviews

Engelbert RH, Juul-Kristensen B, Pacey V, de Wandele I, Smeenk S, Woinarosky N, Sabo S, Scheper MC, Russek L, Simmonds JV
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):158-167. doi: 10.1002/ajmg.c.31545. PMID: 28306230
Kulas Søborg ML, Leganger J, Rosenberg J, Burcharth J
Dig Surg 2017;34(2):161-170. Epub 2016 Dec 9 doi: 10.1159/000449106. PMID: 27931023
Eagleton MJ
J Vasc Surg 2016 Dec;64(6):1869-1880. Epub 2016 Sep 26 doi: 10.1016/j.jvs.2016.06.120. PMID: 27687326
Sinibaldi L, Ursini G, Castori M
Am J Med Genet C Semin Med Genet 2015 Mar;169C(1):97-106. doi: 10.1002/ajmg.c.31430. PMID: 25821094
Guo MH, Stoler J, Lui J, Nilsson O, Bianchi DW, Hirschhorn JN, Dauber A
Am J Med Genet A 2013 Oct;161A(10):2519-27. Epub 2013 Aug 16 doi: 10.1002/ajmg.a.36128. PMID: 23956117Free PMC Article

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