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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
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)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: 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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: 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.
 
Gene (location): COL3A1 (2q32.2)
 
Monarch Initiative: MONDO:0017314
OMIM®: 130050
Orphanet: ORPHA286

Disease characteristics

Excerpted from the GeneReview: Vascular Ehlers-Danlos Syndrome
Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising; characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes); and an aged appearance to the extremities, particularly the hands. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – are most often present in those children ascertained without a major complication. [from GeneReviews]
Authors:
Peter H Byers   view full author information

Additional descriptions

From OMIM
The vascular type of Ehlers-Danlos syndrome is characterized by the major complications of arterial and bowel rupture, uterine rupture during pregnancy, and the clinical features of easy bruising, thin skin with visible veins, and characteristic facial features (summary by Leistritz et al., 2011). Joint hypermobility is largely limited to the digits, and skin hyperextensibility is minimal or absent (McKusick, 1972).  http://www.omim.org/entry/130050
From MedlinePlus Genetics
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.

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.

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 identified more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.

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.

Bleeding problems are common in the vascular type of Ehlers-Danlos syndrome and are caused by unpredictable tearing (rupture) of blood vessels and organs. These complications can lead to easy bruising, internal bleeding, a hole in the wall of the intestine (intestinal perforation), or stroke. During pregnancy, women with vascular Ehlers-Danlos syndrome may experience rupture of the uterus. Additional forms of Ehlers-Danlos syndrome that involve rupture of the blood vessels include the kyphoscoliotic, classical, and classical-like types.

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://medlineplus.gov/genetics/condition/ehlers-danlos-syndrome

Clinical features

From HPO
Chest pain
MedGen UID:
2992
Concept ID:
C0008031
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the chest.
Cervical insufficiency
MedGen UID:
2972
Concept ID:
C0007871
Pathologic Function
A cervix that shows a painless dilation and shortening during the second trimester of pregnancy with resultant recurrent pregnancy loss or delivery is considered incompetent
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Uterine rupture
MedGen UID:
22592
Concept ID:
C0042143
Finding
The complete, nonsurgical disruption of all layers of the uterus.
Clubfoot
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).
Acroosteolysis
MedGen UID:
183017
Concept ID:
C0917990
Disease or Syndrome
Dissolution or degeneration of bone tissue of the phalanges of the hand.
Metacarpophalangeal joint hyperextensibility
MedGen UID:
870640
Concept ID:
C4025092
Anatomical Abnormality
Increased mobility of one ore more metacarpophalangeal joint.
Foot acroosteolysis
MedGen UID:
871259
Concept ID:
C4025744
Pathologic Function
Mitral valve prolapse
MedGen UID:
7671
Concept ID:
C0026267
Disease or Syndrome
One or both of the leaflets (cusps) of the mitral valve bulges back into the left atrium upon contraction of the left ventricle.
Varicose disease
MedGen UID:
21827
Concept ID:
C0042345
Disease or Syndrome
Enlarged and tortuous veins.
Arterial rupture
MedGen UID:
102341
Concept ID:
C0155760
Disease or Syndrome
Sudden breakage of an artery leading to leakage of blood from the circulation.
Carotid cavernous fistula
MedGen UID:
116040
Concept ID:
C0238045
Anatomical Abnormality
An abnormal connection between a carotid artery and the cavernous sinus.
Ascending aortic dissection
MedGen UID:
322966
Concept ID:
C1836653
Disease or Syndrome
A separation of the layers within the wall of the ascending aorta. Tears in the intimal layer result in the propagation of dissection (proximally or distally) secondary to blood entering the intima-media space.
Recurrent intrapulmonary hemorrhage
MedGen UID:
812249
Concept ID:
C3805919
Finding
A recurrent hemorrhage occurring within the lung.
Descending aortic dissection
MedGen UID:
868484
Concept ID:
C4022878
Disease or Syndrome
A separation of the layers within the wall of the descending aorta. Tears in the intimal layer result in the propagation of dissection (proximally or distally) secondary to blood entering the intima-media space.
Dilatation of the cerebral artery
MedGen UID:
1386760
Concept ID:
C4476540
Anatomical Abnormality
The presence of a localized dilatation or ballooning of a cerebral artery.
Diffuse alveolar hemorrhage
MedGen UID:
1381751
Concept ID:
C4476767
Disease or Syndrome
A type of of pulmonary hemorrhage that originates from the pulmonary microcirculation, including the alveolar capillaries, arterioles, and venules. It presents with hemoptysis, anemia, diffuse lung infiltration, and acute respiratory failure. The diagnosis is confirmed by the observation of the accumulation of red blood cells, fibrin, or hemosiderin-laden macrophage in the alveolar space on pathologic biopsy. Hemosiderin, a product of hemoglobin degradation, appears at least 48-72 hours after bleeding and is helpful in distinguishing diffuse alveolar hemorrhage from surgical trauma. Mild interstitial thickening, organizing pneumonia, or diffuse alveolar damage can also be seen.
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 "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Absent earlobe
MedGen UID:
341440
Concept ID:
C1849364
Anatomical Abnormality
Absence of fleshy non-cartilaginous tissue inferior to the tragus and incisura.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
Protrusion of the contents of the abdominal cavity through the inguinal canal.
Uterine prolapse
MedGen UID:
22591
Concept ID:
C0042140
Finding
The presence of prolapse of the uterus.
Finger joint hypermobility
MedGen UID:
154359
Concept ID:
C0574974
Finding
Cystocele
MedGen UID:
730551
Concept ID:
C1394494
Disease or Syndrome
Anterior vaginal wall prolapse with bulging of the bladder into the vagina.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The ability of a joint to move beyond its normal range of motion.
Hypermobility of distal interphalangeal joints
MedGen UID:
338783
Concept ID:
C1851811
Finding
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Hypermobility of interphalangeal joints
MedGen UID:
870718
Concept ID:
C4025172
Anatomical Abnormality
The ability of the interphalangeal joints to move beyond their normal range of motion.
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.
Hemothorax
MedGen UID:
5510
Concept ID:
C0019123
Pathologic Function
The presence of blood in the pleural space.
Pneumothorax
MedGen UID:
19365
Concept ID:
C0032326
Disease or Syndrome
Accumulation of air in the pleural cavity leading to a partially or completely collapsed lung.
Emphysema
MedGen UID:
18764
Concept ID:
C0034067
Disease or Syndrome
A subcategory of chronic obstructive pulmonary disease (COPD). It occurs in people who smoke and suffer from chronic bronchitis. It is characterized by inflation of the alveoli, alveolar wall damage, and reduction in the number of alveoli, resulting in difficulty breathing.
Spontaneous pneumothorax
MedGen UID:
57701
Concept ID:
C0149781
Disease or Syndrome
Pneumothorax occurring without traumatic injury to the chest or lung.
Pulmonary bulla
MedGen UID:
537120
Concept ID:
C0241982
Disease or Syndrome
Pulmonary bullae are rounded focal regions of emphysema with a thin wall which measure more than 1 cm in diameter. They are often subpleural in location and are typically larger in the apices. In some cases, bullae can be very large and result in compression of adjacent lung tissue. A giant bulla is arbitrarily defined as one that occupies at least one third of the volume of a hemithorax. When large, bullae can simulate pneumothorax. The most common cause is paraseptal emphysema but bullae may also be seen in association with centrilobular emphysema.
Pulmonary bleb
MedGen UID:
341774
Concept ID:
C1857434
Disease or Syndrome
A bleb is a small gas-containing space within the visceral pleura or in the subpleural lung, not larger than 1 cm in diameter. CT findings show a bleb as a thin-walled cystic air space contiguous with the pleura.
Repeated pneumothoraces
MedGen UID:
870578
Concept ID:
C4025027
Disease or Syndrome
Nodular pattern on pulmonary HRCT
MedGen UID:
1380219
Concept ID:
C4476750
Finding
A nodular pattern is characterised on pulmonary high-resolution computed tomography by the presence of numerous rounded opacities that range from 2 mm to 1 cm in diameter, with micronodules defined as smaller than 3 mm in diameter.
Combined cystic and ground-glass pattern on pulmonary HRCT
MedGen UID:
1380516
Concept ID:
C4476753
Finding
Co-occurrence of the cystic pattern and the ground-glass pattern on pulmonary high-resolution computed tomography,
Periodontitis
MedGen UID:
45815
Concept ID:
C0031099
Disease or Syndrome
Inflammation of the periodontium.
Premature loss of teeth
MedGen UID:
66678
Concept ID:
C0232513
Finding
Exfoliation of a tooth more than 2 SD earlier than the normal age for the deciduous teeth and not related to traume or neglect. Exfoliation of a permanent tooth is per se abnormal.
Alopecia of scalp
MedGen UID:
658454
Concept ID:
C0574769
Finding
Thin vermilion border
MedGen UID:
108294
Concept ID:
C0578038
Finding
Height of the vermilion of the medial part of the lip more than 2 SD below the mean, or apparently reduced height of the vermilion of the lip in the frontal view. The vermilion is the red part of the lips (and confusingly, the vermilion itself is also often referred to as being equivalent the lips).
Narrow nasal ridge
MedGen UID:
373404
Concept ID:
C1837761
Finding
Decreased width of the nasal ridge.
Ecchymosis
MedGen UID:
8524
Concept ID:
C0013491
Finding
A purpuric lesion that is larger than 1 cm in diameter.
Hyperextensible skin
MedGen UID:
66023
Concept ID:
C0241074
Finding
A condition in which the skin can be stretched beyond normal, and then returns to its initial position.
Fragile skin
MedGen UID:
66826
Concept ID:
C0241181
Finding
Skin that splits easily with minimal injury.
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.
Dermal translucency
MedGen UID:
373141
Concept ID:
C1836646
Finding
An abnormally increased ability of the skin to permit light to pass through (translucency) such that subcutaneous structures such as veins display an increased degree of visibility.
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.
Cigarette-paper scars
MedGen UID:
342099
Concept ID:
C1851828
Finding
Thin (atrophic) and wide scars.
Premature delivery because of cervical insufficiency or membrane fragility
MedGen UID:
377529
Concept ID:
C1851808
Finding
Keratoconus
MedGen UID:
44015
Concept ID:
C0022578
Disease or Syndrome
A cone-shaped deformity of the cornea characterized by the presence of corneal distortion secondary to thinning of the apex.

Professional guidelines

PubMed

Keser Z, Chiang CC, Benson JC, Pezzini A, Lanzino G
Vasc Health Risk Manag 2022;18:685-700. Epub 2022 Sep 2 doi: 10.2147/VHRM.S362844. PMID: 36082197Free PMC Article
Henderson AD, Miller NR
Eye (Lond) 2018 Feb;32(2):164-172. Epub 2017 Nov 3 doi: 10.1038/eye.2017.240. PMID: 29099499Free PMC Article
Pope FM, Daw SC, Narcisi P, Richards AR, Nicholls AC
J Inherit Metab Dis 1989;12 Suppl 1:135-73. doi: 10.1007/BF01799292. PMID: 2572730

Curated

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

Orphanet Emergency Guidelines: Type IV Ehlers-Danlos Syndrome

Recent clinical studies

Etiology

Arici V, Corbetta R, Fossati LG, Odero A
Vascular 2013 Feb;21(1):43-5. Epub 2012 Aug 7 doi: 10.1258/vasc.2011.cr0318. PMID: 22871544

Diagnosis

Arici V, Corbetta R, Fossati LG, Odero A
Vascular 2013 Feb;21(1):43-5. Epub 2012 Aug 7 doi: 10.1258/vasc.2011.cr0318. PMID: 22871544
Paluru P, Ronan SM, Heon E, Devoto M, Wildenberg SC, Scavello G, Holleschau A, Mäkitie O, Cole WG, King RA, Young TL
Invest Ophthalmol Vis Sci 2003 May;44(5):1830-6. doi: 10.1167/iovs.02-0697. PMID: 12714612

Clinical prediction guides

Paluru P, Ronan SM, Heon E, Devoto M, Wildenberg SC, Scavello G, Holleschau A, Mäkitie O, Cole WG, King RA, Young TL
Invest Ophthalmol Vis Sci 2003 May;44(5):1830-6. doi: 10.1167/iovs.02-0697. PMID: 12714612

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