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Ehlers-Danlos syndrome, type 3(EDS3; EDSHMB)

MedGen UID:
75670
Concept ID:
C0268337
Disease or Syndrome
Synonyms: BENIGN HYPERMOBILITY SYNDROME; EDS III; EDS3 (formerly); Ehlers-Danlos syndrome type 3 (formerly); Ehlers-Danlos Syndrome, Hypermobility Type; EHLERS-DANLOS SYNDROME, TYPE III; ORPHA:285
SNOMED CT: Ehlers-Danlos syndrome type III (30652003); Ehlers-Danlos syndrome, type 3 (30652003); Benign hypermobility syndrome (30652003); Ehlers-Danlos syndrome, benign hypermobile form (30652003); Hypermobile Ehlers-Danlos syndrome (30652003)
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.
 
Monarch Initiative: MONDO:0007523
OMIM®: 130020
Orphanet: ORPHA285

Disease characteristics

Excerpted from the GeneReview: Hypermobile Ehlers-Danlos Syndrome
Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by generalized joint hypermobility, joint instability, pain, soft and hyperextensible skin with atrophic scars and easy bruising, dental crowding, abdominal hernias, pelvic organ prolapse, marfanoid body habitus, mitral valve prolapse, and aortic root dilatation. Subluxations, dislocations, and soft tissue injury are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint and chronic soft tissue disorders may arise due to repeated injury. Chronic pain, distinct from that associated with acute injury, is common and often neuropathic in nature. Chronic fatigue, functional bowel disorders, cardiovascular autonomic dysfunction, swallow and phonation disorders, sleep disorders including apnea, migraine, entrapment and peripheral neuropathies, inflammation from mast cell activation disorders, anxiety disorders, and urogynecologic disorders are common. Mitral valve prolapse and aortic root dilatation, when present, are typically of a mild degree with no increased risk of cardiac complications. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Characteristics  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  Chapter Notes  |  References
Authors:
Alan Hakim   view full author information

Additional description

From OMIM
The Ehlers-Danlos syndrome shows phenotypic and genetic heterogeneity; see 130000. Marked joint hyperextensibility without skeletal deformity dominates the clinical picture of hypermobility-type EDS. Skin manifestations are relatively inconspicuous. Differentiation from familial joint laxity (147900) is often uncertain.  http://www.omim.org/entry/130020

Clinical features

From HPO
Exercise-induced myalgia
MedGen UID:
340638
Concept ID:
C1850830
Sign or Symptom
The occurrence of an unusually high amount of muscle pain following exercise.
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.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
Scarring
MedGen UID:
3093
Concept ID:
C0008767
Pathologic Function
A scar refers to a lesion in which wound, burn, or sore has not healed completely and fibrous connective tissue has developed.
Joint dislocation
MedGen UID:
41614
Concept ID:
C0012691
Injury or Poisoning
Displacement or malalignment of joints.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Osteoarthritis
MedGen UID:
45244
Concept ID:
C0029408
Disease or Syndrome
Osteoarthritis (OA) is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis (Meulenbelt et al., 2006). Clinical problems include pain and joint stiffness often leading to significant disability and joint replacement. Osteoarthritis exhibits a clear predilection for specific joints; it appears most commonly in the hip and knee joints and lumbar and cervical spine, as well as in the distal interphalangeal and the first carpometacarpal (base of thumb) and proximal interphalangeal joints of the hand; however, patients with osteoarthritis may have 1, a few, or all of these sites affected (Stefansson et al., 2003). According to a conservative estimate, greater than 70% of the population of the United States at age 65 years is affected by the disease, reflecting its age dependence. Genetic Heterogeneity of Susceptibility to Osteoarthritis Susceptibility to osteoarthritis has been associated with variation in other genes: OS2 (140600) with variation in the MATN3 gene (602109) on chromosome 2p24; OS3 (607850) with variation in the ASPN gene (608135) on chromosome 9q22; and OS5 (612400) with variation in the GDF5 gene (601146) on chromosome 20q11. Other susceptibility loci for osteoarthritis have been mapped to chromosomes 2q33 (OS4; 610839) and 3p24 (OS6; 612401).
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Striae distensae
MedGen UID:
57541
Concept ID:
C0152459
Acquired Abnormality
Thinned, erythematous, depressed bands of atrophic skin. Initially, striae appear as flattened and thinned, pinkish linear regions of the skin. Striae tend to enlarge in length and become reddish or purplish. Later, striae tend to appear as white, depressed bands that are parallel to the lines of skin tension. Striae distensae occur most often in areas that have been subject to distension such as the lower back, buttocks, thighs, breast, abdomen, and shoulders.
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.
Soft skin
MedGen UID:
336730
Concept ID:
C1844592
Finding
Subjective impression of increased softness upon palpation of the skin.

Professional guidelines

PubMed

Jeong HJ, Engel JM, Wilwert O, Muriello M, Basel D, Slavens BA
Phys Occup Ther Pediatr 2023;43(5):630-643. Epub 2023 Jan 16 doi: 10.1080/01942638.2022.2163601. PMID: 36647261
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
Colombi M, Dordoni C, Chiarelli N, Ritelli M
Am J Med Genet C Semin Med Genet 2015 Mar;169C(1):6-22. doi: 10.1002/ajmg.c.31429. PMID: 25821090

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

Recent clinical studies

Etiology

Topan R, Pandya S, Williams S, Ruffle JK, Zarate-Lopez N, Aziz Q, Fikree A
Am J Gastroenterol 2024 Apr 1;119(4):727-738. Epub 2024 Jan 16 doi: 10.14309/ajg.0000000000002586. PMID: 37970870
Tofts LJ, Simmonds J, Schwartz SB, Richheimer RM, O'Connor C, Elias E, Engelbert R, Cleary K, Tinkle BT, Kline AD, Hakim AJ, van Rossum MAJ, Pacey V
Orphanet J Rare Dis 2023 May 4;18(1):104. doi: 10.1186/s13023-023-02717-2. PMID: 37143135Free PMC Article
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Gensemer C, Burks R, Kautz S, Judge DP, Lavallee M, Norris RA
Dev Dyn 2021 Mar;250(3):318-344. Epub 2020 Aug 17 doi: 10.1002/dvdy.220. PMID: 32629534Free PMC Article
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

Diagnosis

Tofts LJ, Simmonds J, Schwartz SB, Richheimer RM, O'Connor C, Elias E, Engelbert R, Cleary K, Tinkle BT, Kline AD, Hakim AJ, van Rossum MAJ, Pacey V
Orphanet J Rare Dis 2023 May 4;18(1):104. doi: 10.1186/s13023-023-02717-2. PMID: 37143135Free PMC Article
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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
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

Therapy

Spanhove V, De Wandele I, Malfait F, Calders P, Cools A
Disabil Rehabil 2023 Jun;45(11):1811-1821. Epub 2022 May 24 doi: 10.1080/09638288.2022.2076932. PMID: 35609204
Hakimi A, Bergoin C, Mucci P
Eur J Appl Physiol 2022 Nov;122(11):2367-2374. Epub 2022 Aug 8 doi: 10.1007/s00421-022-05017-y. PMID: 35941284
O'Shea KM, Aceves SS, Dellon ES, Gupta SK, Spergel JM, Furuta GT, Rothenberg ME
Gastroenterology 2018 Jan;154(2):333-345. Epub 2017 Jul 27 doi: 10.1053/j.gastro.2017.06.065. PMID: 28757265Free PMC Article
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
Galperin G, Berra M, Berra A
Arq Bras Oftalmol 2014 Apr;77(2):119-21. doi: 10.5935/0004-2749.20140030. PMID: 25076479

Prognosis

Topan R, Pandya S, Williams S, Ruffle JK, Zarate-Lopez N, Aziz Q, Fikree A
Am J Gastroenterol 2024 Apr 1;119(4):727-738. Epub 2024 Jan 16 doi: 10.14309/ajg.0000000000002586. PMID: 37970870
Feldman ECH, Homan KJ, Williams SE, Ting TV, Goldschneider KR, Kashikar-Zuck S
Pediatr Rheumatol Online J 2023 Oct 16;21(1):121. doi: 10.1186/s12969-023-00908-6. PMID: 37845704Free PMC Article
Anderson LK, Lane KR
J Am Assoc Nurse Pract 2023 Oct 1;35(10):605-612. doi: 10.1097/JXX.0000000000000900. PMID: 37261967
Baeza-Velasco C, Hamonet C, Montalescot L, Courtet P
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Aubry-Rozier B, Schwitzguebel A, Valerio F, Tanniger J, Paquier C, Berna C, Hügle T, Benaim C
Rheumatol Int 2021 Oct;41(10):1785-1794. Epub 2021 Aug 16 doi: 10.1007/s00296-021-04968-3. PMID: 34398260Free PMC Article

Clinical prediction guides

Topan R, Pandya S, Williams S, Ruffle JK, Zarate-Lopez N, Aziz Q, Fikree A
Am J Gastroenterol 2024 Apr 1;119(4):727-738. Epub 2024 Jan 16 doi: 10.14309/ajg.0000000000002586. PMID: 37970870
Anderson LK, Lane KR
J Am Assoc Nurse Pract 2023 Oct 1;35(10):605-612. doi: 10.1097/JXX.0000000000000900. PMID: 37261967
Tofts LJ, Simmonds J, Schwartz SB, Richheimer RM, O'Connor C, Elias E, Engelbert R, Cleary K, Tinkle BT, Kline AD, Hakim AJ, van Rossum MAJ, Pacey V
Orphanet J Rare Dis 2023 May 4;18(1):104. doi: 10.1186/s13023-023-02717-2. PMID: 37143135Free PMC Article
Spanhove V, De Wandele I, Malfait F, Calders P, Cools A
Disabil Rehabil 2023 Jun;45(11):1811-1821. Epub 2022 May 24 doi: 10.1080/09638288.2022.2076932. PMID: 35609204
Hakim A, O'Callaghan C, De Wandele I, Stiles L, Pocinki A, Rowe P
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):168-174. Epub 2017 Feb 4 doi: 10.1002/ajmg.c.31543. PMID: 28160388

Recent systematic reviews

Alsiri N, Alhadhoud M, Alkatefi T, Palmer S
Semin Arthritis Rheum 2023 Feb;58:152127. Epub 2022 Nov 17 doi: 10.1016/j.semarthrit.2022.152127. PMID: 36462303
Thwaites PA, Gibson PR, Burgell RE
J Gastroenterol Hepatol 2022 Sep;37(9):1693-1709. Epub 2022 Jul 20 doi: 10.1111/jgh.15927. PMID: 35750466Free PMC Article

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