Editing Ehlers–Danlos syndrome (section)

== Types ==
In 2017, 13 subtypes of EDS were classified using specific diagnostic criteria.<ref name="GARD2017"/> According to the [[Ehlers–Danlos Society]], the syndromes can also be grouped by the symptoms determined by specific gene mutations. Group A disorders are those that affect primary collagen structure and processing. Group B disorders affect collagen folding and crosslinking. Group C are disorders of structure and function of myomatrix. Group D disorders are those that affect [[glycosaminoglycan]] biosynthesis. Group E disorders are characterized by defects in the complement pathway. Group F are disorders of intracellular processes, and Group G is considered to be unresolved forms of EDS.<ref name="EDS_2019">{{cite web|url=https://www.ehlers-danlos.com/eds-types/|title=The Types of EDS|website=The Ehlers Danlos Society|access-date=2019-11-06}}</ref>

===Classical===
[[File:PMC3504533 1471-2415-12-47-2 (cropped).png|thumb|Individual with classical EDS displaying skin hyperelasticity.  Not all people with EDS have this trait.]]

Classical EDS is characterized by extremely elastic skin that is fragile and bruises easily and hypermobility of the joints. Molluscoid pseudotumors (calcified [[hematoma]]s that occur over pressure points) and spheroids (cysts that contain fat occurring over forearms and shins) are also often seen. A side complication of the hyperelasticity presented in many EDS cases makes wounds closing on their own more difficult.<ref name="Malfait_2018" /> Sometimes, motor development is delayed and [[hypotonia]] occurs.<ref name=GARD2017>{{cite web|title=Ehlers–Danlos syndromes | work = Genetic and Rare Diseases Information Center (GARD) – an NCATS Program | publisher = U.S. National Institutes of Health |url=https://rarediseases.info.nih.gov/diseases/6322/ehlers-danlos-syndromes |access-date=23 September 2017|date=20 April 2017|url-status=live|archive-url=https://web.archive.org/web/20170924001628/https://rarediseases.info.nih.gov/diseases/6322/ehlers-danlos-syndromes|archive-date=24 September 2017}}{{PD-notice}}</ref> The variation causing this type of EDS is in the genes ''[[COL5A2]], [[COL5A1]],'' and less frequently ''[[COL1A1]]''. It involves the skin more than hEDS.<ref name = "Malfait_2018">{{cite book | vauthors = Malfait F, Wenstrup R, De Paepe A | chapter = Classic Ehlers–Danlos Syndrome| date = July 2018 | chapter-url= http://www.ncbi.nlm.nih.gov/books/NBK1244/| title = GeneReviews |publisher=University of Washington, Seattle |pmid=20301422 |access-date=2019-06-03 | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A}}</ref> In classical EDS, large variation in symptom presentation is seen. Because of this variance, EDS has often been underdiagnosed.<ref>{{cite journal | vauthors = Kapferer-Seebacher I, Lundberg P, Malfait F, Zschocke J | title = Periodontal manifestations of Ehlers–Danlos syndromes: A&nbsp;systematic review | journal = Journal of Clinical Periodontology | volume = 44 | issue = 11 | pages = 1088–1100 | date = November 2017 | pmid = 28836281 | doi = 10.1111/jcpe.12807 | s2cid = 36252998}}</ref> Without genetic testing, healthcare professionals may be able to provide a provisional diagnosis based on careful examination of the mouth, skin, and bones, as well as by neurological assessment.<ref>{{cite journal | vauthors = Castori M | title = Ehlers–Danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations | journal = ISRN Dermatology | volume = 2012 | page = 751768 | date = 2012 | pmid = 23227356 | doi = 10.5402/2012/751768 | pmc = 3512326 | doi-access = free}}</ref>

A good way to begin the diagnostic process is by reviewing a person's family history. EDS is an autosomal dominant condition, so is often inherited from parents.<ref name="Malfait_2018" /> Genetic testing remains the most reliable way to diagnose EDS.<ref>{{cite journal | vauthors = Rakhmanov Y, Maltese PE, Bruson A, Castori M, Beccari T, Dundar M, Bertelli M |date=2018-09-01|title=Genetic testing for vascular Ehlers–Danlos syndrome and other variants with fragility of the middle arteries|url=https://doaj.org/|journal=The EuroBiotech Journal|volume=2|issue=s1|pages=42–44|doi=10.2478/ebtj-2018-0034|s2cid=86589984|issn=2564-615X|doi-access=free}}</ref> No cure for type 1 EDS has been found, but a course of non-weight-bearing exercise can help with muscular tension, which can help correct some EDS symptoms. Anti-inflammatory drugs and lifestyle changes can help with joint pain. Lifestyle choices should also be made with children who have EDS to try to prevent wounds to the skin. Protective garments can help with this. In a wound, deep stitches are often used and left in place for longer than normal.<ref name="Malfait_2018" />

===Classical-like===
Classical-like EDS (clEDS) is characterized by skin hyperextensibility with velvety skin texture and absence of atrophic scarring, generalized joint hypermobility with or without recurrent dislocations (most often shoulder and ankle), and easily bruised skin or spontaneous [[ecchymoses]] (discolorations of the skin resulting from bleeding underneath).<ref name=GARD2017/> It can be caused by variations in the ''[[TNXB]]'' gene.<ref name="Malfait_2017" />

===Arthrochalasia===
Arthrochalasia EDS (aEDS; formerly categorized as types 7A and B) is characterized by severe joint hypermobility and congenital [[hip dislocation]]. Other common features include fragile, elastic skin with easy bruising, [[hypotonia]], [[kyphoscoliosis]] ([[kyphosis]] and [[scoliosis]]), and mild [[osteopenia]].<ref name="GARD2017"/> [[Type I collagen|Type-I collagen]] is usually affected. It is very rare, with about 30 cases reported. It is more severe than the hypermobility type. Variations in the genes'' [[COL1A1]]'' and ''[[COL1A2]] ''cause it.<ref>{{cite journal | vauthors = Klaassens M, Reinstein E, Hilhorst-Hofstee Y, Schrander JJ, Malfait F, Staal H, ten Have LC, Blaauw J, Roggeveen HC, Krakow D, De Paepe A, van Steensel MA, Pals G, Graham JM, Schrander-Stumpel CT | title = Ehlers–Danlos arthrochalasia type (VIIA-B) – expanding the phenotype: from prenatal life through adulthood | journal = Clinical Genetics | volume = 82 | issue = 2 | pages = 121–130 | date = August 2012 | pmid = 21801164 | pmc = 4026000 | doi = 10.1111/j.1399-0004.2011.01758.x}}</ref>

===Brittle-cornea syndrome===
Brittle-cornea syndrome (BCS) is characterized by the progressive thinning of the [[cornea]], early-onset progressive [[keratoglobus]] or keratoconus, nearsightedness, hearing loss, and blue [[sclera]]e.<ref name=GARD2017/><ref name="GARD_2019">{{cite web|url=https://rarediseases.info.nih.gov/diseases/1019/brittle-cornea-syndrome|title=Brittle cornea syndrome | work = Genetic and Rare Diseases Information Center (GARD) – an NCATS Program | publisher = U.S. National Institutes of Health  |access-date=2019-06-03}}</ref> Classic symptoms, such as hypermobile joints and hyperelastic skin, are also seen often.<ref>{{cite web|url=https://www.omim.org/entry/614170|title=OMIM Entry – # 614170 – Brittle Cornea Syndrome 2; BCS2|website=www.omim.org|access-date=2018-06-18}}</ref> It has two types. Type 1 occurs due to variations in the ''[[ZNF469]]'' gene. Type 2 is due to variations in the ''PRDM5'' gene.<ref name="GARD_2019"/>

===Cardiac-valvular===
Cardiac-valvular EDS (cvEDS) is characterized by three major criteria: severe progressive cardiac-valvular problems (affecting aortic and mitral valves), skin problems such as hyperextensibility, atrophic scarring, thin skin, and easy bruising, and joint hypermobility (generalized or restricted to small joints).<ref name=GARD2017/> Four minor criteria may aid in the diagnosis of cvEDS.<ref name="EDS_2019" /> cvEDS is an autosomal recessive disorder, inherited through variation in both [[allele]]s of the gene ''[[COL1A2]].''<ref>{{cite journal | vauthors = Guarnieri V, Morlino S, Di Stolfo G, Mastroianno S, Mazza T, Castori M | title = Cardiac valvular Ehlers–Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2 | journal = American Journal of Medical Genetics. Part A | volume = 179 | issue = 5 | pages = 846–851 | date = May 2019 | pmid = 30821104 | doi = 10.1002/ajmg.a.61100 | s2cid = 73470267}}</ref>

===Dermatosparaxis===
Dermatosparaxis EDS (dEDS; formerly categorized as type 7C) is associated with extremely fragile skin leading to severe bruising and scarring; saggy, redundant skin, especially on the face; hypermobility ranging from mild to serious; and hernias. Variations in the ''[[ADAMTS2]]'' gene cause it. It is extremely rare, with around 11 cases reported worldwide.<ref>{{cite web|url=https://rarediseases.info.nih.gov/diseases/2089/dermatosparaxis-ehlers-danlos-syndrome|title=Dermatosparaxis Ehlers–Danlos syndrome  | work = Genetic and Rare Diseases Information Center (GARD) – an NCATS Program | publisher = U.S. National Institutes of Health |access-date=2019-06-03}}</ref>

===Hypermobile ===
Hypermobile EDS (hEDS, formerly categorized as type 3) is mainly characterized by hypermobility that affects both large and small joints. It may lead to frequent joint [[subluxations]] (partial dislocations) and dislocations. In general, people with this variant have skin that is soft, smooth, and velvety and bruises easily, and may have chronic muscle or bone pain.<ref name="GARD2017"/> It affects the skin less than other forms. It has no available genetic test.<ref name="Levy_2018"/> hEDS is the most common of the 19 types of connective tissue disorders. Since no genetic test exists, providers have to diagnose hEDS based on what they know about the condition and the patient's physical attributes. Other than the general signs, attributes can include faulty connective tissues throughout the body, musculoskeletal issues, and family history. Along with these general signs and side effects, patients can have trouble healing.<ref>{{cite web|url=https://www.ehlers-danlos.org/what-is-eds/information-on-eds/hypermobile-eds-and-hypermobility-spectrum-disorders/|title=Hypermobile EDS and Hypermobility Spectrum Disorders| vauthors = Carter K | work = Ehlers–Danlos Support UK}}</ref>

Pregnant individuals who have hEDS are at an increased risk for complications. Some possible complications are pre-labor rupture of membranes, a drop in blood pressure with anesthesia, [[precipitate delivery|precipitated birth]] (very fast, active labor), malposition of the fetus, and increased bleeding. Individuals with hEDS may run the risk of falling, [[postpartum depression]] (more than the general population), and slow healing from the birthing process.<ref>{{cite web|url=https://www.ehlers-danlos.org/information/pregnancy-birth-feeding-and-hypermobile-ehlers-danlos-syndrome-hypermobility-spectrum-disorders/|title=Pregnancy, birth, feeding, and hypermobile Ehlers–Danlos syndrome/hypermobility spectrum disorders | work = The Ehlers–Danlos Support UK|access-date=2019-11-22}}</ref>

The Medical University of South Carolina discovered a gene variant common with hEDS patients.<ref>{{Cite web | vauthors = Cantu L | date = 14 July 2021 |title=MUSC researchers announce gene mutation discovery associated with EDS |url=https://web.musc.edu/about/news-center/2021/07/14/musc-researchers-announce-gene-mutation-discovery-associated-with-eds-ehlers-danlos |access-date=2023-02-08 | work = Medical University of South Carolina}}</ref>

====Genetics====

While 12 of the 13 subtypes of EDS have genetic variations that can be tested for by [[genetic testing]], there is no known genetic cause of hEDS. Recently, several labs and research initiatives have been attempting to uncover a potential hEDS gene. In 2018, the [[Ehlers–Danlos Society]] began the Hypermobile Ehlers–Danlos Genetic Evaluation (HEDGE) study.<ref>{{cite web |url=https://www.ehlers-danlos.com/hedge/|title=HEDGE Study| website= ehlers-danlos.com| publisher= | date= | access-date=}}</ref> The ongoing study has screened over 1,000 people who have been diagnosed with hEDS by the 2017 criteria to evaluate their genome for a common mutation. To date,{{When|date=March 2025}} 200 people with hEDS have had [[whole genome sequencing]], and 500 have had whole [[Exome sequencing|exome]] sequencing; this study aims to increase those numbers significantly. <ref>{{cite web |url=https://www.ehlers-danlos.com/hedge/|title=HEDGE Study| website= ehlers-danlos.com| publisher= | date= | access-date=}}</ref>

Promising outcomes of this increased screening have been reported by the Norris Lab, led by Russell Norris, in the Department of Regenerative Medicine and Cell Biology at [[Medical University of South Carolina]].<ref>{{cite web |url=https://www.thenorrislab.com/home|title= About the Lab| publisher= Norris Lab, [[Medical University of South Carolina]]| date= | access-date=}}</ref> Using [[CRISPR]] Cas-9 mediated genome editing on mouse models of the disease, the lab has recently identified a "very strong candidate gene"<ref>{{cite journal | vauthors = Gensemer C, Burks R, Kautz S, Judge DP, Lavallee M, Norris RA | title = Hypermobile Ehlers–Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes | journal = Developmental Dynamics | volume = 250 | issue = 3 | pages = 318–344 | date = March 2021 | pmid = 32629534 | pmc = 7785693 | doi = 10.1002/dvdy.220}}</ref> for hEDS. This finding, and a greater understanding of cardiac complications associated with the majority of EDS subtypes, has led to the development of multiple druggable pathways involved in [[Aorta|aortic]] and [[mitral valve]] diseases. While this candidate gene has not been publicly identified, the Norris lab has conducted several studies involving small population genome sequencing and come up with a working list of possible hEDS genes. A mutation in [[Collagen, type III, alpha 1|''COL3A1'']]<ref>{{cite journal | vauthors = Narcisi P, Richards AJ, Ferguson SD, Pope FM | title = A family with Ehlers–Danlos syndrome type III/articular hypermobility syndrome has a glycine 637 to serine substitution in type III collagen | journal = Human Molecular Genetics | volume = 3 | issue = 9 | pages = 1617–1620 | date = September 1994 | pmid = 7833919 | doi = 10.1093/hmg/3.9.1617}}</ref> in a single family with autosomal dominant hEDS phenotype was found to cause reduced collagen secretion and an over-modification of collagen. In 35 families, copy number alterations in ''[[TPSAB1]]'',<ref>{{cite journal | vauthors = Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, Ho N, Zhao M, Liu Y, O'Connell MP, Trivedi NN, Nelson C, DiMaggio T, Jones N, Matthews H, Lewis KL, Oler AJ, Carlson RJ, Arkwright PD, Hong C, Agama S, Wilson TM, Tucker S, Zhang Y, McElwee JJ, Pao M, Glover SC, Rothenberg ME, Hohman RJ, Stone KD, Caughey GH, Heller T, Metcalfe DD, Biesecker LG, Schwartz LB, Milner JD | title = Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number | journal = Nature Genetics | volume = 48 | issue = 12 | pages = 1564–1569 | date = December 2016 | pmid = 27749843 | pmc = 5397297 | doi = 10.1038/ng.3696}}</ref> encoding alpha-tryptase, were associated with increased basal serum [[tryptase]] levels, associated with [[Dysautonomia|autonomic dysfunction]], [[Gastrointestinal disease|gastrointestinal disorders]], allergic and cutaneous symptoms, and connective tissue abnormalities, all concurrent with hEDS phenotype. An unknown number of people diagnosed with hEDS may have a reduced [[Tenascin X]],and/or mutations in the [[TNXB]] gene.<ref>Zweers, Manon C et al. “Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome.” American journal of human genetics vol. 73,1 (2003): 214-7. doi:10.1086/376564</ref><ref name="Kaufman_2016">{{cite journal | vauthors = Kaufman CS, Butler MG | title = Mutation in TNXB gene causes moderate to severe Ehlers-Danlos syndrome | journal = World Journal of Medical Genetics | volume = 6 | issue = 2 | pages = 17–21 | date = May 2016 | pmid = 28344932 | pmc = 5363719 | doi = 10.5496/wjmg.v6.i2.17 | doi-access = free }}</ref>

Another way the Norris lab is attempting to find this gene is by looking at genes involved in the formation of the aorta and mitral valves, as these valves are often prolapsed or malformed as a symptom of EDS. Because hEDS is such a complex, multi-organ disease, focusing on one hallmark trait has proven successful. One gene found this way is ''[[DZIP1]]'', which regulates cardiac valve development in mammals through a [[CBY1]]-beta-catenin mechanism. Mutations at this gene affect the [[Catenin beta-1|beta-catenin]] cascade involved in development, causing malformation of the extracellular matrix, resulting in loss of collagen. A lack of collagen here is consistent with hEDS and explains the "floppy" mitral and aortic valve heart defects. A second genetic study specific to mitral valve prolapse focused on the [[Platelet-derived growth factor|PDGF]] signaling pathway, which is involved in growth factor ligands and receptor isoforms.<ref>{{cite journal | vauthors = Moore K, Fulmer D, Guo L, Koren N, Glover J, Moore R, Gensemer C, Beck T, Morningstar J, Stairley R, Norris RA | title = PDGFRα: Expression and Function during Mitral Valve Morphogenesis | journal = Journal of Cardiovascular Development and Disease | volume = 8 | issue = 3 | date = March 2021 | page = 28 | pmid = 33805717 | doi = 10.3390/jcdd8030028 | pmc = 7999759 | doi-access = free}}</ref> Mutations in this pathway affect the ability to localize [[cilia]] in various cell types, including cardiac cells. With the resulting [[ciliopathies]], structures such as the [[cardiac outflow tract]], [[heart tube]] assembly, and cardiac fusion are limited and/or damaged.{{citation needed|date=September 2022}}

===Kyphoscoliosis===
Kyphoscoliosis EDS (kEDS; formerly categorized as type 6) is associated with severe [[hypotonia]] at birth, delayed motor development, progressive [[scoliosis]] (present from birth), and scleral fragility. People may also have easy bruising, fragile arteries that are prone to rupture, unusually small corneas, and [[osteopenia]] (low bone density). Other common features include a "[[marfanoid]] habitus" characterized by long, slender fingers ([[arachnodactyly]]), unusually long limbs, and a sunken chest ([[pectus excavatum]]) or protruding chest ([[pectus carinatum]]).<ref name="GARD2017"/> It can be caused by variations in the gene ''[[PLOD1]]'', or rarely, in the ''[[FKBP14]]'' gene.<ref>{{cite web|url=https://rarediseases.info.nih.gov/diseases/2083/kyphoscoliotic-ehlers-danlos-syndrome|title=Kyphoscoliotic Ehlers–Danlos syndrome | work = Genetic and Rare Diseases Information Center (GARD) – an NCATS Program | publisher = U.S. National Institutes of Health |access-date=2019-06-03}}</ref>

===Musculocontractural===
Musculocontractural EDS (mcEDS) is characterized by congenital multiple contractures, characteristically adduction-flexion contractures and/or [[talipes equinovarus]] ([[clubfoot]]), characteristic craniofacial features, which are evident at birth or in early infancy, and skin features such as skin hyperextensibility, bruising, skin fragility with atrophic scars, and increased palmar wrinkling.<ref name=GARD2017/> It can be caused by variations in the ''[[CHST14]]'' gene. Some other cases can be caused by variations in the ''[[DSE (gene)|DSE]]'' gene.<ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/gtr/conditions/C1866294/|title=Ehlers–Danlos syndrome, musculocontractural type - Conditions – GTR – NCBI|website=www.ncbi.nlm.nih.gov|access-date=2019-09-22}}</ref>

As of 2021, 48 individuals have been reported to have mcEDS-CHST14, while 8 individuals have mcEDS-DSE.<ref>{{cite journal | vauthors = Nitahara-Kasahara Y, Mizumoto S, Inoue YU, Saka S, Posadas-Herrera G, Nakamura-Takahashi A, Takahashi Y, Hashimoto A, Konishi K, Miyata S, Masuda C, Matsumoto E, Maruoka Y, Yoshizawa T, Tanase T, Inoue T, Yamada S, Nomura Y, Takeda S, Watanabe A, Kosho T, Okada T | title = A new mouse model of Ehlers–Danlos syndrome generated using CRISPR/Cas9-mediated genomic editing | journal = Disease Models & Mechanisms | volume = 14 | issue = 12 | pages = dmm048963 | date = December 2021 | pmid = 34850861 | pmc = 8713987 | doi = 10.1242/dmm.048963 | doi-access = free}}</ref>

===Myopathic===
[[Bethlem myopathy|Bethlem myopathy 2]], formally known as Myopathic EDS (mEDS), is characterized by three major criteria: congenital muscle [[hypotonia]] and/or [[muscle atrophy]] that improves with age, proximal joint contractures of the knee, hip, and elbow, and hypermobility of distal joints (ankles, wrists, feet, and hands).<ref name=GARD2017/> Four minor criteria may also contribute to a diagnosis of mEDS. This disorder can be inherited through either an autosomal dominant or an autosomal recessive pattern.<ref name="EDS_2019" /> Molecular testing must be completed to verify that mutations in the ''[[COL12A1]]'' gene are present; if not, other collagen-type myopathies should be considered.<ref name="EDS_2019" />

===Periodontal===
Periodontal EDS (pEDS) is an autosomal-dominant disorder<ref name="EDS_2019" /> characterized by four major criteria of severe and intractable [[Periodontal disease|periodontitis]] of early-onset (childhood or adolescence), lack of attached [[Gums|gingiva]], pretibial plaques, and family history of a first-degree relative who meets clinical criteria.<ref name=GARD2017/> Eight minor criteria may also contribute to the diagnosis of pEDS. Molecular testing may reveal mutations in ''[[C1R]]'' or ''[[C1S]]'' genes affecting the [[C1r]] protein.<ref name="EDS_2019" />

===Spondylodysplastic===
Spondylodysplastic EDS (spEDS) is characterized by short stature (progressive in childhood), muscle [[hypotonia]] (ranging from severe congenital to mild later-onset), and bowing of limbs.<ref name=GARD2017/> It can be caused by variations in both copies of the ''[[B4GALT7]]'' gene. Other cases can be caused by variations in the ''B3GALT6'' gene. People with variations in this gene can have [[kyphoscoliosis]], tapered fingers, [[osteoporosis]], [[aortic aneurysm]]s, and problems with the lungs. Other cases can be caused by the ''SLC39A13'' gene. Those with variations in this gene have protuberant eyes, wrinkled palms of the hands, tapering fingers, and distal joint hypermobility.<ref>{{cite web|url=https://rarediseases.info.nih.gov/diseases/9991/spondylodysplastic-ehlers-danlos-syndrome/cases/31481#4870|title=Spondylodysplastic Ehlers–Danlos syndrome | work = Genetic and Rare Diseases Information Center (GARD) – an NCATS Program | publisher = U.S. National Institutes of Health  |access-date=2019-09-22|archive-date=2020-07-08|archive-url=https://web.archive.org/web/20200708114805/https://rarediseases.info.nih.gov/diseases/9991/spondylodysplastic-ehlers-danlos-syndrome/cases/31481#4870|url-status=dead}}</ref>

===Vascular===
Vascular EDS (vEDS; formerly categorized as type 4) is identified by skin that is thin, translucent, extremely fragile, and bruises easily. It is also characterized by fragile blood vessels and organs that can easily rupture. Affected people are frequently short, and have thin scalp hair. It also has characteristic facial features, including large eyes, an undersized chin, sunken cheeks, a thin nose and lips, and ears without lobes.<ref name="Eagleton2016">{{cite journal | vauthors = Eagleton MJ | title = Arterial complications of vascular Ehlers–Danlos syndrome | journal = Journal of Vascular Surgery | volume = 64 | issue = 6 | pages = 1869–1880 | date = December 2016 | pmid = 27687326 | doi = 10.1016/j.jvs.2016.06.120 | url = https://www.jvascsurg.org/article/S0741-5214(16)30876-X/fulltext | doi-access = free}} {{open access}}</ref> Joint hypermobility is present, but generally confined to the small joints (fingers, toes). Other common features include [[Clubfoot|club foot]], tendon and/or muscle rupture, [[acrogeria]] (premature aging of the skin of the hands and feet), early-onset [[varicose veins]], [[pneumothorax]] (collapse of a lung), the recession of the gums, and a decreased amount of fat under the skin.<ref name="GARD2017" /> It can be caused by the variations in the ''[[COL3A1]]'' gene.<ref name="Eagleton2016" /> Rarely, ''[[COL1A1]]'' variations can also cause it.<ref name="Malfait_2017"/>