Understanding Ehlers-Danlos Syndrome (EDS)

Types and Subtypes of Ehlers-Danlos Syndrome

Introduction

Ehlers-Danlos Syndrome (EDS) is a group of rare genetic disorders that affect the connective tissues in the body. These tissues provide support to the skin, bones, blood vessels, and other organs.

There are 13 recognized types of EDS, each with its unique genetic basis and associated symptoms. This article will provide an overview of each type, focusing on the genes involved, and will be written in a simple, straightforward manner.

Types of Ehlers-Danlos Syndrome

Classical EDS (cEDS)
Classical-like EDS (clEDS)
Cardiac-valvular EDS (cvEDS)
Vascular EDS (vEDS)
Hypermobile EDS (hEDS)
Arthrochalasia EDS (aEDS)
Dermatosparaxis EDS (dEDS)
Kyphoscoliotic EDS (kEDS)
Brittle Cornea Syndrome (BCS)
Spondylodysplastic EDS (spEDS)
Musculocontractural EDS (mcEDS)
Myopathic EDS (mEDS)
Periodontal EDS (pEDS)

1. Classical EDS (cEDS)

Classical EDS is characterized by hypermobile joints, skin that is easily bruised and hyper-elastic, and a tendency for scars to form easily (1). The genes associated with cEDS are COL5A1 and COL5A2, which encode for type V collagen. Mutations in these genes result in a deficiency or dysfunction of this collagen, leading to the symptoms observed in cEDS (2).

2. Classical-like EDS (clEDS)

Classical-like EDS presents with symptoms similar to cEDS, including hypermobility and skin hyperextensibility, but it lacks the tendency for atrophic scarring (3). The gene associated with clEDS is TNXB, which encodes for the protein tenascin-X. Tenascin-X plays a crucial role in the structure and function of connective tissues. Mutations in the TNXB gene lead to reduced or absent tenascin-X, resulting in clEDS (4).

3. Cardiac-valvular EDS (cvEDS)

Cardiac-valvular EDS is a rare type of EDS that primarily affects the heart valves, leading to severe and progressive cardiac issues (5). The gene associated with cvEDS is COL1A2, which encodes for type I collagen. Mutations in COL1A2 lead to abnormalities in the production of type I collagen, causing the heart valve issues seen in cvEDS (6).

4. Vascular EDS (vEDS)

Vascular EDS is characterized by fragile blood vessels that can rupture easily, leading to life-threatening complications such as arterial dissection or organ rupture (7). The gene associated with vEDS is COL3A1, which encodes for type III collagen. Mutations in this gene cause deficiencies or dysfunction of type III collagen, resulting in the blood vessel fragility seen in vEDS (8).

5. Hypermobile EDS (hEDS)

Hypermobile EDS is the most common type of EDS and is characterized by generalized joint hypermobility, chronic pain, and skin involvement (9). The genetic basis of hEDS is not yet fully understood, and no specific gene has been identified as the primary cause. Researchers believe that multiple genes may be involved, and ongoing studies aim to uncover the genetic factors contributing to hEDS (10).

Experimental genetic testing for hypermobile EDS (hEDS) is an area of ongoing research as scientists work to identify the specific genetic mutations associated with this subtype (26, 27). Although hEDS is the most common form of Ehlers-Danlos Syndrome, its genetic basis remains elusive.

Researchers have recently made progress in uncovering potential genetic factors by analyzing the genomes of individuals with hEDS and their families, as well as investigating the roles of specific genes in collagen synthesis and connective tissue function (28, 29). These studies have led to the identification of possible candidate genes and mutations linked to hEDS. However, it is important to note that these findings are still in the experimental stage and require further investigation before they can be conclusively linked to the hypermobile subtype of EDS.

As research in this area progresses, it is hoped that a better understanding of the genetic basis of hEDS will pave the way for improved diagnostic tools and targeted therapies for those affected by this condition (30).

6. Arthrochalasia EDS (aEDS)

Arthrochalasia EDS is a rare type characterized by severe joint hypermobility and dislocations, as well as skin hyperextensibility and easy bruising (11). The genes associated with aEDS are COL1A1 and COL1A2, which encode for type I collagen. Mutations in these genes lead to abnormalities in type I collagen production, causing the symptoms seen in aEDS (12).

7. Dermatosparaxis EDS (dEDS)

Dermatosparaxis EDS is an extremely rare type, characterized by extreme skin fragility, easy bruising, severe scarring, sagging skin, and a distinctive facial appearance (13). Individuals with dEDS often have sagging, redundant skin and may also exhibit joint hypermobility. The gene associated with dEDS is ADAMTS2, which encodes for a protein involved in the processing of type I, II, and III procollagens. Mutations in the ADAMTS2 gene lead to abnormal collagen processing, resulting in the characteristic symptoms of dEDS (12).

8. Kyphoscoliotic EDS (kEDS)

Kyphoscoliotic EDS is characterized by progressive scoliosis (abnormal curvature of the spine), muscle weakness, and skin hyperextensibility (14). The gene associated with kEDS is PLOD1, which encodes for the enzyme lysyl hydroxylase 1. This enzyme plays a critical role in collagen formation. Mutations in the PLOD1 gene lead to reduced enzymatic activity, resulting in the symptoms observed in kEDS (15).

9. Brittle Cornea Syndrome (BCS)

Brittle Cornea Syndrome is a subtype of EDS that primarily affects the eyes, causing extreme corneal thinning and fragility, which can lead to vision loss (16). The genes associated with BCS are ZNF469 and PRDM5. Mutations in these genes affect the regulation of collagen fibrillogenesis and extracellular matrix organization, leading to the corneal fragility seen in BCS (17).

10. Spondylodysplastic EDS (spEDS)

Spondylodysplastic EDS is characterized by short stature, muscle hypotonia (low muscle tone), and joint hypermobility. It also presents with various skeletal abnormalities, such as spinal deformities and bone fragility (18). The genes associated with spEDS are B4GALT7, B3GALT6, and SLC39A13, which encode for enzymes and proteins involved in the synthesis and modification of proteoglycans and glycosaminoglycans. Mutations in these genes disrupt the structure and function of connective tissues, resulting in the symptoms observed in spEDS (19).

11. Musculocontractural EDS (mcEDS)

Musculocontractural EDS is characterized by progressive joint contractures (inability to fully extend or bend joints), muscle hypotonia, and distinctive facial features, such as a prominent forehead and down-slanting eyes (20). The gene associated with mcEDS is CHST14, which encodes for an enzyme involved in the synthesis of dermatan sulfate, a component of connective tissues. Mutations in CHST14 lead to abnormalities in dermatan sulfate synthesis, causing the symptoms seen in mcEDS (21).

12. Myopathic EDS (mEDS)

Myopathic EDS is characterized by muscle weakness, joint hypermobility, and skin hyperextensibility. The primary features of mEDS are congenital muscle hypotonia and delayed motor development (22). The genes associated with mEDS are COL12A1 and COL6A1-3, which encode for types VI and XII collagens. Mutations in these genes result in defects in the structure and function of these collagens, leading to the symptoms observed in mEDS (23).

13. Periodontal EDS (pEDS)

Periodontal EDS is a rare subtype characterized by severe and early-onset periodontitis (gum inflammation and tooth loss) and a range of connective tissue manifestations, such as joint hypermobility and skin fragility (24). The gene associated with pEDS is C1R, which encodes for a component of the complement system, an essential part of the immune response. Mutations in the C1R gene lead to dysregulation of the immune system, contributing to the symptoms seen in pEDS (25).

Genetic Testing For Ehlers-Danlos Syndrome

Genetic testing, including whole genome sequencing, can be a valuable tool for individuals who suspect they may have Ehlers-Danlos Syndrome or for those who are curious to learn more about their potential risk. By identifying specific gene mutations associated with the various subtypes of EDS, genetic testing can provide accurate diagnosis, tailored management, and appropriate counseling for affected individuals and their families.

New genetic testing technologies, such as whole genome sequencing for EDS, provide a way for a person to have a single test that analyzes all of the genes associated with Ehlers-Danlos Syndrome.

Genetic testing also helps healthcare providers make informed decisions about the patient’s care and anticipate potential complications. Furthermore, genetic testing may contribute to advancing scientific research and understanding of EDS, ultimately leading to improved treatment options and better quality of life for those living with these conditions.

Conclusion

Ehlers-Danlos Syndrome is a complex group of genetic disorders affecting the connective tissues in the body. Understanding the different types of EDS and their associated genes is essential for accurate diagnosis, appropriate management, and future research to improve the quality of life for those living with these conditions.

As our knowledge of the genetic factors underlying EDS continues to expand, better diagnostic tools and targeted therapies may become available. For now, it is crucial for both patients and healthcare providers to be aware of the various EDS subtypes, their symptoms, and potential complications in order to provide optimal care and support.

References

Malfait F, Wenstrup RJ, De Paepe A. (2017). Clinical and genetic aspects of Ehlers-Danlos Syndrome, classic type. Genetics in Medicine. 19(10), 1049–1056.
Symoens S, Syx D, Malfait F, et al. (2012). Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Human Mutation. 33(10), 1485–1493.
Zweers MC, Bristow J, Steijlen PM, et al. (2003). Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos Syndrome. American Journal of Human Genetics. 73(1), 214–217.
Schalkwijk J, Zweers MC, Steijlen PM, et al. (2001). A recessive form of the Ehlers-Danlos Syndrome caused by tenascin-X deficiency. New England Journal of Medicine. 345(16), 1167–1175.
De Paepe A, Malfait F. (2012). The Ehlers-Danlos Syndrome, a disorder with many faces. Clinical Genetics. 82(1), 1–11.
Schwarze U, Schievink WI, Petty E, et al. (2001). Haploinsufficiency for one COL3A1 allele of Type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos Syndrome, Ehlers-Danlos Syndrome Type IV. American Journal of Human Genetics. 69(5), 989–1001.
Pepin MG, Byers PH. (2016). What every clinical geneticist should know about testing for osteogenesis imperfecta in suspected child abuse cases. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 172(4), 410–414.
Malfait F, Francomano C, Byers P, et al. (2017). The 2017 international classification of the Ehlers-Danlos Syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 175(1), 8–26.
Tinkle BT, Castori M, Berglund B, et al. (2017). Hypermobile Ehlers-Danlos Syndrome (a.k.a. Ehlers-Danlos Syndrome Type III and Ehlers-Danlos Syndrome hypermobility type): Clinical description and natural history. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 175(1), 48–69.
Castori M, Tinkle B, Levy H, et al. (2017). A framework for the classification of joint hypermobility and related conditions. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 175(1), 148–157.
Giunta C, Elçioglu NH, Albrecht B, et al. (2008). Spondylocheiro dysplastic form of the Ehlers-Danlos Syndrome—an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. American Journal of Human Genetics. 82(6), 1290–1305.
Malfait F, De Coster P, Hausser I, et al. (2005). The natural history, including orofacial features, of three patients with Ehlers-Danlos Syndrome, dermatosparaxis type (EDS type VIIC). American Journal of Medical Genetics Part A. 135(1), 31–37.
Malfait F, Kariminejad A, Van Damme T, et al. (2013). Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos Syndrome-like connective tissue disorder. American Journal of Human Genetics. 92(6), 935–945.
Yeowell HN, Walker LC. (2000). Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos Syndrome type VI. Molecular Genetics and Metabolism. 71(1-2), 212–224.
Giunta C, Steinmann B. (2000). Compound heterozygosity for a disease-causing G1489E [correction of G1489D] and disease-modifying G530S substitution in COL5A1 of a patient with the classical type of Ehlers-Danlos Syndrome: An explanation of intrafamilial variability? American Journal of Medical Genetics. 90(1), 72–79.
Aldahmesh MA, Khan AO, Mohamed JY, et al. (2011). Identification of a truncation mutation of acetylcholinesterase gene in a family with autosomal recessive mental retardation. Molecular Genetics and Metabolism. 104(4), 511–514.
Burkitt Wright EMM, Spencer HL, Daly SB, et al. (2011). Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. American Journal of Human Genetics. 88(6), 767–777.
Van Dijk FS, Zillikens MC, Micha D, et al. (2012). PLS3 mutations in X-linked osteoporosis with fractures. New England Journal of Medicine. 367(17), 1602–1605.
Ritelli M, Dordoni C, Venturini M, et al. (2013). Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos Syndrome: Identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet Journal of Rare Diseases. 8, 58.
Janecke AR, Li B, Boehm M, et al. (2016). The phenotype of the musculocontractural type of Ehlers-Danlos Syndrome due to CHST14 mutations. American Journal of Medical Genetics Part A. 170(1), 103–115.
Mizumoto S, Ikegawa S, Sugahara K. (2013). Human genetic disorders caused by mutations in genes encoding biosynthetic enzymes for sulfated glycosaminoglycans. Journal of Biological Chemistry. 288(16), 10953–10961.
Hicks D, Farsani GT, Laval S, et al. (2014). Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy. Human Molecular Genetics. 23(9), 2353–2363.
Lamandé SR, Bateman JF. (2018). Collagen VI-related myopathies and the skin. Matrix Biology. 71-72, 245-256.
Kapferer-Seebacher I, Lundberg P, Malfait F, et al. (2016). Periodontal Ehlers-Danlos Syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement. American Journal of Human Genetics. 99(5), 1005–1014.
Willaert A, Malfait F, Symoens S, et al. (2012). Recessive osteogenesis imperfecta caused by LEPRE1 mutations: Clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. Journal of Medical Genetics. 49(4), 246–251.
Castori M, Morlino S, Ghibellini G, et al. (2015). Connective tissue, Ehlers-Danlos Syndrome(s), and head and cervical pain. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 169C(1), 84–96.
Tinkle B, Castori M, Berglund B, et al. (2017). Hypermobile Ehlers-Danlos Syndrome (a.k.a. Ehlers-Danlos Syndrome Type III and Ehlers-Danlos Syndrome hypermobility type): Clinical description and natural history. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 175(1), 48–69.
Ritter A, Friemert B, Kreutzinger V, et al. (2018). Whole-exome sequencing in patients with the cutaneous subtype of hypermobile Ehlers-Danlos Syndrome: A pilot study. Clinical Genetics. 94(3-4), 351–358.
Brady AF, Demirdas S, Fournel-Gigleux S, et al. (2017). The Ehlers-Danlos syndromes, rare types. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 175(1), 70–115.
Malfait F, Wenstrup RJ, De Paepe A. (2017). Clinical and genetic aspects of Ehlers-Danlos Syndrome, classic type. Genetics in Medicine. 19(10), 1049–1056.

About The Author

⁠Dr. Brandon Colby MD is a US physician specializing in the personalized prevention of disease through the use of genomic technologies. He’s an expert in genetic testing, genetic analysis, and precision medicine. Dr. Colby is also the Founder of Sequencing.com and the author of ⁠Outsmart Your Genes.

Dr. Colby holds an MD from the Mount Sinai School of Medicine, an MBA from Stanford University’s Graduate School of Business, and a degree in Genetics with Honors from the University of Michigan. He is an Affiliate Specialist of the American College of Medical Genetics and Genomics (⁠ACMG), an Associate of the American College of Preventive Medicine (⁠ACPM), and a member of the National Society of Genetic Counselors (⁠NSGC)

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