What is Ehlers-Danlos Syndrome Type VIIC?Ehlers-Danlos Syndrome (EDS) Type VIIC is a connective tissue disorder that is a rare type of the 13 types of Ehlers-Danlos Syndromes. A person afflicted with EDS Type VIIC lacks proper fibrillar collagen type 1 processing pathways [1]. Fibrillar collagen is a connective protein that gives animal tissue such as skin, tendon, and bone tensile strength and structure when properly assembled and structured [1]. The formation of fibrillar collagen is a multi-step process that takes three smaller collagen fibers and wraps them around each other into a rope-like structure that forms procollagen [1,2]. Disturbing the normal process and causing collagen to form incorrectly can cause severe damage in the skin, tendon, and bones. In EDS Type VIIC, the main type of damage is labeled as dermatosparaxis: tearing of skin due to collagen defects. This leads to EDS Type VIIC being also referred to as dermatosparaxis-type EDS, or dEDS for short.
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The many tissue types that collagen effects [13].
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Symptoms
In EDS Type VIIC, main symptoms are spread throughout the body's connective and structural tissues since these tissues rely on type I collagen.
Symptoms include:
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This is a video produced by Special Books by Special Kids of a short interview with Henny, one of the few people in the world diagnosed with EDS Type VIIC [13].
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Testing and Treatment
Testing and DiagnosisThe clinical diagnosis for the many types of EDS requires family history, clinical features, and laboratory testing such as genetic testing [6]. For EDS Type VIIC, clinical features (symptoms) are split into major and minor criteria. The most important major criteria are extreme skin fragility and characteristic craniofacial features [7]. However, one more major criteria and/or three other minor criteria are necessary. These criteria can be found at https://rarediseases.info.nih.gov [7]. MRIs and CT scans can be particularly helpful in diagnosis because these tests can show hernias and other internal issues present in the body [6].
Genetic testing usually is the final diagnosis and confirmation for EDS Type VIIC after major and minor criteria are classified [3]. Results should come back positive for loss of function mutations in ADAMTS2 [3]. |
ManagementSince there is no specific treatment for EDS Type VIIC, treatment is focused on management and relief of symptoms and preventing serious complications.
Management options include:
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ADAMTS2: Function and ImportanceEDS Type VIIC is caused by a homozygous or compound heterozygous mutation in the gene ADAMTS2 that codes for the ADAMTS2 protein [3]. ADAMTS2 is a metalloproteinase that is the main procollagen N-endopeptidase [3]. An endopeptidase is an enzyme that cleaves the peptide bonds between the amino acids in a peptide chain, except for the terminal bond. During the processing of type I procollagen to type I collagen, normal ADAMTS2 clips a short chain of amino acids off the Nitrogen (N) side of the procollagen [5]. This clipping step is necessary for the proper function of collagen molecules and for the ability for collagen to form into fibrils outside of cells [5]. When dysfunctional or present in reduced amounts, ADAMTS2 fails to cleave the N side of the procollagen, leading to pN-collagen type I (collagen fibers with their N-side still intact) and a ribbon like morphology once assembled into fibrils [3,5,Figure 1]. This ribbon-like morphology in collagen assembly help cause the symptoms indicative of EDS Type VIIC.
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Figure 1: ADAMTS2 is critical for fibrillar collagen formation [1].
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Gaps in Knowledge
While a lot is known about ADAMTS2 and its role in EDS Type VIIC, much is still a mystery that needs to be unraveled to fully understand the disease and various functions of ADAMTS2. Some of these questions include:
- What is the precise mechanism for how other proteins inhibit ADAMTS2?
- What are the functional consequences of ADAMTS2 mutations in collagen crosslinking, and is crosslinking dysregulated in ADAMTS2 patients?
- How does ADAMTS2 cause bone growth defects like the shortening of limbs?
InheritanceTwo mutations instead of one are required to develop EDS Type VIIC, and therefore it is classified as an autosomal recessive disorder [5]. An autosomal recessive disorder means that both parents need at least one mutant copy of the gene on a chromosome, and they have to give that chromosome to their offspring instead of their non-mutant chromosome. Figure 2 outlines what an autosomal recessive disorder is when both parents have one copy of the mutated chromosome/gene. If one of the parents has the disease (two copies of the bad gene), then the chance for their offspring to have the disease increases. Up until 2017, only 8 biallelic mutations in ADAMTS2 have been recorded in 15 patients that have lead to deficiency of ADAMTS2 and development of EDS Type VIIC [3]. This gives EDS Type VIIC its rare EDS subtype. ADAMTS2 is located on the long q-arm of chromosome 5 at the end (terminus) of the arm (5q35.3), from base pair 178,473,473 to base pair 178,704,934 [4].
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Figure 2: Autosomal recessive inheritance pattern when both parents are a carrier [9].
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References
[1] Bekhouche, M., & Colige, A. (2015). The procollagen N-proteinases ADAMTS2, 3 and 14 in pathophysiology. Matrix Biol, 44-46, 46-53. https://doi.org/10.1016/j.matbio.2015.04.001
[2] Canty, E. G., & Kadler, K. E. (2005). Procollagen trafficking, processing and fibrillogenesis. J Cell Sci, 118(Pt 7), 1341-1353. https://doi.org/10.1242/jcs.01731
[3] Brady, A. F., Demirdas, S., Fournel-Gigleux, S., Ghali, N., Giunta, C., Kapferer-Seebacher, I., Kosho, T., Mendoza-Londono, R., Pope, M. F., Rohrbach, M., Van Damme, T., Vandersteen, A., van Mourik, C., Voermans, N., Zschocke, J., & Malfait, F. (2017). The Ehlers-Danlos syndromes, rare types. Am J Med Genet C Semin Med Genet, 175(1), 70-115. https://doi.org/10.1002/ajmg.c.31550
[4] https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADAMTS2
[5] Rincón-Sánchez, A. R., Arce, I. E., Tostado-Rabago, E. A., Vargas, A., Padilla-Gómez, L. A., Bolaños, A., Barrios-Guyot, S., Anguiano-Alvarez, V. M., Ledezma-Rodríguez, V. C., Islas-Carbajal, M. C., Rivas-Estilla, A. M., Feria-Velasco, A., & Dávalos, N. O. (2012). Ehlers-Danlos Syndrome Type VIIC: A Mexican Case Report. Case Rep Dermatol, 4(1), 104-113. https://doi.org/10.1159/000338277
[6] Islam, M., Chang, C., & Gershwin, M. E. (2021). Ehlers-Danlos Syndrome: Immunologic contrasts and connective tissue comparisons. J Transl Autoimmun, 4, 100077. https://doi.org/10.1016/j.jtauto.2020.100077
[7] https://rarediseases.info.nih.gov/diseases/2089/dermatosparaxis-ehlers-danlos-syndrome#:~:text=Summary,-Listen&text=Dermatosparaxis%20Ehlers%2DDanlos%20syndrome%20(dEDS,mild%20to%20severe%20joint%20hypermobility.
Image References:
[8] Header Image: Photo by Shmma Quraishe at https://www.southampton.ac.uk/biu/galleries/annualmicrographcomp/2015.page
[9] https://www.geneticsupport.org/wp-content/uploads/2017/09/AR-inheritance.jpg
[10] www.collaborativehp.com/employers/physical-therapy.html
[11] https://synappsehealth.com/en/articles/i/preparation-for-laboratory-tests-blood-and-urine-in-10-steps/
[12] http://www.clker.com/clipart-blank-pill-bottle-3.html
[13] https://www.theenduranceedge.com/2018/08/collagen-peptides/
Video References:
[14] https://www.youtube.com/watch?v=Io4T-2F1L0k&t=12s
[1] Bekhouche, M., & Colige, A. (2015). The procollagen N-proteinases ADAMTS2, 3 and 14 in pathophysiology. Matrix Biol, 44-46, 46-53. https://doi.org/10.1016/j.matbio.2015.04.001
[2] Canty, E. G., & Kadler, K. E. (2005). Procollagen trafficking, processing and fibrillogenesis. J Cell Sci, 118(Pt 7), 1341-1353. https://doi.org/10.1242/jcs.01731
[3] Brady, A. F., Demirdas, S., Fournel-Gigleux, S., Ghali, N., Giunta, C., Kapferer-Seebacher, I., Kosho, T., Mendoza-Londono, R., Pope, M. F., Rohrbach, M., Van Damme, T., Vandersteen, A., van Mourik, C., Voermans, N., Zschocke, J., & Malfait, F. (2017). The Ehlers-Danlos syndromes, rare types. Am J Med Genet C Semin Med Genet, 175(1), 70-115. https://doi.org/10.1002/ajmg.c.31550
[4] https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADAMTS2
[5] Rincón-Sánchez, A. R., Arce, I. E., Tostado-Rabago, E. A., Vargas, A., Padilla-Gómez, L. A., Bolaños, A., Barrios-Guyot, S., Anguiano-Alvarez, V. M., Ledezma-Rodríguez, V. C., Islas-Carbajal, M. C., Rivas-Estilla, A. M., Feria-Velasco, A., & Dávalos, N. O. (2012). Ehlers-Danlos Syndrome Type VIIC: A Mexican Case Report. Case Rep Dermatol, 4(1), 104-113. https://doi.org/10.1159/000338277
[6] Islam, M., Chang, C., & Gershwin, M. E. (2021). Ehlers-Danlos Syndrome: Immunologic contrasts and connective tissue comparisons. J Transl Autoimmun, 4, 100077. https://doi.org/10.1016/j.jtauto.2020.100077
[7] https://rarediseases.info.nih.gov/diseases/2089/dermatosparaxis-ehlers-danlos-syndrome#:~:text=Summary,-Listen&text=Dermatosparaxis%20Ehlers%2DDanlos%20syndrome%20(dEDS,mild%20to%20severe%20joint%20hypermobility.
Image References:
[8] Header Image: Photo by Shmma Quraishe at https://www.southampton.ac.uk/biu/galleries/annualmicrographcomp/2015.page
[9] https://www.geneticsupport.org/wp-content/uploads/2017/09/AR-inheritance.jpg
[10] www.collaborativehp.com/employers/physical-therapy.html
[11] https://synappsehealth.com/en/articles/i/preparation-for-laboratory-tests-blood-and-urine-in-10-steps/
[12] http://www.clker.com/clipart-blank-pill-bottle-3.html
[13] https://www.theenduranceedge.com/2018/08/collagen-peptides/
Video References:
[14] https://www.youtube.com/watch?v=Io4T-2F1L0k&t=12s
This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.