The Ehlers–Danlos Syndromes

Bernadette Riley, DO, FACOFP, FILM | briley@nyit.edu

No relevant financial affiliations or conflicts of interest.

physician can become familiar with each subtype and learn when to look for EDS in the hypermobile patient.

absence of a collagen chain. This subtype of EDS is considered rare.6 “Absence of confirmatory genetic findings does not exclude the diagnosis as specific types of mutations may go undetected by standard diagnostic molecular techniques.”1

thought to have an AD form of inheritance.1 Many patients with hEDS present with joint hypermobility, skin issues, fatigue and chronic pain.17

Many patients with hEDS can also have a variety of co- morbidities.18 Along with hypermobility, there could be chronic pain, cardiovascular issues, psychological issues, bone mass issues and GI symptoms.18 Since there is a variety of symptoms the osteopathic family physician should become familiar with the presentation.

For the osteopathic family physician who sees pediatric patients, hEDS and hypermobility may be difficult to diagnose for children, as children are typically more flexible and hypermobile than adults.18 It is particularly important to rule out a HCTD in children, as some of the signs and symptoms of hEDS overlap with other connective tissues disorders.18

Since there are many systems that the hypermobile patient may present with, it is important the osteopathic family physician become familiar with EDS. There is a chance that the osteopathic family physician may be the first provider the EDS patient contacts. Due to the diverse nature of the EDS and hEDS in particular, a multidisciplinary approach to the EDS patient including Primary Care, pain management, Cardiology, Physical Therapy, Occupational Therapy, Psychology, and Geneticist (if applicable) is needed.17 Since EDS affects many systems of the body, and there is currently no genetic basis of hEDS it is important for the osteopathic family physician to become familiar with the Ehlers Danlos Syndromes as they may be the first one to recognize some of the signs, symptoms and co-morbid conditions seen in this condition. The osteopathic family physician may also be the one in contact with a geneticist to assist in the identification of a specific subtype. The importance of the diagnosis and proper surveillance for the EDS patient is imperative. With further research, the osteopathic family physician can be helpful in treating an EDS patient. Literature and education is needed for providers to become aware of this condition and this article seeks to be an introduction for the osteopathic family physician to all the EDS subtypes.

REFERENCES:

1. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 175 (1):8-26. (2017).

2. Blackburn PR, Xu Z, Tumelty KE, et al. Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome. Am J Hum Genet. 102(4):696-705 (2018).

3. Malfait F, Wenstrup R, De Paepe A. Classic Ehlers-Danlos Syndrome. Gene Reviews. https://www.ncbi.nlm.nih.gov/books/NBK1244/ Assessed July 23, 2019.

4. Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, Francomano CA. Ehlers–Danlos syndrome, classical type. Am J Med Genet Part C Semin Med Genet 175C:27–39 (2017).

5. Kaufman CS, Butler MG. Mutation in TNXB gene causes moderate to severe Ehlers-Danlos syndrome. World J Med Genet. 6(2):17-21 (2017).

6. Brady AF, Demirdas S, Fournel-Gigleux S, Ghali N, Giunta C, Kapferer- Seebacher I, Kosho T, Mendoza-Londono R, Pope MF, Rohrbach M, Van Damme T, Vandersteen A, van Mourik C,Voermans N, Zschocke J, Malfait F. The Ehlers–Danlos syndromes, rare types. Am J Med Genet Part C Semin Med Genet 175C:70–115 (2017).

7. Inokuchi R, Kurata H, Endo K, et al. Vascular Ehlers-Danlos syndrome without the characteristic facial features: a case report. Medicine. 93(28):e291 (2014).

8. Byers PH, Belmont J, Black J, De Backer J, Frank M, Jeunemaitre X, Johnson D, Pepin M, Robert L, Sanders L, Wheeldon N. Diagnosis, natural history, and management in vascular Ehlers–Danlos syndrome. Am J Med Genet Part C Semin Med Genet 175C:40–47 (2017).

9. Maraj, B., Harding-Theobald, E. & Karaki, F. Vascular Ehlers-Danlos Syndrome Presenting as a Pulsatile Neck Mass: a Case Report and Review of Literature. J Gen Intern Med. 33: 1192(2018).

10. Georgios Makrygiannis, Bart Loeys, Jean-Olivier Defraigne, Natzi Sakalihasan. Cervical artery dissections and type A aortic dissection in a family with a novel missense COL3A1 mutation of vascular type Ehlers– Danlos syndrome. Eur J Med Genet. 58(11):634-6 (2015).

11. Klaassens M, Reinstein E, Hilhorst-Hofstee Y, et al. Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood. Clin Genet. 82(2):121-30 (2011).

12. Van Damme T, Colige A, Syx D, Giunta C, Lindert U, Rohrbach M, Aryani O, Alanay Y, Simsek-Kiper PÖ, Kroes HY, Devriendt K, Thiry M, Symoens S, De Paepe A, Malfait F. Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis type. Genetics in Medicine. 18 (9):882-891 (2016).

13. Yeowell HN, Steinmann B. PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1462/ Assessed July 23, 2019.

14. Ritelli M, Dordoni C, Cinquina V, Venturini M, Calzavara-Pinton P, Colombi M. Expanding the clinical and mutational spectrum of B4GALT7- spondylodysplastic Ehlers-Danlos syndrome. Orphanet J Rare Dis. 12(1):153 (2017).

15. Rinner A, Zschocke, J, Schossig A, Grobner R, Strobl H, Kapferer- Seebacher I. High risk of peri-implant disease in periodontal Ehlers-Danlos Syndrome. A case series. Clin Oral Implants Res. (2018).

16. Brady AF, Demirdas S, Fournel-Gigleux S, Ghali N, Giunta C, Kapferer- Seebacher I,Kosho T, Mendoza-Londono R, Pope MF, Rohrbach M, Van Damme T, Vandersteen A, van Mourik C,Voermans N, Zschocke J, Malfait F. The Ehlers–Danlos syndromes, rare types. Am J Med Genet Part C Semin Med Genet 175C:70–115 (2017).

17. Sulli A, Talarico R, Scirè CA, et al. Ehlers-Danlos syndromes: state of the art on clinical practice guidelines. RMD Open. 1-6 (2018).

18. Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H, Levy H. Hypermobile Ehlers–Danlos syndrome (a.k.a. Ehlers–Danlos syndrome Type III and Ehlers–Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet Part C Semin Med Genet 175C:48–69 (2017).

19. The Ehlers Danlos Society. Diagnostic Criteria for Hypermobile Ehlers- Danlos Syndrome (hEDS). https://www.ehlers-danlos.com/wp-content/ uploads/hEDS-Dx-Criteria-checklist-1.pdf Accessed December, 2019.

    
    

    FIGURE 1:

    Diagnostic Criteria for Hypermobile Ehlers-Danlos Syndrome (hEDS)19

    Reprinted with permission from Ehlers-Danlos Society (www.ehlers-danlos.com)

    
    

     

    Diagnostic Criteria for Hypermobile Ehlers-Danlos Syndrome (hEDS)

    This diagnostic checklist is for doctors across all disciplines to be able to diagnose EDS

    
    

     

    Distributed by

    
    

    Patient name:                                 DOB:                   DOV:                          Evaluator:                       The clinical diagnosis of hypermobile EDS needs the simultaneous presence of all criteria, 1 and 2 and 3.

    CRITERION 1 – Generalized Joint Hypermobility

     

    One of the following selected:

    • ≥6 pre-pubertal children and adolescents

    • ≥5 pubertal men and woman to age 50 Beighton Score:       /9

    • ≥4 men and women over the age of 50

      If Beighton Score is one point below age- and sex-specific cut off, two or more of the following must also be selected to meet criterion:

    • Can you now (or could you ever) place your hands flat on the floor without bending your knees?

    • Can you now (or could you ever) bend your thumb to touch your forearm?

    • As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?

    • As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?

    • Do you consider yourself “double jointed”?

      CRITERION 2 – Two or more of the following features (A, B, or C) must be present

      Feature            A            (five              must              be              present)                                                                

    • Unusually soft or velvety skin

    • Mild skin hyperextensibility

    • Unexplained striae distensae or rubae at the back, groins, thighs, breasts and/or abdomen in adolescents, men or pre-pubertal women without a history of significant gain or loss of body fat or weight

    • Bilateral piezogenic papules of the heel

    • Recurrent or multiple abdominal hernia(s)

    • Atrophic scarring involving at least two sites and without the formation of truly papyraceous and/or hemosideric scars as seen in classical EDS

    • Pelvic floor, rectal, and/or uterine prolapse in children, men or nulliparous women without a history of morbid obesity or other known predisposing medical condition

    • Dental crowding and high or narrow palate

    • Arachnodactyly, as defined in one or more of the following:

      (i) positive wrist sign (Walker sign) on both sides, (ii) positive thumb sign (Steinberg sign) on both sides

    • Arm span-to-height ratio ≥1.05

    • Mitral valve prolapse (MVP) mild or greater based on strict echocardiographic criteria

    • Aortic root dilatation with Z-score >+2 Feature A total:     /12

      Feature                                                                          B                                                                            

    • Positive family history; one or more first-degree relatives independently meeting the current criteria for hEDS

      Feature            C            (must            have            at            least            one)                                                              

    • Musculoskeletal pain in two or more limbs, recurring daily for at least 3 months

    • Chronic, widespread pain for ≥3 months

    • Recurrent joint dislocations or frank joint instability, in the absence of trauma

    CRITERION 3 - All of the following prerequisites MUST be met

    1. Absence of unusual skin fragility, which should prompt consideration of other types of EDS

    2. Exclusion of other heritable and acquired connective tissue disorders, including autoimmune rheumatologic conditions. In patients with an acquired CTD (e.g. Lupus, Rheumatoid Arthritis, etc.), additional diagnosis of hEDS requires meeting both Features A and B of Criterion 2. Feature C of Criterion 2 (chronic pain and/or instability) cannot be counted toward a diagnosis of hEDS in this situation.

    3. Exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity. Alternative diagnoses and diagnostic categories include, but are not limited to, neuromuscular disorders (e.g. Bethlem myopathy), other hereditary disorders of the connective tissue (e.g. other types of EDS, Loeys-Dietz syndrome, Marfan syndrome), and skeletal dysplasias (e.g. osteogenesis imperfecta). Exclusion of these considerations may be based upon history, physical examination, and/or molecular genetic testing, as indicated.

Diagnosis:                                                                             

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