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Reviews in Musculoskeletal Medicine  |   January 2020
The Many Facets of Hypermobile Ehlers-Danlos Syndrome
Bernadette Riley, DO
Author Notes
  • Financial Disclosures: None reported. 
  • Support: None reported. 
  •  *Address correspondence to: Bernadette Riley, DO, Ehlers-Danlos Syndrome/Hypermobility Treatment Center, Department of Family Medicine, New York Institute of Technology College of Osteopathic Medicine, Northern Blvd, Old Westbury, NY, 11568-8000. Email: briley@nyit.edu
     
Article Information
Cardiovascular Disorders / Pain Management/Palliative Care / Pediatrics
Reviews in Musculoskeletal Medicine   |   January 2020
The Many Facets of Hypermobile Ehlers-Danlos Syndrome
The Journal of the American Osteopathic Association, January 2020, Vol. 120, 30-32. doi:https://doi.org/10.7556/jaoa.2020.012
The Journal of the American Osteopathic Association, January 2020, Vol. 120, 30-32. doi:https://doi.org/10.7556/jaoa.2020.012
Web of Science® Times Cited: 1
Abstract

Of the 13 subtypes of Ehlers-Danlos Syndromes (EDSs) identified in the 2017 international classification of EDSs, 12 have a recognized, associated genetic mutation. However, hypermobile EDS (hEDS) currently has no identifiable associated gene. Therefore, patients with hEDS are identified through a set of clinical diagnosis guidelines and criteria, which are meant to differentiate hEDS from other hypermobile joint conditions and other EDSs subtypes. In this article, the authors provide an overview of hEDS symptoms and comborbidities, current treatment options, and the clinical criteria currently guiding the standard of care.

The Ehlers-Danlos syndromes (EDSs) are a rare group of heritable connective tissue diseases characterized by hypermobility and hyperextensibile skin.1 According to the 2017 international classification of EDSs, there are 13 subtypes.1 A rare 14th subtype was found in 2018.2 Each subtype has unique aspects, and a genetic cause has been identified in all subtypes except hypermobile EDS (hEDS).1 Hypermobile EDS is “probably the most common EDS subtype,”3 and there are new clinical guidelines for diagnosis.1 To aid in accurate clinical diagnosis, the hypermobility and skin manifestations experienced by patients with hEDS need to be differentiated from those experienced by patients with other types of EDSs, connective tissue diseases, or heritable diseases such as Marfan syndrome.1,4 In addition to joint hypermobility and skin issues, patients with hEDS may also present with fatigue, chronic pain,3 cardiovascular issues, bone mass issues, neurologic and spinal issues, psychological issues, and gastrointestinal (GI) symptoms.5 Although there is no cure, hEDS is treatable.3 Since so many systemic symptoms are seen in hEDS, this article reviews the clinical markers of hEDS, its comorbidities, and current treatment options, along with its relevance to musculoskeletal medicine. 
Pain in hEDS
The degree and frequency of pain experienced by patients with hEDS varies widely, with many patients reporting daily musculoskeletal pain.5,6 Although pain severity in these patients sometimes correlates with their degree of joint instability, this is not always the case7; the pain may be neuropathic and not due to a musculoskeletal dysfunction.8 A multidisciplinary approach, including nonpharmacologic pain management, physical therapy, occupational therapy, and psychological treatment alongside primary care interventions (eg, preventive care, therapeutic injections), has been recommended for the EDS patient.3 It has been suggested that adding osteopathic manipulative treatment (OMT) to this multidisciplinary approach can improve quality of life for these patients,3 which may be because much of the pain experienced by hEDS patients as a result of their hypermobility is multifactorial. Pain affects sleep, thereby causing physical and emotional stress to the patient.4,9 Managing all of these associated symptoms and comorbidities can be beneficial, and further studies on that topic are warranted. Lack of clinical guidelines in the management of hEDS has limited past research in this population.3 
Cardiac Manifestations in hEDS
Postural orthostatic tachycardia syndrome (POTS) is defined as a heart rate increase of at least 30 beats/min or an increase to a rate higher than 120 beats/min within the first 10 minutes of standing, in the absence of orthostatic hypotension.10 It is an autonomic disorder (dysautonomia) that can be associated with EDSs.10 The symptoms of POTS include poor sleep quality, fatigue, dizziness, GI symptoms, esophageal hypomobility, gastroesophageal reflux disease, urinary issues, and skin manifestations.10 Previous studies have shown a high concurrence rate between hEDS and POTS.11 Excessive catecholamine and histamine may be a mechanism for POTS in hEDS, although the exact cause is unknown.12 Patients with hEDS may have orthostatic intolerance, which is a term used for patients who have symptoms similar to POTS but do not meet the criteria for POTS.13 
In terms of treatment for POTS, hydration, salt supplementation, and some medications are options14; there has also been a case report15 of a patient with POTS whose symptoms promptly and dramatically improved after OMT. It is intriguing to consider the role of somatic dysfunction in this autonomic disorder, but there is a paucity of previous literature assessing the potential association of these conditions. Two of the hEDS diagnostic criteria are aortic root dilatation and mitral valve prolapse,1 both of which are diagnosed with echocardiograms. A 2017 study16 showed that there is no significant progression in aortic root size in young adults followed up over time; therefore, there is no clinical practice guideline regarding when to obtain serial echocardiograms. 
Mast Cell Activation Disorders in hEDS
Patients with hEDS may also have mast cell activation disorders, diagnosed by an increase in the number or activity of mast cells.17 Mast cell activation disorders may be associated with fatigue, urticaria, skin manifestations, cardiac issues, and GI symptoms.17 Current treatment options include antihistamines, dietary restrictions, and leukotriene receptor blockers; some monoclonal antibodies are also being used as treatment.17 While research on nutrition and diet in hEDS is lacking, we do know that avoiding exposure to triggers, whether they be food, drugs, or stressors, helps the patient with mast cell activation disorder become asymptomatic.17 
Neurologic and Spinal Manifestations in hEDS
Chiari Type 1 has been reported as a comorbid condition with hEDS.18 Women seem to be at higher risk, and the age of presentation is younger.18 Headaches are a common symptom of Chiari malformation and hEDS.18,19 Atlantoaxial instability and craniocervical instability can be seen in patients with hEDS,18 which is important to keep in mind if a clinician is considering applying OMT to those areas.18 Atlantoaxial and craniocervical instability may cause pain symptoms for the hEDS patient, along with sensory, motor, and reflex changes.18 
Psychological and Psychiatric Aspects of hEDS
Psychological manifestations of hEDS may include anxiety and depression.20 It is important to have a psychologist (and/or psychiatrist when applicable) involved as part of a multidimensional team approach. Many patients with hEDS have chronic pain and have visited multiple physicians, which can contribute to anxiety. Brain imaging findings suggest changes in the reactive centers of the brain in patients with hEDS.20 Research is also warranted on cognitive behavioral therapy for hEDS patients. Also, some symptoms of POTS present similarly to anxiety and panic attacks; therefore, a thorough workup is warranted to rule out dysautonomia in hEDS patients. 
Conclusion
Patients with hEDS experience symptoms in most systems of their bodies; therefore, it is important for the osteopathic physician to become familiar with all potential comborbidities and treatment modalities. These patients would benefit from research in the field of pain, and research is especially needed on the effects of OMT on hEDS. Research on psychological treatments could help make cognitive behavioral therapy part of the treatment protocol for hEDS. A multidisciplinary approach to the patient with hEDS, as well as physician familiarity with EDSs and hypermobility, would help patients receive the best treatment possible and optimize their quality of life. 
References
Malfait F, Francomano C, Byers P, et al The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26. doi: 10.1002/ajmg.c.31552
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. 2018;102(4):696-705. doi: 10.1016/j.ajhg.2018.02.018 [CrossRef] [PubMed]
Sulli A, Talarico R, Scirè CA, et al Ehlers-Danlos syndromes: state of the art on clinical practice guidelines. RMD Open. 2018;4(suppl 1):e000790. doi: 10.1136/rmdopen-2018-000790 [CrossRef] [PubMed]
Tinkle B. Joint hypermobility handbook: A guide for the issues & management of Ehlers-Danlos syndrome hypermobility type and the hypermobility syndrome. 1st ed. Greens Fork, IN: Left Paw Press, 2010.
Tinkle B, Castori M, Berglund B, et al. 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. 2017;175(1):48-69.
Zhou Z, Rewari A, Shanthanna H. Management of chronic pain in Ehlers-Danlos syndrome: two case reports and a review of literature. Medicine (Baltimore. ). 2018;97(45):e13115. [CrossRef] [PubMed]
Gazit Y, Jacob G, Grahame R. Ehlers-Danlos syndrome-hypermobility type: a much neglected multisystemic disorder. Rambam Maimonides Med J. 2016;7(4):e0034. doi: 10.5041/RMMJ.10261 [CrossRef]
Cazzato D, Castori M, Lombardi R, et al. Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology. 2016;87(2):155-159. [CrossRef] [PubMed]
Chopra P, Tinkle B, Hamonet C, et al. Pain management in the Ehlers–Danlos syndromes. Am J Med Genet Part C Semin Med Genet. 2017;175(1):212-219. [CrossRef] [PubMed]
Anjum I, Sohail W, Hatipoglu B, Wilson R. Postural orthostatic tachycardia syndrome and its unusual presenting complaints in women: a literature minireview. Cureus. 2018;10(4):e2435. doi: 10.7759/cureus.2435 [PubMed]
Cohen S, Markham F. Ehlers-Danlos hypermobility type in an adult with chronic pain and fatigue: a case study. Clin Case Rep. 2017;5(8):1248-1251. [CrossRef] [PubMed]
Bonamichi-Santos R, Yoshimi-Kanamori K, Giavina-Bianchi P, Aun MV. Association of postural tachycardia syndrome and Ehlers-Danlos syndrome with mast cell activation disorders. Immunol Allergy Clin North Am. 2018;38(3):497-504. doi: 10.1016/j.iac.2018.04.004 [CrossRef] [PubMed]
Celletti C, Camerota F, Castori M, et al. Orthostatic intolerance and postural orthostatic tachycardia syndrome in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type: neurovegetative dysregulation or tutonomic failure? Biomed Res Int. 2017;2017:9161865.
Fu Q, Levine BD. Exercise and non-pharmacological treatment of POTS. Auton Neurosci. 2018;215:20-27. doi: 10.1016/j.autneu.2018.07.001 [CrossRef] [PubMed]
Goodkin M, Bellew LJ. Osteopathic manipulative treatment for postural orthostatic tachycardia syndrome. J Am Osteopath Assoc. 2014;114(11):874-877. [CrossRef] [PubMed]
Ritter A, Atzinger C, Hays B, et al. Natural history of aortic root dilation through young adulthood in a hypermobile Ehlers-Danlos syndrome cohort. Am J Med Genet Part A. 2017;173(6):1467-1472. doi: 10.1002/ajmg.a.38243. [CrossRef] [PubMed]
Seneviratne SL, Maitland A, Afrin L. Mast cell disorders in Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet. 2017;175(1):226-236. [CrossRef] [PubMed]
Sr Henderson FC, Austin C, Benzel E, et al. Neurological and spinal manifestations of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):195-211. doi: 10.1002/ajmg.c.31549. [CrossRef] [PubMed]
Castori M, Voermans NC. Neurological manifestations of Ehlers-Danlos syndrome(s): a review. Iran J Neurol. 2014;13(4):190-208. [PubMed]
Bulbena A, Baeza-Velasco C, Bulbena-Cabre A, et al Psychiatric and psychological aspects in the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):237-245. [CrossRef] [PubMed]