Evidence Base

References & Sources

Peer-reviewed citations and clinical references supporting each provider guide.

All Informed Patient Project guides are grounded in peer-reviewed research and established clinical guidelines. Sources are listed by specialty guide below. Where a source is cited across multiple guides, it is listed in full in each relevant section for ease of provider reference.

Last reviewed: March 2026. This page is updated as new literature is incorporated into our guides. Sources reflect the evidence base at time of publication for each guide. For questions about specific citations, contact us.

hEDS Primary Care Guide & Family & Friends Guide

These sources inform the systemic overview, diagnostic criteria, hEDS trifecta framework, and general clinical guidance shared across both guides.

  1. 1

    Malfait F, Francomano C, Byers P, et al.

    The 2017 international classification of the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175C:8–26.

    DOI PubMed
  2. 2

    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.

    American Journal of Medical Genetics Part C. 2017;175C:48–69.

    DOI PubMed
  3. 3

    Daylor V, Griggs M, Weintraub A, et al.

    Defining the chronic complexities of hEDS and HSD: A global survey of diagnostic challenges, life-long comorbidities, and unmet needs.

    Journal of Clinical Medicine. 2025;14(16):5636.

    DOI PMC
  4. 4

    The Ehlers-Danlos Society.

    Clinical resources, diagnostic criteria, and patient/provider education materials for hEDS and related conditions.

    ehlers-danlos.com. Accessed 2025–2026.

    Website
  5. 5

    Fairweather D, Bruno KA, et al.

    An overview of Ehlers-Danlos syndrome and the link between postural orthostatic tachycardia syndrome and gastrointestinal symptoms with a focus on gastroparesis.

    Frontiers in Physiology. 2024. PMC11390471.

    PMC
  6. 6

    Fikree A, Akbar A, Grahame R, Costigan C, Aziz Q.

    The suggested relationships between common GI symptoms and joint hypermobility, POTS, and MCAS.

    Gastro-Hep Communications. 2024. PMC11348541.

    PMC

hEDS GI Specialist Guide

These sources inform GI manifestations of hEDS, MCAS and histamine intolerance, dysmotility, and the hEDS/POTS/MCAS trifecta as it presents in gastroenterology.

  1. 1

    Malfait F, Francomano C, Byers P, et al.

    The 2017 international classification of the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175C:8–26.

    DOI PubMed
  2. 2

    Tinkle B, Castori M, Berglund B, et al.

    Hypermobile Ehlers-Danlos syndrome: Clinical description and natural history.

    American Journal of Medical Genetics Part C. 2017;175C:48–69.

    DOI PubMed
  3. 3

    Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A.

    A framework for the classification of joint hypermobility and related conditions.

    American Journal of Medical Genetics Part C. 2017;175C:148–157.

    DOI PubMed
  4. 4

    Afrin LB, Self S, Menk J, Lazarchick J.

    Characterization of mast cell activation syndrome.

    Immunology and Allergy Clinics of North America. 2017.

    PubMed
  5. 5

    The Ehlers-Danlos Society.

    Clinical resources for hEDS and related conditions.

    ehlers-danlos.com. Accessed 2025–2026.

    Website
  6. 6

    Fairweather D, Bruno KA, et al.

    An overview of Ehlers-Danlos syndrome and the link between POTS and gastrointestinal symptoms with a focus on gastroparesis.

    Frontiers in Physiology. 2024. PMC11390471.

    PMC
  7. 7

    Fikree A, Akbar A, Grahame R, Costigan C, Aziz Q.

    The suggested relationships between common GI symptoms and joint hypermobility, POTS, and MCAS.

    Gastro-Hep Communications. 2024. PMC11348541.

    PMC

hEDS Cardiology Guide

These sources inform POTS diagnosis and treatment, dysautonomia in hEDS, cardiovascular screening, and autonomic nervous system considerations relevant to cardiologists.

  1. 1

    Malfait F, Francomano C, Byers P, et al.

    The 2017 international classification of the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175C:8–26.

    DOI PubMed
  2. 2

    Tinkle B, Castori M, Berglund B, et al.

    Hypermobile Ehlers-Danlos syndrome: Clinical description and natural history.

    American Journal of Medical Genetics Part C. 2017;175C:48–69.

    DOI PubMed
  3. 3

    Sheldon RS, Grubb BP, Olshansky B, et al.

    2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope.

    Heart Rhythm. 2015;12(6):e41–e63.

    DOI PubMed PMC
  4. 4

    Raj SR.

    Postural tachycardia syndrome (POTS).

    Circulation. 2013;127(23):2336–2342.

    DOI PubMed
  5. 5

    Afrin LB, Self S, Menk J, Lazarchick J.

    Characterization of mast cell activation syndrome.

    Immunology and Allergy Clinics of North America. 2017.

    PubMed
  6. 6

    Benarroch EE.

    Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.

    Neurology. 2012;78(24):1940–1950.

    DOI PubMed
  7. 7

    The Ehlers-Danlos Society.

    Clinical resources for hEDS and related conditions.

    ehlers-danlos.com. Accessed 2025–2026.

    Website
  8. 8

    Fairweather D, Bruno KA, et al.

    An overview of Ehlers-Danlos syndrome and the link between POTS and GI symptoms.

    Frontiers in Physiology. 2024. PMC11390471.

    PMC
  9. 9

    Fikree A, Akbar A, Grahame R, Costigan C, Aziz Q.

    The suggested relationships between common GI symptoms and joint hypermobility, POTS, and MCAS.

    Gastro-Hep Communications. 2024. PMC11348541.

    PMC

Neurology, Rheumatology, OB/GYN & Pediatrics Guides

The following foundational sources are cited across these guides and inform the systemic overview, diagnostic criteria, and multisystem considerations covered in each specialty PDF.

  1. 1

    Malfait F, Francomano C, Byers P, et al.

    The 2017 international classification of the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175C:8–26.

    DOI PubMed
  2. 2

    Tinkle B, Castori M, Berglund B, et al.

    Hypermobile Ehlers-Danlos syndrome: Clinical description and natural history.

    American Journal of Medical Genetics Part C. 2017;175C:48–69.

    DOI PubMed
  3. 3

    Daylor V, Griggs M, Weintraub A, et al.

    Defining the chronic complexities of hEDS and HSD: A global survey of diagnostic challenges, life-long comorbidities, and unmet needs.

    Journal of Clinical Medicine. 2025;14(16):5636.

    DOI PMC
  4. 4

    The Ehlers-Danlos Society.

    Clinical resources for hEDS and related conditions.

    ehlers-danlos.com. Accessed 2025–2026.

    Website

hEDS Allergy & Immunology Guide

These sources inform MCAS diagnosis, mediator testing, trigger management, and the relationship between MCAS and hEDS.

  1. 1

    Malfait F, Francomano C, Byers P, et al.

    The 2017 international classification of the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175C:8–26.

    DOI PubMed
  2. 2

    Tinkle B, Castori M, Berglund B, et al.

    Hypermobile Ehlers-Danlos syndrome: Clinical description and natural history.

    American Journal of Medical Genetics Part C. 2017;175C:48–69.

    DOI PubMed
  3. 3

    Daylor V, Griggs M, Weintraub A, et al.

    Defining the chronic complexities of hEDS and HSD: A global survey of diagnostic challenges, life-long comorbidities, and unmet needs.

    Journal of Clinical Medicine. 2025;14(16):5636.

    DOI PMC
  4. 4

    The Ehlers-Danlos Society.

    Clinical resources for hEDS and related conditions.

    ehlers-danlos.com. Accessed 2025–2026.

    Website
  5. 5

    Kucharik M, Chang A.

    Mast cell activation syndrome: a primer for the gastroenterologist.

    Clinical Reviews in Allergy & Immunology. 2020.

    PubMed
  6. 6

    Afrin LB, Ackerley MB, Bluestein LS, et al.

    Diagnosis of mast cell activation syndrome: a global "consensus-2."

    American Journal of Medical Genetics Part C. 2021.

    PubMed

hEDS Orthopedic Guide

These sources inform surgical precautions, tissue fragility, joint instability, anesthesia and wound healing considerations, and orthopedic-specific symptom management.

  1. 1

    Malfait F, Francomano C, Byers P, et al.

    The 2017 international classification of the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175C:8–26.

    DOI PubMed
  2. 2

    Tinkle B, Castori M, Berglund B, et al.

    Hypermobile Ehlers-Danlos syndrome: Clinical description and natural history.

    American Journal of Medical Genetics Part C. 2017;175C:48–69.

    DOI PubMed
  3. 3

    Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A.

    A framework for the classification of joint hypermobility and related conditions.

    American Journal of Medical Genetics Part C. 2017;175C:148–157.

    DOI PubMed
  4. 4

    Russek LN, Block NP, Byrne E, et al.

    Presentation and physical therapy management of upper quadrant hypermobility in patients with generalized hypermobility spectrum disorder and hypermobile Ehlers-Danlos syndrome.

    Physical Therapy Journal. 2023.

    PubMed
  5. 5

    Chopra P, Tinkle B, Hamonet C, et al.

    Pain management in the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175(1). First published February 10, 2017.

    PubMed
  6. 6

    The Ehlers-Danlos Society.

    Clinical resources for hEDS and related conditions.

    ehlers-danlos.com. Accessed 2025–2026.

    Website
  7. 7

    PMC7188237

    Physical therapy considerations in hypermobile Ehlers-Danlos syndrome.

    PMC7188237.

    PMC
  8. 8

    PMC9292069

    Exercise and rehabilitation considerations in hEDS and hypermobility spectrum disorders.

    PMC9292069.

    PMC

hEDS Physical Therapy Guide

These sources inform safe exercise programming, the Muldowney Protocol, proprioception and stabilization priorities, pacing principles, and PT-specific symptom tracking.

  1. 1

    Malfait F, Francomano C, Byers P, et al.

    The 2017 international classification of the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175C:8–26.

    DOI PubMed
  2. 2

    Tinkle B, Castori M, Berglund B, et al.

    Hypermobile Ehlers-Danlos syndrome: Clinical description and natural history.

    American Journal of Medical Genetics Part C. 2017;175C:48–69.

    DOI PubMed
  3. 3

    Daylor V, Griggs M, Weintraub A, et al.

    Defining the chronic complexities of hEDS and HSD: A global survey of diagnostic challenges, life-long comorbidities, and unmet needs.

    Journal of Clinical Medicine. 2025;14(16):5636.

    DOI PMC
  4. 4

    The Ehlers-Danlos Society.

    Clinical resources for hEDS and related conditions.

    ehlers-danlos.com. Accessed 2025–2026.

    Website
  5. 5

    Brittain MG, Flanagan S, Foreman L, Teran-Wodzinski P.

    Physical therapy interventions in generalized hypermobility spectrum disorder and hypermobile Ehlers-Danlos syndrome: a scoping review.

    Disability and Rehabilitation. 2024;46(10):1936–1953. PMID: 37231592.

    DOI PubMed
  6. 6

    Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A.

    A framework for the classification of joint hypermobility and related conditions.

    American Journal of Medical Genetics Part C. 2017;175C:148–157.

    DOI PubMed
  7. 7

    PMC7188237

    Physical therapy considerations in hypermobile Ehlers-Danlos syndrome.

    PMC7188237.

    PMC
  8. 8

    PMC9292069

    Exercise and rehabilitation considerations in hEDS and hypermobility spectrum disorders.

    PMC9292069.

    PMC

hEDS Dentistry & Oral Surgery Guide

These sources inform anesthesia resistance, TMJ considerations, tissue fragility, and oral manifestations relevant to dentists and oral surgeons treating patients with hEDS.

  1. 1

    Malfait F, Francomano C, Byers P, et al.

    The 2017 international classification of the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175C:8–26.

    DOI PubMed
  2. 2

    Tinkle B, Castori M, Berglund B, et al.

    Hypermobile Ehlers-Danlos syndrome: Clinical description and natural history.

    American Journal of Medical Genetics Part C. 2017;175C:48–69.

    DOI PubMed
  3. 3

    Daylor V, Griggs M, Weintraub A, et al.

    Defining the chronic complexities of hEDS and HSD: A global survey of diagnostic challenges, life-long comorbidities, and unmet needs.

    Journal of Clinical Medicine. 2025;14(16):5636.

    DOI PMC
  4. 4

    The Ehlers-Danlos Society.

    Clinical resources for hEDS and related conditions.

    ehlers-danlos.com. Accessed 2025–2026.

    Website
  5. 5

    Mitakides J, Tinkle BT.

    Oral and mandibular manifestations in the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175(1):220–225. PMID: 28192626.

    DOI PubMed
  6. 6

    Lepperdinger U, Zschocke J, Kapferer-Seebacher I.

    Oral manifestations of Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2021;187(4):520–526. PMID: 34741498.

    DOI PubMed

hEDS Pain Management Guide

These sources inform central sensitization, chronic pain patterns, medication considerations including LDN, and pain-specific symptom tracking in hEDS.

  1. 1

    Malfait F, Francomano C, Byers P, et al.

    The 2017 international classification of the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175C:8–26.

    DOI PubMed
  2. 2

    Tinkle B, Castori M, Berglund B, et al.

    Hypermobile Ehlers-Danlos syndrome: Clinical description and natural history.

    American Journal of Medical Genetics Part C. 2017;175C:48–69.

    DOI PubMed
  3. 3

    Daylor V, Griggs M, Weintraub A, et al.

    Defining the chronic complexities of hEDS and HSD: A global survey of diagnostic challenges, life-long comorbidities, and unmet needs.

    Journal of Clinical Medicine. 2025;14(16):5636.

    DOI PMC
  4. 4

    The Ehlers-Danlos Society.

    Clinical resources for hEDS and related conditions.

    ehlers-danlos.com. Accessed 2025–2026.

    Website
  5. 5

    Chopra P, Tinkle B, Hamonet C, et al.

    Pain management in the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175(1). First published February 10, 2017.

    PubMed

hEDS Psychiatry & Psychology Guide

These sources inform the high prevalence of anxiety, depression, ADHD/autism overlap, medical trauma, and mental health treatment considerations in hEDS.

  1. 1

    Malfait F, Francomano C, Byers P, et al.

    The 2017 international classification of the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175C:8–26.

    DOI PubMed
  2. 2

    Tinkle B, Castori M, Berglund B, et al.

    Hypermobile Ehlers-Danlos syndrome: Clinical description and natural history.

    American Journal of Medical Genetics Part C. 2017;175C:48–69.

    DOI PubMed
  3. 3

    Daylor V, Griggs M, Weintraub A, et al.

    Defining the chronic complexities of hEDS and HSD: A global survey of diagnostic challenges, life-long comorbidities, and unmet needs.

    Journal of Clinical Medicine. 2025;14(16):5636.

    DOI PMC
  4. 4

    The Ehlers-Danlos Society.

    Clinical resources for hEDS and related conditions.

    ehlers-danlos.com. Accessed 2025–2026.

    Website
  5. 5

    Bulbena A, Baeza-Velasco C, Bulbena-Cabré A, et al.

    Psychiatric and psychological aspects in the Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2017;175(1). First published February 10, 2017.

    DOI PubMed
  6. 6

    Baeza-Velasco C.

    Neurodevelopmental atypisms in the context of joint hypermobility, hypermobility spectrum disorders, and Ehlers-Danlos syndromes.

    American Journal of Medical Genetics Part C. 2021;187(4):491–499. PMID: 34741402.

    DOI PubMed
  7. 7

    Bucknill E, Quadt L, Dew R, Colasanti A, Muller-Pollard CS, Critchley HD, Eccles JA.

    Embracing complexity: connecting bipolar affective disorder, joint hypermobility and neurodivergence.

    British Journal of Psychiatry. 2026 Jan 20:1–9. PMID: 41554535.

    DOI PubMed
  8. 8

    Casanova EL, Baeza-Velasco C, Buchanan CB, Casanova MF.

    The relationship between autism and Ehlers-Danlos syndromes/hypermobility spectrum disorders.

    Journal of Personalized Medicine. 2020;10(4):260. PMID: 33271870.

    DOI PubMed
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