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The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS)

Abstract

In recent years, an association between hypermobile Ehlers-Danlos syndrome (hEDS), mast cell activation syndrome (MCAS), and postural orthostatic tachycardia syndrome (POTS) has garnered attention and patients are increasingly presenting with this triad. However, a real relationship between these entities is unclear due to a lack of scientific validity. We conducted an extensive review of the literature using two different search strategies. A narrower strategy included 88 searches of various combinations of terms for each of the three conditions, yielding 19 unique papers. A broader search included 136 searches of various combinations of terms but included all forms of EDS and yielded 40 unique papers. Of these, only four and nine papers from the narrower and broader search strategies were original research articles. None of these papers resulted from a combination of the search terms for the three conditions. All three clinical entities are controversial in either existence or pathogenesis. MCAS is a poorly defined clinical entity, and many studies do not adhere to the proposed criteria when establishing the diagnosis. Patients previously diagnosed with EDS hypermobility type may not meet the new, stricter criteria for hEDS but may for a less severe hypermobility spectrum disorder (HSD). The pathophysiology of POTS is still unclear. An evidence-based, common pathophysiologic mechanism between any of the two, much less all three conditions, has yet to be described. Our review of the literature shows that current evidence is lacking on the existence of MCAS or hEDS as separate or significant clinical entities. Studies proposing a relationship between the three clinical entities are either biased or based on outdated criteria. The reason behind the purported association of these entities stems from an overlapping pool of vague, subjective symptoms, which is inadequate evidence to conclude that any such relationship exists.

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References

  1. 1.

    Beighton P, Grahame R, Bird H (2012) Introduction to hypermobility. In: Hypermobility of joints. Springer, p 1

  2. 2.

    Parapia LA, Jackson C (2008) Ehlers-Danlos syndrome – a historical review. Br J Haematol. 141(1):32–35

    PubMed  Article  Google Scholar 

  3. 3.

    Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ (1999) Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet. 77(1):31–37

    Article  Google Scholar 

  4. 4.

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

    PubMed  Article  Google Scholar 

  5. 5.

    Steinmann B, Royce PM, Superti-Furga A (2003) The Ehlers-Danlos syndrome. In: Connective tissue and its heritable disorders. Wiley-Blackwell, pp 431–523

  6. 6.

    Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H 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. Am J Med Genet C Semin Med Genet. 175(1):48–69

    PubMed  Article  Google Scholar 

  7. 7.

    De Paepe A, Malfait F (2012) The Ehlers–Danlos syndrome, a disorder with many faces. Clin Genet. 82(1):1–11

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Castori M, Camerota F, Celletti C, Grammatico P, Padua L (2010) Ehlers-Danlos syndrome hypermobility type and the excess of affected females: possible mechanisms and perspectives. Am J Med Genet A. 152A(9):2406–2408

    PubMed  Article  Google Scholar 

  9. 9.

    Levy HP (2018) Ehlers-Danlos syndrome, hypermobility type. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K et al (eds) GeneReviews. University of Washington, Seattle, Seattle

    Google Scholar 

  10. 10.

    Zweers MC, Bristow J, Steijlen PM, Dean WB, Hamel BC, Otero M et al (2003) Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome. Am J Hum Genet. 73(1):214–217

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Morissette R, Chen W, Perritt AF, Dreiling JL, Arai AE, Sachdev V et al (2015) Broadening the spectrum of Ehlers Danlos syndrome in patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 100(8):1143

    Article  CAS  Google Scholar 

  12. 12.

    Narcisi P, Richards AJ, Ferguson SD, Pope FM (1994) A family with Ehlers-Danlos syndrome type III/articular hypermobility syndrome has a glycine 637 to serine substitution in type III collagen. Hum Mol Genet. 3(9):1617–1620

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Syx D, Symoens S, Steyaert W, De Paepe A, Coucke PJ, Malfait F (2015) Ehlers-Danlos syndrome, hypermobility type, is linked to chromosome 8p22-8p21.1 in an extended Belgian family. Dis Markers 2015:e828970

    Article  CAS  Google Scholar 

  14. 14.

    Castori M, Camerota F, Celletti C, Danese C, Santilli V, Saraceni VM et al (2010) Natural history and manifestations of the hypermobility type Ehlers-Danlos syndrome: a pilot study on 21 patients. Am J Med Genet A. 152A(3):556–564

    PubMed  Article  Google Scholar 

  15. 15.

    Castori M, Dordoni C, Morlino S, Sperduti I, Ritelli M, Valiante M et al (2015) Spectrum of mucocutaneous manifestations in 277 patients with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. Am J Med Genet C Semin Med Genet. 169C(1):43–53

    PubMed  Article  Google Scholar 

  16. 16.

    Castori M, Morlino S, Celletti C, Ghibellini G, Bruschini M, Grammatico P et al (2013) Re-writing the natural history of pain and related symptoms in the joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type. Am J Med Genet A. 161(12):2989–3004

    Article  Google Scholar 

  17. 17.

    Castori M, Sperduti I, Celletti C, Camerota F, Grammatico P (2011) Symptom and joint mobility progression in the joint hypermobility syndrome (Ehlers-Danlos syndrome, hypermobility type). Clin Exp Rheumatol. 29(6):998–1005

    PubMed  Google Scholar 

  18. 18.

    Castori M, Celletti C, Camerota F, Grammatico P (2011) Chronic fatigue syndrome is commonly diagnosed in patients with Ehlers-Danlos syndrome hypermobility type/joint hypermobility syndrome. Clin Exp Rheumatol. 29(3):597–598

    CAS  PubMed  Google Scholar 

  19. 19.

    Maeland S, Assmus J, Berglund B (2011) Subjective health complaints in individuals with Ehlers-Danlos syndrome: a questionnaire study. Int J Nurs Stud. 48(6):720–724

    PubMed  Article  Google Scholar 

  20. 20.

    Fikree A, Chelimsky G, Collins H, Kovacic K, Aziz Q (2017) Gastrointestinal involvement in the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 175(1):181–187

    PubMed  Article  Google Scholar 

  21. 21.

    Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A (2017) A framework for the classification of joint hypermobility and related conditions. Am J Med Genet C Semin Med Genet. 175(1):148–157

    PubMed  Article  Google Scholar 

  22. 22.

    Beighton P, Solomon L, Soskolne C (1973) Articular mobility in an African population. Ann Rheum Dis. 32(5):413–418

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Juul-Kristensen B, Schmedling K, Rombaut L, Lurd H, Engelbert RHH (2017) Measurement properties of clinical assessment methods for classifying generalized joint hypermobility—a systematic review. Am J Med Genet C Semin Med Genet. 175(1):116–147

    PubMed  Article  Google Scholar 

  24. 24.

    Hakim AJ, Grahame R (2003) A simple questionnaire to detect hypermobility: an adjunct to the assessment of patients with diffuse musculoskeletal pain. Int J Clin Pract. 57(3):163–166

    CAS  PubMed  Google Scholar 

  25. 25.

    Chopra P, Tinkle B, Hamonet C, Brock I, Gompel A, Bulbena A et al (2017) Pain management in the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 175(1):212–219

    PubMed  Article  Google Scholar 

  26. 26.

    Hakim A, O’Callaghan C, De Wandele I, Stiles L, Pocinki A, Rowe P (2017) Chronic fatigue in Ehlers–Danlos syndrome—hypermobile type. Am J Med Genet C Semin Med Genet. 175(1):168–174

    PubMed  Article  Google Scholar 

  27. 27.

    Hakim A, O’Callaghan C, De Wandele I, Stiles L, Pocinki A, Rowe P (2017) Cardiovascular autonomic dysfunction in Ehlers–Danlos syndrome—hypermobile type. Am J Med Genet C Semin Med Genet. 175(1):168–174

    PubMed  Article  Google Scholar 

  28. 28.

    Bathen T, Hångmann AB, Hoff M, Andersen LØ, Rand-Hendriksen S (2013) Multidisciplinary treatment of disability in Ehlers-Danlos syndrome hypermobility type/hypermobility syndrome: a pilot study using a combination of physical and cognitive-behavioral therapy on 12 women. Am J Med Genet A. 161A(12):3005–3011

    PubMed  Article  Google Scholar 

  29. 29.

    Raj SR (2006) The postural tachycardia syndrome (POTS): pathophysiology, diagnosis & management. Indian Pacing Electrophysiol J. 6(2):84–99

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Schondorf R, Low PA (1993) Idiopathic postural orthostatic tachycardia syndrome. Neurology 43(1 Part 1):132–137

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Wooley CF (1976) Where are the diseases of yesteryear? DaCosta’s syndrome, soldiers heart, the effort syndrome, neurocirculatory asthenia--and the mitral valve prolapse syndrome. Circulation. 53(5):749–751

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Stewart J (2013) Common syndromes of orthostatic intolerance. Pediatrics. 131(5):968–980

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Robertson D (1999) The epidemic of orthostatic tachycardia and orthostatic hypotension. Am J Med Sci. 319:75–77

    Article  Google Scholar 

  34. 34.

    Goldstein DS, Robertson D, Esler M, Straus SE, Eisenhofer G (2002) Dysautonomias: clinical disorders of the autonomic nervous system. Ann Intern Med. 137(9):753–763

    PubMed  Article  Google Scholar 

  35. 35.

    Miller AJ, Raj SR. Pharmacotherapy for postural tachycardia syndrome. Auton Neurosci. 2018;S1566–0702(18):30025–0.

  36. 36.

    Garland EM, Raj SR, Black BK, Harris PA, Robertson D (2007) The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome. Neurology. 69:790–798

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Thieben M, Sandroni P, Sletten D, Benrud-Larson L, Fealey R, Vernino S et al (2007) Postural orthostatic tachycardia syndrome: the Mayo Clinic experience. Mayo Clin Proc. 82(3):308–313

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Arnold AC, Ng J, Raj SR (2018) Postural tachycardia syndrome – diagnosis, physiology, and prognosis. Auton Neurosci. S1566–0702(17):30354–30355

    Google Scholar 

  39. 39.

    Smith JJ, Porth CM, Erickson M (1994) Hemodynamic response to the upright posture. J Clin Pharmacol. 34(5):375–386

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Raj SR (2013) Postural tachycardia syndrome (POTS). Circulation. 127(23):2336

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Bonyhay I, Freeman R (2004) Sympathetic nerve activity in response to hypotensive stress in the postural tachycardia syndrome. Circulation. 110(20):3193–3198

    PubMed  Article  Google Scholar 

  42. 42.

    Haensch C, Tosch M, Katona I, Weis J, Isenmann S (2014) Small-fiber neuropathy with cardiac denervation in postural tachycardia syndrome. Muscle Nerve. 50(6):956–961

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M et al (2000) The neuropathic postural tachycardia syndrome. N Eng J Med. 343(14):1008–1014

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Sheldon R, Grubb B, Olshansky B, Shen W, Calkins H, Brignole M et al (2015) 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 12(6):e63

    Article  Google Scholar 

  45. 45.

    Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I et al (2000) Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med. 342(8):541–549

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Robertson D, Flattem N, Tellioglu T, Carson R, Garland E, Shannon JR et al (2001) Familial orthostatic tachycardia due to norepinephrine transporter deficiency. Ann N Y Acad Sci. 940:527–543

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Marques FZ, Eikelis N, Bayles RG, Lambert EA, Straznicky NE, Hering D et al (2017) A polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism. Mol Psychiatry. 22(1):134–141

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Bayles R, Harikrishnan KN, Lambert E, Baker EK, Agrotis A, Guo L et al (2012) Epigenetic modification of the norepinephrine transporter gene in postural tachycardia syndrome. Arterioscler Thromb Vasc Biol. 32(8):1910–1916

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Lambert E, Eikelis N, Esler M, Dawood T, Schlaich M, Bayles R et al (2008) Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome. Circ Arrhythm Electrophysiol. 1(2):103–109

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Schroeder C, Tank J, Boschmann M, Diedrich A, Sharma AM, Biaggioni I et al (2002) Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance. Circulation. 105(3):347–353

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Green EA, Raj V, Shibao CA, Biaggioni I, Black BK, Dupont WD et al (2013) Effects of norepinephrine reuptake inhibition on postural tachycardia syndrome. J Am Heart Assoc. 2(5):e000395

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Raj SR, Biaggioni I, Yamhure PC, Black BK, Paranjape SY, Byrne DW et al (2005) Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome. Circulation. 111(13):1574–1582

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Parsaik A, Allison TG, Singer W, Sletten DM, Joyner MJ, Benarroch EE et al (2012) Deconditioning in patients with orthostatic intolerance. Neurology. 79(14):1435–1439

    PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Nagiub M, Moskowitz W, Fortunato J (2018) Systematic literature review of pathophysiology of postural orthostatic tachycardia syndrome (angiotensin II receptor subtypes imbalance theory). Prog Pediatr Cardiol

  55. 55.

    Sandroni P, Opfer-Gehrking TL, McPhee BR, Low PA (1999) Postural tachycardia syndrome: clinical features and follow-up study. Mayo Clin Proc. 74(11):1106–1110

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Goodman B (2018) Evaluation of postural tachycardia syndrome (POTS). Auton Neurosci 18(18):30015–30018

    Google Scholar 

  57. 57.

    Bagai K, Wakwe CI, Malow B, Black BK, Biaggioni I, Paranjape SY et al (2013) Estimation of sleep disturbances using wrist actigraphy in patients with postural tachycardia syndrome. Auton Neurosci. 177(2):260–265

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Agarwal G, Ritch S (2007) Postural orthostatic tachycardia syndrome. Postgrad Med J. 83(981):478–480

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Fu Q, Vangundy TB, Shibata S, Auchus RJ, Williams GH, Levine BD (2011) Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome. Hypertension. 58(2):167–175

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Fu Q, Vangundy TB, Galbreath MM, Shibata S, Jain M, Hastings JL et al (2010) Cardiac origins of the postural orthostatic tachycardia syndrome. J Am Coll Cardiol. 55(25):2858–2868

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Winker R, Barth A, Bidmon D, Ponocny I, Weber M, Mayr O et al (2005) Endurance exercise training in orthostatic intolerance: a randomized, controlled trial. Hypertension. 45(3):391–398

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Sousa A, Lebreiro A, Freitas J, Maciel MJ (2012) Long-term follow-up of patients with postural tachycardia syndrome. Clin Auton Res. 22(3):151–153

    PubMed  Article  Google Scholar 

  63. 63.

    Lai CC, Fischer PR, Brands CK, Fisher JL, Porter CJ, Driscoll SW et al (2009) Outcomes in adolescents with postural orthostatic tachycardia syndrome treated with midodrine and beta-blockers. Pacing Clin Electrophysiol. 32(2):234–238

    PubMed  Article  Google Scholar 

  64. 64.

    Kimpinski K, Figueroa JJ, Singer W, Sletten DM, Iodice V, Sandroni P et al (2012) A prospective, 1-year follow-up study of postural tachycardia syndrome. Mayo Clin Proc. 87(8):746–752

    PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Afrin LB (2013) Presentation, diagnosis, and management of mast cell activation syndrome. In: Murray DB (ed) Mast cells: phenotypic features, biological functions and role in immunity. Nova Science Publishers, Inc, pp 155–232

  66. 66.

    Travis WD, Li CY, Bergstralh EJ, Yam LT, Swee RG (1988) Systemic mast cell disease. Analysis of 58 cases and literature review. Medicine (Baltimore) 67(6):345–368

    CAS  Article  Google Scholar 

  67. 67.

    Metcalfe DD (1991) Classification and diagnosis of mastocytosis: current status. J Invest Dermatol. 96(3 Suppl):65S

    Google Scholar 

  68. 68.

    Roberts LJ, Oates JA (1991) Biochemical diagnosis of systemic mast cell disorders. J Invest Dermatol. 96(3 Suppl):65S

    Google Scholar 

  69. 69.

    Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K et al (2007) Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 37(6):435–453

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB et al (2001) Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 25(7):603–625

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Sonneck K, Florian S, Müllauer L, Wimazal F, Födinger M, Sperr WR et al (2007) Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome. IAA. 142(2):158–164

    Google Scholar 

  72. 72.

    Akin C, Valent P, Metcalfe DD (2010) Mast cell activation syndrome: proposed diagnostic criteria: towards a global classification for mast cell disorders. J Allergy Clin Immunol. 126(6):1099–1104

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC et al (2012) Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 157(3):215

    Article  PubMed  Google Scholar 

  74. 74.

    Valent P, Akin C, Metcalfe DD (2017) Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 129(11):1420–1427

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Brockow K (2014) Epidemiology, prognosis, and risk factors in mastocytosis. Immunol Allergy Clin N Am. 34(2):283–295

    Article  Google Scholar 

  76. 76.

    Kettelhut BV, Metcalfe DD (1991) Pediatric mastocytosis. J Invest Dermatol. 96(3 Suppl):65S

    Google Scholar 

  77. 77.

    Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS et al (1995) The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest. 96(6):2702–2710

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Dahlin JS, Hallgren J (2015) Mast cell progenitors: origin, development and migration to tissues. Mol Immunol. 63(1):9–17

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Silva EZ (2014) Marcelino da, Jamur MC, Oliver C. Mast cell function: a new vision of an old cell. J Histochem Cytochem. 62(10):698–738

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Akin C (2017) Mast cell activation syndromes. J Allergy Clin Immunol. 140(2):349–355

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Molderings GJ, Brettner S, Homann J, Afrin LB (2011) Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol 4(1):10

    PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Valent P (2013) Mast cell activation syndromes: definition and classification. Eur J Allergy Clin Immunol 68:417–424

    CAS  Article  Google Scholar 

  83. 83.

    Cardet J, Castells M, Hamilton M (2013) Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep. 13(1):10–18

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Seneviratne S, Maitland A, Afrin L (2017) Mast cell disorders in Ehlers–Danlos syndrome. Am J Med Genet C Semin Med Genet. 175C(1):226–236

    Article  Google Scholar 

  85. 85.

    Molderings GJ, Haenisch B, Brettner S, Homann J, Menzen M, Dumoulin FL et al (2016) Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmacol 389:671

    CAS  Article  Google Scholar 

  86. 86.

    Sokol KC, Ghazi A, Kelly BC, Grant JA (2014) Omalizumab as a desensitizing agent and treatment in mastocytosis: a review of the literature and case report. J Allergy Clin Immunol Pract. 2(3):266–270

    PubMed  Article  Google Scholar 

  87. 87.

    Garriga MM, Friedman MM, Metcalfe DD (1988) A survey of the number and distribution of mast cells in the skin of patients with mast cell disorders. J Allergy Clin Immunol. 82(3 Pt 1):425–432

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P et al (2007) Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood. 110(7):2331–2333

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Astle JM, Rose MG, Racke FK, Tormey CA, Siddon AJ (2017) R634W KIT mutation in an adult with systemic mastocytosis. Lab Med. 48(3):253–257

    PubMed  Article  Google Scholar 

  90. 90.

    Pollard WL, Beachkofsky TM, Kobayashi TT (2015) Novel R634W c-kit mutation identified in familial mastocytosis. Pediatr Dermatol. 32(2):267–270

    PubMed  Article  Google Scholar 

  91. 91.

    Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD (2004) A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood. 103(8):3222–3225

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Sotlar K, Escribano L, Landt O, Möhrle S, Herrero S, Torrelo A et al (2003) One-step detection of c-kit point mutations using peptide nucleic acid-mediated polymerase chain reaction clamping and hybridization probes. Am J Pathol. 162(3):737–746

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Grahame R, Bird HA, Child A (2000) The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol. 27(7):1777–1779

    CAS  PubMed  Google Scholar 

  94. 94.

    Tinkle BT, Bird HA, Grahame R, Lavallee M, Levy HP, Sillence D (2009) The lack of clinical distinction between the hypermobility type of Ehlers-Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome). Am J Med Genet A. 149A(11):2368–2370

    PubMed  Article  Google Scholar 

  95. 95.

    Castori M, Dordoni C, Valiante M, Sperduti I, Ritelli M, Morlino S et al (2014) Nosology and inheritance pattern(s) of joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type: a study of intrafamilial and interfamilial variability in 23 Italian pedigrees. Am J Med Genet A. 164(12):3010–3020

    Article  Google Scholar 

  96. 96.

    Rowe P, Barron D, Calkins H, Maumenee I, Tong PY, Geraghty MT (1999) Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatr. 135(4):494–499

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Grigoriou E, Boris JR, Dormans JP (2015) Postural Orthostatic Tachycardia Syndrome (POTS): association with Ehlers-Danlos syndrome and orthopaedic considerations. Clin Orthop Relat Res 473(2):722

    PubMed  Article  Google Scholar 

  98. 98.

    Wallman D, Weinberg J, Hohler AD. Ehlers–Danlos syndrome and postural tachycardia syndrome: a relationship study. J Neurol Sci. 2014;340(1–2):99–102.

    PubMed  Article  Google Scholar 

  99. 99.

    Gazit Y, Nahir AM, Grahame R, Jacob G (2003) Dysautonomia in the joint hypermobility syndrome. Am J Med. 115(1):33–40

    PubMed  Article  Google Scholar 

  100. 100.

    Miglis M, Schultz B, Muppidi S (2017) Postural tachycardia in hypermobile Ehlers-Danlos syndrome: a distinct subtype? Auton Neurosci. 208:146–149

    PubMed  Article  Google Scholar 

  101. 101.

    Shibao C, Jackson Roberts IIL, Raj S, Black B, Harris P, Biaggioni I (2005) Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 45(3):385–390

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Doherty T, White A (2018) Postural orthostatic tachycardia syndrome and the potential role of mast cell activation. Auton Neurosci. S1566–0702(17):30338–30337

    Google Scholar 

  103. 103.

    Cheung I, Vadas P (2015) A new disease cluster: mast cell activation syndrome, postural orthostatic tachycardia syndrome, and Ehlers-Danlos syndrome. J Allergy Clin Immunol. 135(2):AB65

    Article  Google Scholar 

  104. 104.

    Vengoechea J (2018) In reply to “Mast Cell Disorders in Ehlers-Danlos Syndrome”. Am J Med Genet. 176(1):250

    PubMed  Article  Google Scholar 

  105. 105.

    Beighton P, Grahame R, Bird H (2012) The molecular basis of joint hypermobility. In: Hypermobility of joints. Springer, pp 27–47

  106. 106.

    Zweers MC, Hakim AJ, Grahame R, Schalkwijk J (2004) Joint hypermobility syndromes: the pathophysiologic role of tenascin-X gene defects. Arthritis Rheum. 50(9):2742–2749

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Hirai S, Ohyane C, Kim Y, Lin S, Goto T, Takahashi N et al (2014) Involvement of mast cells in adipose tissue fibrosis. Am J Physiol Endocrinol Metab. 306(3):247

    Article  CAS  Google Scholar 

  108. 108.

    Hügle T (2014) Beyond allergy: the role of mast cells in fibrosis. Swiss Med Wkly. 144:w13999

    PubMed  Google Scholar 

  109. 109.

    Bradding P, Pejler G (2018) The controversial role of mast cells in fibrosis. Immunol Rev. 282(1):198–231

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Cairns JA, Walls AF (1997) Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. J Clin Invest. 99(6):1313–1321

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Garbuzenko E, Nagler A, Pickholtz D, Gillery P, Reich R, Maquart F et al (2002) Human mast cells stimulate fibroblast proliferation, collagen synthesis and lattice contraction: a direct role for mast cells in skin fibrosis. Clin Exp Allergy. 32(2):237–246

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Manel J, Befus D, Newhouse M, Bienenstock J, Gauldie J, McMaster U (1988) Effect of histamine on proliferation of normal human adult lung fibroblasts. Thorax. 43(7):552–558

    Article  Google Scholar 

  113. 113.

    Hatamochi A, Fujiwara K, Ueki H (1985) Effects of histamine on collagen synthesis by cultured fibroblasts derived from guinea pig skin. Arch Dermatol Res. 277(1):60–64

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Russel JD, Russell SB, Trupin KM (1977) The effect of histamine on the growth of cultured fibroblasts isolated from normal and keloid tissue. J Cell Physiol. 93(3):389–393

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Abe M, Kurosawa M, Ishikawa O, Miyachi Y (2000) Effect of mast cell-derived mediators and mast cell-related neutral proteases on human dermal fibroblast proliferation and type I collagen production. J Allergy Clin Immunol. 106(1 Pt 2):78

    Article  Google Scholar 

  116. 116.

    De Wandele I, Rombaut L, Leybaert L, Van de Borne P, De Backer T, Malfait F et al (2014) Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers–Danlos syndrome. Semin Arthritis Rheum. 44(1):93–100

    PubMed  Article  Google Scholar 

  117. 117.

    Bonamichi-Santos R, Yoshimi-Kanamori K, Giavina-Bianchi P, Aun MV (2018) Association of postural tachycardia syndrome and Ehlers-Danlos syndrome with mast cell activation disorders. Immunol Allergy Clin N Am 38(3):497–504

    Article  Google Scholar 

  118. 118.

    Sabato V, Van De Vijver E, Hagendorens M, Vrelust I, Reyniers E, Fransen E et al (2014) Familial hypertryptasemia with associated mast cell activation syndrome. J Allergy Clin Immunol 134(6):1450.e3

    Article  Google Scholar 

  119. 119.

    Lyons JJ, Sun G, Stone KD, Nelson C, Wisch L, O’Brien M et al (2014) Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities. J Allergy Clin Immunol. 133(5):1471–1474

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y et al (2016) Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 48(12):1564–1569

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Cardamone C, Parente R, Feo GD, Triggiani M (2016) Mast cells as effector cells of innate immunity and regulators of adaptive immunity. Immunol Lett 178:10–14

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Galli SJ, Tsai M (2010) Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity. Eur J Immunol. 40(7):1843–1851

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Suurmond J, Dorjée AL, Knol EF, Huizinga TWJ, Toes REM (2015) Differential TLR-induced cytokine production by human mast cells is amplified by FcɛRI triggering. Clin Exp Allergy. 45(4):788–796

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Gallenga CE, Pandolfi F, Caraffa A, Kritas SK, Ronconi G, Toniato E et al (2019) Interleukin-1 family cytokines and mast cells: activation and inhibition. J Biol Regul Homeost Agents 33(1):1–6

    CAS  PubMed  Google Scholar 

  125. 125.

    Yu Y, Blokhuis BR, Garssen J, Redegeld FA (2016) Non-IgE mediated mast cell activation. Eur J Pharmacol 778:33–43

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Jakate S, Demeo M, John R, Tobin M, Keshavarzian A (2006) Mastocytic enterocolitis: increased mucosal mast cells in chronic intractable diarrhea. Arch Pathol Lab Med. 130(3):362–367

    PubMed  Google Scholar 

  127. 127.

    Hahn HP, Hornick JL (2007) Immunoreactivity for CD25 in gastrointestinal mucosal mast cells is specific for systemic mastocytosis. Am J Surg Pathol. 31(11):1669–1676

    PubMed  Article  Google Scholar 

  128. 128.

    Sethi A, Jain D, Roland BC, Kinzel J, Gibson J, Schrader R et al (2015) Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med. 139(2):225–232

    PubMed  Article  Google Scholar 

  129. 129.

    Doyle LA, Sepehr GJ, Hamilton MJ, Akin C, Castells MC, Hornick JL (2014) A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol. 38(6):832–843

    PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Obrenovich MEM (2018) Leaky gut, leaky brain? Microorganisms 6(4)

    CAS  PubMed Central  Article  Google Scholar 

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Correspondence to Christopher Chang.

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Kohn, A., Chang, C. The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS). Clinic Rev Allerg Immunol 58, 273–297 (2020). https://doi.org/10.1007/s12016-019-08755-8

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Keywords

  • Hypermobile Ehlers-Danlos syndrome
  • Mast cell activation syndrome
  • Mast cell disorder
  • Postural orthostatic tachycardia syndrome
  • Leaky gut
  • Fibromyalgia