Vera AM, Peterson LE, Dong D, et al. High prevalence of connective tissue gene variants in professional ballet. Am J Sports Med. 2020;48(1):222-228.
To determine the prevalence of connective tissue gene variants in professional ballet dancers and understand if increased joint hypermobility or presence of gene variants improved a ballet dancer’s position within a company.
This study included 51 adults, male (n=26) and female (n=25) professional ballet dancers from a large metropolitan ballet company, 32 of whom completed genetic testing. Ages ranged from 18 to 35 years with a mean of 23.9 years.
Study Parameters Assessed
The authors evaluated all 51 participants for generalized joint hypermobility using a Beighton Score, hip and ankle turnout scores, and the Brighton Criteria, a clinical tool that aids diagnosis of generalized joint hypermobility syndromes. Thirty-two participants consented to genetic testing and were evaluated for 60 different connective tissue variants. These variants were grouped in the following clusters: Ehlers-Danlos syndrome (EDF); Marfan; Loeys-Dietz; Bethlem myopathy; and morphology of muscle, skeleton, and connective tissue.
Primary Outcome Measures and Key Findings
Of the 32 dancers who participated in DNA analysis, 28 (88%) had at least 1 variant in the 60 genes tested. The researchers found a total of 80 variants. In at least 1 dancer, they found a variant in 26 of the 60 genes. The Brighton Criteria was positive in 31.3% of the participants, and 53.1% had a positive Beighton Score. No other connective tissue disease variants were found.
The authors did not find any advantage within the company (principal versus apprentice) for those with connective tissue variants. They found that dancers with variants in the Marfan and Loeys-Dietz clusters had decreased hip turnout.
Hereditary hypermobile spectrum disorders (HSD) are an emerging cause of chronic pain and multisystem dysfunction.1 This study helps define the prevalence of previously unreported and underreported connective tissue variants. The researchers evaluated 8 genes that have never been reported on or are reported to occur in <0.0001% of the population.
These data are astounding. Either these connective tissue gene variants are significantly more prevalent than previously reported, or ballet dancers are substantially overrepresented, or both. This information can help clinicians suspicious of secondary causes of pain to look for underlying HSD by obtaining a pertinent history. Simply asking your patients if they have a history of ballet, gymnastics, or cheerleading may be helpful for screening.
There are many myths perpetuated regarding HSD. For example, patients do not need a history of frank joint dislocation to meet the 2017 diagnostic criteria for hypermobile Ehlers-Danlos syndrome (hEDS) or HSD.2 Physicians may overlook HSD in their differential in patients with chronic pain due to the perceived rarity of these disorders. Twenty years ago, prevalence was reported in 1/5,000 (0.0002%),3 and recent studies report it in 1/500 (0.002%).4 The true prevalence is unknown due to lack of recognition and lack of application of appropriate diagnostic criteria. This insufficient understanding has led to increased patient suffering and mistaken diagnoses such as fibromyalgia, central pain sensitization, and/or psychiatric disorders.5
This study is substantially limited by the lack of an age-matched control population. Age-matched controls could have helped define if underreported variants are truly overrepresented in ballet dancers. While it is impressive that 88% of participants had an identifiable variant, many of the most common variants are not reported in the Human Gene Mutation Database or Ensembl, and thus, we have no way of knowing if these variants are significantly higher compared to a nonballet population. For instance, the most common variant identified was the TTN gene, which is involved with muscle morphology. This variant was found 22 times, but the frequency in the general population is unknown. Moreover, there are no data recorded on ethnicity, which likely impacts frequency of variants.
These data are astounding. Either these connective tissue gene variants are significantly more prevalent than previously reported, or ballet dancers are substantially overrepresented, or both.
The authors, disappointingly, did not report or analyze the patients who had >1 variant present. This was likely due to the small sample size. For instance, they found 3 variants at the TNXB gene, 2 at the ADAMTS2, 2 at COL1A2, and 1 at COL1A1. These are associated, respectively, with the following forms of Ehlers-Danlos syndrome: classical-like, dermatosparaxis, cardiac-valvular, and classical. The authors should have performed echocardiograms on all dancers who had Marfan, EDS, or Loeys-Dietz genes. The authors do not comment if these dancers with known EDS variants were more likely to fulfill the Brighton Criteria. If this information had been reported, it could help us understand these disorders better. This is likely present in their data but not reported.
This study used the antiquated 1998 Brighton Criteria to identify participants with a hypermobile disorder.6 The Brighton Criteria were replaced in 2017.7 Brighton Criteria were previously used to identify patients with benign joint hypermobility syndrome (BJHD). We no longer use this terminology, and this disorder is now referred to as hypermobile spectrum disorders (HSD), of which hypermobile Ehlers-Danlos syndrome (hEDS) is part.
Additionally, the researchers used no validated outcome measures for evaluating chronic pain. While there may be benefits of being hypermobile—for example, improved performance in a discipline that requires excessive joint movement such as ballet—it is important to understand that there can be debilitating consequences.8,9
My suspicion based on clinical experience with more than 1,000 HSD patients is that more profoundly affected patients are less likely to advance in professional careers due to severe pain, joint instability, injury, and the presence of other comorbid disorders such as postural orthostatic tachycardia syndrome (POTS) or mast cell activation syndrome (MCAS).10,11
Researchers are still elucidating the true frequency of these overlapping comorbidities, but evidence is growing that suggests disability is greater in patients with multisystem disorders.12 Clinicians must understand that these disorders can lead to global disability. Integrative medicine is well poised to help these patients improve joint stability and autonomic nervous system and immune function if the practitioner is willing to take a deep dive into the literature.
Overall this study improved our understanding of hypermobile connective tissue gene variants. Future studies must include matched controls to define the true incidence in ballet dancers compared to the general population. This paper is ultimately unable to support its hypothesis that variants within hypermobility-associated genes would be overrepresented in professional ballet dancers. We must also explore dancers’ ethnicities, validated pain scales, and quality of life. Current diagnostic criteria and nomenclature of hypermobile spectrum disorders and hypermobile Ehlers-Danlos syndrome should be used. While this study did not compare prevalence of HSD with age-matched controls, clinicians should still consider questioning their chronic-pain patients about past ballet, gymnastic, and cheerleading participation.
- Syx D, De Wandele I, Rombaut l, Malfait F. Hypermobility, the Ehlers-Danlos syndromes and chronic pain. Clin Exp Rheumatol. 2017;35 Suppl 107(5):116-122.
- 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 C Semin Med Genet. 2017;175(1):48-69.
- Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998;77(1):31-37.
- Demmler JC, Atkinson MD, Reinhold EJ, Choy E, Lyons RA, Brophy ST. Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case-control comparison. BMJ Open. 2019;9(11):e031365.
- Berglund B, Anne-Cathrine M, Randers I. Dignity not fully upheld when seeking health care: experiences expressed by individuals suffering from Ehlers-Danlos syndrome. Disabil Rehabil. 2010;32:1-7.
- Simpson MR. Benign joint hypermobility syndrome: evaluation, diagnosis, and management. J Am Osteopath Assoc. 2006;106(9):531-536.
- 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.
- Chua JR, Castrejon I, Pincus T. Assessment of pain and other patient symptoms in routine clinical care as quantitative, standardised, “scientific” data. Clin Exp Rheumatol. 2017;35 Suppl 107(5):13-20.
- Morlino S, Dordoni C, Sperduti I, et al. Italian validation of the functional difficulties questionnaire (FDQ-9) and its correlation with major determinants of quality of life in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder. Am J Med Genet B Neuropsychiatr Genet. 2019;180(1):25-34.
- Roma M, Marden CL, De Wandele I, Francomano CA, Rowe PC. Postural tachycardia syndrome and other forms of orthostatic intolerance in Ehlers-Danlos syndrome. Auton Neurosci. 2018;215:89-96.
- 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.
- Copetti M, Morlino S, Colombi M, Grammatico P, Fontana A, Castori M. Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients. Rheumatology (Oxford). 2019;58(10):1722-1730.