Hypermobility Spectrum Disorder

Aug 01, 2019

There has been various confusion over the past 2 decades as to who fits into which 'bendy-box' (Hypermobile Ehlers-Danlos Syndrome (hEDS), Joint Hypermobility Syndrome, Benign-JHS, Double jointedness, Hypermobility)

To date, no gene has been found to explain the prevalence and spectrum of hypermobility in the general population. Nor why these individuals become so ill with such a wide range of not easily explainable symptoms, including: white matter lesions; hormone disruptions; autoimmune diseases; and MCAS, psychiatric issues and why some individuals with hypermobile relatives develop these same conditions without hypermobility.

There have been several significant findings over the past few years which shed some  light on this.

The genes comprising the RCCX cluster code for enzymes and proteins which substantially influence responses to stressors and cell danger signaling. They also affect innate immune responses as well as synaptic and dendritic pruning (important for the developing brain), sex hormone levels, fluid and salt balance, and the integrity of the extracellular matrix (ECM).  TNXB gene duplications, also found in the 'RCCX' cluster have recently been classified as a 'new type' of EDS.

NIH.gov - TNXB gene

Some people with a condition called benign joint hypermobility syndrome (BJHS) also make a reduced amount of tenascin-X protein, although no TNXB gene mutations have been identified in these individuals. This condition causes hypermobility and chronic joint pain. The signs and symptoms of benign joint hypermobility syndrome overlap significantly with those of the hypermobile type of Ehlers-Danlos syndrome. Studies suggest that they may be forms of the same condition.

CYP21A2 on the RCCX clusters travels in tandem with a psuedogene and the high degree of sequence similarity betweem them indicates that these two genes are evolving in tandem through intergenic exchange of DNA. This is where our genome evolves.

TNXB and C4 overlap CYP21A2, and one specific mutation in TNXB as seen above, was classified a new type of 'rare' EDS that was added in 2017 (Tenascin-X Deficient Classical-like EDS - Called so because the hyperelasticity is present but no deep scarring). This finding is just one of 150+ possible mutations likely on TXNB.

C4 has a proven link to Lupus, Schizophrenia and type 1 diabetes.  CYP21A2 gene mutations affect aldosterone & cortisol (21-hydroxylase), progesterone (closely tied to Vitamin D - and deficiency shares a lot of symptoms). These mutations make us 'hypersensitive' and hyper-reactive. You may be sensitive to noises, touch, and  smell, or food, toxins, infection, medication - and just about anything.

These mutations are present in ~30% of the population and could confer a stress vulnerability for the development of chronic medical illness via “21-hydroxylase overwhelm” (as described by Navuex 2017 in CFS/ME)

Psychological vulnerability to stress in carriers of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2017) - Mutations are associated with an exaggerated stress response in the setting of low basal cortisol

Then NIH scientists identified a genetic disorder that affect 1 in 20

This is due to duplications in the TPSAB1 gene - Which only accounts for 5% - A small subset of the 30% affected. The TSPAB1 mutations is another symptom - rather than the cause, as most with POTS/MCAS/EDS do not have elevated tryptase. Similarly TXNB being duplicated in Tenascin-X EDS as an epigenetic response for requring more mast-cell mediators). Corticotropin-releasing hormone (CRH) turns on other inflammation, and causing a domino effect of disorders.

Mast cell disorders in Ehlers–Danlos syndrome (2017)

Several investigators have noted a possible link between EDS and MCAD, primarily patients with the hypermobility type of EDS. Immunohistochemisty analysis identified an increased content of chymase positive MCs in undamaged skin of patients with signs suggestive of CTDs (hyperelasticity of the skin, joint hypermobility, spine and thorax deformities, thumb sign, wrist sign, vascular fragility, varicose veins, and telangiectasias) [Luzgina et al., 2011]. Louisias et al. [2013] described symptoms compatible with a non‐IgE mediated MC disorder in patients with the joint hypermobility syndrome: most reported naso‐ocular symptoms, asthma, and history of anaphylaxis and describe a positive response to classical MC/MC mediator antagonists. Plasma histamine and serum tryptase levels were normal and prostaglandin measurements were not undertaken. Cheung and Vadas [2015] suggested a possible new disease cluster: Mast Cell Activation Syndrome (MCAS), Postural Orthostatic Tachycardia Syndrome (POTS), and EDS. Patients having a diagnosis of POTS and EDS were given a screening questionnaire to look for symptoms consistent with MCAS, and 66% of the respondents reported such symptoms. Recently, Milner et al. identified families with an elevated, baseline serum tryptase, which was associated with the triad of dysautonomia, MCAD, and joint hypermobility [Lyons et al., 2016]. The elevated tryptase level was not consistent with SM. Instead, increased copy numbers of the TPSAB gene, that encodes alpha tryptase, were detected. Moreover, these observations highlight the role of MCA, impacting the structure and function of connective tissue, as described in inflammatory arthritis [Nigrovic and Lee, 2005].

And this is only a tiny bit of the evidence showing mutations in the RCCX gene may be the diathesis in the stress diathesis model of disease leading to
CFS/FM/ME/MS/Dysautonomia(POTS)/EDS/ADHD/ASD/Asthma/Autoimmune/Crohn/IBS + Gender fluidity & 'Brilliance' + anything tied to the immune system.

RCCX Theory preposes that co-inheritance of the highly mutable genes of the RCCX module (CYP21A2, TNXB, C4) may confer vulnerability to familial clusters ((including the weird clustering of these diseases you just noticed in your family)  of overlapping syndromes of chronic illness (hyper-mobility, autoimmune disease, CFS/ME, MCAS, POTS, and 80% of Psychiatric and neurodevelopmental disorders) - due to atypical non-IgE reactions (pesticies/progestrone/histamines/DAO/mold/lyme) and stress.

Clustering of co-occurring conditions in autism spectrum disorder during early childhood: A retrospective analysis of medical claims data. (2019)

The first cluster was characterized by generally high rates of COC diagnosis and comprised 23.7% (n = 776) of the cohort. Diagnoses of developmental delays were dominant in the second cluster containing 26.5% (n = 870) of the cohort. Children in the third cluster, making up 49.8% (n = 1,632) of the cohort, had the lowest rates of COC diagnosis, which were slightly higher than rates observed in the POP cohort. A secondary analysis using these data found that gastrointestinal and immune disorders showed similar longitudinal patterns of prevalence, as did seizure and sleep disorders. These findings may help to better inform the development of diagnostic workup and treatment protocols for COCs in children with ASD

Recent Insights in the Epidemiology of Autoimmune Diseases: Improved Prevalence Estimates and Understanding of Clustering of Diseases (2009)

Rapid expansion of knowledge related to the genetics of autoimmune disease is currently underway. Data from twin, linkage and association studies point to a complex mode of inheritance, and indicate that genes involved in autoimmune disorders are pleiotropic rather than disease specific. Becker describes the “common variant/multiple disease” hypothesis stating that common alleles manifesting in a given disorder under particular genetic/environmental conditions may have the potential to give rise to alternate clinical phenotypes when combined with a different set of genetic and environmental factors [164]. Accumulating data support the premise that clinically distinct autoimmune diseases may have common susceptibility genes. For instance, a major United Kingdom–based genome-wide association study published in 2007 identified several loci with associations to more than one autoimmune disease { 2007 #432}. As summarized by Lettre and Rioux, at least 68 genetic risk variants have now been associated with various autoimmune diseases, in contrast to only 15 that were recognized prior to 2006

An incomplete list of associated disorders


  • Ehlers-Danlos Syndrome, Hypermobility Type (EDS-HT)
  • Chronic fatigue Syndrome (CFS)/Myalgic Encephalomyelitis (ME)
  • Fibromyalgia (FM)
  • Mast Cell Activation Syndrome (MCAS): histamine intolerance, migraines, diarrhea, sinus pain, burning eyes, syncope, distractibility, brain fog, irritability, interstitial cystitis, hyper-adrenergic POTS, etc., depending on location of the mast cells
  • Postural Orthostatic Tachycardia (POTS), Dysautonomia, Orthostatic Intolerance, Low Blood volume
  • Pain Syndromes: Neuropathic Pain Syndromes/Chronic Regional Pain Syndrome/Myofascial Pain Disorder/Frequent Dislocations/Dysmenorrhea/Chronic Headache/Migraines/Interstitial Cystitis/Vulvodynia/Temporomandibular Joint Disorder (TMJ)
  • GI Syndromes: Irritable Bowel Syndrome/Cyclical Vomiting/Gastroparesis/Food Intolerance/Gut dysbiosis/Candida overgrowth/Leaky Gut Syndromes/Malabsorption Syndromes
  • Raised Intracranial Pressure Conditions: Pseudotumor Cerebri/Benign Intracranial Hypertension/Posterior Reversible Encephalopathy/Acquired
  • Chiari Malformation
  • Neurological Issues
  • Mitochondrial Disorders
  • Immune Dysregulation:
  • Psychiatric Issues:
  • Hormonal Disorders:
  • Autoimmune & Autoantibody diseases : Lupus, Raynaulds, CADASIL, Hashimoto's, etc.
  • GU/Renal Issues: Fibromuscular Dysplasia, Diabetes Insipidus, Interstitial Cystitis, Vesicoureteral Reflux

...more research here showing this clear connection.

Oh, and we've pretty much suspected this was the case since 1999.

The burdens are the accompanying genetic or autoimmune diseases such as CAH, systemic lupus erythematosus, and possibly EDS, caused by unequal crossovers and incorporations of deleterious mutations in the constituents of the RCCX.

These announcements are leading the way for more research, but there is plenty you can do today to with this knowledge

Metabolic features and regulation of the healing cycle — A new model for chronic disease pathogenesis and treatment (2019)

Interruptions in the molecular stages of the healing cycle may be at the root of many complex, chronic illnesses. Three stages of the cell danger response(CDR1, 2, and 3) comprise the healing cycle. These stages are triggered by stress or injury and controlled by changes in mitochondrial function and metabolism. A small clinical trialof the antipurinergic drug suraminin autism spectrum disorder (ASD) has shown promise for this approach (Naviaux, 2017; Naviaux et al., 2017).Metabolic addiction to the chemistry produced by different stages of the CDR can occur. When this happens, it can create a life-long risk of relapse or slow return to chronic illness if diet and lifestyle interventions are not maintained. 

Immune, Autonomic, and Endocrine Dysregulation in Autism and Ehlers-Danlos Syndrome/Hypermobility Spectrum Disorders Versus Unaffected Controls (2019)

These data suggest that EDS/HSD and autism share aspects of immune/autonomic/endocrine dysregulation, pain, and some tissue fragility, This overlap, as well as documented comorbidity, suggests some forms of autism may be hereditary connective tissue disorders (HCTD). —[source]

Rationale for Dietary Antioxidant Treatment of ADHD (2018)

ADHD might thus be a (non) allergic hypersensitivity disorder caused by an environmental trigger.

Hypermobility and autonomic hyperacitivty (2019)

It is likely that the importance of hypermobility and autonomic dysfunction to the generation and maintenance of psychopathology in neurodevelopmental disorders is poorly appreciated. This mechanism might explain increased vulnerability to stress sensitive and developmental neuropsychiatric conditions. — [source]

Rationale for Dietary Antioxidant Treatment of ADHD (2018)

The potential involvement of the immune system in ADHD has long been suspected due to the increased prevalence of allergic diseases including atopic dermatitis, asthma and rhinitis in patients with ADHD [69].

ADHD might thus be a (non) allergic hypersensitivity disorder caused by an environmental trigger. — [source]

Application of immunotherapy for neurological manifestations in hypermobile Ehlers–Danlos syndrome (2018)

It has recently been proposed that the diverse clinical features of EDS, including neurological and immunological manifestations,can be attributed to mast cell activation.9,10Roles of mast cells have also been indicated in the pathogenesis ofautoimmune diseases, MS, and rheumatoid arthritis. These case reports and case series suggest that the pathogenesis of hEDS can be partly associated with an autoimmune mechanism. While the underlying mechanisms of hEDS remain unclear, autoimmunity and mast cell activation may play key roles.