Sep 02, 2019

The Major Histocompatibility Complex (MHC) region on chromosome 6 is the most gene-dense region in the human genome, containing gene families essential to the immune system. There is a cluster of 4 genes which have have escaped medical scrutiny -  These genes make multiple copies of themselves, which are called copy number variations. They often behave as one unit with the genes deleted and duplicated together, instead of as four separate units. RCCX is the only place in the human genome where genes travel together in this way.

RCCX Theory preposes that co-inheritance of the highly mutable genes of the RCCX module may confer vulnerability to familial clusters of overlapping syndromes of chronic illness (hyper-mobility, autoimmune disease, CFS/ME, FM, MCAS, POTS, and 80% of Psychiatric and Neurodevelopmental disorders) and may be the diathesis in the stress diathesis model of disease for 20-30% of the population.

  • CYP21A2 : Responsible for 21-hydroxylase, which hydroxylates Progesterone into Cortisol and Aldrostrone. EDS/POTS/MCAS
  • TNXB : Hypermobility, hEDS, Tenascin-X Deficient Classical-like EDS.
  • C4 : Autoimmune, Diabetes and Schizophrenia.
  • Rendovirus HERV-K on C4 has shown to be overexpressed in CFS/ME

While this is a theory, the mechanistic and associative data is solid - There has also been several significant findings published in the years since RCCX Theory was published in 2015. I've outlined some of the most significant evidence below.

The prevalence of hypermobility is between 20% and 30% in the general population, with a wide variance in hypermobility on a scale from intestinal permutability only to chronic dislocations and sublaxations.  (45% of girls and 29% of boys had hypermobile fingers)

Joint Hypermobility Syndrome (JHS) is considered by many experts in rheumatology and in clinical genetics to be indistinguishable from, if not identical to, the most common variant of Ehlers-Danlos syndrome Hypermobile Type (EDS-HT)

EDS is a multi-systemic disease with a wide variance in symptoms

Ehlers-Danlos syndrome is often misunderstood by doctors because of their lack of knowledge about Ehlers-Danlos disease and its physiopathological mechanisms. The published descriptions remain limited, and neglect many elements of the clinical picture of this multi-systemic disease (2018)

A 'Chronic Constellation' of conditions (MCAS/EDS/POTS) have been repeatedly shown to appear by more than chance

The adrenal gland is a gland that sits on the kidney and produces the stress hormone cortisol and other important hormones that help to maintain adequate salt and water in the body. This is important in maintaining blood pressure. In adrenal insufficiency the lack of these hormones can lead to orthostatic symptoms and a low blood pressure. In addition there is weakness and fatigue and many of the other symptoms associated with POTS.

CYP21A2 mutations may be the diathesis in the stress diathesis model of disease — conferring the vulnerability to stress with resulting neurological and immunological issues in patients with and without  hypermobility and that CAPS Personality (Mild ADHD - prone to PTSD/Anxiety) may represent the spectrum disorder which links all 5 of the major psychiatric disorders (Anxiety, ADD, schizophrenia, Mood Disorders, Autism) and vulnerability to the development downstream complications including: POTS, MCAS, EDS, neurological and immunological disorders all with enhanced vulnerability in women, and clustering in families. - RCCX Theory


Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones. CAH effects the adrenal glands located at the top of each kidney. The pathogenic genes for CAH are located on CYP21A2 in the RCCX Region.

The most common form of CAH is characterised by a deficiency of 21-hydroxylase. This means that Progesterone builds up, and the excess ends up being dumped into the 'Backdoor pathway' - Androgens)

It is surprising how frequently hypermobility, which was only slightly worse at the time of normal unmodified menstruation, becomes significantly worse with certain contraceptive pills, especially those containing progesterone alone or with progesterone depo contraception preparations or with mechanical devices impregnated with progesterone...In general, patients with hypermobility are safer avoiding injectable progesterone and progesterone impregnated devices. They might also be better avoiding contraceptive pills that contain progesterone derivatives alone." - Prof. Howard Bird

There are 230 identified pathogenic variants on CYP21A2, ~10% of people have NCAH and don't even realise it, and that's only for 2 of the ezyme changes.

One CYP21A2 mutation - p.H62L - which is found in 12.5% of the population was classified as Pathogenic in 2008 for Non-Classical CAH with a shown reduction in ezyme activity, but downgraded to Benign in 2015 because 12.5% of the population weren't presenting with progesterone issues, at least not as they're currently defined.

The number of modules and type of C4 complement genes within the RCCX regions vary between individuals, and gene dosage of C4A and C4B has been associated with various disorders. For instance, lower levels of C4A have been associated with susceptibility to systemic lupus erythematosis, while lower levels of C4B have been associated with increased rates of acute myocardial infection and stroke.

Rendovirus HERV-K on C4 has shown to be overexpressed in CFS/ME

Predisposition to chronic psychiatric illness via:

  • CYP21A2 gene mutations create a hormone milieu which could affect the developing brain, making it a “brain wired for danger” by age 5, also known as CAPS (CYP21A2 Mutation Associated Psychiatric Spectrum). CAPS likely predisposes to 4/5 of the major psychiatric illnesses due to exaggerated stress response, low basal arousal and resultant harm-avoidance and threat circuits

Predisposition to chronic medical illness via:

  • CYP21A2 gene mutations could confer a stress vulnerability for the development of chronic medical illness via “21hydroxylase overwhelm” and via PTSD-wiring from CAPS plus negative events which could likely result in stress-induced mitochondrial shutdown (as described by Naviaux MD PhD [ref]).

To date, no gene has been found to explain the prevalence 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, MCAS, psychiatric issues and why some individuals with hypermobile relatives develop these same conditions without hypermobility.


Since RCCX Theory was published in 2015, several developments support it's hypothesis