Back in July, I had the honor of spending an afternoon with Dr. Sharon Meglathery in her home near Tucson, Arizona. Dr. Meglathery is board-certified in psychiatry and has noted a high percentage of patients suffering from chronic illness, including mast cell activation syndrome (MCAS), in her patient population.

Dr. Meglathery devised a hypothesis called the “RCCX Theory” which aims to explain the connections between a wide range of chronic overlapping medical diagnoses. Specifically, she theorizes that mutations along the RCCX gene module (specifically, CYP21A2, TNXB and C4 genetic mutations) are responsible for predisposition in individuals and families to psychiatric illness and medical illness.



Dr. Meglathery notes that “unlike contiguous gene mutations in other parts of the genome, these genetic mutations are often inherited together, conferring vulnerabilities to multiple genetic issues at one time.” The RCCX Theory associates changes in the CYP21A2 gene with vulnerability to an altered acute stress response, changes in the TNXB gene with tissue characteristics seen in hypermobility of the joints, and changes in the C4 gene with a variety of autoimmune diseases, immunodeficiency states and changes in dendritic branching in the brain. Dr. Meglathery ​states that “CYP21A2 mutations are between 10- 20% of the population… TNXB and C4 mutations are also extremely common.”

Mutations to the RCCX gene region are not the epigenetic/SNP types that are commonly discussed with methylation, but are rather a copy number variation type of mutation. RCCX mutations are not identified in commercial “over-the-counter” genetic testing like 23 and Me. Currently, testing is not readily available to most patients. The three areas of RCCX need not be affected simultaneously in order to trigger illness. Some patients may have mutations of all the RCCX genes, while others may have a single mutation in one area.

Not all patients with MCAS have RCCX mutations, and not all patients with RCCX mutations have MCAS. Dr. Meglathery believes that MCAS is one of the many physiological states that can occur as a downstream side effect from a CYP21A2 RCCX genetic mutation.

Dr. Meglathery connects genetic mutations of CYP21A2 to conditions such as postural orthostatic tachycardia syndrome (POTS), MCAS, hypermobile Ehlers-Danlos syndrome, fibromyalgia, chronic fatigue syndrome, Lyme disease, Epstein Barr infection, mold toxicity as well as a spectrum of psychiatric conditions including autistic features and high intelligence. Her website lists a great number of conditions that are often comorbid with the MCAS population, such as adrenal fatigue and thyroid disorders, interstitial cystitis, gastrointestinal findings such as small intestinal bacterial overgrowth, candida overgrowth, and fungal infections, temperature dysregulation, Raynaud’s disease, connective tissue irregularities, and much more.

The physiological mechanisms behind the RCCX Theory are extremely complicated, at best. Dr. Meglathery showed me diagrams and flow charts that left my mind spinning as I tried to grasp how factors like corticotropin releasing hormone, androgens, aldosterone, cholesterol, cortisol, and others appear to interact extensively in the development of dysfunctional systems leading to chronic symptoms.

Dr. Sharon Meglathery

CYPA21A2 Mutation

The RCCX Theory maintains that the presence of one or more mutations at CYP21A2 may be enough to trigger an aberrant stress response in utero and in infancy that “wires the brain for danger” and results in chronic problems with cortisol and post-traumatic stress disorder (PTSD)-like responses due to epigenetic stress effects. When people with CYP21A2 mutations are exposed to prolonged stress, known elevated corticotropin releasing hormone (CRH) turns on inflammatory cascades and stimulates mast cells, which can trigger a clinical picture of MCAS.

Acute stress emerging from factors like exposure to mold or Lyme bacteria via CYP21A2 mutations also appears to lead to the same inflammatory cascades and activation of mast cells in the brain and in the body. Dr. Meglathery notes that viruses like Epstein-Barr virus or strong bacterial infections or physical trauma could indeed be strong enough to “flip” a CYP21A2 mutation carrying population into chronic illness.

Dr. Meglathery believes that there are 2 groups of MCAS patients:

  • Patients who likely have CYP21A2 RCCX genetic mutations driven by stress who tend to be very “unique psychologically,” and
  • Patients who have MCAS without RCCX mutations who lack the psychological profile

Specifically, Dr. Meglathery notes that a large subgroup of patients that have a CYP21A2 RCCX genetic mutation exhibit unique psychological characteristics like elevated intelligence levels or other special abilities. These patients tend to be empathic, highly reactive, and sensitive to the environment. Patients in this category may have clinical symptoms of PTSD, many without significant traumas. She believes that patients with mild CYP21A2 mutations (not requiring treatment at birth) have a resulting neuropsychiatric profile with the brain wired for danger by the age of five which she terms “CAPS” or the psychological profile “CYP21A2 associated neuropsychiatric spectrum.” Patients with CAPS tend to have enlarged limbic structures which correspond to increased emotions and fear, high levels of stress arousal, sensory sensitivities, intersex tendencies, and some meet the criteria for autism spectrum disorders. They may have clinical diagnoses of conditions such as Asperger’s or bipolar disorder, but often have no clear psychiatric diagnosis.

CYP21A2 codes for a crucial enzyme called 21 hydroxylase which is involved with stress reactions. Initially, patients with a CYP21A2 mutation have elevated cortisol in response to stress and low basal cortisol.  In response to prolonged or strong stressors, 21 hydroxylase becomes blocked which can transition the patient into a more chronic illness state, where cortisol is actually low and orthostatic stress and POTS may potentially develop. This pathway can then lead to elevated CRH, which increases norepinephrine and mast cell activation and decreases stomach acid, leading to dysbiosis. Basal cortisol decreases more dramatically with inappropriately low stress cortisol and high cholesterol, and progesterone and androgens can develop. According to Dr. Meglathery, the elevated progesterone can lead to a number of symptoms and can also trigger an increase in mast cell activation.

The resulting inflammation from CYP21A2 RCCX mutations may be tied to a variety of neuroimmune symptoms. Epigenetic stress wiring in the brain pushes toward increasing danger responses in the form of fight or flight, freeze and shutdown. Initially, most patients exhibit fight or flight sympathetic nervous system activity, characterized by elevated heart rate and blood pressure, increased sweating, and decreased gut motility.

Over time, many patients move toward the freeze phase in response to perceived danger, where they tend to experience a lower heart rate, breath holding, muscle tension (especially in the shoulders, neck and back), hearing changes and sometimes immobility. The freezing state is triggered by neural memory networks from PTSD and can result in a catatonic or dystonic state. Shutdown can also occur when there is opiate dumping preparation in addition to freeze.  Patients may predominantly experience one side of the nervous system spectrum but can also shift between states over the course of time. Pseudoseizures are sometimes observed with CYP21A2 mutations and may be associated with the danger response and PTSD wiring.

Patients with CAPS tend to experience various phases of dysautonomia-associated stress responses. Dr. Meglathery explains that there is a “wired for danger scale” dependent on factors in-utero that appears to determine whether a person will be more of an extroverted thrill seeker or more fearful and anxious. Likewise, she notes that patients with presumed CYP21A2 RCCX mutations tend to be either more of an empath, or more of a narcissist; both personality types tend to read people well.

TNXB Mutation

TNXB gene mutations increase levels of TGF-beta in the system, which can lead to (slow, gradual) changes in the extracellular matrix that influence collagen, joint mobility and orthostatic stress. If a patient has abnormal connective tissue from a TNXB mutation, the body is more predisposed to dysfunctional movement and chronic overuse issues with a greater inflammatory cascade in the tissues. Clinically, this could present as something like myofascial pain or joint issues noted in patients who have the hypermobile type of Ehlers-Danlos syndrome. Dr. Meglathery notes that as the body responds to an increasing danger response, more stooped and twisted postures often develop.

She adds, “Additionally, TNXB mutations increase orthostatic stress due to floppy blood vessels with resultant blood pooling in the extremities contributing to the stress load which activates the CYP21A2 mutation-associated issues.  Further, TNXB mutations are associated with TGF beta signaling abnormalities which can result in fibrotic and inflammatory conditions as well.” TNXB mutations may trigger changes in the extracellular matrix that influence factors like lymphatic function and glial cells, among others.

C4 Mutation

If a particular patient also has a mutation at C4, the inflammatory responses may be more severe, and the patient may also go on to develop autoimmune problems or immunodeficiencies and abnormal dendritic branching patterns in the brain. Specifically, C4 gene mutations influence the development of autoantibodies which are associated with the development of autoimmune conditions as well as POTS.

Patients with C4 mutations tend to have slower onset symptoms that wax and wane­—often across the lifetime—but may experience a sudden deterioration or collapse associated with stress. Dr. Meglathery believes that some patients with immunodeficiencies like CVID and IgG issues are likely carrying C4 mutations. They tend to present with longstanding immunodeficiency-associated problems, like difficulty clearing Epstein-Barr virus (EBV).

Putting it all Together

It appears that variations in symptom onset may be related to the type of RCCX mutation present, as well as presence of stressors. Certain downstream effects of CYP21A2 mutations develop slowly (like PTSD/danger wiring and rises in norepinephrine) while others (like drops in cortisol and mast cell activation) can develop suddenly and intensely. In contrast, TNXB mutations lead to slow, gradual changes and C4 mutations tend to have an underlying current of dysfunction that can go overboard with sudden severe stress.

According to Dr. Meglathery, additional subgroups are emerging that appear to have certain tendencies. For example, some people with presumed CYP21A2 mutation without TNXB mutations experience 21 hydroxylase block with stress, endocrine issues, chronic illness, mast cell activation issues and psychological manifestations without exhibiting hypermobility. In addition, some patients with CAPS seem to have a normal immune system prior to becoming sick and once ill with MCAS, they demonstrate a highly functioning system where they never get the common cold but suffering recurrent herpes and fungal infections.

Dr. Meglathery supports the relationships postulated in the Driscoll Theory regarding intracranial pressure and acquired cases of Chiari malformation from the brain getting pushed down in the skull. She noted that factors like elevated progesterone, mast cell activation, neuroinflammation and low cortisol (resulting from the cascade of influences of RCCX genetic mutations) can elevate intracranial pressure.

Dr. Meglathery notes that, based on Dr. Naviaux’s research, mitochrondrial shutdown can occur in these types of patients. Mutations to any or all three RCCX genes may shut down the mitochondria, the energy powerhouse of the cell, which can contribute significantly to chronic fatigue, the cell danger response, and (lack of) healing.

Treatment for Patients with an RCCX Mutation

Dr. Meglathery considers a number of factors in her patient care with this population. She determines where the patient is on the continuum of danger responses, and evaluates for mast cell activation, which she considers the first priority in treatment. She notes, “With mast cell activation, when the whole body is in protective mode, the patient cannot get well.”

Once the mast cell activation has been addressed and calmed down, Dr. Meglathery utilizes a number of additional treatments to facilitate healing. She encourages trauma processing through EMDR treatment sessions and a focus on mindfulness (“I notice _____”) and non-judgmental awareness (“Put yourself in the audience”). She encourages patients to cut out toxic (passive aggressive, narcissistic) relationships to restore nervous system health. “You have to own your body and make yourself well.”

Dr. Meglathery works with patients to stabilize the nervous system, utilizing techniques for grounding and controlled sensory input. She works with patients on body and positional awareness as well as important education to help patients gain tools for self-care. Dr. Meglathery teaches patients to avoid breath-holding and to add exercises like singing that bring the fight or flight response down, as well as physical exercise focusing on the bigger muscle groups without overextending the joints. She notes that physical therapy can help reduce the pain and stiffness that tends to go hand in hand with chronic postural changes from the danger response.

Dr. Meglathery also addresses any malabsorption, vitamin or mineral deficiency issues in this patient population, ensuring that patients are getting appropriate vitamin D, magnesium, certain B vitamins, vitamin C, and electrolytes and hydration as appropriate. She may also utilize mast cell medications like ketotifen, mast cell supplements like quercetin, medications for sleep, low dose naltrexone for patients who are shutdown (not in fight or flight), and berberine for certain subgroups of patients.

Of course, patient care is strictly individualized and comprehensive treatment plans should always be guided with the help of a licensed medical professional.


Dr. Meglathery and her horse, Cheetah


“Over time, it became clear to me that there seems to be a frequently disabling epidemic involving a large number of syndromes/symptoms/diseases with overlapping symptoms affecting mainly young, vibrant, talented people (predominantly women) and if you look, many, but not all, have joint hypermobility (double jointedness, ligament laxity).”

Dr. Meglathery adds, “There are still many people who believe that these chronic illness conditions are completely separate in pathophysiology, e.g. all of the symptoms associated with EDS are solely caused by a genetic defect of collagen, all of the symptoms of Lyme disease are caused by borrelia burgdorferi, all symptoms of CIRS are caused by the inciting agent, etc. But, every day, it is becoming more clear that these conditions all go down a common pathway.  There are just too many very specific overlapping symptoms for it to be any other way.”

Like MCAS, the breadth of issues and potential triggers is enormous, and there is no single hallmark clinical picture for patients with RCCX genetic mutations. The RCCX Theory supports that MCAS is one of many physiological changes that can occur as a result of genetic mutation(s) coupled with the right environmental factors, as opposed to pointing a finger of blame at mast cell activation as the main trigger for comorbid conditions.

Dr. Meglathery is a patient herself who knows firsthand what it’s like to suffer with chronic invisible illness. She has worked tirelessly in order to raise awareness among physicians and patients alike, all while managing her own daily health challenges. I was captivated by her personal story and floored by the scientific connections that theoretically explain how MCAS relates to other conditions.

Dr. Meglathery is the first to note that despite compelling indicators of these connections, the RCCX Theory is (currently) just that: a theory. Hopefully future research will focus on this area and more clinicians will incorporate comprehensive care that can assist patients in restoring health and vitality in the face of chronic overlapping illness.

The world needs more experts like Dr. Meglathery. As I was leaving her home, I accidentally grabbed her car keys instead of my own. It turns out that we both have the exact same blue pepper spray keychain! We had a good laugh over our many (perhaps RCCX-driven) similarities and I departed feeling inspired, mind buzzing with new information, and full of gratitude for encountering a top-notch provider who truly “gets it.”

Check out these links to Dr. Meglathery’s websites to learn more about her story, her practice and the RCCX Theory:   *this website has a downloadable flowchart that goes into greater detail about the physiological mechanisms occurring with RCCX genetic mutations

Dr. Meglathery also manages a Facebook page called RCCX and Chronic Illness:



Meglathery S. RCCX and Illness. Accessed September 27, 2017.

Meglathery, S. In-person interview conducted in Tucson, Arizona on 7/25/18.

Driscoll D, De A, Doherty C, Ferreira JP, Meglathery S, Pazun J. The Driscoll Theory Newly Revised: The Cause of POTS in Ehlers-Danlos Syndrome and How to Reverse the Process. Warnick Publishing; 2015.

Naviaux RK. Metabolic features and regulation of the healing cycle—A new model for chronic disease pathogenesis and treatment. Mitochondrion. August 2018. doi:10.1016/J.MITO.2018.08.001


This content is Copyright © Mast Cells United and is not intended to diagnose or treat anyone. Always consult your medical professional for any health guidance or advice.

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