Meglathery MD: Coinherited CYP21A2, TNXB, C4 Genes in Chronic illness (CFS, FM, Lyme, MCAS, POTS, Pain, Psychiatric Spectrum, Immunological, Endocrine) +- Hypermobility +- Autoimmune Diseases
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    • RCCX THEORY: Part I Genes and Properties of the RCCX Module Explain Clusters of Illness in Families and all the Symptoms/Syndromes Found in Chronic Illness
    • RCCX THEORY: Part II Connecting RCCX Theory to Mitochondrial Shutdown
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    • The No Longer Current Journal Article Introducing Early Version of the RCCX Theory, July 2015
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    • CYP21A2 Mutations May Be the Diathesis in the Stress-Diathesis Model for Chronic Medical and Mental Illness and May Cause a Psychiatric Spectrum, CAPS
  • New Developments

The No Longer Current JOURNAL ARTICLE

Submitted September 2015
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This following journal article was written July 2015 and submitted for publication in an attempt to bring this theory to someone who may be able to pursue it.  Unfortunately, I think it was ahead of its time.

It is no longer current, but it demonstrates my initial thought process and shows the evidence supporting the RCCX Theory at that time.  It has a very detailed review of the evidence for hormonal disruptions in chronic illness, showing that CYP21A2 mutations could certainly cause them.


Since then I have come to believe that CYP21A2 homozygosity as well as heterozygosity underlie chronic illness, that TNXB mutations can be associated with musculoskeletal stiffness as well as hypermobility, that the psychiatric profile, CAPS, (now called CYP21A2 Mutation Associated Psychiatric Spectrum) is actually a brain wired for danger and at high risk for dissociative limbic and brainstem PTSD wiring.  I also now believe that CYP21A2 mutation-associated PTSD wiring AND/OR 21hydoxylase overwhelm predisposes to Cell Danger Response (mitochondrial shutdown, Naviaux MD PhD), the likely final common pathway in CFS/ME (David PhD and Naviaux MD PhD), via a built-in evolutionary switch designed to remove individuals unsuited to the level of environmental stress from the gene pool (see RCCX Theory Part II).   
 
Also, since I wrote this article, several large important discoveries support the RCCX Theory:
  • C4 being linked with schizophrenia (C4 often co-segregates with CYP21A2)
  • CRH being found to be elevated in fibromyalgia (I posit that CRH elevation is the switch which turns on mast cell activation in the chronically ill)
  • Physical findings indicating that the various populations of people with chronic illness are actually united by one disease process which is stress-induced: similar white matter lesions in MS, EDS and CAH; raised ICP throughout these populations, small fiber polyneuropathy in EDS, Gulf War veterans, fibromyalgia, CFS
  • ​Indications that Cell Danger Response (mitochondrial shutdown, Naviaux MD PhD) as the final common pathway in CFS/ME, etc.


Sharon Meglathery MD
Sharon Meglathery MD PC
1661 N. Swan Road, Suite 102
Tucson, Arizona 85712
No supports or grants used for this article.
 
Title: Congenital Adrenal Hyperplasia Heterozygosity (CAH1), Due to One Non-Functional CYP21A2 gene, May Be the Diathesis in the Stress-Diathesis Model for A Great Deal of Physical and Mental Illness.  CAH1 May Cause a Distinct Psychiatric Spectrum Phenotype (CAPS) at Risk for the Development of a Variety of Psychiatric Diagnoses.  The Unique Characteristics of the RCCX Module Can Explain the Familial Clustering of Multiple Overlapping Phenotypes  (Joint Hypermobility (EDS-HT), Mast cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome, Endocrine Dysfunction, A Distinct Psychiatric Spectrum Disorder Likely involving Congenital Adrenal Hyperplasia Heterozygosity (CAPS), Bipolar Affective Disorder, Chronic Fatigue Syndrome, Fibromyalgia, Neurological and Immunological Disorders) Via Combinations of Overlapping and Co-segregating Contiguous Mutations of CYP21A2, TNXB and C4 Genes and a High Rate Spontaneous Inter-Generational Mutations.  Contiguous and Overlap Mutations of these Genes May Explain Why These Conditions Frequently Co-Occur with Joint Hypermobility. 

Abstract: Joint Hypermobility Syndrome, considered to be the same as Ehlers-Danlos, Hypermobility Type (EDS-HT), is very common and often progresses, especially in women in the presence of prolonged stress, hormonal changes or an infectious insult, into a disabling complex multisystem condition which is not well-recognized within the medical community.  Sometimes called EDS plus, EDS-HT which has progressed is often comorbid with such diverse conditions as postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), chronic fatigue syndrome (CFS), fibromyalgia (FM), 2 recently recognized psychiatric phenotypes (neuro-visceral phenotype, ALPIM), bipolar disorder, many neurological conditions (e.g. Chiari malformation, neuropathic pain syndromes, abnormal intracranial pressure) and immune system abnormalities/diseases (e.g. immunodeficiency syndromes, autoimmune diseases, multiple sclerosis). In order to understand how mechanistically these comorbidities can develop, a wide perspective is necessary. After becoming ill with EDS plus, MCAS, POTS, CFS and raised intracranial pressure, I applied my broad psychiatric and internal medicine expertise toward years of clinical observations of patients to understand the relationship between these conditions. In this paper, I outline the array of symptoms which I developed, grouping them into several distinct syndromes. Next, I describe my observations of patients with hypermobility, CFS, FM and/or autistic traits presenting with combinations of these syndromes as well. Finally, I show how a recent development in the search for the genetic underpinnings of EDS–HT focused my attention on the unique characteristics of the RCCX module, a high density gene complex on chromosome 6P 21.3 containing RP (function unknown), C4 (complement cascade and found in autoimmune disorders), CYP 21 (21 hydroxylase associated with congenital adrenal hyperplasia (CAH) in recessive form) and TNXB (leading candidate for the gene underlying EDS–HT). RCCX is prone to a high rate of homologous recombination, frequently developing contiguous mutations with resulting overlapping phenotypes along with frequent new mutations. I posit that combinations of co-segregating contiguous, overlapping and spontaneous mutations of these genes explain the cluster of phenotypes and syndromes which can develop in patients and within their families. Further, I posit that there is a very common psychiatric spectrum phenotype (CAPS) resulting from CAH heterozygosity (CAH1) plus or minus the AD hypermobility phenotype involving TNXB (TNXB1) which predisposes to the development of many DSM-V diagnoses, CFS, FM, Chronic Lyme, MCAS, POTS, neurological and immunological disorders, dependent on the manifestations of this multifaceted endocrine disorder, and is the genetic diathesis for the stress-diathesis model for physical and psychiatric illness.  If correct, this theory has the potential to shape the future of psychiatry, expand endocrinology and provide relief for many suffering from these medical mysteries in desperate need of a paradigm shift.  Unfortunately, it is evident that most of these potentially clinically important mutations have yet to be characterized so there is work to be done.
 
Background
I present my personal experience with EDS-HT/POTS/MCAS/CFS and raised intracranial pressure (ICP) to illustrate the path I observed in myself, my patients and fellow sufferers on the forums which led to my hypothesis.   
In childhood, I had painful ankle sprains, easy bruising, epistaxis, stretch marks, and I was cold and constipated. I pursued my interests with perfectionism and fervor. My social rhythm was off, but I was very sensitive to others’ feelings. I worried a lot, often associated with physical symptoms, but despite this, I was independent with some adrenaline-fueled hobbies.  Puberty was late and arrived with orthostatic hypotension, palpitations, insomnia, dysmenorrhea and ovarian cysts. The demands of an Ivy League university, resulted in worsening insomnia, worrying and fatigue. My obsessive mind latched on to the mysteries of psychiatry and determination led me to the Biological Psychiatry Branch of the NIH where, rather than socializing, I attended every medical lecture offered.  Tenacity and a lack of concern for social convention led to a solo backpacking trip around Asia and Africa, during which several episodes of dehydration required medical intervention.  At medical school, my almost photographic memory and ability to turn on the “turbo” (reading a thick textbook in 2 days), along with my ability to process and analyze large amounts of information quickly helped me immeasurably.  However, the “turbo” faltered.  Episodes of exhaustion, mental dullness and concentration challenges increased. I developed rituals to access the “turbo” involving caffeine, salt and music to drown out distractions.
In a combined internal medicine/psychiatry residency program at a very demanding institution, I had no control over my sleep patterns, time standing in place or meal timing, and I was having palpitations, painful TMJ, migraines, insomnia, muscle cramps and pre-syncope with standing still associated with overwhelming bursts of physical anxiety.  The high standards I set for myself made the situation worse. Instead of being sharp or focused, I was over-stimulated. I transferred to another program where I was able to have more control of my self-care, adopted a low carb/high-protein diet, lost 30 pounds and excelled again, receiving awards for my performance and attention to detail. I finished both residencies, becoming board-certified in both psychiatry and internal medicine and headed to a warm climate.  I became very interested in therapy, and I learned a repertoire of techniques for lowering stress response which were of great benefit to both me and my patients.
In 2008, I was hit with a multitude of stressors. Over several months, I developed facial flushing, burning eyes, migraines, a feeling of imbalance when I was standing or turning my head, head pressure and over-stimulation again. Coincidentally, I realized that I scored a 9 out of 9 on the Beighton scale, the 9 point scale used to assess hypermobility in EDS-HT (1), and I found that I had many of the known comorbidities associated with this syndrome: loose joints, migraines, asthma, bleeding/bruising, TMJ, orthostatic intolerance, etc. (2).  The diagnosis was confirmed and I started supplementation with magnesium as I knew that EDS-HT is often associated with malabsorption and resulting vitamin and mineral deficiencies.  Very quickly, most of the symptoms resolved, but fatigue lingered. 
In 2013, I was again under stress and the magnesium deficiency symptoms returned, along with a few new symptoms. I was very distractible as sensory stimulation was overwhelming; I was exhausted, yet wired and very orthostatic.  I could only drive short distances as blood pooling in my legs gave me bursts of panic from sympathetic nervous system (SNS) activation.  Beta blockers were necessary for a racing heart when I was upright, so that I could sleep and work.  My handwriting was large, sloppy and there were often extra loops in the letters; I had dysphagia for liquids, hives, dermatographism, asthma, nasal/sinus congestion, burning eyes, flushing, throbbing migraines and explosive diarrhea and brain fog within minutes after eating. Also, a sense of dread/disgust would jolt through my body after an alarming thought or when falling asleep, followed by the need to run with a restless, akathisia-like feeling in my legs.  “Disgust/jolt/run” I called it. The pressure in my head and vertigo worsened, and I developed nystagmus and lost the ability to track with my left eye. Aware of the EDS-HT association with Chiari malformation, I scheduled an appointment with a neurosurgeon well-versed in this condition. I wondered if I was developing CFS or FM as I knew that hypermobility was highly associated with both (3, 4, 5).
I joined the Ehlers-Danlos National Foundation (EDNF) patient forum where, I learned about the association of EDS with POTS and MCAS, years prior to its appearance in the medical literature (6). POTS refers to clinical symptoms of orthostatic intolerance in upright posture with heart rate greater than 120 bpm or heart rate 30 bpm higher than a resting heart rate after standing for 10 minutes (7).  Its etiology is multifactorial, and it is frequently comorbid with EDS plus/CFS/FM/MCAS and infectious conditions.  MCAS is due to pathological activation of mast cells leading to inappropriate degranulation and symptoms due to liberated mediators; Lab testing is usually inconclusive.  I had all of the symptoms of both conditions: postural orthostatic tachycardia, hives, dermatographism, nasal/sinus congestion, burning eyes, flushing, migraines, asthma, food sensitivities and diarrhea (8).  I started anti-histamines and mast cell stabilizers as recommended on a website started by a fellow EDS patient, Diana Driscoll OD (9). Within several weeks, all that remained was fatigue and a small amount of malaise.  I cancelled my neurosurgery appointment and twice tried to taper my medication unsuccessfully.  I could ride my bike for an hour, work 2 days in a row, with salt and fluid loading between patients, but would require a recovery day afterwards and did not tolerate shopping trips or standing in line. 
Several months later, I developed 1+ pitting edema in my feet and ankles, puffy hands; my breasts became tender and swollen; adipose tissue started to appear, my period stopped, and, instead of being cold all of the time, I was overheated and sweaty.  My joints started subluxing.  Again, I had severe orthostasis but without the pronounced tachycardia/anxiety I had experienced with POTS/MCAS.  I couldn’t raise my arms above my head without dizziness and I was short of breath, weak, struggling to ride the bike.  I cut out all non-essential routines. The disgust/jolt/run episodes returned and a deep, crampy pain in my leg muscles became more prominent.  I only slept for about an hour between episodes, each ending in a night sweat followed by intense shivering.  I would wake up retching, and in the morning, I was sore and irritable.  My hair was thinning.  I was now active in multiple forums (EDS, CFS, POTS, MCAS, chronic Lyme) and these same symptoms were described in much younger women, so I knew this was not menopause.  Additionally, in the forums I saw multiple sclerosis (MS) and other classic autoimmune diseases, hormone abnormalities and neuropathic pain syndromes.  I asked myself, what was it about EDS-HT that put people at risk for all of this and why were women more susceptible? 
I tried berberine, an alkaloid used in Chinese medicine to favorably alter gut flora (10). All of the symptoms disappeared within 12 hours and over the next couple of weeks, my LDL dropped 60 points, I lost 15 pounds, my periods restarted and my elevated blood sugar normalized.   From this point onward, I started cycles of berberine whenever my orthostasis, subluxations, pain and fatigue crept back.  I avoided anything that was exciting, good or bad, because activation triggered MCAS symptoms and hyperadrenergic states, despite my mast cells being in pharmacological lock-down. My personality morphed from being bold and extroverted to inhibited and isolated.  I was found to have hepatic steatosis on MRI.  (Later, in 2015, I was found to have bilateral adrenal hyperplasia on a CT scan ordered after a horse riding accident.)
I was seeing my patients with new eyes. I have the opportunity to perform very detailed psychiatric and psychological evaluations with follow-up therapy appointments at least every week or every other week for months to years.  Because a large number of my patients seemed to have the same sort of stress vulnerability, perfectionism and anxiety I saw in myself, I began obtaining Beighton scores on everyone. I could predict hypermobility based on physical signs (livedo reticularis, squirminess, pretzel sitting, head propping, being cold, dilated pupils), medical history (migraines, GI, asthma, insomnia, pre-syncope, pain issues, etc.), family history (CFS, chronic Lyme and FM in female relatives, ASD) and psychological profile before doing the Beighton scale. The hypermobile patients fell into 2 groups: highly successful, driven, tenacious athletes/students/professionals with physical anxiety/compulsive behaviors and formerly traumatized, rigid, perfectionistic, stress/harm-avoidant individuals with procrastination. Psychologically, there was little variability from patient to patient, but the DSMV diagnoses would vary because the symptoms did not always meet diagnostic thresholds.  An all or none phenomenon was apparent: if the person was hypermobile, he/she would have the full package.  Severity of physical or psychological/psychiatric symptoms did not predict the degree of hypermobility, only that some would be found.
In the literature, hypermobility was associated with panic, phobias and anxiety (11), a larger than normal amygdala (fear center), a smaller than normal anterior cingulate (higher cognitive input to the amygdala) with perhaps increased interoceptive awareness (12).  78% of patient with EDS were known to have significant dysautonomia (13), and with this, according to Pocinki, SNS activation/adrenaline dumping in response to hypotension with occasional seesawing of the SNS and parasympathetic nervous system (PNS) to correct the imbalance.  This would occur throughout the night, interfering with sleep and then during the days following a night of poor sleep, creating a vicious cycle (14, 15).   
This was not the whole story.  The distinct spectrum disorder that I had noticed also included:  autistic features: sensory integration/over-stimulation (ADD-like), difficulty with social rhythms/eye contact/speaking in turn, alternating hyperfocus/distraction, special interests/obsessions, special abilities, an independent stance with a disregard for societal rules/conventions, a sense of vision and tenacity which could result in successful risk-taking, and a sensitivity to emotions in others with a systems approach to empathy; emotional dysregulation with small triggers (sensory overload, attachment issues); poor stress response in situations with external locus of control resulting in physical and psychological symptoms; PTSD/easy traumatization with resulting isolation and harm avoidance (harm-avoidant OCD, perfectionism, rigidity, routines); a bipolar-like presentation due to exaggerated stress response and adrenaline dumping followed by crashing; anxiety states associated with orthostatic intolerance.  Initially, I resisted the idea that severe mental illness could be associated with the hypermobile brain, but I had several patients who developed psychosis, often in concert with MCAS symptoms very familiar to me.   I googled pictures of famous creative geniuses and found hypermobile hands and knee hyper-extension.  I recalled that a hypermobile friend of mine has psychotic disorders in his family.  Beighton exams on acutely ill patients might be very revealing, I thought.  It seemed that men and women were equally affected in terms of the hypermobile brain, but the women had more of the physical symptoms associated with EDS-HT, including the anxiety-producing adrenaline-dumping.  A good number complained of “head pressure” and tinnitus without signs of brainstem compression or systemic MCAS, although intermittent mild allergic symptoms were common. I developed a protocol for the “hypermobile brain” (see CAPS at end).
Hypermobility was present in about 50% in the eating disorder population and about 80% in my private practice, but the published prevalence of EDS at that point was 1/ 5000 patients (2). Since the family histories were fraught with hypermobility/CFS/FM/ASD and I was seeing this in both my private practice as well as at the eating disorder facility, I knew that this was not an effect of malnutrition.  At the 2012 EDNF Learning Conference physician-only meeting, one of the experts asked another expert, “how common do you think this is?” The agreed upon answer was 1/100 people. I was on to something big.
Psychiatric knowledge moved further toward characterizing the hypermobile brain. Eccles released data linking hypermobility with neuro-developmental disorders and coined “neuro-visceral syndrome” to describe her findings in hypermobiles (16,17), and another group applied the term “ALPIM syndrome” for comorbid anxiety, ligament laxity, pain syndromes, immunological issues and mood disorders, noting a very high rate of bipolar disorder in this population with mood disorders (18). Sinibaldi performed a literature review and found depression, attention deficit disorder, autism spectrum disorders, and obsessive-compulsive personality disorder to be associated with joint hypermobility syndrome (19).  
I realized that the hypermobility itself was not directly linked with the source of this profile as I would sometimes see non-hypermobile people with the hypermobile brain who had hypermobile family members.  I also started to notice that every once in a while, a non-hypermobile person with a hypermobile brain and no hypermobile family members would present with this brain and physical characteristics.  Because of my dual training in psychiatry and internal medicine, people with chronic illness associated with mold toxicity, chronic Lyme disease, FM and CFS  were drawn to my private practice, and when I received inquiry calls, I asked about hypermobility which was often present or present in family members but previously unrecognized.  They all had the hypermobile brain.  The storyline was familiar: active, gifted, perfectionistic young woman with occasional allergies under stress who experienced a sudden and dramatic emergence of MCAS symptoms with brain fog, migraines, food intolerance, diarrhea, POTS followed by exhaustion interspersed with paroxysmal bursts of over-stimulation, panicky anxiety and disgust/jolt/run, but occasionally, these issues developed gradually after a series of stressors or associated with major hormonal shifts, i.e. puberty, pregnancy, menopause.  I recalled that the brother of a friend of mine with the hypermobile brain had almost died from what was felt to be chronic Lyme disease.  His symptoms retrospectively were consistent with MCAS and the literature supports that Borrelia burgdorferi activates mast cells in vulnerable people (20).  My friend was not hypermobile and no one in his family was, but somehow they possessed this vulnerability for MCAS.  This again showed me that while hypermobile joints were highly associated with the hypermobile brain, hypermobility was not necessary for the development of MCAS or for the development of the hypermobile brain (now clearly a misnomer).  The severe physical decompensation which occurred in people with EDS plus/CFS/FM/MCAS/POTS and at least some with chronic Lyme had to do with something which frequently travelled with hypermobility but was a separate entity. 
By this time, I had met several MCAS-affected patients with no hypermobility, no hypermobility in the family and without the hypermobile brain.  It seemed to me that there were early events creating the hypermobile brain, one of which was probably mast cell activation triggering abnormal dendritic branching in infancy resulting in autistic features (21), but what was triggering the MCAS so early in life and how did some people with MCAS who were not hypermobile avoid this early trigger?  Further, the amygdala and anterior cingulate size differences had origins also not present in these MCAS patients.  Were these findings due to an issue with neural migration in utero or due to post-delivery influences affecting development?  What could do that?  Cytokines? Toxins? Hormones? What an incredible story.  
The EDS specialists blamed worsening dysautonomia for the symptoms of fatigue associated with EDS (more pronounced if MCAS present as histamine is a vasodilator) and repetitive injury for the worsening pain syndromes.  This didn’t account for all of my symptoms and didn’t explain why people without hypermobility would develop the same issues. The MCAS experts added sensory neuropathy syndromes, chronic fatigue, psychiatric disturbances and interestingly, hypermobility, to their list of manifestations of MCAS (8,22). Treatment with mast cell stabilizers greatly improved functioning and even severe symptoms of irritability, depression, hopelessness often resolved.  I decided that since berberine was used by herbalists to treat PCOS and dysbiosis (23, 24), conditions known to be common in EDS plus/CFS/FM and associated with psychiatric symptoms, I could discuss its use with patients.  For those who opted to try it, the response was as dramatic as it had been with me.  It worked so well that when I found an article implicating berberine in in vitro neuronal death (25), not a single person wanted to stop cycling with it. Me included.    Berberine held a big clue, but it has a myriad of clinical effects: it is antibacterial, antifungal, anti-inflammatory; studies have shown efficacy for treating hormonal imbalances (PCOS), metabolic syndrome, diabetes, hyperlipidemia and obesity (26). 
My net widened to include toxic exposure forums and websites, including toxic mold.  Clearly, the condition responsible for causing the hypermobile brain also caused some vulnerability to physical, emotional or infectious triggers resulting in EDS plus/CFS/FM/MCAS/POTS plus the other syndrome I was seeing in myself and the sick patients which did not respond to treatment for MCAS, but did respond to berberine.  I was amazed to find an article discussing enlarged amygdalae being found in patients with serious complications following mold exposure (27).  My assumption at this point was that there was likely a genetic disorder of the immune system directing brain formation in utero and after birth via cytokines, creating the hypermobile brain, creating a deranged autonomic nervous system, variably affecting collagen formation and then becoming triggered to create EDS plus/CFS/FM/POTS/MCAS/neurological and immunological disorders in some; hypermobiles were more vulnerable.  Some then developed autoimmune diseases.  I did not share my theory with my overachieving, healthy young patients seeking help to cope with their faltering “turbo” and stress. 
In July 2015, Martha G. Cassell, sent me articles about the RCCX module. Years of clinical observations made sense. 
The RCCX module is a high density gene unit comprised of 4 genes in tandem repeat sequences and accompanied by non-active pseudogenes: RP (function unknown), C4 (complement system), CYP 21A2 (21 hydroxylase) and TNXB (tenascin) located within the other class III HLA genes (28). C4 mutations are strongly implicated in the pathogenesis of autoimmune diseases (29, 30 31). CYP 21 mutations, affecting 21 hydroxylase are associated with an autosomal recessive (AR) endocrine disorder called congenital adrenal hyperplasia (CAH), characterized by elevated progesterone and androgens with low cortisol and aldosterone.  TNXB, a prime candidate gene for both AR and AD forms of EDS-HT (32,33), codes for tenascin X, an extracellular matrix protein secreted by fibroblasts in the skin, tendons, muscle and blood vessels.  The RCCX module is very unstable and prone to non-allelic rearrangements due to misalignments during meiosis as a result of the tandem repeats and pseudogenes. Furthermore, the resulting diversity has included overlap and contiguous mutations co-segregating and causing overlapping phenotypes including CAH and EDS-HT.  In fact, TNXB heterozygosity (TNXB1) in conjunction with the (AR) CAH, called CAH–X is present in 8.5% of CAH patients due to a TNXA/TNXB chimera associated with CYP 21 deletions and other novel TNXB variants resulting in individuals with an EDS phenotype, CAH and disrupted TGF-beta signaling; subsequent analysis has demonstrated many additional mutations occurring commonly (34, 35, 36).
 
The Hypothesis
Since co-occurring mutations involving TNXB and CYP21A2 could appear at a high rate in RCCX, it follows that heterozygous CYP21A2 (henceforth CAH1) in combination with TNXB1, henceforth CAH1-TNXB1, could be very prevalent in the general population, as CAH1 is present in 10% of people (37) and this number does not include the large number of currently uncharacterized mutations involving CYP21A2.  CAH1-TNXB1 would confer an EDS-HT phenotype along with a presumably clinically unimportant endocrine condition.  I believe that CAH1, even more prevalent, can become clinically significant in settings of prolonged stress and could predispose to abnormal brain development.  In fact, I posit that CAH1 is the underlying condition causing the CAH1 Psychiatric Spectrum Phenotype, previously “hypermobile brain”, conferring the vulnerability to stress with resulting CFS/FM/MCAS/MCAS/POTS/neurological and immunological issues in patients with and without the EDS-HT phenotype.  I also posit that CAH1 is the genetic diathesis in the stress-diathesis model for medical and psychiatric disease.  Derangements of the hormones involved in CAH: cortisol, aldosterone, progesterone and androgens fit my clinical observations perfectly if they could occur in the heterozygous condition with the right trigger, stress.  Since CYP21A2 codes for 21 hydroxylase, a chief enzyme in the acute stress response, I knew my hypothesis was very likely to be true. The addition of a copy of the C4 mutation would add the autoimmune diseases sometimes seen and increase the likelihood of reaching the stress threshold to trigger illness. Furthermore, the permutations of possible mutations involving the components of the RCCX module match the phenotypes and levels of vulnerability I have observed in patients. The reasoning behind the vulnerability levels will be made clear in the discussion of pathophysiology: (CAPS=CAH1 Associated Psychiatric Spectrum Disorder, previously the hypermobile brain)
 
CAH1: CAPS, moderate vulnerability for CFS/FM/MCAS/POTS, women>men
TNXB1-normal brain, moderate vulnerability to anxiety/insomnia/over-arousal due to orthostasis with SNS activation (no CAPS), EDS-HT phenotype, low to no vulnerability for EDS plus/CFS/FM/MCAS/POTS, women>men
CAH1-TNXB1: CAPS, EDS-HT phenotype, hypermobile brain, very high vulnerability for EDS plus/CFS/FM/MCAS/POTS; possibly TGF beta issues (fibrosis and inflammation), women>men
CAH1-C4(1): CAPS, moderate to high vulnerability for EDS plus/CFS/FM/MCAS/POTS, higher vulnerability for autoimmune diseases, women>men,
CAH1-TNXB1-C4(1): CAPS, EDS-HT phenotype, high vulnerability for EDS plus/CFS/FM/MCAS/POTS; possibly TGF beta issues (fibrosis and inflammation), higher vulnerability for autoimmune diseases, women>men
In April 2015, an article in JAMA Psychiatry based on a genome wide association study of 33,332 psychiatric patients and 27,888 controls revealed that that there may be just a few genes responsible for the wide range of psychopathology. (38)  Could this be CAH1 and CAPS?   Furthermore, CAH1 may turn out to be the ultimate predisposing factor for stress-related illness, medical and psychiatric, and thus could be the diathesis in the stress diathesis model of disease.
 
The Evidence:
What would a person with CAH1 could look like clinically?  As CAH carriers are rarely recognized, we must extrapolate from the pathophysiology and presentation of AR CAH involving 21 hydroxylase deficiency, the most common form of CAH.   From an extensive review of CAH (37):  21 hydroxylase converts progesterone into 11–Deoxycorticosterone to ultimately become aldosterone and 17 hydroxyprogesterone into 11-deoxycortisol to make cortisol.  Ineffective 21 hydroxylase results in low cortisol which signals the hypothalamus to secrete CRH to stimulate the anterior pituitary to secrete ACTH which then acts on the adrenal glands, making them hyperplastic, not necessarily larger in size.  Progesterone precursors are shunted into pathways resulting in the production of active androgens (testosterone, dihydrotestosterone) and in smaller amounts to estrogens (estrone and estradiol).    The heterogeneity of the mutations of the gene for this enzyme result in a wide range of clinical presentations, but the inheritance of 2 faulty genes is almost always clinically apparent.  The most common mutation, affects 1/15000 newborns, and prenatal screening has greatly reduced mortality.  Affected female infants may have ambiguous external genitalia from the shunting of built-up precursors into the androgen production pathway, but the males appear physically unremarkable.  Less common mutations of this gene result in people who escape detection at birth and learn to adapt to their tendencies towards salt depletion and hypotension, with the females often developing issues at puberty with virilization/acne/hirsutism and failure to develop breasts or later, they experience sexual dysfunction due to a shortened vaginal canal or infertility.
It is known that people with CAH1 have an exaggerated response to immediate stressors via increased cortisol release, but they have lower basal cortisol levels (39).  Regarding their outward physical characteristics, there is no evidence for an increase in the incidence of gross congenital malformations or virilization in the children of women with CAH, but 37 out of 53 women presenting with signs of hyper-androgenism were found to have CAH1, and children referred to a clinic for hirsutism or premature puberty had a higher prevalence of CAH1 compared with 80 adults not screened (37). 
Other than the exaggerated stress response, we can probably assume that CAH1 would present clinically as an intermediate phenotype between the mildest form of CAH, untreated non-classical CAH (NCCAH) and normals.  Much of NCCAH remains undiagnosed so consequently, little is known about the clinical picture of living with suboptimal aldosterone or cortisol.  Also, unfortunately for us, those who are diagnosed are treated for the mineralocorticoid and corticosteroid deficiencies, changing the clinical appearance as repletion of cortisol via feedback loops halts the shunting resulting in the over-production of androgens.  Female infants with mild NCCAH have no virilization at birth.  Like classical CAH, an early growth spurt (between 5 and 8 years old) can occur, but unlike classical CAH, adult stature is similar to parents and siblings.  Decreased insulin sensitivity is found in young women.  Adult males with NCCAH are diagnosed most often in family studies presumably because they feel they are phenotypically unremarkable, but adult males with classical CAH have enlarged penises and smaller but functional testes.  It is usually acne or infertility which leads to recognition.  Women with NCCAH sometimes have hirsutism, cystic acne and oligomenorrhea, but family studies report normal function of their reproductive tracts in contrast to inadequately treated women with classical CAH who have late menarche, anovulation and evidence of multiple ovarian cysts detected ultrasonically.
Most of the studies regarding the brain and neuropsychiatric/psychological aspects of CAH have been done on people with classical CAH or mixed populations.  Some report higher IQ’s, but others contradict this.  CAH girls have superior spatial abilities and have personalities less embracing of traditional sex roles: less doll play, more aggressive, tomboyish, not as much interest in child rearing with male pattern of distance in relationships, although a few studies refute this.  An increase in homosexual behaviors is sometimes shown.  Women with CAH marry and procreate less, but social inhibition due to unusual genital appearance and hirsutism could contribute to this.  Interestingly, high androgens and high rates of PCOS have been found in female to male transsexuals.   Both sexes are reported to be more likely to be left handed, but normal patterns of brain lateralization prevail.   
The hormone abnormalities associated with CAH can affect the development of the hippocampus and amygdala. The amygdala, measured via MRI scan, has been found to be smaller in children with CAH and at face value, this goes against my hypothesis, however, there are some reasons to explain this.  The amygdala is rich with androgen and cortisol receptors and is known to increase in size after birth as a result of exposure to stress and androgen stimulation (40, 41).  It is also larger in autism (42). Thus people born with CAH and CAH1 are also likely born with small amygdalae due to low cortisol but those with CAH receive physiologic doses of hydrocortisone, driving down androgen levels, allowing a normal amount of growth as an infants, while those with CAH1 have spiking cortisol in response to stress after birth, high androgens due to low basal cortisol and autistic features, all associated with increased growth of the amygdala in the postnatal period.  The expected result would be a small amygdala in children with CAH and a larger than normal amygdala in those with CAH1, as is seen.  As an aside and of unclear significance, patients with CAH have been found to have more white matter abnormalities on MRI brain imaging than normals.
Reviewing all of this information, it seems safe to assume that the CAH1 physiology with its increased stress vulnerability, a larger than normal amygdala, possible increased androgen:estrogen effects and probable decreased secretion of aldosterone with associated tendency for salt wasting/low blood pressure/low blood volume triggering SNS compensation provides a perfect canvas for observed clinical features, including CAPS.
My attention to turned to looking for clinical correlates for the endocrine imbalances expected in CAH1 within the EDS/CFS/FM populations.  When looking at this, I realized that clinically important hormonal changes may only develop when the production capacity of 21 hydroxylase becomes overwhelmed for example, during times of prolonged stress requiring increased cortisol production as would be seen in EDS plus/CFS/FM but not in EDS-HT. 
 
Evidence for Underlying CAH1-TNX Phenotype Causing Hormone Abnormalities in EDS-HT
The fact that EDS is assumed to be solely due to a genetic disorder of collagen means that there are very few studies looking at abnormalities separate from those which would be associated with a collagen disorder.  I have found no studies directly measuring corticosteroid, mineralocorticoid, progesterone or androgen levels in EDS patients in the medical literature.   However, patients with EDS plus are noted to have quite a few comorbidities possibly associated with disturbances involving these hormones: POTS/orthostatic intolerance (OI) (present in 78%), MCAS, “adrenal fatigue” diagnosed by naturopaths with low basal salivary cortisol (in the forums), salt craving, CAPS, evidence of high androgen exposure (personality and physical signs), neurological (neuropathic pain, raised ICP, acquired Chiari), immunological (immunodeficiency) and gynecological issues (PCOS, menstrual abnormalities).   All to be discussed.  On to the specifics:
The experts treating POTS/OI with electrolyte tablets and Florinef with great improvement (as long as no raised ICP is present) provides evidence for corticosteroid and mineralocorticoid disturbance in EDS.  CAH1-associated sex hormone abnormalities in women would produce more obvious evidence of disturbance than they do in men.  Regarding the possibility of high androgens, there is very little mention of functional or cosmetic issues with genitalia either on the forums or in my practice, but I attribute this to modesty.  There is no evidence concerning whether female EDS patients are masculinized, although women in my practice relate to this and people with have large amygdalae and autistic traits, both possibly influenced by high androgen exposure shortly after birth (43).  Additionally, in my practice, all checked, without exception, have longer 4th digits than 2nd digits, i.e. low D2/D4 ratios (masculinized pattern) which is a simple way to assess androgen exposure in utero.  Androgen-driven growth of the 4th digit in utero is greater because of a higher density of androgen receptors than present on the index finger.  Of note, women patients with CAH also have masculinized patterns (44) as do women with autism (45).  Women with low D2/D4 have been found to be more likely to pursue traditionally male careers and a high percentage of women in positions of power have longer ring fingers (46) which is true of most of my female hypermobile patients.  Few of my patients had hormone testing, but one reported such high testosterone that she was put on estrogen to counteract it.  All reported being diagnosed with multiple ovarian cysts.
Regarding issues potentially due to high progesterone:estrogen from CAH1 presenting in hypermobile patients, I will separate the issues manifesting as sexual and menstrual dysfunction from the general symptoms possibly due progesterone excess.  Sexual function issues associated with progesterone: estrogen imbalance include: vaginal dryness, puberty, menstruation/fertility issues and polycystic ovaries (androgen-related, too).  In fact, vaginal dryness, severe dysmenorrhea, dyspareunia, metrorrhagias and irregular menses are frequently reported (47-50), but these studies lump together all of the types of EDS, assuming the underlying issue causative issue is disordered collagen, rather than an endocrine issue as I posit is a contributing cause in people with EDS-HT.  Because EDS-HT is by far the most common type, enrolled in un-typed studies, there is still value in the results of the above studies.  As all types of EDS would be predisposed to menstrual bleeding abnormalities due to fragile tissue, bleeding abnormalities are not specific for hormone irregularities.  Comparing the 2 biggest studies, one looking at 775 EDS patients of the 3 most common types (including hypermobile type) (51) and another looking at 82 patients with joint hypermobility syndrome (aka EDS-HT) (50) provides convincing evidence.  The rate of intermenstrual bleeding/metrorrhagia was 18.6% in the mixed group, and 53.7% in the joint hypermobility group suggesting that the increased rate in the hypermobiles is related to something other than tissue fragility.  Additionally, Castori found the rate of irregular menses in the hypermobile group to be 46.3% (50), and this strongly suggests hormonal issues rather than underlying tissue issues.  Amenorrhea, infertility, pubertal issues and polycystic ovaries are also more specific for hormonal imbalances is unstudied in this population.  However, an EDNF 2011 Conference talk given by Brad Hurst MD concluded that there is likely an increase in infertility in EDS (52).   PCOS and menstrual abnormalities are frequently mentioned on the forums, and both of these are present in all of my hypermobile female patients asked.  Finally, chronic low estrogen:progesterone ratio could be responsible for the high prevalence of fractures, osteoporosis and abnormal bone formation found in EDS, but the prevailing thinking is that this is multifactorial involving abnormal collagen, vitamin D deficiency and poor conditioning (53). 
Medically important conditions of high progesterone:estrogen ratio include luteal phase (premenstrual) issues and menopause.  Surprisingly, other conditions of high progesterone are not well considered in the medical literature. However, progesterone is considered important by the EDS experts because cyclical progesterone-exacerbated tissue laxity is blamed for increases in injury potential (subluxations) and increases in “dysautonomia” due to increased vessel laxity contributing to hypotension in women. There have been multiple studies looking at ACL injuries, finding a high rate of ACL injuries on days 1 and 2 of the menstrual cycle, just after a prolonged period of progesterone elevation (54). It is common to see on the forums that subluxations increase when other symptoms increase. 
Progesterone is associated with many of the unpleasant physical symptoms associated with the luteal phase of the menstrual cycle: water retention, irritability, breast tenderness/swelling and mood swings/irritability. Additionally, a review (55) reveals that progesterone increases: core basal temperature, sweating, shivering response in response to small temperature drops, neuroendocrine activation, minute ventilation, heart rate, intracranial pressure in some (56) and decreases glucose tolerance and muscle strength; it may negatively impact cognitive functioning, as high estrogen:progesterone ratio benefits cognitive function and verbal memory.  Hair loss is blamed on the progesterone and androgen dominance on many alternative health websites. 
Anecdotally, many women with EDS report all of these symptoms.  Invariably, all of my female hypermobile patients relate to having severe physical and emotional disturbance pre-menstrually.  In his video lecture about dysautonomia in EDS, Dr. Burkholder, a pediatric cardiologist/EDS POTS expert, makes frequent reference to the unusual idiopathic breathlessness he often sees in patients with EDS (57).  Interestingly, many studies have shown an association between pseudotumor cerebri and cystic ovaries (56) and many patients with EDS report head pressure and tinnitus suggestive of this.  I witnessed a non-hypermobile woman develop erythromelalgia, and widespread neuropathic pain, shortly after starting an aromatase inhibitor. I am not aware of any mechanism linking a high progesterone:estrogen with neuropathic pain syndromes, but many people with EDS have neuropathic pain/erythromelalgia, and many are diagnosed with FM.  It is important to note that these symptoms of high progesterone may be happening in some men, too.  I recall a male hypermobile patient with worsening irritability, depression, binge-eating, muscle weakness/soreness and fluid retention who was very convinced that his sex hormones were disturbed due to “feeling like I have PMS and am losing testosterone”.  Lab work ordered by his PCP revealed high normal testosterone levels.  Psychiatric medications helped marginally until he developed mast cell symptoms and marginal psychosis.  With recovery, he lost 12 pounds of water weight in a week.  Finally, the above described high progesterone symptoms exactly mirror the symptoms which developed in me and my patients, in the syndrome separate from MCAS which responded to berberine.  Also, I found an article showing that berberine (in mice) in a single dose upregulates the expression of testicular CYP17 (converts progesterone to sex hormones), possibly reducing symptoms due to the effect of toxic progesterone build-up due to a faulty 21-hydroxylase hormone (58). It seemed I had my answer for which clinical effect was at the root of berberine’s efficacy. 
CAH1 With Decompensation Connects the dots between HPA Abnormalities and EDS plus/CFS/FM/POTS/MCAS, A Stress Diathesis Model
With prolonged stress exposure or perhaps the presence of a C4 mutation triggering autoimmune disease, the enhanced cortisol stress response associated with CAH1 would increase in frequency as the body would attempt to provide adequate cortisol to deal with the stress. The exact response and its downstream effects would be variable due to genetics and circumstances but we would expect that this increased demand would fall on the impaired 21 hydroxylase which would respond by shifting from aldosterone to cortisol production, dropping the basal cortisol lower in order to provide spiking stress responses.  The stress responses would seem much more pronounced in contrast to the background level of fatigue and under-arousal due to low basal cortisol.  Hypotension due to lower basal cortisol would be compounded by increasingly impaired aldosterone production, increasing salt and water loss, lowering blood volume and increasing orthostasis.  Compensatory SNS activity would be even more exaggerated if the person is female or hypermobile.  Additionally, downstream, the acute stress bursts of cortisol would also be activating the SNS as well. 
As cortisol tends to be higher at night, night time activation with higher cortisol levels at night and adrenaline dumping would interfere with deep sleep, oftentimes resulting in the dramatic SNS/PNS see-saw effect, eventually making sleep impossible (15).  Over time, the body would be in a constant state of distress, and the need for acute stress cortisol would increase even further, at the expense of basal cortisol.  Even lower basal cortisol would be associated with periods of fatigue during which obligations would not be met, creating even more distress. Cortisol withdrawal is associated with raised ICP. 
The person previously able to turn on the “turbo” is now distressed by the inappropriately stimulated, activated, wired feeling (and woozy if see-sawing) accompanying activities and even small stressors. The hypermobile brain would go on high alert, exacerbating the situation.  The person would be unable to reset through sleep.  The perfectionistic, problem-solving, obsessive nature of the hypermobile brain, coupled with the large amygdala would be adding even more fuel to the fire. 
CRH and ACTH would rise in an attempt to stimulate the production of cortisol from the adrenals and the elevated CRH would activate mast cells, causing microglial inflammation with sensory gating issues, fatigue, brain fog, malaise, depression, anxiety, psychosis and possibly pressure headaches/raised ICP (as it seemed to have happened with me), as well as systemic symptoms including rashes, dermatographism, migraines, burning eyes, sinus issues, food intolerances, increased hypotension from histamine.  Mast cell activation would also increase eosinophil recruitment causing eosinophilic conditions (20, 21, 8).  Finally, CRH would cause mesenteric dilatation, further increasing hypotension and stimulate the release of catecholamines, potentially resulting in hyper-adrenergic POTS (59).  The body’s need for salt and fluid to counter orthostasis would be extreme. 
Additionally, as most of the 21 hydroxylase enzyme activity would be directed at making cortisol, progesterone levels would rise, adding a layer of unpleasant but nonspecific symptoms: weakness, sweating, water retention, irritability, flushes and breast pain) and symptoms associated with increased tissue laxity: subluxation with soreness, and worsening orthostatic stress.  Neuropathic pain syndromes could develop possibly triggered by either centrally elevated CRH effects on cytokines levels, through mast cell activation (59) or perhaps through elevated progesterone as mentioned above.   High androgens would cause acne, hair loss and increased competitiveness.  The immune system, now exposed to an unusual profile of cytokines may stop resisting fungus, bacterial infections and HSV, while increasing activity against the common cold, as is reported on the EDS/CFS/FM/MCAS forums.  I haven’t have a cold since 2009.  The presence of a C4 mutation could send the person further down the path of immune dysfunction toward autoimmune disease at any point during this course.   
Elevated TGF beta could further complicate the phenotypes associated with TNX by putting an additional stress load on the body.  
If the inciting stressor was infectious, the diagnosis of CFS would likely be applied, if Lyme testing reveals past exposure, the diagnosis of chronic Lyme disease may be given.  If the patient is clearly hypermobile and a physician is aware of EDS, then appointments with geneticists would be made for confirmation of the EDS diagnosis.  Many of these patients would be directed to psychiatry for CBT and urged to increase their exercise. 
 
Evidence: CAH1 With Decompensation is Behind EDS plus/CFS/FM/Comorbid Syndromes
It is important to define these entities.  The term EDS plus is casually used to refer to a hypermobile person meeting criteria for EDS-HT who has developed other systemic symptoms beyond hypermobile joints and dysautonomia, CFS is characterized by persistent debilitating fatigue for at least 6 months without a medical diagnosis, and FM is now defined as consisting of widespread pain for >3 months with no underlying medical condition that could cause the pain. Since a high proportion of people with FM, CFS are found to be hypermobile after diagnosis (3,4,5), I believe that people with EDS plus have the same underlying pathophysiology as non-hypermobiles with CFS and FM.  However, it is important to bear in mind that these conditions are syndromes and may contain patients with different underlying pathophysiology.  Further, while EDS plus/CFS/FM have many overlapping symptoms, the symptoms they don’t share can have significant effects on hormone levels.  For example, pain, present in FM but not in CFS, has recently been demonstrated to alter many brain systems, and certainly has the potential to cause endocrine changes as well (60).  Finally, functional hormonal assessments can be fraught with errors due to the dynamic nature of body systems, for example protein-binding and receptor sensitivity, and even the reliability/validity of the assays themselves. 
A compelling piece of evidence endorsing CAH1 as a feasible predisposing condition for EDS plus/CFS/FM is that the pattern of the symptoms seen in these syndromes matches what would be expected with CAH1 decompensation better than any of the other prevailing explanations for these syndromes.  As my course of illness is representative of what I have observed in my patients and on the forums, we will examine my course of illness for illustration.  As stated above, I meet criteria for EDS plus/CFS and I have CAPS.  I have had several separate syndromes including MCAS, POTS, raised ICP and magnesium deficiency, all of which responded to dramatically to treatment with magnesium repletion and mast cell stabilizers.  Additionally, I developed a separate syndrome in which nearly all of the symptoms were consistent with a high progesterone state and those symptoms responded very rapidly after starting berberine, a supplement known for treating PCOS and decreasing progesterone by increasing the activity of CYP17.  In terms of remaining symptoms, I have underlying mild fatigue and mental sluggishness which will disappear under conditions of stress, for instance on the days I work, if there is a special event, or if I am on a trip.  Generally, after this, I am tired and need a day to recover.  If something more stressful happens, the engine can rev, but the turbo isn’t there anymore.  My mind will obsess and hyper-focus until I find a way to resolve the problem; I’ll need sympatholytics to sleep; I’ll feel over-aroused, tired and wired, with some mild MCAS symptoms surfacing.  Still, though, I will make good decisions and my course of action is rapid and effective, but springing into action comes with an energy debt. I avoid stressful situations, including socializing; I practice mindfulness always and keep antihistamines and sympatholytics on hand.  I have 4-5 jumbo glasses of salt water a day, along with well-timed cups of strong coffee; I do most of my reading and thinking with my legs elevated; I ride my bike with gusto most mornings and sluggishly some afternoons.  These remaining symptoms and the rapidity with which they come on with stress jibe perfectly with a hormonal issue with a maladaptive stress response and a strong tendency for lowered blood volume as the etiology.  This pattern is difficult to reconcile with any of the other of the currently active theories, i.e. MTHFR abnormalities, mitochondrial issues, raging undetected inflammation, stealth infection, heavy metal intoxication, dysbiosis or ongoing toxin exposure, although in some people these issues certainly may contribute to the picture.
Also the predicted levels of vulnerability to developing these syndromes based on possible combinations of RCCX mutations adds credence to my theory as they mirror what I observe clinically.  To understand the levels of vulnerability predicted from highest to lowest: CAH1-TNXB1-C4, CAH1-TNXB1, CAH1-C4, CAH1, TNXB1, normal women, normal men, it is important to realize that the degree of tissue/vessel laxity and the added stress of C4 disturbance increases the severity of the medical and psychiatric symptoms by increasing the stress response.   Regarding laxity: TNXB mutations code for defective tenascin, resulting in an EDS-HT phenotype associated with significant tissue laxity.  CAH1 increases laxity via elevated levels of progesterone, possibly vasodilation from histamine liberated in CRH-induced MCAS and mesenteric vessel dilation.  Women naturally have more laxity than men and thus are significantly more vulnerable to these syndromes with or without these mutations.  The hypotensive effects of these laxity-associated conditions is additive as is the body’s compensatory responses to them.  Co-presence of CAH1-TNXB1 and female gender would result in severe issues with orthostatic intolerance and subsequent stress vulnerability.  Females with CAH1 (without the TNXB mutation) could still get CFS/FM/MCAS/POTS but the trigger required to push them in this direction would need to be large.  On the lower end of the scale, people, even women, with TNXB alone would have EDS-HT but would not have CAPS most likely avoiding psychiatric care as they would not have the underlying endocrine vulnerabilities exacerbating their SNS activation due solely to laxity.
The fact that the path to all of these syndromes starts with an overwhelming emotional or physical trigger and leads to a total physical collapse certainly jibes with a disruption of the endocrine stress response as the root of the problem. My pathophysiological description of CAH1 decompensation matches what is seen clinically to a tee.  But it is important to examine the evidence for these HPA abnormalities in patients with EDS plus/CFS/FM.  If there is an underlying problem with the function of the 21 hydroxylase enzyme, we would expect to see low cortisol in the setting of a stressed body with high ACTH and high CRH in these patients.  There are extensive reviews of the studies performed in patients with CFS looking at the levels of these hypothalamic pituitary axis (HPA) hormones throughout the day, in serum, urine and saliva, as well as after various challenges (61,62).  They show that, while the results and conclusions drawn regarding ACTH and CRH and organ responsivity have been somewhat contradictory and confusing, attributed to confounding factors such as sleep disturbance, psychiatric comorbidities, medication and ongoing stress, across studies in most patients with CFS a problem with low basal cortisol and a disturbance in the circadian pattern of cortisol release. Regarding FM, as mentioned above, there tend to be even more confounding variables due downstream effects of chronic pain itself and comorbid depression and anxiety.  Many of the studies have shown abnormally low basal cortisol levels (63, 64, 65) and one has shown lower urinary cortisol levels (66).  Griep and Crofford have attributed these findings to low levels to adrenal hypo-responsiveness (67,63) which would be consistent with lowered levels of 21 hydroxylase.   Elevated ACTH and hyperactive ACTH response have also been shown (67).  Although CRH levels have not been directly measured, Reidel is convinced based on the provocative tests completed that it is likely high and clinically significant (68).  Two studies looked at whether low dose cortisol repletion would improve any of the symptoms associated with CFS.  McKenzie treated 70 patients with CFS and found that the wellness score increased significantly but the adrenal glands demonstrated further suppression which he felt warranted a discontinuation of the supplementation after risk:benefit analysis (69).  Cleare also treated patients with low dose cortisol.  Less fatigue was noted and the previously blunted response to CRH decreased (70). 
A few words about CRH (71): CRH is released from the hypothalamus in pulsatile waves in response to low basal levels of cortisol; it is found in the brain (as a neuromodulator), spinal cord, adrenal medulla, testis, ovaries, GI tract, pancreas, skin, myometrium, endometrium and placenta and has autocrine and paracrine effects. CRH can cause mesenteric vasodilation with resulting hypotension and tachycardia, both of which are prominent symptoms in EDS plus/CFS/FM/POTS.  Additionally, intracerebral injection of CRH has been shown to cause behavioral changes in animals and has been linked with anxiety and depression (72), symptoms very much associated with MCAS.  CRH increases catecholamines, possibly contributing to hyper-adrenergic POTS or even the mania associated with hypermobility; it increases ANS activation (prominent in EDS plus/CFS/FM/POTS and decreases gastric acid secretion, possibly responsible for vitamin malabsorption and dysbiosis seen in these conditions.  Finally, elevated CRH has been suspected to be involved in the pathogenesis of FM based on the measurement of urinary metabolites following stimulation tests (68, 73). CRH also modulates the immune system via secretion of cytokines, encouragement of lymphocytes and macrophage proliferation and is one of the most potent mast cell activators.  MCAS is highly prevalent in these conditions, it is likely responsible for the presence of autistic wiring in CAPS, it causes many of the associated symptoms and it provides a link to neurological and immunological disease.  I have seen MCAS in mild and severe forms in my patients with hypermobility and on the forums.  MCAS can trigger eosinophilia (21), hypermobility has been linked with eosinophilic esophagitis in the literature (74), and my hypermobile patients frequently have elevated eosinophils in their lab work.  Eosinophilia is also frequently mentioned in the other forums.    Additionally, CRH has a role in inflammatory conditions including rheumatoid arthritis, ulcerative colitis, endometriosis and Hashimoto’s thyroiditis, all conditions that I have seen frequently comorbid with EDS plus/CFS/FM on the forums (75).  As CRH is released in pulsatile waves when the body is in need of cortisol, I wondered if pulses of CRH be related to the disgust/jolt/run response which I have only seen in people in stressful situations. 
We would assume that people with decompensated CAH1 would have elevated ACTH, but in fact, people with EDS plus/CFS/FM/POTS frequently report having decreased ACTH and some experts conclude that the HPA abnormalities originate in the pituitary gland rather than from the adrenals (61). One explanation for the finding of decreased ACTH may involve raised ICP as empty sella syndrome is frequently found on MRI, as reported on the forums and found in my patients who had brain MRI’s.  Empty sella results from raised ICP pushing cerebrospinal fluid against the pituitary gland, and can be associated with pituitary dysfunction sometimes resulting in an inappropriately low ACTH in the setting of decreased cortisol (76).  Low ACTH from raised ICP would further exacerbate the presentation of CAH1 as cortisol would drop even lower without ACTH to stimulate its production, and pulsatile bursts of CRH would increase, perhaps increasing neuro-inflammation via immune system activation and liberation of cytokines.  It would make sense that the clinical picture at this point would include severe chronic fatigue as the acute stress response would be suppressed altogether and arousal would drop.  One of my previously very sick, young EDS patients had evidence of empty sella on her MRI, low ACTH and is currently bedbound and sleeps about 20 hours a day. 
Regarding the evidence for disrupted sex hormones in EDS plus/CFS/FM, it is important to note that the female predominance for these syndromes is striking.  The role of sex hormones in the pathophysiology of these disorders has remained unclear.  As mentioned above, the monthly physiological changes in progesterone levels affecting tissue laxity is offered as an explanation for the female predominance in EDS plus, and if subclinical CAH1 was the predisposing factor, we would expect women with these conditions to have substantial elevations in progesterone precursors, possible virilization and slightly lower estrogen.  The resulting pathological progesterone:estrogen balance would cause issues with anovulation, menstruation, and possibly early menopause depending on the timing and severity of the 21 hydroxylase decompensation.  Compared to controls, Boneva et al. note that in 36 women with CFS, there is a greatly increased prevalence of gynecological issues and specifically, menopause was 4.4 years earlier in women with CFS, amenorrhea rates were higher (53.9 versus 46.2%) and 56% of patients with CFS had had an oopherectomy compared to 34.3% (possible evidence of cystic disease) (77).   A study employing questionnaires compared 150 women with CFS with non-gynecological patients revealed a significantly higher rate of irregular menstrual cycles, episodes of amenorrhea, sporadic bleeding between periods and cystic ovaries, hirsutism, ovarian cysts in the CFS patients (78).  Murphy et al found that the mean values for progesterone and all of its metabolites were higher in CFS patients, with a striking level of isopregnanolone 2.3 times the level of that found in controls (79).  There is no readily apparent explanation for this, but a blockage of the 21 hydroxylase enzyme, as I propose, would provide a good explanation.   Regarding FM, Soyepek screened 40 PCOS patients for FM, finding a 4 fold increase in prevalence compared with a matched control population (32.5% versus 7.7%) (80).  Additionally, Reidel found decreased estrogen levels in a small group of women with FM (81).   From what I can tell there have been no studies looking at androgen levels in these conditions, but in my experience, CAPS is always present and requires androgen for development.  Clearly the evidence is very suggestive of significant alterations of sex hormone levels in these conditions, consistent with what would be found in decompensated CAH1.
 
Review of the Pathophysiology of the Comorbid Syndromes Which Could Be Explained by the Presence of CAH1:
POTS:
Orthostasis due to: Tissue laxity due to female gender, co-segregating TNXB mutation, high progesterone, decreased blood volume due to low aldosterone (via salt and water wasting), low basal cortisol-mediated decreases in blood pressure, histamine-induced vasodilation (due to CRH-triggered MCAS), CRH-caused increases in mesenteric vasodilation 
Direct SNS stimulation due to: SNS compensation for above orthostasis, exaggerated stress response with increased cortisol when stressed, CRH-induced increases in catecholamines, sleep deprivation due to adrenaline dumping, emotional stress, input from large amygdala
Dysautonomia due to: Brainstem compression possibly due to high progesterone or MCAS
 
MCAS:
Due to: Intermittent pulsatile release of CRH in response to low basal cortisol during stress, dysbiosis due to CRH-induced hypochlorydia
Associated with: Autistic features: abnormal dendritic branching, “Allergy” flares, severe systemic MCAS, POTS, psychiatric complications, possible raised ICP after prolonged stressor
 
Neurological Issues:
Neuropathic Pain Syndromes and Raised ICP Neuropathic Pain Syndromes:
Due to:
High cortisol demand in the setting of impaired production results in elevated CRH which then either directly or via MCAS liberates cytokines which result in alterations in central and/or peripheral pain processing, elevated progesterone: estrogen ratio may alter pain perception via alterations in central and/or peripheral pain processing
 
Raised ICP: (Chiari, brainstem compression, empty sella)
Due to: magnesium deficiency, elevated progesterone, MCAS/cytokine mediated brain inflammation with swelling, venous outflow blockage (TGF beta vasculitis/cytokines in EDS-HT), cortisol withdrawal as basal cortisol drops
 
CAH1 Associated Psychiatric Spectrum Disorder (CAPS) and Treatment Recommendations
Due to and characterized by:
-Abnormal hormone levels (low cortisol, low aldosterone, high progesterone, high androgen) in utero affecting development of limbic system. 
-High androgens and spiking cortisol directing postpartum brain development toward an enlarged amygdala, smaller anterior cingulate, possible virilization.  Enlarged amygdala results in strong emotional (good and bad) and fear responses without the benefit of a strong anterior cingulate to provide balance.  Possible stress-induced alteration in brain circuits could explain the similarities with PTSD physiology/observations as well: low PNS tone, high SNS tone, brainstem reactions: orienting, fight, slight, freeze and submission (perhaps with intermittent opiate disturbance, explaining atypical response to opiates and response to LDN in both of these conditions), emotional dysregulation (numbing/shutdown, overarousal)
-Low level central MCAS triggered by elevated CRH (due to low basal cortisol) directing abnormal dendritic branching resulting in autistic features-sensory issues, special abilities, tenacity, special interests, systems approach, unconventionality, social awkwardness, often empath qualities, attentional issues
-Exaggerated stress response and orthostasis causing physical and emotional strain during stress, SNS activation/over-arousal/anxiety, insomnia, tired and wired, hyper-focus/”turbo” (possible orienting response), lower trauma threshold for the development of PTSD symptoms (flashbacks, nightmares, startle, hyper-vigilance, harm avoidance behavior: perfectionism, mild OCD, increased ritualistic behavior/rigidity)
-Low basal cortisol causing under-arousal, fatigue, slowed reactions, attentional issues, thrill-seeking behaviors in an attempt to increase arousal.  This state alternates with the above state, possibly causing bipolar disorder.  This low arousal state can become more prominent as 21 hydroxylase activity becomes increasingly impaired. 
-CRH pulses trigger systemic MCAS, increase in sympathetic activation and subsequent parasympathetic response (see-saw) causing severe anxiety, fatigue and insomnia and wooziness.  Cytokine release from CRH acting on mast cells and acting directly can possibly cause depression, anxiety, psychosis.  CRH-induced catecholamine increase can possibly contribute to mania.
 
Responsive to: (in my experience)
-Education aimed at enhancing self-care/arousal optimization (good sleep, adequate salt and water repletion, positional changes to enhance blood return to the heart, deep breathing and exercise to increase parasympathetic tone, pacing and dividing tasks into manageable pieces, avoiding sensory overstimulation)
-Bolstering coping/grounding, stress management skills
-Improving social skills
-DBT skills for emotional regulation
-ACT for enhancing psychological flexibility
-EMDR/trauma work for reducing harm avoidance/rigidity/over-arousal
-Sympatholytic medications can be very helpful to decrease sympathetic activation.  Norepinephrine-raising medications should be used with caution.  Consider mood stabilizers and/or atypical antipsychotics, especially if there is evidence of active mast cell activation or severe shifting between over and under-arousal with emotional dysregulation.  Mast cell activation is probably multifactorial as discussed above and could be managed with mast cell stabilizers, antihistamines as needed and perhaps CRH antagonists if they should become available. 
-Management of mast cell activation can greatly reduce irritability and depressive symptoms.    
 
Summary:
In summary, I propose that these overlapping syndromes, EDS plus/CFS/FM/Chronic Lyme may share the above described psychiatric phenotype, CAPS, and that patients with these syndromes are also vulnerable to POTS, MCAS, neurological and immunological issues via the underlying presence of CAH1. Autoimmune diseases can occur if C4 is present.  My theory is supported based on evidence for HPA, mineralocorticoid and sex hormone disruptions and the clinical course of symptoms in these patient populations.  The unique quality of the RCCX module would allow for the creation of several phenotypes resulting from co-segregation of various permutations of contiguous, overlapping and spontaneous mutations of TNXB, CYP21 and C4, all with distinct clinical profiles and vulnerability to the development downstream complications including: POTS, MCAS, CAPS, neurological and immunological disorders all with enhanced vulnerability in women, clustering in families.  Patients carrying only the TNXB mutations would have the EDS phenotype but would not susceptible to the above complications.  Thus, I believe that CAH1 (heterozygosity for a CYP21A2 mutation) may be the genetic diathesis for the stress-diathesis model of physical and psychiatric disease and that CAPS may represent the spectrum disorder which links all 5 of the major psychiatric disorders (Anxiety, ADD, schizophrenia, Mood Disorders, Autism).    
Implications:
If I am correct, the implications of this theory will be far-reaching.  We will be much closer to understanding the neurological basis for a multitude of psychiatric conditions.  Furthermore, the explosion of autoimmune and fatiguing conditions affecting often middle-aged highly successful women (OCPD, special abilities, laser focus, high androgens) may also be explained.  The recognition of the frequently comorbid syndromes of EDS plus, CFS, FM, POTS, MCAS, neurological and immunological disorders would improve and specialists would no longer be required for diagnosis or care.  More directed treatments could be developed.  Appropriate screening and prevention could be instituted before the downstream issues progress and disability ensues.   
Research Questions:
Determine if the hypothesis is correct by testing patients with EDS plus/CFS/FM/ MCAS/CAPS/chronic Lyme:
-for elevated 17 OH progesterone at baseline or after stimulation with ACTH (would expect false negatives with both, though (82))
-for common mutations of CYP21A2
-for the contiguous mutation involving CAH and the TNX chimera known to be common in patients with CAH (if hypermobile).
-for other novel mutations involving TNXB (if hypermobile) and CYP21A2, contiguous or separate which would need to be characterized
 
Determine if there is a higher incidence of EDS plus/CFS/FM/ MCAS/CAPS/chronic Lyme in families with CAH.
Determine what the RP component of the module encodes?  Would contiguous mutations with RP contribute to these phenotypes?
 
If my hypothesis is correct:
-determine if the low basal cortisol in these fatigue syndromes should be replaced to avoid the other hormonal perturbations.
-determine if there is a role for direct CRH antagonists or progesterone antagonists in treatment.  Could these be developed and tested?
-determine frequency of CAH1 in autistic spectrum disorders.
-determine if CAH1 is linked with disorders involving raised ICP.
I have no conflicts of interest to report. 
References:
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As a result of tremendous positive response to the RCCX Theory:

Karen Herbst MD PhD  (Endocrinology) and I have set up a non-profit corporation to fund research investigating the possible role of the RCCX Module in familial ch
ronic illness clusters 
(Ehlers-Danlos Hypermobility Type, Chronic Fatigue Syndrome, Fibromyalgia, Chronic Lyme, Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome, Pain Syndromes, Psychiatric Spectrum Disorder (including PTSD, Anxiety Disorders, Autism Spectrum Disorder, Bipolar Disorder, Psychosis, Depression, ADHD), Autoimmune/Immunological Disorders, Endocrine disorders,Subcutaneous Adipose Tissue Disorders and Neurological Conditions (Including raised Intracranial Pressure, Chiari, Chronic Migraine, etc.), etc.).

Our study will attempt to define and characterize mutations in the RCCX module in terms of phenotypic/clinical  presentation.  We will be gathering a large amount of genetic, family, clinical and laboratory data from people with chronic illness (CFS, chronic Lyme, FM, etc), hypermobility, the CAPS profile and subcutaneous adipose tissue disorders and comparing with normal controls.

We have been approached to fund other researchers eager to explore the RCCX Module as well and we hope to be able to do so. 
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  • Home
  • BACKGROUND
    • About Me
    • The RCCX module Explains Years of Clinical Observations
  • RCCX Theory: Chronic Illness
    • RCCX THEORY: Part I Genes and Properties of the RCCX Module Explain Clusters of Illness in Families and all the Symptoms/Syndromes Found in Chronic Illness
    • RCCX THEORY: Part II Connecting RCCX Theory to Mitochondrial Shutdown
    • Recap/Summary
    • Summary for Scientists
    • Downloads
    • Pathophysiology Diagrams
    • The No Longer Current Journal Article Introducing Early Version of the RCCX Theory, July 2015
  • RCCX Theory: Psychiatry
    • CYP21A2 Mutations May Be the Diathesis in the Stress-Diathesis Model for Chronic Medical and Mental Illness and May Cause a Psychiatric Spectrum, CAPS
  • New Developments