What is the most likely cause of severe fatigue and exhaustion in a patient with hypermobile Ehlers-Danlos Syndrome (hEDS), fibromyalgia, Attention Deficit Hyperactivity Disorder (ADHD), and severe femoroacetabular impingement syndrome with normal laboratory results?

Most Likely Cause of Severe Fatigue in hEDS with Fibromyalgia and ADHD

The severe fatigue in this patient is most likely multifactorial, driven primarily by the overlapping central sensitization mechanisms shared between hEDS, fibromyalgia, and chronic pain, compounded by potential unrecognized autonomic dysfunction (POTS) and possibly undertreated ADHD. 1, 2

Primary Contributing Mechanisms

Central Sensitization and Pain-Fatigue Cycle

• hEDS is strongly associated with chronic pain due to both peripheral and central sensitization, with large overlap with fibromyalgia and chronic fatigue/myalgic encephalomyelitis (ME). 1 This represents a core feature of the condition rather than a separate comorbidity.
• The severe femoroacetabular impingement with labral tears creates ongoing nociceptive input that perpetuates central sensitization, amplifying fatigue through chronic pain pathways. 2
• Fibromyalgia and hEDS share common neurophysiologic patterns where fatigue becomes the most invalidating symptom, with central processing problems rather than peripheral muscle disorders. 3, 4

Dysautonomia (POTS) - Likely Undiagnosed

• In a survey of 616 hEDS patients, 37.5% reported a diagnosis of POTS, and those with concomitant POTS were significantly more likely to have fibromyalgia. 1
• POTS causes profound fatigue through impaired autonomic responses, chronic orthostatic intolerance, and dysregulated cardiovascular function. 1
• Testing for POTS should be targeted to patients presenting with clinical manifestations including lightheadedness upon standing, palpitations, brain fog, and exercise intolerance—symptoms often attributed to other conditions. 1
• The mechanistic basis involves vascular laxity from connective tissue abnormalities and/or peripheral neuropathy, with newer evidence implicating autoimmune etiologies. 1

ADHD as a Fatigue Driver

• Adult ADHD (predominantly inattentive type) may develop into a syndrome of chronic fatigue and pain over time, sharing common underlying mechanisms with chronic fatigue syndrome and fibromyalgia. 5, 4
• ADHD medications have demonstrated amelioration of both core ADHD symptoms AND associated pain and fatigue symptoms through their arousal and enhanced filtering properties. 5, 4
• The utility lies in addressing central processing problems rather than peripheral disorders. 4

Critical Evaluation Steps

Rule Out Occult Autonomic Dysfunction

• Perform orthostatic vital signs testing: measure heart rate and blood pressure supine, then at 2,5, and 10 minutes of standing. POTS is diagnosed by sustained heart rate increase ≥30 bpm (≥40 bpm in adolescents) within 10 minutes of standing without orthostatic hypotension. 1
• Assess for clinical manifestations including orthostatic intolerance, lightheadedness, palpitations, and exercise intolerance that worsen with upright posture. 1

Evaluate for Mast Cell Activation Syndrome (MCAS)

• MCAS should be suspected if the patient has multisystem symptoms (GI tract, skin, cardiac, nervous system) triggered by foods, heat, emotion, or mechanical stimuli. 1
• In one prospective study of 139 MCAS patients with refractory GI symptoms, 23.7% had EDS and 15.1% had both EDS and POTS. 1
• However, testing for MCAS should be targeted to patients with clinical manifestations of multisystem involvement, not performed for isolated symptoms. 1

Assess ADHD Treatment Adequacy

• Evaluate whether current ADHD treatment adequately addresses inattention, distractibility, and cognitive symptoms, as undertreated ADHD can manifest as severe fatigue. 5, 4
• Consider that stimulant medications for ADHD may be confounding autonomic assessment and should be factored into POTS evaluation. 1

Screen for Sleep Disorders and Deconditioning

• Sleep disorders, chronic pain, and deconditioning commonly contribute to fatigue in hEDS and must be systematically evaluated. 2
• Chronic pain from the hip pathology likely disrupts sleep architecture, perpetuating the fatigue cycle. 2

Management Algorithm

First-Line Interventions

• If POTS is confirmed, initiate conservative management with increased fluid intake to 2-3 liters daily, salt intake to 10-12 grams daily, and lower body compression garments during upright activities. 6
• Implement tailored physical activity interventions with low-resistance exercise combined with myofascial release techniques to increase muscle tone and improve joint stability, addressing deconditioning without exacerbating joint instability. 1, 6
• Offer structured psychoeducational interventions exploring thoughts, feelings, and behaviors related to fatigue, as recommended for inflammatory rheumatic diseases with similar fatigue patterns. 1

Pharmacological Considerations

• If ADHD symptoms remain prominent despite treatment, consider optimizing stimulant therapy, as case studies demonstrate improvement in both fatigue and pain with adequate ADHD treatment. 5, 4
• If MCAS is confirmed with multisystem involvement, start H1 receptor antagonist (cetirizine 10mg daily) combined with H2 receptor antagonist (famotidine 20mg twice daily). 6
• Avoid opioids entirely for pain management, especially with GI manifestations, as they worsen outcomes, increase complications, and may mimic features of chronic intestinal pseudo-obstruction. 1, 6

Multidisciplinary Coordination

• Coordinate care among gastroenterology, cardiology or neurology (for POTS), pain management, physical medicine, and psychology specialists. 6
• Regular follow-up with the multidisciplinary team is required for all hEDS patients given the complex, overlapping nature of symptoms. 6

Critical Pitfalls to Avoid

• Never assume normal labs exclude significant pathology in hEDS—the fatigue mechanisms are primarily neurophysiologic and autonomic rather than biochemical. 2, 3
• Do not attribute all symptoms to fibromyalgia or psychological factors without systematically evaluating for POTS and MCAS, which have specific treatments. 1
• Avoid prescribing opioids for chronic pain management in hEDS, particularly with any GI manifestations, as they worsen the clinical picture. 1, 6
• Do not overlook ADHD as a contributor to fatigue—it may be the most modifiable factor if currently undertreated. 5, 4
• Failing to recognize fatigue as a legitimate symptom requiring active intervention is the most dangerous pitfall, as many clinicians acknowledge its importance but fail to routinely offer structured support. 7