What other diagnoses should be considered in a patient with hypersomnia, POTS, and gastrointestinal symptoms including diarrhea and nausea, especially upon waking, with a history of previous colonoscopy?

Differential Diagnoses to Consider

Given the constellation of hypersomnia, POTS, and gastrointestinal symptoms (diarrhea and nausea, especially upon waking), the most critical diagnoses to consider are hypermobile Ehlers-Danlos syndrome (hEDS)/Hypermobility Spectrum Disorders (HSDs) and Mast Cell Activation Syndrome (MCAS), as these conditions frequently coexist with POTS and explain the multisystem presentation. 1

Primary Diagnostic Considerations

Hypermobile Ehlers-Danlos Syndrome (hEDS) or Hypermobility Spectrum Disorders (HSDs)

• Screen for joint hypermobility using the Beighton score (≥5/9 points from puberty to age 50, ≥4/9 after age 50), as hEDS/HSDs are strongly associated with both POTS and gastrointestinal symptoms 1
• Over 60% of hEDS/HSDs patients have at least one GI symptom, and those with concomitant POTS are more likely to have IBS, GERD, or dysmotility 1
• In a survey of 616 hEDS/HSDs patients, 37.5% reported a diagnosis of POTS, establishing a clear epidemiological link 1
• Look for additional features: soft/velvety skin, easy bruising, chronic pain, pelvic floor dysfunction, and family history of similar symptoms 1

Mast Cell Activation Syndrome (MCAS)

• MCAS should be suspected when episodic symptoms affect at least 2 organ systems (GI tract, skin, cardiac, nervous system) triggered by food, heat, emotion, or mechanical stimuli 1
• In one prospective study of 139 patients with MCAS and refractory GI symptoms, 23.7% had EDS, 25.2% had POTS, and 15.1% had both, demonstrating significant overlap 1
• Obtain baseline serum tryptase level and collect tryptase 1-4 hours following symptom flares; diagnostic threshold is increase of 20% above baseline plus 2 ng/mL 1
• Additional symptoms to assess: flushing, urticaria, angioedema, wheezing, anaphylaxis-like episodes 1

Secondary Diagnostic Considerations

Celiac Disease

• Testing for celiac disease should be considered earlier in patients with hEDS/HSDs who report various GI symptoms, not limited to those with diarrhea alone 1, 2
• This is particularly relevant given the patient's diarrhea and nausea 1

Gastroparesis or Gastric Motor Dysfunction

• Abnormal gastric emptying may be more common in patients with POTS than in the general population due to underlying autonomic dysfunction 1, 3, 2
• Consider gastric emptying study or gastric accommodation testing in patients with chronic upper GI symptoms (nausea, early satiety) after excluding structural disease 1, 3
• Nausea, pain, and early satiety are the most predictive symptoms of abnormal GI motility in POTS 1

Pelvic Floor Dysfunction

• Given the high prevalence of pelvic floor dysfunction in hEDS/HSDs, particularly rectal hyposensitivity, consider anorectal manometry, balloon expulsion test, or defecography if symptoms include incomplete evacuation or constipation alternating with diarrhea 1, 2

Post-Viral Dysautonomia

• Up to 40% of patients with POTS self-report a viral upper respiratory or GI infection as the precipitating event to their symptoms 1
• Recent association between acute and long COVID-19 and POTS has been described 1
• Assess for temporal relationship between viral illness and symptom onset 1

Autonomic Dysfunction Beyond POTS

Broader Dysautonomia Assessment

• The GI symptoms (bloating, nausea, diarrhea, abdominal pain) are recognized manifestations of POTS itself, not necessarily requiring separate diagnosis 1
• Cognitive and bladder dysfunction and GI symptoms attributable to visceral hypersensitivity and/or dysmotility are not uncommon in POTS 1
• Consider autonomic function testing including tilt table or sudomotor testing for comprehensive evaluation, especially if POTS diagnosis is not yet confirmed 2

Sleep Disorder Evaluation

Hypersomnia Etiology

• One-third of children with hypersomnia disorders exhibit orthostatic intolerance at initial presentation, with female predominance 4
• Distinguish between narcolepsy types 1 and 2, idiopathic hypersomnia, and behaviorally induced insufficient sleep syndrome 5, 6, 7
• The hypersomnia may be secondary to autonomic dysfunction and poor sleep quality rather than a primary sleep disorder 4

Critical Diagnostic Algorithm

1. Perform Beighton score assessment for joint hypermobility screening 1
2. If Beighton score positive (≥5/9 or ≥4/9 depending on age), apply 2017 diagnostic criteria for hEDS or refer to appropriate specialist 1
3. Obtain baseline serum tryptase if episodic multisystem symptoms suggest MCAS 1
4. Order celiac serologies (tissue transglutaminase IgA with total IgA) given the GI symptom pattern 1, 2
5. Consider gastric emptying study if nausea is prominent and refractory to initial management 1, 3
6. Evaluate for pelvic floor dysfunction if bowel evacuation symptoms are present 1, 2

Common Pitfalls to Avoid

• Do not attribute all symptoms solely to POTS without screening for hEDS/HSDs and MCAS, as these conditions frequently coexist and require specific management 1
• Avoid universal testing for POTS/MCAS in all patients with hEDS/HSDs; testing should be targeted to those with clinical manifestations 1
• Do not overlook the female predominance of these conditions when considering differential diagnoses 4
• Recognize that the nausea "especially if has to wake up early" may reflect circadian dysregulation related to autonomic dysfunction rather than a primary GI disorder 1
• Be cautious with opioid use for abdominal pain in this population, as it can worsen GI dysmotility 1