What could be causing my recurring facial flushing, episodes of lightheadedness, dizziness, nausea, vomiting, fatigue, and skin rashes, along with nasal polyps and lymph node swelling?

Systemic Mastocytosis Should Be Ruled Out Immediately

Your constellation of symptoms—facial flushing (especially nocturnal and stress-induced), episodic lightheadedness with nausea/vomiting, fatigue, papulovesicular rash progressing to crusted plaques, nasal polyps with epistaxis, and lymphadenopathy—raises serious concern for systemic mastocytosis or a mast cell activation disorder, which can be life-threatening if unrecognized. 1

Critical Diagnostic Pathway

Immediate Workup Required

• Serum tryptase level must be obtained urgently, ideally during a symptomatic episode but also at baseline, as elevated tryptase (>20 ng/mL) strongly suggests systemic mastocytosis 1
• Complete blood count with differential to evaluate for eosinophilia, leukocytosis, or other hematologic abnormalities 1
• Comprehensive metabolic panel including liver function tests, as systemic mastocytosis can involve multiple organ systems 1
• 24-hour urinary histamine metabolites (N-methylhistamine) provide additional evidence of mast cell activation when tryptase is equivocal 1

Skin Lesion Evaluation

• The papulovesicular rash evolving into a crusted brown plaque in the axillary region is highly suspicious for urticaria pigmentosa (cutaneous mastocytosis), which appears as fixed hyperpigmented macules or plaques that may blister 2
• Lesional skin biopsy is mandatory to evaluate for mast cell infiltration with special stains (tryptase, CD117/c-kit) 2
• Document whether stroking the lesions produces urticaria (Darier's sign), pathognomonic for mastocytosis 2

Nasal and Sinus Assessment

• The nasal polyp with bloody nose, headache, and lymph node swelling occurring weeks after the skin eruption suggests either systemic disease progression or a separate inflammatory process 1, 3
• Nasal endoscopy should be performed to characterize the polyp (unilateral vs bilateral, appearance, extent) 1
• Unilateral nasal polyps in adults mandate exclusion of malignancy or invasive fungal disease, requiring CT scan of paranasal sinuses and possible biopsy 1
• Blood eosinophil count and serum IgE help differentiate type 2 inflammatory chronic rhinosinusitis from other etiologies 1

Differential Diagnoses That Cannot Be Ignored

Systemic Mastocytosis (Primary Concern)

• Flushing episodes triggered by stress, heat, and occurring nocturnally are classic for mast cell mediator release 1
• Gastrointestinal symptoms (nausea, vomiting) occur in 60-80% of systemic mastocytosis patients 1
• Hypotension and lightheadedness result from massive histamine release causing vasodilation 1
• Skin involvement (urticaria pigmentosa) is present in most cases of systemic mastocytosis 2

Carcinoid Syndrome

• Episodic flushing, especially facial, with gastrointestinal symptoms and potential right-sided heart involvement 1
• 24-hour urinary 5-HIAA (5-hydroxyindoleacetic acid) and serum chromogranin A should be measured 1
• Abdominal CT or MRI with contrast to evaluate for primary tumor (typically small bowel or bronchial) 1

Pheochromocytoma

• Episodic hypertension, headache, diaphoresis, and palpitations with flushing 1
• 24-hour urinary metanephrines and catecholamines or plasma free metanephrines 1
• Abdominal MRI to evaluate adrenal glands 1

Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss)

• Nasal polyps, sinusitis, asthma, eosinophilia, and systemic vasculitis with skin involvement 1
• ANCA testing (particularly p-ANCA/MPO), eosinophil count, and inflammatory markers (ESR, CRP) 1, 2
• Tissue biopsy showing eosinophilic infiltration and necrotizing vasculitis 1

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

• Nasal obstruction, rhinorrhea, facial pressure, and hyposmia for >12 weeks 1, 3
• However, unilateral presentation and associated systemic symptoms make this less likely as a standalone diagnosis 1
• Requires nasal endoscopy showing polyps and/or CT demonstrating sinus opacification 1

Critical Management Algorithm

If Systemic Mastocytosis Confirmed

1. Immediate referral to hematology/oncology for bone marrow biopsy to determine extent of disease 1
2. Avoid known mast cell degranulation triggers: NSAIDs (especially aspirin), alcohol, temperature extremes, physical/emotional stress, certain medications (opioids, vancomycin) 1
3. Prescribe emergency epinephrine auto-injector due to risk of anaphylaxis 1
4. H1 and H2 antihistamine therapy (e.g., cetirizine + ranitidine/famotidine) to control mediator symptoms 1
5. Mast cell stabilizers (cromolyn sodium) may reduce symptom frequency 1

If Carcinoid or Pheochromocytoma Suspected

• Urgent oncology and/or endocrinology referral for surgical evaluation 1
• Medical management to control symptoms and prevent hypertensive crisis (pheochromocytoma) or carcinoid crisis 1

If EGPA or Other Vasculitis Suspected

• Urgent rheumatology referral for immunosuppressive therapy (glucocorticoids ± cyclophosphamide or rituximab) 1
• Delay in treatment can lead to irreversible organ damage 1

Nasal Polyp Management

• If bilateral polyps with type 2 inflammation (elevated eosinophils/IgE), initiate intranasal corticosteroids (mometasone or fluticasone) 1, 4, 5
• If unilateral or atypical features, biopsy before treatment to exclude malignancy or invasive fungal disease 1
• Short course of oral corticosteroids (prednisone 0.5-1 mg/kg for 5-7 days) for severe symptoms, but only after excluding systemic mastocytosis (steroids can trigger mast cell degranulation) 4, 5

Common Pitfalls to Avoid

• Do not dismiss flushing as simple rosacea or anxiety without measuring tryptase and excluding systemic causes 1
• Do not attribute all symptoms to chronic rhinosinusitis when systemic features (fatigue, episodic collapse, skin lesions) are present 1
• Do not perform nasal polyp surgery without tissue diagnosis if presentation is unilateral or associated with systemic symptoms 1
• Do not administer NSAIDs, aspirin, or opioids until systemic mastocytosis is excluded, as these can precipitate life-threatening anaphylaxis 1
• Do not delay referral to appropriate specialists (hematology, rheumatology, allergy/immunology) when red flags are present 1

Urgent Specialist Referrals Needed

• Hematology/oncology for suspected systemic mastocytosis or other hematologic malignancy 1
• Allergy/immunology for comprehensive evaluation of flushing disorders and potential mast cell activation syndrome 1
• Rheumatology if vasculitis suspected based on multi-system involvement 1
• Otolaryngology for nasal endoscopy, polyp biopsy, and potential surgical management 1