Monoclonal Mast Cell Activation Syndrome

Monoclonal mast cell activation syndrome is mast cell activation with a clonal mast cell population (KIT D816V or aberrant CD25 expression) that does not meet the full criteria for systemic mastocytosis. It causes severe anaphylaxis, often with hypotension and no skin signs.

Pathophysiology. A somatic KIT variant (most often D816V) drives expansion and hyperactivity of clonal mast cells, which degranulate in response to triggers. Venom, drugs, heat and exercise are common triggers.

It is uncommon. Patients tend to be older men with recurrent syncope, and without urticaria and angio oedema.

A clinical score (REMA) helps to predict clonality: add 1 for male sex, add 1 for syncope, subtract 1 for female sex, subtract 2 for urticaria, itching or angio oedema, subtract 1 for baseline tryptase under 15 microgram/L, and add 2 for baseline tryptase over 25 microgram/L. A total of 2 or more suggests a clonal disorder.

• Recurrent anaphylaxis with hypotension and syncope
• Absent urticaria or angio oedema in many
• Triggers: hymenoptera stings, drugs, exercise, heat, alcohol, stress
• Flushing, palpitations and gastrointestinal symptoms
• Osteoporosis or fragility fractures
• Normal or mildly raised baseline tryptase, with a rise during episodes

• Diagnostic criteria for mast cell activation (episodic symptoms in 2 or more organ systems, tryptase rise of more than 20% over baseline plus 2 microgram/L, response to mediator targeted treatment).
• Clonality: KIT D816V testing on peripheral blood (sensitive allele specific PCR or digital PCR), and bone marrow biopsy with mast cell immunophenotyping (CD25, CD2, CD30) when the REMA score is 2 or more, or the baseline tryptase is raised.
• Exclude systemic mastocytosis: the bone marrow must show fewer than the required major and minor criteria, with no multifocal aggregates of 15 or more mast cells.
• Baseline tryptase, and TPSAB1 copy number for hereditary alpha tryptasaemia.
• Venom and drug allergy testing where relevant.
• Bone density scan and full blood count, liver enzymes and calcium.

Differential diagnosis.

• Systemic mastocytosis (indolent or smouldering)
• Primary idiopathic mast cell activation syndrome
• Hereditary alpha tryptasaemia
• Venom allergy without clonality
• Idiopathic anaphylaxis
• Carcinoid syndrome and phaeochromocytoma

• Acute episode: adrenaline 0.5 mg intramuscularly (children 0.01 mg/kg, maximum 0.5 mg) into the anterolateral thigh, repeated after 5 minutes if no improvement, plus oxygen and intravenous fluids, and observation for at least 6 hours.
• Adrenaline auto injector: 150 microgram for 7.5 to 25 kg, 300 microgram for 25 to 50 kg, 500 microgram for over 50 kg, with a written action plan and training.
• Prophylaxis: cetirizine 10 mg orally once or twice daily, famotidine 20 mg orally twice daily, and montelukast 10 mg at night. Sodium cromoglicate 200 mg orally four times daily for gastrointestinal symptoms.
• Omalizumab 300 mg subcutaneously every 4 weeks for refractory anaphylaxis, in specialist care.
• Venom immunotherapy lifelong for venom triggered reactions: maintenance 100 microgram of venom every 4 weeks (200 microgram if reactions continue).
• Bone health: calcium, vitamin D and bisphosphonate when osteoporosis is present.
• Cytoreductive therapy is reserved for aggressive or progressive disease (avapritinib or other KIT inhibitors in specialist centres).
• Perioperative plan: premedication, careful choice of anaesthetic and opioid, and monitored setting.
• Avoid triggers: alcohol, NSAIDs, opioid triggers and heat when relevant.

Special groups.

• Patients with venom anaphylaxis: lifelong venom immunotherapy and an auto injector.
• Patients on beta blockers: glucagon 1 to 2 mg intravenously may be needed in adrenaline resistant episodes.

Monitoring. Review every 3 to 6 months. Baseline tryptase, full blood count and liver enzymes yearly. Bone density every 2 years. KIT D816V allele burden if available.

Referral and escalation. Refer to a mastocytosis or haematology allergy service. Urgent for unexplained hypotension, cytopenia or organomegaly. Emergency for anaphylaxis.