Hereditary Alpha-tryptasaemia

Hereditary alpha tryptasaemia is an autosomal dominant trait of extra copies of the alpha tryptase gene (TPSAB1), causing a raised baseline serum tryptase. It is common, and many carriers are well, but some have mast cell mediator symptoms and more severe anaphylaxis.

Pathophysiology. Duplications or triplications of TPSAB1 raise tryptase production, and each extra copy raises baseline tryptase by roughly 3 to 5 microgram/L. Extra alpha tryptase may increase mast cell reactivity.

About 5 to 7% of people of European descent carry extra copies. It is over represented among people with systemic mastocytosis and venom anaphylaxis, and among those with idiopathic anaphylaxis.

Symptoms vary from none to flushing, gastrointestinal disease, joint hypermobility, autonomic problems and severe anaphylaxis.

• Many carriers have no symptoms
• Flushing, itching, urticaria, angio oedema
• Abdominal pain, diarrhoea, reflux, irritable bowel symptoms
• Joint hypermobility, skin elasticity and chronic pain
• Dysautonomia, palpitations, presyncope, fatigue
• Severe anaphylaxis to venom or drugs
• Eosinophilic oesophagitis and other allergic disease

• Baseline serum tryptase over 8 microgram/L on at least 2 occasions, measured when well and at least 24 hours after any reaction.
• TPSAB1 copy number testing by digital droplet PCR: 3 or more alpha tryptase copies confirm the trait.
• Exclusion of clonal mast cell disease: KIT D816V in blood, and bone marrow biopsy when tryptase is over 20 microgram/L or other features are present, since both can coexist.
• Exclusion of other causes of raised tryptase: chronic kidney disease, myeloid neoplasm, eosinophilic disease.
• Allergy testing after any anaphylaxis (venom, food, drugs).
• Family testing (parents, siblings and children).

Differential diagnosis.

• Systemic mastocytosis and monoclonal mast cell activation syndrome
• Idiopathic mast cell activation syndrome
• Chronic kidney disease or myeloid neoplasm with raised tryptase
• Ehlers-Danlos syndromes and joint hypermobility disorders
• Eosinophilic gastrointestinal disease
• Postural tachycardia syndrome

• Carriers without symptoms: reassurance and genetic counselling. No treatment is needed.
• Symptomatic mast cell mediator symptoms: the stepwise approach used for mast cell activation:
  • Cetirizine 10 mg orally once daily, which may be raised to twice daily (children 1 to 5 years 2.5 mg twice daily; 6 to 11 years 5 mg twice daily).
  • Famotidine 20 mg orally twice daily (reduce at creatinine clearance under 50 mL/min).
  • Sodium cromoglicate 200 mg orally four times daily before meals for gastrointestinal symptoms.
  • Montelukast 10 mg orally at night.
  • Omalizumab 150 to 300 mg subcutaneously every 4 weeks for refractory disease in specialist care.
• Venom allergy: venom immunotherapy (maintenance 100 microgram of venom every 4 weeks, 200 microgram if reactions continue) is lifelong or long term, because the risk of severe anaphylaxis is higher.
• Anaphylaxis plan: adrenaline 0.5 mg intramuscularly (children 0.01 mg/kg, maximum 0.5 mg), with an auto injector (150 microgram for 7.5 to 25 kg, 300 microgram for 25 to 50 kg, 500 microgram for over 50 kg), a written action plan and training.
• Trigger avoidance: heat, alcohol, NSAIDs and opioids where relevant.
• Procedural planning: premedication and careful choice of agents for surgery.
• Treat comorbidities: eosinophilic oesophagitis, hypermobility and dysautonomia.

Special groups.

• Families: autosomal dominant inheritance, so each child of a carrier has a 50% chance of inheriting extra copies.

Monitoring. Baseline tryptase yearly. Review symptoms every 6 to 12 months. Reassess for clonal disease if tryptase rises over the level expected for the copy number or new features appear.

Referral and escalation. Refer to allergy or immunology for raised tryptase with symptoms, or anaphylaxis. Urgent when tryptase is over 20 microgram/L, or there are unexplained cytopenias or organomegaly. Emergency for anaphylaxis.