Hereditary alpha-tryptasaemia

Hereditary alpha-tryptasaemia syndrome is the clinical manifestation of a genomic trait leading to raised baseline serum tryptase levels. It is asymptomatic in the majority of cases, but affected patients are more likely to have frequent allergic-type symptoms, such as urticarial rash (hives), anaphylaxis and gastrointestinal dysmotility. There is a gene-dose effect, with higher TPSAB1 copy numbers correlating with higher tryptase levels and increased symptom severity.

The main clinical feature of the genomic trait is constitutively raised alpha-tryptase (greater than 11.4µg/L).

In symptomatic patients, features occur with increased mast cell activation and mediator release.

Clinical features include:

• increased frequency of type 1 immediate hypersensitivity reactions, particularly hymenoptera venom (wasp or bee stings)-induced anaphylaxis;
• increased likelihood of monoclonal mastocytosis;
• flushing;
• urticarial rash;
• angioedema;
• anxiety;
• gastrointestinal dysmotility symptoms, such as diarrhoea, bloating and abdominal pain; and
• cardiovascular symptoms, such as labile blood pressure and tachycardia.

Clinical features can vary significantly between affected people.

Hereditary alpha-tryptasaemia is a relatively frequent genetic trait caused by increased copy number of the alpha (α)-tryptase isoform of the TPSAB1 gene. This may be present in duplication (ααβ genotype) or triplication (αααβ genotype). This causes a direct gene-dose effect, with triplication more likely to result in higher tryptase levels and more severe symptoms. In addition, it is thought that the increased ratio of the alpha-isoform of tryptase creates more functional heterotetramers, which may potentiate its effect.

The TPSAB1 gene is located at chromosome 16p13.3, within a complex region featuring multiple highly homologous sequences, which likely contributes to the mechanism by which duplications and triplications occur. This also makes the copy number present in an individual difficult to measure using standard microarray.

Hereditary alpha-tryptasaemia is present in up to 6% in European populations, with only a third of those affected experiencing symptoms.

In patients with suggestive clinical features and/or raised serum tryptase levels, baseline tryptase level should be taken. Repeated levels above 11.4µg/L are considered more likely, with 20% of those with hereditary alpha-tryptasaemia shown to have levels greater than 20µg/L.

Tryptase levels are typically measured when considering anaphylaxis or in the investigation of mast cell disease. Patients with hereditary alpha-tryptasaemia have raised baseline levels, which can be increased further during immediate hypersensitivity reactions.

Other causes of raised baseline serum tryptase should be considered, such as renal disease and monoclonal mastocytosis.

Where hereditary alpha-tryptasaemia co-occurs with monoclonal mast cell disorders, additional diagnostic criteria other than raised baseline serum tryptase should be used.

For information about genomic testing, see ‘Child with persistently raised baseline serum tryptase‘.

Hereditary alpha-tryptasaemia is a relatively common genetic trait, and it is likely that most people with the trait are asymptomatic. It is inherited in an autosomal dominant pattern.

• Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
• The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
• Incomplete penetrance can occur (that is, not everyone who has the variant develops the disease).

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Note that de novo variants may also arise.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

There is no specific treatment for hereditary alpha-tryptasaemia. Management focuses on symptom control and surveillance for monoclonal mast cell disorders.

Antihistamines (non-sedating, H1 targeting) are most commonly used to control symptoms. They are often required for longer durations and at higher doses than would normally be expected. In patients with history of anaphylaxis, adrenaline auto-injectors should be available.

Gastrointestinal symptoms may benefit from antispasmodic medications and proton-pump inhibitors for gastro-oesophageal reflux disease. Low histamine diets may be beneficial in a small number of cases.

For clinicians

References:

• Chantran Y and Arock M. ‘Hereditary alpha-tryptasemia and monoclonal mast cell disorders‘. Frontiers Allergy 2025: volume 6. DOI: 10.3389/falgy.2025.1600680
• Robey RC, Wilcock A, Bonin H and others. ‘Hereditary alpha-tryptasemia: UK prevalence and variability in disease expression‘. The Journal of Allergy and Clinical Immunology in Practice 2020: volume 8, issue 10, pages 3,549–3,556. DOI: 10.1016/j.jaip.2020.05.057

For patients

• UK Masto: Mastocytosis, mast cell activation syndrome and hereditary alpha tryptasemia syndrome