The Clinical Features of Hereditary Alpha-Tryptasemia—Implications for Interdisciplinary Practice

Abstract

Background: Hereditary alpha-tryptasemia (HAT) is a genetic predisposition of autosomal dominant inheritance that leads to a high normal (≥ 8-11.4 μg/L) or pathologically elevated (>11.4 μg/L) basal serum tryptase (BST) concentration. Its prevalence in the United Kingdom and France is reportedly 5%-6%; its prevalence in Germany is unknown. Symptomatic persons with HAT suffer from a complex constellation of symptoms. As described in this review, HAT is an important differential diagnosis in interdisciplinary practice.

Methods: This review is based on publications about HAT retrieved by a selective search in PubMed, on relevant presentations at scientific meetings, and on our clinical experience. We also collected our own data on the prevalence and clinical manifestations of HAT.

Results: According to the literature, HAT is very common among patients in medical centers with BST values of 8 μg/L or above (64-74%). HAT is most commonly associated with neuropsychiatric symptoms such as exhaustion (85%), depressive episodes (59%), sleep disturbances (69%), and memory impairment (59%-68%), followed by gastrointestinal symptoms such as irritable bowel (30%-60%), nausea (51%), and reflux (49%-77%). Typical mast cell-mediated symptoms, such as flushing (47%), itch (69%), urticaria (37%), and anaphylaxis (14%-28%), are reported as well. Less commonly reported are cardio vascular manifestations, such as hypotonia, dizziness, and tachycardia (34%), and joint hyper - mobility (28%). HAT is more common among patients with systemic mastocytosis (SM; 12%-21%). It is often associated with severe anaphylaxis induced by insect toxins or unknown triggers. The therapeutic options include treatment with antihistamines, mastcell stabilizers, or IgE antibodies.

Conclusion: A diagnosis of hereditary alphatryptasemia can be strongly suspected on the basis of thorough history-taking and BST measurement and then confirmed by molecular genetic testing.

Figure 1

The haplotypes and genotypes (with their prevalences) in a wild-type gene for TPSAB1 and in hereditary alpha-tryptasemia (HAT) (39). Red type: the TPSAB1 gene, which makes the difference between HAT and non-HAT. n, Variable number of copies of the TPSAB1 gene

Figure 2

Prevalence of HAT and other causes of BST ≥ 8 μg/L by BST range in our allergy clinic prevalence cohort (n = 130). BST, Basal serum tryptase; GFR, glomerular filtration rate; HAT, hereditary alpha-tryptasemia; SM, systemic mastocytosis

Figure 3

Flow chart for investigation of insect-venom anaphylaxis as recommended by the authors at he mast cell center of UKSH, Campus Lübeck. In all cases of insect-venom allergy, allergological investigation should be accompanied by determination of BST. Persons with a BST level ≥ 8 μg/L should be referred to a mast cell center for molecular genetic testing for HAT and cKIT D816V. In cases of Müller grade III–IV insect-venom anaphylaxis, cKIT D816V testing should take place regardless of the BST level. In BST < 8 μg/L and Müller grade I–II, only allergological investigation is necessary, with no further testing for HAT or cKIT D816V. We recommend referral of all cKIT D816V-positive patients to a hemato-oncologist. Because the mutation is very specific for systemic mastocytosis (SM), bone marrow aspiration is recommended at the Lübeck center. BST, Basal serum tryptase concentration; HAT, hereditary alpha-tryptasemia