Clinical Review

Cutaneous Manifestations in Hereditary Alpha Tryptasemia

Author and Disclosure Information

Hereditary alpha tryptasemia (HaT) is a recently identified disorder that is associated with dermatologic manifestations such as urticaria, flushing, pruritus, and atopic dermatitis (AD), as well as a broad range of other symptoms affecting multiple systems. Given the potential cutaneous manifestations and the fact that dermatologic symptoms may be the initial presentation of HaT, awareness and recognition of this condition by dermatologists are essential for diagnosis and treatment. This review aims to summarize cutaneous presentations consistent with HaT and various conditions that share overlapping dermatologic symptoms with HaT.

Practice Points

  • Chronic or episodic urticaria, flushing, and pruritus are the most consistent cutaneous abnormalities associated with hereditary alpha tryptasemia (HaT), but HaT also may augment symptoms of other underlying inflammatory skin disorders, such as atopic dermatitis and psoriasis.
  • Individuals with episodic dermatologic manifestations indicative of mast cell activation accompanied by symptoms affecting 1 or more organ systems should be evaluated for mast cell activation syndrome as well as HaT.


 

References

Hereditary alpha tryptasemia (HaT), an autosomal-dominant disorder of tryptase overproduction, was first described in 2014 by Lyons et al.1 It has been associated with multiple dermatologic, allergic, gastrointestinal (GI) tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities. These multisystem concerns may include cutaneous flushing, chronic pruritus, urticaria, GI tract symptoms, arthralgia, and autonomic dysfunction.2 The diverse symptoms and the recent discovery of HaT make recognition of this disorder challenging. Currently, it also is believed that HaT is associated with an elevated risk for anaphylaxis and is a biomarker for severe symptoms in disorders with increased mast cell burden such as mastocytosis.3-5

Given the potential cutaneous manifestations and the fact that dermatologic symptoms may be the initial presentation of HaT, awareness and recognition of this condition by dermatologists are essential for diagnosis and treatment. This review summarizes the cutaneous presentations consistent with HaT and discusses various conditions that share overlapping dermatologic symptoms with HaT.

Background on HaT

Mast cells are known to secrete several vasoactive mediators including tryptase and histamine when activated by foreign substances, similar to IgE-mediated hypersensitivity reactions. In their baseline state, mast cells continuously secrete immature forms of tryptases called protryptases.6 These protryptases come in 2 forms: α and β. Although mature tryptase is acutely elevatedin anaphylaxis, persistently elevated total serum tryptase levels frequently are regarded as indicative of a systemic mast cell disorder such as systemic mastocytosis (SM).3 Despite the wide-ranging phenotype of HaT, all individuals with the disorder have an elevated basal serum tryptase level (>8 ng/mL). Hereditary alpha tryptasemia has been identified as another possible cause of persistently elevated levels.2,6

Genetics and Epidemiology of HaT—The humantryptase locus at chromosome 16p13.3 is composed of 4 paralog genes: TPSG1, TPSB2, TPSAB1, and TPSD1.4 Only TPSAB1 encodes for α-tryptase, while both TPSB2 and TPSAB1 encode for β-tryptase.4 Hereditary alpha tryptasemia is an autosomal-dominant disorder resulting from a copy number increase in the α-tryptase encoding sequence within the TPSAB1 gene. Despite the wide-ranging phenotype of HaT, all individuals identified with the disorder have a basal serum tryptase level greater than 8 ng/mL, with mean (SD) levels of 15 (5) ng/mL and 24 (6) ng/mL with gene duplication and triplication, respectively (reference range, 0–11.4 ng/mL).2,6 Hereditary alpha tryptasemia likely is common and largely undiagnosed, with a recently estimated prevalence of 5% in the United Kingdom7 and 5.6% in a cohort of 125 individuals from Italy, Slovenia, and the United States.5

Implications of Increased α-tryptase Levels—After an inciting stimulus, the active portions of α-protryptase and β-protryptase are secreted as tetramers by activated mast cells via degranulation. In vitro, β-tryptase homotetramers have been found to play a role in anaphylaxis, while α-homotetramers are nearly inactive.8,9 Recently, however, it has been discovered that α2β2 tetramers also can form and do so in a higher ratio in individuals with increased α-tryptase–encoding gene copies, such as those with HaT.8 These heterotetramers exhibit unique properties compared with the homotetramers and may stimulate epidermal growth factor–like module-containing mucinlike hormone receptor 2 and protease-activated receptor 2 (PAR2). Epidermal growth factor–like module-containing mucinlike hormone receptor 2 activation likely contributes to vibratory urticaria in patients, while activation of PAR2 may have a range of clinical effects, including worsening asthma, inflammatory bowel disease, pruritus, and the exacerbation of dermal inflammation and hyperalgesia.8,10 Thus, α- and β-tryptase tetramers can be considered mediators that may influence the severity of disorders in which mast cells are naturally prevalent and likely contribute to the phenotype of those with HaT.7 Furthermore, these characteristics have been shown to potentially increase in severity with increasing tryptase levels and with increased TPSAB1 duplications.1,2 In contrast, more than 25% of the population is deficient in α-tryptase without known deleterious effects.5

Cutaneous Manifestations of HaT

A case series reported by Lyons et al1 in 2014 detailed persistent elevated basal serum tryptase levels in 9 families with an autosomal-dominant pattern of inheritance. In this cohort, 31 of 33 (94%) affected individuals had a history of atopic dermatitis (AD), and 26 of 33 (79%) affected individuals reported symptoms consistent with mast cell degranulation, including urticaria; flushing; and/or crampy abdominal pain unprovoked or triggered by heat, exercise, vibration, stress, certain foods, or minor physical stimulation.1 A later report by Lyons et al2 in 2016 identified the TPSAB1 α-tryptase–encoding sequence copy number increase as the causative entity for HaT by examining a group of 96 patients from 35 families with frequent recurrent cutaneous flushing and pruritus, sometimes associated with urticaria and sleep disruption. Flushing and pruritus were found in 45% (33/73) of those with a TPSAB1 duplication and 80% (12/15) of those with a triplication (P=.022), suggesting a gene dose effect regarding α-tryptase encoding sequence copy number and these symptoms.2

A 2019 study further explored the clinical finding of urticaria in patients with HaT by specifically examining if vibration-induced urticaria was affected by TPSAB1 gene dosage.8 A cohort of 56 volunteers—35 healthy and 21 with HaT—underwent tryptase genotyping and cutaneous vibratory challenge. The presence of TPSAB1 was significantly correlated with induction of vibration-induced urticaria (P<.01), as the severity and prevalence of the urticarial response increased along with α- and β-tryptase gene ratios.8

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