Cutaneous Manifestations in Hereditary Alpha Tryptasemia
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.
There is substantial overlap in the clinical pictures of HaT and MCAS, and HaT is considered a heritable risk factor for MCAS. Consequently, any patient undergoing workup for MCAS also should be tested for HaT. Although HaT is associated with consistently elevated tryptase, MCAS is episodic in nature, and an increase in tryptase levels of at least 20% plus 2 ng/mL from baseline only in the presence of other symptoms reflective of mast cell activation (Table) is a prerequisite for diagnosis.9 Chronic signs and symptoms of atopy, chronic urticaria, and severe asthma are not indicative of MCAS but are frequently seen in HaT.
Another cause of persistently elevated tryptase levels is SM. Systemic mastocytosis is defined by aberrant clonal mast cell expansion and systemic involvement11 and can cause persistent symptoms, unlike MCAS alone. However, SM also can be associated with MCAS.9 Notably, a baseline serum tryptase level greater than 20 ng/mL—much higher than the threshold of greater than 8 ng/mL for suspicion of HaT—is seen in 75% of SM cases and is part of the minor diagnostic criteria for the disease.9,11 However, the 2016 study identifying increased TPSAB1 α-tryptase–encoding sequences as the causative entity for HaT by Lyons et al2 found the average (SD) basal serum tryptase level in individuals with α-tryptase–encoding sequence duplications to be 15 (5) ng/mL and 24 (6) ng/mL in those with triplications. Thus, there likely is no threshold for elevated baseline tryptase levels that would indicate SM over HaT as a more likely diagnosis. However, SM will present with new persistently elevated tryptase levels, whereas the elevation in HaT is believed to be lifelong.5 Also in contrast to HaT, SM can present with liver, spleen, and lymph node involvement; bone sclerosis; and cytopenia.11,14
Mastocytosis is much rarer than HaT, with an estimated prevalence of 9 cases per 100,000 individuals in the United States.11 Although HaT diagnostic testing is noninvasive, SM requires a bone marrow biopsy for definitive diagnosis. Given the likely much higher prevalence of HaT than SM and the patient burden of a bone marrow biopsy, HaT should be considered before proceeding with a bone marrow biopsy to evaluate for SM when a patient presents with persistent systemic symptoms of mast cell activation and elevated baseline tryptase levels. Furthermore, it also would be prudent to test for HaT in patients with known SM, as a cohort study by Lyons et al5 indicated that HaT is likely more common in those with SM (12.2% [10/82] of cohort with known SM vs 5.3% of 398 controls), and patients with concurrent SM and HaT were at a higher risk for severe anaphylaxis (RR=9.5; P=.007).
Studies thus far surrounding HaT have not evaluated timing of initial symptom onset or age of initial presentation for HaT. Furthermore, there is no guarantee that those with increased TPSAB1 copy number will be symptomatic, as there have been reports of asymptomatic individuals with HaT who had basal serum levels greater than 8 ng/mL.7 As research into HaT continues and larger cohorts are evaluated, questions surrounding timing of symptom onset and various factors that may make someone more likely to display a particular phenotype will be answered.
Treatment—Long-term prognosis for individuals with HaT is largely unknown. Unfortunately, there are limited data to support a single effective treatment strategy for managing HaT, and treatment has varied based on predominant symptoms. For cutaneous and GI tract symptoms, trials of maximal H1 and H2 antihistamines twice daily have been recommended.4 Omalizumab was reported to improve chronic urticaria in 3 of 3 patients, showing potential promise as a treatment.4 Mast cell stabilizers, such as oral cromolyn, have been used for severe GI symptoms, while some patients also have reported improvement with oral ketotifen.6 Other medications, such as tricyclic antidepressants, clemastine fumarate, and gabapentin, have been beneficial anecdotally.6 Given the lack of harmful effects seen in individuals who are α-tryptase deficient, α-tryptase inhibition is an intriguing target for future therapies.
Conclusion
Patients who present with a constellation of dermatologic, allergic, GI tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities consistent with HaT may receive a prompt diagnosis if the association is recognized. The full relationship between HaT and other chronic dermatologic disorders is still unknown. Ultimately, heightened interest and research into HaT will lead to more treatment options available for affected patients.
