Hereditary Alpha Tryptasemia

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Hereditary Alpha Tryptasemia

10 Interesting Facts

HαT (hereditary α-tryptasemia) is a common genetic trait characterized by extra-allelic copies of the α-tryptase gene at the TPSAB1 locus²
Approximately 5% to 7% of humans in the United States, United Kingdom, and European Union have HαT⁹
Most patients with HαT are asymptomatic
Patients with history of anaphylaxis, especially to Hymenoptera venom, and/or SM (systemic mastocytosis) require further evaluation for HαT
Baseline (asymptomatic) level of tryptase greater than 8 ng/mL suggests HαT
Gold standard for diagnosing HαT is tryptase genotyping
Treatment for HαT is targeted at specific symptoms (eg, antihistamines for pruritus)
Retrospective studies indicate the promising use of omalizumab in treating symptomatic HαT refractory to antihistamines
Patients with HαT are at high risk for Hymenoptera venom anaphylaxis and should be evaluated for VIT (venom immunotherapy)
HαT is only recently described and a large body of ongoing research is needed to better understand clinical phenotypes and associated conditions

Alarm Signs and Symptoms

Anaphylaxis to Hymenoptera venom requires immediate referral to a specialist for further evaluation and consideration of VIT

Basic Information

Terminology

HαT (hereditary α-tryptasemia) is an autosomal dominant genetic trait defined by elevated baseline serum tryptase and extra-allelic copies of the α-tryptase gene¹
α-Tryptase is encoded by the TPSAB1 gene located on the short arm of chromosome 16 (Figure 1)²

Background Information

Figure 1. Human tryptase genes located on chromosome 16p13.3. – Top: wild-type tryptase genes. Bottom: HαT. HαT, hereditary α-tryptasemia.From Lyons JJ. Hereditary alpha tryptasemia: genotyping and associated clinical features. Immunol Allergy Clin North Am. 2018;38(3):483-495, Figure 2.

Tryptase is a serine protease expressed principally in mast cells³
Secretion of tryptase is constitutive with an acute increase during mast cell activation⁴
- Baseline tryptase is measured in an asymptomatic patient
- Acute tryptase is measured within 30 minutes to 4 hours of acute symptoms such as anaphylaxis
HαT is defined in the laboratory as an elevated baseline serum tryptase
HαT is the most common cause of elevated baseline serum tryptase in Western populations⁵
The laboratory-defined “normal” is baseline serum tryptase less than 11.5 ng/mL
- However, multiple studies have described patients with HαT whose tryptase levels were less than 11.5 ng/mL⁶
- Consider HαT in any patient with a tryptase greater than 8 ng/mL
HαT is a genetic trait (not a disease)
- Most patients with HαT are asymptomatic
- HαTs (hereditary α-tryptasemia syndrome) is the term used to describe symptomatic patients
  - Many symptomatic patients may also meet criteria for a mast cell activation disorder
Data do not support an association with HαT in the following conditions:
- Ehlers-Danlos syndrome⁷
- POTS (postural orthostatic tachycardia syndrome)⁸

Epidemiology

HαT has an estimated prevalence of 5% to 7% in the United States, United Kingdom, and European Union⁹¹⁰¹¹
No study has comprehensively investigated the prevalence of HαT in non-White populations

Etiology and Risk Factors

Etiology

HαT is an autosomal dominant genetic trait
Extra-allelic copies of α-tryptase are inherited in the typical Mendelian pattern and display linkage disequilibrium¹²¹³
Multiple copies of α-tryptase may be inherited (duplication, triplication) and serum tryptase range can be estimated based on the copy number variant⁵⁶

Risk Factors

The primary risk factor is an affected biologic parent, which conveys a 50% risk of heritability (assuming α duplication on 1 allele)
There are no known modifiable risk factors that affect the heritability of HαT
There is no association between connective tissue disorders and HαT¹⁴

Diagnosis

Approach to Diagnosis

Diagnosis can be challenging as there is not a defined clinical phenotype
- Presentation can be highly variable
- Additionally, clinical findings are not correlated to numeric laboratory values
Most patients with HαT are asymptomatic¹⁰
The following clinical presentations, either in isolation or in combination, may raise suspicion for HαT:
- Grade III to IV Hymenoptera venom anaphylaxis¹⁵
- Vibratory (or other) urticaria⁷
- SM (systemic mastocytosis)¹¹
- Mast cell activation syndrome
In patients in which HαT is suspected, screen with baseline serum tryptase levels
Elevated serum tryptase requires further confirmation with tryptase genotyping

Workup

History

HαT is diagnosed almost exclusively in White populations of European descent
- α-Tryptase and β-tryptase expression differ based on ethnicity¹⁶¹⁷
While there are no diagnostic features in clinical history, several scenarios may suggest HαT
- History of anaphylaxis
  - Moderate severity (eg, Grade III or IV)¹⁸
    - Mild cardiovascular, neurologic, or respiratory symptoms (eg, dizziness, weakness, confusion, chest tightness, dyspnea)
    - Moderate cardiovascular, neurologic, or respiratory symptoms or severe angioedema (eg, syncope, Glascow Coma Scale 13 or 14, cough or increased work of breathing)
  - Especially to Hymenoptera species
- History of idiopathic anaphylaxis
  - Systemic allergic response without identifiable cause
- History of SM
  - Association of SM and HαT
  - 12% to 18%, more than expected¹⁰¹¹
  - Reason for the association is unknown
  - Constellation of symptoms may include urticaria, flushing, bloating, diarrhea, tachycardia, anaphylaxis
  - Approximately 80% have cutaneous lesions, termed maculopapular cutaneous mastocytosis
- History of vibratory urticaria
  - Urticaria evident within minutes of exposure to vibration
- Repeated episodes of flushing, vertigo, tachycardia, and urticaria/angioedema that do not meet formal definition of anaphylaxis

Physical Examination

Given the wide phenotypic spectrum, there are no physical findings that are specific and/or diagnostic for HαT
Hepatosplenomegaly
- Can be a chronic finding in patients with SM
- Can be suggestive of HαT as there is clinical overlap with SM

Laboratory Tests

Serum tryptase
- Indicated in the setting of anaphylaxis or other allergic manifestations such as chronic urticaria and/or angioedema, especially without an etiology
- Elevated baseline (asymptomatic) level greater than 8 ng/mL is suggestive of HαT
- Screening for HαT must be obtained when asymptomatic
- Markedly elevated baseline tryptase greater than 20 ng/mL
  - Suggestive of SM
  - Minor criteria for diagnosis of SM¹⁹
- Variable levels of baseline tryptase elevation is common
Comprehensive metabolic panel
- Elevated BUN and creatinine can suggest renal failure, which can result in elevations of tryptase
- Elevated liver enzymes may suggest liver dysfunction, which can also result in elevated levels of tryptase
CBC with differential and peripheral blood smear
- Markedly low or markedly high cell counts or dysplastic appearance of cells may suggest myeloproliferative or myelodysplastic syndromes
Genetic testing
- Tryptase genotyping is gold standard for diagnosis¹
  - Tryptase genotyping is conducted via PCR (polymerase chain reaction) amplification of α-tryptase and β-tryptase
  - Genotype is computationally determined using PCR data
  - Gene by Gene is the only CLIA-certified (Clinical Laboratory Improvement Amendments) laboratory currently offering tryptase genotyping
- KIT D816V is diagnostic for clonal mast cell disorders
  - Rule out the presence of clonal mast cell disorder
  - Can be screened with blood sample using a high-sensitivity PCR-based assay
  - Definitive diagnosis with bone marrow sample

Diagnostic Procedures

Bone marrow biopsy
- Gold standard to determine the presence of a clonal mast cell disorder²⁰
- Indications include:
  - Clinical suspicion for a clonal mast cell disorder
  - Cutaneous mastocytosis on physical examination
  - CBC abnormalities indicating a myelodysplastic disorder
  - History of severe anaphylaxis particularly with hypotensive syncope
- HαT is associated with bone marrow abnormalities²¹
  - Mast cells may display small clusters and spindle-shaped nuclei
- Both HαT and SM may exist simultaneously
  - If HαT is suspected (in the setting of a normal bone marrow), the definitive test is tryptase genotyping (described above)
- Bone marrow biopsy should be considered in the following situations:
  - Severe anaphylaxis, particularly with hypotensive syncope²²
  - Anaphylaxis with absence of urticaria and angioedema²³
  - Tryptase greater than 25 ng/mL²²
  - Abnormalities on blood count or smear that suggest myeloproliferative or myelodysplastic disorders

Differential Diagnosis

Table

Table 1. Differential Diagnosis: HαT.

Condition	Description	Differentiated by
SM	Clonal myeloproliferative disorder characterized by activating mutation in the KIT gene (eg, KIT D816V)	Abnormal phenotype and appearance of mast cells in the bone marrow Presence of KIT D816V in serum or bone marrow SM and HαT may co-occur
Idiopathic mast cell activation syndrome²⁴	Recurrent episodes of flushing, urticaria, angioedema, asthma-like symptoms, and anaphylaxis controlled with antihistamines or mast cell stabilizers	Negative for KIT D816V Normal baseline tryptase Meet criteria for mast cell activation syndrome²⁰
Anaphylaxis	Episodic systemic hypersensitivity reaction	Anaphylaxis is an acute process characterized by elevated acute tryptase Baseline serum tryptase will be normal
Chronic spontaneous urticaria	Urticaria and/or angioedema	Symptoms are isolated to the skin Baseline serum tryptase is normal
Myeloproliferative and myelodysplastic disorders	Broad category of disorders involving abnormal myelopoiesis	CBCs show evidence of myeloproliferation or cytopenias Bone marrow biopsy with dysplasia of affected cell lineage
CKD	Disorder involving decreased kidney function as measured by serum creatinine	Patients with CKD have increased tryptase in the serum Tryptase genotyping and bone marrow biopsy are both normal

Caption: CKD, chronic kidney disease; HαT, hereditary α-tryptasemia; SM, systemic mastocytosis.

Treatment

Approach to Treatment

There is no therapy specific to HαT
In general, in acutely symptomatic patients, therapy is directed at the underlying symptoms (eg, urticaria, anaphylaxis)
At present, therapies used for clonal mast cell disorders are utilized for patients with symptomatic HαT
No prospective studies have assessed the efficacy of any therapy in HαT

Nondrug and Supportive Measures

Given the progressive nature of anaphylaxis, patients presenting with acute symptoms require frequent clinical assessments
Remain vigilant in ensuring patent airway. Anticipate impending airway obstruction requiring intubation
Patients with tachycardia or hypotension require fluid resuscitation

Drug Therapy

Drug therapy should only be considered for symptomatic patients
H₁-antihistamines
- One retrospective study suggests improvement in cutaneous symptoms such as pruritus with second-generation oral antihistamines⁶
- First-generation antihistamines such as diphenhydramine have been associated with cognitive adverse effects and should generally be avoided²⁵
Omalizumab
- Omalizumab has been shown to improve symptoms in patients with SM²⁶²⁷
- Retrospective data indicate a reduction in cutaneous symptoms as well as anaphylaxis in HαT²⁸²⁹
- No prospective or randomized trials have studied dosage and/or efficacy of omalizumab in HαT, thus used off-label
- In practice, most patients are treated with omalizumab 300 mg subcutaneously every 28 days²⁹
Epinephrine prefilled syringes or autoinjectors
- Prescribe in patients with an indication for epinephrine such as patients with food allergy or history of anaphylaxis
- Adult dosing is 0.3 mg intramuscularly³⁰

Treatment Procedures

Patients with Hymenoptera anaphylaxis should receive VIT (venom immunotherapy) (see below)

Special Considerations

Hymenoptera Anaphylaxis

HαT increases risk for severe anaphylaxis to Hymenoptera venom¹⁵³¹
Fatalities despite completion of VIT have been reported in clonal mast cell disorders such as mastocytosis³²
Thus, patients with Hymenoptera venom anaphylaxis are at high risk for poor outcomes if not treated
All patients with Hymenoptera anaphylaxis require further evaluation
- Consider referral to an allergy and immunology specialist for venom sensitivity testing
- Screen for mast cell disorders with a baseline serum tryptase
- If baseline tryptase is elevated, consider additional evaluation
  - Tryptase genotyping to rule out HαT
  - Consider bone marrow biopsy if patient has severe anaphylaxis, particularly including hypotensive syncope following sting
VIT is strongly recommended for all patients with HαT and venom anaphylaxis
- VIT exposes patients to progressively increasing doses of venom to achieve desensitization
VIT may be administered via standard protocols³³
Lifelong VIT should be considered for all patients with HαT given the possibility of poor outcomes following a sting

Ongoing Research

Because HαT is a more recently described entity, ongoing research is investigating clinical phenotypes and potentially associated conditions
HαT has been associated with modification of allergic inflammation and anaphylaxis
Several other disease associations have been suggested but are not confirmed by primary data
- IBS (irritable bowel syndrome)
  - Initial study described a nonsignificant association with IBS¹
  - The results were not reproduced in a larger study³⁴
  - Immunologic abnormalities including pyroptosis (cell death mediated by inflammatory pathways) and gastrointestinal-associated autoantibodies were noted³⁴
- Arthralgia and connective tissue disorders
  - Arthralgia was associated with HαT in early studies although the association was not statistically significant
  - Ehler-Danlos syndrome does not appear to have an association with HαT¹⁴
- Small fiber neuropathy
  - One small study suggests an increase in small fiber neuropathy and decreased cerebral blood flow in patients with HαT
Penetrance and clinical symptoms
- It is generally accepted that most individuals with HαT are asymptomatic¹⁰
  - No large-scale, population-level studies have confirmed this hypothesis
- Given the frequency of HαT in the general population, association studies are difficult as they require large numbers of individuals to determine a specific clinical phenotype
- The likelihood that asymptomatic individuals will become symptomatic is unclear

Follow-Up

Monitoring

Periodic assessment of serum tryptase is not necessary
As management is largely symptomatic, patient follow-up is dependent on specific manifestations. Routine monitoring should focus on the specific disease (eg, chronic spontaneous urticaria)

Referral

Refer patients with elevated tryptase and symptoms consistent with mast cell activation (eg, anaphylaxis, urticaria) to an immunologist for further evaluation and diagnosis

Screening and Prevention

Screening

Screening of the general population and/or asymptomatic individuals is not recommended¹⁰
- Most patients with HαT are asymptomatic and identification of this genetic trait would not change management
Screen all patients with a history of anaphylaxis with a baseline serum tryptase

Author Affiliations

Matthew Giannetti, MD
Assistant Professor of Medicine
Department of Internal Medicine
Division of Allergy and Clinical Immunology
Brigham and Women’s Hospital, Harvard Medical School

References

1.Lyons JJ et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016;48(12):1564-1569.

Hereditary Alpha Tryptasemia

10 Interesting Facts

Alarm Signs and Symptoms

Basic Information

Terminology

Background Information

Epidemiology

Etiology and Risk Factors

Etiology

Risk Factors

Diagnosis

Approach to Diagnosis

Workup

History

Physical Examination

Laboratory Tests

Diagnostic Procedures

Differential Diagnosis

Treatment

Approach to Treatment

Nondrug and Supportive Measures

Drug Therapy

Treatment Procedures

Special Considerations

Hymenoptera Anaphylaxis

Ongoing Research

Follow-Up

Monitoring

Referral

Screening and Prevention

Screening

Author Affiliations

References

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