The Spectrum of Mast Cell Activation Syndromes

2.4.1 Hereditary alpha-tryptasemia (HaT) 

Hereditary alpha-tryptasemia (HaT) is an autosomal dominant genetic trait that appears to act as a modifier of clonal and non-clonal mast cell activation disorders, clinically leading to more severe mast cell-associated symptoms. HaT results from a  germline copy number increase in the TPSAB1 gene. It is estimated that approximately 4- 6% of the general population has HaT [42-48]. Patients with HaT typically have a baseline serum tryptase level > 8ng/mL [49]. HaT is a completely penetrant trait with variable expressivity, with about a third of patients being asymptomatic [42, 50-54]. Clinical symptoms of HaT appear to be similar to that of typical MCAS patients (with pruritus, flushing, urticaria, angioedema, abdominal pain and cramping, diarrhea), but may also include gastroesophageal reflux, hypermobility, neuropsychiatric symptoms, and dysautonomia, although referral bias may alter phenotypic detection [39, 42, 50]. Patients with HaT have more pronounced allergic presentations, especially with regard to venom-associated anaphylaxis and idiopathic anaphylaxis. It has also been shown that the higher the copy number increase in the TPSAB1 gene, the more marked the symptoms [39, 42, 46]. Additionally, there is an increased frequency of HaT in patients with mastocytosis [55]. 

Treatment for HaT primarily focuses on symptom control with the use of H1 & H2 anti-histamines, anti-leukotrienes, mast cell stabilizing agents, and epinephrine for anaphylaxis [39, 42, 50]. Omalizumab has been used in these patients with variable benefit [56]. 

2.4.2 Cutaneous mastocytosis (CM) 

In cutaneous mastocytosis (CM), there is mast cell hyperplasia limited to the skin with no evidence of systemic involvement [10, 35]. Clinically, patients present with  typical skin lesions, itching, flushing, and urticaria. All forms of CM can entail systemic symptoms secondary to mast cell mediator release, with gastrointestinal symptoms (abdominal pain, diarrhea) occurring in up to 40% children [57]. CM most commonly presents in childhood, impacting males and females approximately equally, although some studies report a slight male predominance [34]. 

In order to be diagnosed with CM, a patient must meet the major criterion and one minor criteria. The major criterion for CM is the presence of typical skin lesions of mastocytosis with positive Darier’s sign. Darier’s sign is positive if, upon stroking the lesion, the skin becomes red, swollen and itchy. Minor criteria include: 1) increased number of mast cells on lesional skin biopsy, and 2) activating KIT mutation detection in  the lesional skin tissue [34]. 

There are three main CM variants: 1) maculopapular cutaneous mastocytosis  (MPCM, also called urticaria pigmentosa [UP]) 2) diffuse cutaneous mastocytosis (DCM), and 3) mastocytoma [23, 24]. MPCM is the most common form of CM (>70% [58]). MPCM can be subdivided into monomorphic (small maculopapular lesions, more typical in adults but can be seen in pediatrics) and polymorphic (macular, nodular and/or plaque-like variably shaped lesions, predominant type in pediatrics) [34, 59]. Typical MPCM skin lesions are small (< 2cm) diffusely scattered reddish-brown macules, usually in highest frequency on the trunk and extremities. As with all forms of CM, the lesions will have a positive Darier’s sign [34, 35, 59, 60]. MPCM is typically noted in early childhood (< 2 years, sometimes in infancy) and lesions usually self-resolve by puberty [34, 59, 61]. If the lesions appear and/or increase in frequency in adulthood, further evaluation should be undertaken as this could be suggestive of systemic involvement [34,  59]. Telangiectasia macularis eruptive perstans (TMEP) is a controversial classification, with its use being discontinued in the 2016 consensus report; it was previously thought of  as a rare subvariant of MPCM that was often adult-onset with a more prominent flat and  telangiectatic vascular component [62-64]. Prognosis of MPCM is favorable, with the  majority of childhood-onset MPCM resolving over 15 years [65].  

DCM is very rare (1-5% of all CM cases), and patients tend to be more symptomatic [57, 58]. The patient's skin is often hyperpigmented with erythematous lesions and lichenified with a leathery feel due to mast cell infiltration [21]. Patients often have numerous skin lesions, which may develop bullae, blisters, and/or crusting. Blistering often improves over 3-4 years, and lesions usually improve by adolescence [34]. As the name implies, DCM affects the skin throughout the body, with the trunk and scalp typically affected more severely [24, 34, 57, 66].  

Mastocytomas are benign aggregates of mast cells localized in the skin, larger in size than MPCM lesions, with nodular or bullous characteristics and positive Darier’s sign [10, 24, 35]. These lesions usually onset in early childhood, sometimes present at  birth, and are extremely rare in adults [34, 57]. Many patients have solitary lesions, although some may have > 1 lesion; it has been proposed that ≤ 3 lesions should be classified as mastocytoma and ≥ 4 as MPCM [67, 68]. Serum tryptase in these patients is usually normal. The prognosis of mastocytoma is excellent, with the majority of pediatric  patients having complete resolution by adolescence or adulthood [57].  

CM prognosis is associated with onset of skin lesions. Lesions that present in early childhood (< 2 years of age) have a more favorable prognosis, often with improvement, if not complete resolution, before puberty [10, 34, 59, 69]; conversely, CM that appears in adulthood is often associated with SM [34]. Childhood-onset polymorphic MPCM may have a higher rate of resolution versus childhood-onset monomorphic MPCM [34]. Overall, the prognosis of CM is more favorable than SM [10, 34, 61, 69].  KIT mutations also differ amongst adults compared to pediatric patients with CM, with  > 80% of adults, but only 35% of pediatric, patients having D816V mutation; 40% of  pediatric patients have other mutations and 25% have no detectable mutation [57, 58, 70].  For diagnosis, caution needs to be exerted regarding eliciting Darier’s sign, as it may provoke a systemic reaction, including hypotension [34]. Some patients may show prolonged bleeding secondary to heparin release, especially in DCM [34]. In pediatrics, a thorough exam, serum tryptase, CBC with differential and CMP should be performed [57]. A skin biopsy for H&E, Giemsa, tryptase and KIT immunostaining can be  performed if there are questions regarding the diagnosis or consideration for other skin  diseases [57]. Bone marrow biopsy is not routinely indicated, but should be considered if  tryptase is very high and/or severe systemic symptoms, poor medication response or  organomegaly are present [57]. Skin lesion severity does not appear to be correlated with  systemic involvement, and the extent of skin involvement does not appear to correlate  with tryptase level [34, 57].  

Treatment of CM is primarily symptomatic, with avoiding triggers and utilizing non-sedating H1 anti-histamines preferred. Addition of sedating anti-histamines, H2  antagonists, leukotriene receptor antagonists, topical steroids PUVA, omalizumab, topical  calcineurin inhibitors, and oral cromolyn can be considered depending on symptoms [57,  71]. Rarely, surgery can be used for mastocytoma if there are significant symptoms despite pharmacotherapy [72]. 

2.4.3 Localized mast cell tumors 

The only two localized mast cell tumors that have been reported in the literature are mastocytomas and mast cell sarcomas. Mast cell sarcomas are a rare, malignant localized solid tumor that results from rapidly expanding immature mast cells that can invade any organ system. Mast cell sarcomas can occur at any age. Mast cell sarcomas are aggressive and prognosis is poor, as there is a high rate of progression to MCL [10,  13, 23, 24]. Individuals do not meet SM criteria, and mast cell activation symptoms are less common (< 20%) and KIT D816V mutations are found in a minority of patients [21].