Unusual Urticaria Pigmentosa in an Asian Man With Indolent Systemic Mastocytosis: A Case Report

Chamard Wongsa Mahidol University Faculty of Medicine Siriraj Hospital https://orcid.org/0000-0002-5721-4881 Mongkhon Sompornrattanaphan Mahidol University Faculty of Medicine Siriraj Hospital Torpong Thongngarm Mahidol University Faculty of Medicine Siriraj Hospital Weerapat Owattanapanich Mahidol University Faculty of Medicine Siriraj Hospital Panitta Sitthinamsuwan Mahidol University Faculty of Medicine Siriraj Hospital Sanya Sukpanichnant Mahidol University Faculty of Medicine Siriraj Hospital Thanisorn Sukakul (  kimthanisornsu@gmail.com ) Faculty of Medicine Siriraj Hospital, Mahidol University https://orcid.org/0000-0002-5351-2988

maculopapular cutaneous mastocytosis. His clinical ndings and an elevated baseline tryptase level triggered a thorough systemic mastocytosis investigation. The skin and bone marrow were in ltrated by abnormal, spindle-shaped mast cells, and KIT and TET2 mutations were in the patient's serum. The honeybee anaphylaxis mechanism in this patient was IgE mediated, supported by a positive result of speci c IgE to honeybee. The nal diagnosis was indolent systemic mastocytosis with IgE-mediated honeybee anaphylaxis. As venom immunotherapy is unavailable in Thailand, we prescribed treatment with a regular, oral, nonsedating H 1 -antihistamine and an epinephrine self-injector. At the 2-year follow-up, the patient had not progressed to advanced systemic mastocytosis nor experienced any anaphylactic episodes.
Conclusion: Urticaria pigmentosa is a small, round, brown, or red maculopapular lesion. In the Asian population with dark brown skin color, physician should be exclusively careful examination, particularly in a hidden area and in anaphylaxis cases. Early recognition of urticaria pigmentosa in the adult patient might reduce the delay in diagnosis of indolent systemic mastocytosis.

Background
Mastocytosis is a rare, mast-cell, clonal disorder classi ed as cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma under the 2017 World Health Organization classi cation of tumors of hematopoietic and lymphoid tissues. 1 In adult patients, SM is the most common, particularly the subvariant indolent SM (ISM). 2 The prevalence of ISM in Denmark and the Netherlands is 9.6-13 per 100,000 people. 2 As epidemiological and clinical cohort studies of ISM were mainly conducted on Caucasians, Asian ISM information is scarce. We present the rst case report of adult ISM in Thailand who had unusual urticaria pigmentosa, with a 23-year lag time to diagnosis.
Case Presentation anaphylaxis during a 23-year period. About 30 minutes after each honeybee sting, he felt itching at the palms before suddenly losing consciousness. On each occasion, the emergency medical staff attending to him reported that he had pronounced hypotension. For the most recent incident, initial treatment with epinephrine and hemodynamic resuscitation was provided at a primary-care hospital. He improved, and the symptoms completely resolved within a few days. He was referred to Siriraj Hospital, a tertiary-care hospital in Thailand, for further management. A physical examination was unremarkable except for multiple, discrete, ill-de ned, light-brown macules on the chest and abdomen (Figure 1). Darier's sign was negative. Erythematous linear patches without edematous wheals were demonstrated when the lesions were stroked. The patient had never perceived the rash on his chest and abdomen before visiting the clinic. He denied a history of itching, ushing, abdominal discomfort, bronchospasm, fever, fatigue, and weight loss. Interestingly, he had a sister with recurrent re ant anaphylaxis.
Skin and bone marrow biopsies con rmed a diagnosis of SM. Although the bone marrow biopsy found spindle-shaped mast cells aggregated at more than 15 cells/high power eld ( Figure 2), they were sparsely demonstrated in the skin biopsy ( Figure 3). Blood for 25-targeted gene sequencing by a nextgeneration sequencing method (QIAseq; QIAGEN, Hilden, Germany) was positive for KIT mutation (gain of function, c.2247A>T p.D816V) and TET2 mutation (normal function, c.2440C>T p.R814C). The baseline serum tryptase was persistently high (22.4-22.6 microgram/liter; normal range < 11.4 micrograms/liter).
The patient was reasonably diagnosed with ISM with skin involvement, as per the 2017 World Health Organization classi cation of tumors of hematopoietic and lymphoid tissues.
Blood for speci c IgE (sIgE) was obtained to con rm the cause of anaphylaxis. sIgE to honeybee and Api m1 (Phadia ImmunoCAP) were 0.33 kUA/L and 0.16 kUA/L, respectively. The total IgE was undetectable (the lower normal limit was < 4.23 IU/ml). Although sIgE was low relative to the undetectable total IgE, it was still high. Because of the strong relevant history of severe anaphylaxis after honeybee exposure, and using 0.1 kUA/L as the cutoff level for positive sIgE, we diagnosed this patient as having IgE-mediated honeybee anaphylaxis.
The standard treatment for ISM with IgE-mediated honeybee anaphylaxis is lifelong venom immunotherapy. Unfortunately, the insect venom extracts are unavailable in Thailand. We prescribed regular, oral, nonsedating H 1 -antihistamine and an epinephrine self-injector, and prepared an anaphylaxis action plan for the patient. At the 2-year follow-up, he had not progressed to advanced SM, nor experienced any anaphylactic episodes.

Discussion
Most mastocytosis patients have skin lesions. Urticaria pigmentosa, or maculopapular cutaneous mastocytosis (MPCM), has monomorphic and polymorphic variants, depending on the size, shape, and color of the lesions. 3 Monomorphic MPCM, most commonly seen in adult patients, is associated with ISM. 3 Our patient had small, brownish macules on his chest and abdomen, which is compatible with monomorphic MPCM. The degree of skin involvement was minimal. The rash extension and density of monomorphic MPCM positively correlate with bone marrow severity, pruritus, and ushing, but not anaphylaxis. 2,4 Anaphylaxis is more common in ISM without skin involvement (59%) than in ISM with skin involvement (20%). 5 Darier's sign has a positive rate of 67% in ISM patients. 6 Hyperpigmentation is sometimes di cult to discern, especially with the dark brown skin of Southeast Asians; hence, ISM might be underreported in the Asian population. There is no clear evidence that ethnic differences affect the degree and morphology of the rash in mastocytosis. An investigation of MPCM in various ethnicities found it was di cult to identify in Asians, unlike the other races studied. 7 With our patient, the probable reasons for the delayed diagnosis were he had never noticed the lesions and his past physicians had not thoroughly examined his unexposed skin.
There is a rm linkage between anaphylaxis and mastocytosis. If patients present with one of these conditions, the other should be carefully investigated. Among adults with mastocytosis, 49% were found to have experienced anaphylactic episodes. 8 In a study of patients with anaphylaxis, 7.7% were diagnosed with mastocytosis. 9 Moreover, the prevalence of mastocytosis in patients presenting with insect sting anaphylaxis (ISA) has been reported to range from 1-7.9%. 10 The unique features of anaphylaxis in SM are male gender; triggered by an insect sting; anaphylaxis with the absence of cutaneous symptoms; and predominately cardiovascular symptoms. 2 Although the patient in the current case had the classic clinical manifestations, the time between onset and diagnosis was 23 years. In contrast, the mean time lag to diagnosis for a Dutch cohort was 8 years. 5 In the case of the patient described in the present study, the delay in diagnosis might have arisen from a limited awareness of primary care physicians, a lack of specialized laboratories, and a lack of consultation. The Spanish Network on Mastocytosis (REMA) developed the REMA score for mastocytosis, a clinical tool to predict mast cell clonal abnormality in bone marrow or SM. 11 It draws upon 3 simple parameters (sex, clinical symptoms, and baseline serum tryptase) and has a sensitivity of 87% and speci city of 73%. 11 Our patient scored 2 points, indicating a high probability of SM. 11 There is no clear evidence that some mastocytosis patients have a low or undetectable total IgE and speci c IgE. 12,13 This might be due to the binding of IgE to excessive mast cells, resulting in lower free IgE in the serum. 12 The mechanism of ISA in mastocytosis is IgE and non-IgE mediated. 12 It is crucial to identify the mechanism because patients diagnosed with IgE-mediated ISA need lifelong venom immunotherapy. The cutoff value for positive sIgE has ranged from 0.1 to 0.35 kUA/L. Michel et al. demonstrated that 8.2% of patients with mastocytosis or elevated baseline serum tryptase with a strong history of ISA would be misdiagnosed if a value of 0.35 kUA/L were used. 13 Therefore, an sIgE value > 0.1 kUA/L has been proposed as the appropriate cutoff for mastocytosis patients with ISA. 13 We used 0.1 kUA/L as the cutoff for our patient.
The KIT-D816V mutation, found in 70% of adult SM patients, 14 causes an increase in mast cell proliferation and survival. Apart from the KIT-D816V mutation, the TET2 mutation was found in our patient. The clinical manifestations associated with a TET2 mutation are female, monocytosis, and nonindolent SM. 15 However, this mutation has been found in only 15% of ISM patients. 15 ISM has the most favorable outcome among the SM variants. The overall survival ranges from 25.1 to 28.4 years. 6,14 The chance of progression to advanced SM has been reported as 2.9%. 6 As well, the ISM predictors affecting event-free survival are an older age, male sex, low-performance status, and lymphadenopathy. 6 In our case, the patient's disease remained indolent throughout the 2-year follow-up.

Conclusion
The current case highlights the importance of skin examinations and extensive workups for patients with clinical anaphylaxis. Treating physicians should carefully examine unexposed skin to check whether the patients have overlooked mastocytosis. To provide the best patient care, a multidisciplinary care team approach is required for the management of mastocytosis. Ethic approval and consent to participate: An informed consent was obtained from the patient to use his data.

List Of Abbreviations
Consent for publication: Consent for publication was obtained from the patient.
Availability of data and materials: The data analyzed for the current case are not publicly available due the patient's privacy. Data are available from the corresponding author upon reasonable request.
Competing interests: The author declare that they have no competing interests.