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Aggressive Systemic Mastocytosis

Aggressive systemic mastocytosis (ASM) is a rare form of systemic mastocytosis. Affected individuals may present with symptoms due to organopathies caused by mast cell infiltration, bone marrow failure and subsequent cytopenias, and symptoms of mast cell activation - clinical presentations are heterogeneous. Diagnosis of ASM relies on diagnostic criteria as published by the World Health Organization and require bone marrow biopsies and aspirations. Curative treatment is not available. Patients are treated with tyrosine kinase inhibitors, cytoreductive chemotherapeutics, and stem cell transplantation, but response rates vary largely and mean survival times don't exceed seven years.


Presentation

ASM patients may present with symptoms resulting from enhanced mast cell activation and release of mediators like histamine or with organopathies due to mast cell infiltration [1].

With regards to organopathies, almost any organ can be affected. Bone marrow, skeleton, liver, spleen, and gastrointestinal tract are most frequently involved. In fact, bone marrow failure is associated with cytopenias and patients suffering from anemia, leukopenia, or thrombocytopenia may present with pallor, weakness, and fatigue, increased susceptibility to infectious diseases, or hemorrhagic diathesis. While osteolytic lesions may not be recognizable unless diagnostic imaging is applied, they predispose for pathological fractures, whereby vertebral fractures are most frequently reported [2] [3]. Hepatic and splenic mast cell infiltration cause palpable hepatomegaly and splenomegaly and may ensue loss of appetite, aszites, and portal hypertension as well as hypersplenism. However, loss of appetite due to hepatomegaly is not the only condition that causes ASM patients to lose weight: Mast cells also infiltrate the intestinal walls, which causes malabsorption. ASM patients may present with maculopapular skin lesions [1], although skin changes are not characteristic of this form of mastocytosis [4].

As has been mentioned above, excessive mast cell activation may be associated with considerable histamine release. Histamine exerts its effects on a wide variety of target structures and increased histamine levels may provoke flushing, skin itching, nausea, vomiting, diarrhea, and anaphylaxis.

The disease may follow a slowly progressive or rapid course. Patients with rapidly progressive ASM are considered at particularly high risks of transformation to systemic mastocytosis with associated clonal hematological non–mast cell-lineage disease and mast cell leukemia [1].

Splenomegaly
  • Abstract A 43 year-old woman presented with fever, abdominal pain, epato-splenomegaly, ascites, cholestasis, anemia, thrombocytopenia and previous diagnosis of sclerosing cholangitis based on liver biopsy and endoscopic retrograde cholangiopancreatography[ncbi.nlm.nih.gov]
  • Retro-orbital injections of P815 NT cells in syngeneic DBA/2 mice resulted in rapid development of aggressive SM within 13-16 days characterized by splenomegaly, extramedullary hematopoiesis, and multifocal liver tumors.[ncbi.nlm.nih.gov]
  • Hepatic and splenic mast cell infiltration cause palpable hepatomegaly and splenomegaly and may ensue loss of appetite, aszites, and portal hypertension as well as hypersplenism.[symptoma.com]
Pain
  • Abstract A 43 year-old woman presented with fever, abdominal pain, epato-splenomegaly, ascites, cholestasis, anemia, thrombocytopenia and previous diagnosis of sclerosing cholangitis based on liver biopsy and endoscopic retrograde cholangiopancreatography[ncbi.nlm.nih.gov]
  • Patients present with severe symptoms related to mast cell invasion and the intense release of mediators including syncope, recurrent flushing, diarrhea, pain, organomegaly and organ dysfunction, impairment of hematopoietic function (which may result[orpha.net]
  • […] of mast cells (a type of white blood cell) occurs in one or more organs, including the GI tract, spleen, lymph nodes and bone marrow. 1 Mast cells release substances, such as histamine, which can lead to symptoms including itching, fever, abdominal pain[novartisoncology.com]
  • Degenerated mast cells interfere with organ function and therefore, ASM patients may develop bone marrow failure with subsequent anemia, susceptibility to infections, and bleeding diathesis, bone pain and pathological fractures, and dysfunction of liver[symptoma.com]
  • Abstract Ultrasonography (US) is often the first imaging study performed in patient with abdominal pain or vague symptoms related to the gastrointestinal tract.[ncbi.nlm.nih.gov]
Anemia
  • A rapidly progressive anemia and thrombocytopenia dictated a splenectomy.[ncbi.nlm.nih.gov]
  • Abstract A 43 year-old woman presented with fever, abdominal pain, epato-splenomegaly, ascites, cholestasis, anemia, thrombocytopenia and previous diagnosis of sclerosing cholangitis based on liver biopsy and endoscopic retrograde cholangiopancreatography[ncbi.nlm.nih.gov]
  • In fact, bone marrow failure is associated with cytopenias and patients suffering from anemia, leukopenia, or thrombocytopenia may present with pallor, weakness, and fatigue, increased susceptibility to infectious diseases, or hemorrhagic diathesis.[symptoma.com]
  • […] caused in many people by a KIT mutation. 3 KIT D816V is the most common mutation in SM, occurring in about 90% of patients. 4 In advanced SM, mast cells collect in such high quantities that they lead to organ damage and dysfunction, bone fractures and anemia[novartisoncology.com]
Weight Loss
  • The latter usually leads to significant weight loss. Because mast cells release histamine, ASM is also associated with histamine-mediated symptoms like flushing, skin itching, nausea, vomiting, diarrhea, and anaphylaxis.[symptoma.com]
Fatigue
  • In fact, bone marrow failure is associated with cytopenias and patients suffering from anemia, leukopenia, or thrombocytopenia may present with pallor, weakness, and fatigue, increased susceptibility to infectious diseases, or hemorrhagic diathesis.[symptoma.com]
Pallor
  • In fact, bone marrow failure is associated with cytopenias and patients suffering from anemia, leukopenia, or thrombocytopenia may present with pallor, weakness, and fatigue, increased susceptibility to infectious diseases, or hemorrhagic diathesis.[symptoma.com]
Vomiting
  • A 46-year-old woman was admitted to the hospital with complaints of chronic diarrhoea, vomiting and severe muscle weakness. Clinical examination showed a lethargic, malnourished, dehydrated patient with ascites and bilateral leg oedema.[ncbi.nlm.nih.gov]
  • Because mast cells release histamine, ASM is also associated with histamine-mediated symptoms like flushing, skin itching, nausea, vomiting, diarrhea, and anaphylaxis.[symptoma.com]
  • […] type of white blood cell) occurs in one or more organs, including the GI tract, spleen, lymph nodes and bone marrow. 1 Mast cells release substances, such as histamine, which can lead to symptoms including itching, fever, abdominal pain, nausea and vomiting[novartisoncology.com]
Abdominal Pain
  • Abstract A 43 year-old woman presented with fever, abdominal pain, epato-splenomegaly, ascites, cholestasis, anemia, thrombocytopenia and previous diagnosis of sclerosing cholangitis based on liver biopsy and endoscopic retrograde cholangiopancreatography[ncbi.nlm.nih.gov]
  • pain, nausea and vomiting. 2 The uncontrolled growth and reproduction of mast cells is caused in many people by a KIT mutation. 3 KIT D816V is the most common mutation in SM, occurring in about 90% of patients. 4 In advanced SM, mast cells collect in[novartisoncology.com]
  • Abstract Ultrasonography (US) is often the first imaging study performed in patient with abdominal pain or vague symptoms related to the gastrointestinal tract.[ncbi.nlm.nih.gov]
Nausea
  • Because mast cells release histamine, ASM is also associated with histamine-mediated symptoms like flushing, skin itching, nausea, vomiting, diarrhea, and anaphylaxis.[symptoma.com]
  • […] mast cells (a type of white blood cell) occurs in one or more organs, including the GI tract, spleen, lymph nodes and bone marrow. 1 Mast cells release substances, such as histamine, which can lead to symptoms including itching, fever, abdominal pain, nausea[novartisoncology.com]
Diarrhea
  • Patients present with severe symptoms related to mast cell invasion and the intense release of mediators including syncope, recurrent flushing, diarrhea, pain, organomegaly and organ dysfunction, impairment of hematopoietic function (which may result[orpha.net]
  • Because mast cells release histamine, ASM is also associated with histamine-mediated symptoms like flushing, skin itching, nausea, vomiting, diarrhea, and anaphylaxis.[symptoma.com]
Loss of Appetite
  • Hepatic and splenic mast cell infiltration cause palpable hepatomegaly and splenomegaly and may ensue loss of appetite, aszites, and portal hypertension as well as hypersplenism.[symptoma.com]
Hepatosplenomegaly
  • The patient was a 37-week-old male, born by caesarean section owing to hepatosplenomegaly and ascites diagnosed in utero, who exhibited extensive cutaneous and systemic manifestations of mastocytosis at birth.[ncbi.nlm.nih.gov]
  • Respective clinical findings (so called C-Findings) include cytopenias, osteolysis (or osteoporosis) with pathologic fractures, hepatosplenomegaly with impaired liver function and ascites, and malabsorption.[ncbi.nlm.nih.gov]
  • A 58-year-old man was first seen with aggressive systemic mastocytosis manifested by urticaria pigmentosa, hepatosplenomegaly, generalized bone lesions, anemia, thrombocytopenia, monoclonal gammopathy, and increased urine histamine levels.[ncbi.nlm.nih.gov]
Hepatomegaly
  • Hepatic and splenic mast cell infiltration cause palpable hepatomegaly and splenomegaly and may ensue loss of appetite, aszites, and portal hypertension as well as hypersplenism.[symptoma.com]
Fracture
  • A 43-year-old female was referred to our hospital because of a vertebral compression fracture, multiple lytic bone lesions, and eosinophilia in February 2011.[ncbi.nlm.nih.gov]
  • Respective clinical findings (so called C-Findings) include cytopenias, osteolysis (or osteoporosis) with pathologic fractures, hepatosplenomegaly with impaired liver function and ascites, and malabsorption.[ncbi.nlm.nih.gov]
  • While osteolytic lesions may not be recognizable unless diagnostic imaging is applied, they predispose for pathological fractures, whereby vertebral fractures are most frequently reported.[symptoma.com]
  • […] organomegaly and organ dysfunction, impairment of hematopoietic function (which may result in disruption of the blood count ranging from isolated cytopenia to more or less marked pancytopenia), bone involvement in the form of osteoporosis with the risk of fracture[orpha.net]
  • […] mast cells is caused in many people by a KIT mutation. 3 KIT D816V is the most common mutation in SM, occurring in about 90% of patients. 4 In advanced SM, mast cells collect in such high quantities that they lead to organ damage and dysfunction, bone fractures[novartisoncology.com]
Osteoporosis
  • Respective clinical findings (so called C-Findings) include cytopenias, osteolysis (or osteoporosis) with pathologic fractures, hepatosplenomegaly with impaired liver function and ascites, and malabsorption.[ncbi.nlm.nih.gov]
  • […] flushing, diarrhea, pain, organomegaly and organ dysfunction, impairment of hematopoietic function (which may result in disruption of the blood count ranging from isolated cytopenia to more or less marked pancytopenia), bone involvement in the form of osteoporosis[orpha.net]
Urticaria
  • A 58-year-old man was first seen with aggressive systemic mastocytosis manifested by urticaria pigmentosa, hepatosplenomegaly, generalized bone lesions, anemia, thrombocytopenia, monoclonal gammopathy, and increased urine histamine levels.[ncbi.nlm.nih.gov]
  • Urticaria. Medscape, Last Update September 13, 2016. Available at: . Accessed December 20, 2016. Rasool HJ. Myeloproliferative Disease. Medscape, Last Update February 26, 2016 . Available at: . Accessed December 20, 2016. Klapproth JM, Yang VW.[rarediseases.org]
Flushing
  • Patients present with severe symptoms related to mast cell invasion and the intense release of mediators including syncope, recurrent flushing, diarrhea, pain, organomegaly and organ dysfunction, impairment of hematopoietic function (which may result[orpha.net]
  • Because mast cells release histamine, ASM is also associated with histamine-mediated symptoms like flushing, skin itching, nausea, vomiting, diarrhea, and anaphylaxis.[symptoma.com]

Workup

The World Health Organization has published diagnostic criteria for variants of systemic mastocytosis [4]. There are general criteria to be met before making a diagnose of systemic mastocytosis, and there are specific criteria that apply for certain subtypes like ASM. With regards to the general criteria for systemic mastocytosis, one major criterion and four minor criteria have been defined. Systemic mastocytosis can be diagnosed if the major criterion and one minor criterion, or three minor criteria are met:

  • Multifocal, dense infiltrates of mast cells are observed in sections of bone marrow and/or other extracutaneous organs, with infiltrates being considered dense if there are at least 15 mast cells in aggregates (major criterion)
  • More than 25% of the mast cells identified in bone marrow biopsy sections are spindle-shaped or of atypical morphology, or more than 25% of the mast cells detected in bone marrow aspirate smears are immature or atypical (minor criterion)
  • Genetic analyses of specimens derived from bone marrow, blood or other extracutaneous organs reveal a gain-of-function mutation of the KIT gene at codon 816 (minor criterion)
  • Mast cells identified in samples derived from bone marrow, blood or other extracutaneous organs express CD2 and/or CD25 (minor criterion)
  • Total tryptase levels in serum persistently exceed 20 ng/ml, except in the case of an associated clonal myeloid disorder, when this parameter doesn't apply (minor criterion)

The World Health Organization has defined a number of so-called B findings and C findings, which are characteristic of certain subtypes of systemic mastocytosis. As per definition, the diagnosis of ASM requires one or more of the following C findings:

Additionally, there should be no evidence of mast cell leukemia. The latter is characterized by a diffuse infiltration of the bone marrow by immature, atypical mast cells. Additionally, more than 20% of all nucleated cells visible in bone marrow aspirate smears are identified as mast cells. Consequently, if these criteria apply, the diagnosis of ASM should be reconsidered. It should be recalled that ASM may progress to mast cell leukemia [5].

Cytopenia
  • […] cell invasion and the intense release of mediators including syncope, recurrent flushing, diarrhea, pain, organomegaly and organ dysfunction, impairment of hematopoietic function (which may result in disruption of the blood count ranging from isolated cytopenia[orpha.net]
  • Respective clinical findings (so called C-Findings) include cytopenias, osteolysis (or osteoporosis) with pathologic fractures, hepatosplenomegaly with impaired liver function and ascites, and malabsorption.[ncbi.nlm.nih.gov]
  • Affected individuals may present with symptoms due to organopathies caused by mast cell infiltration, bone marrow failure and subsequent cytopenias, and symptoms of mast cell activation - clinical presentations are heterogeneous.[symptoma.com]

Treatment

Although several therapeutic approaches have been proposed - and are taken in clinical practice - effective treatment is not available.

  • Most patients receive tyrosine kinase inhibitors in an effort to reduce c-Kit activity and to normalize mast cell proliferation, but response rates vary largely. Precise knowledge of the underlying KIT mutation is indispensable since determined sequence anomalies are associated with permanently active c-Kit that cannot be targeted by certain drugs. In this regard, KIT mutation D816V is generally considered a contraindication for treatment with imatinib [6]. Novel tyrosine kinase inhibitors may overcome that resistance: Midostaurin, which is otherwise known as PKC412, induced an overall response rate of 60%, with mostly major responses with a more than 50% reduction in serum tryptase levels and bone marrow mast cells [7]. Other agents are currently on trial, such as dasatinib, masitinib, and nilotinib.
  • Polychemotherapy with intensive induction regimens may also be carried out but is generally considered a last resort [8]. Cladribine, interferon-α, and corticosteroids are often administered to this end.
  • Finally, allogeneic stem cell transplantation shall be named as a potentially curative therapeutic option. Relatively high response rates are reached in systemic mastocytosis with associated clonal hematological non–mast cell-lineage disease, but response rates are lower in case of ASM and very low in individuals with mast cell leukemia: Seven patients suffering from ASM have been included in a global study to assess the effectiveness of allogeneic stem cell transplantation. Three of them responded to the intervention and the three-year survival rate was 43% [9].
  • Additionally, histamine receptor antagonists and corticosteroids are often applied to provide relief from constitutive symptoms [3].

Prognosis

Because curative treatment is not available, the goal of therapy is to reduce the systemic mast cell burden, to alleviate symptoms and to maintain life quality as high as possible. Thus, ASM treatment should be understood as palliative therapy. Mean survival times have been estimated to less than 4 [5] and 6 to 7 years [10].

Etiology

Gain-of-function mutations of the KIT gene have long since been assumed to be the single cause of proliferative mast cell disease, but comprehensive genetic analyses have revealed that the vast majority of ASM patients carries additional mutations affecting other genes. Those additional mutations may serve as an explanation as to why certain KIT mutations may result in different forms of mastocytosis:

  • Gain-of-function mutations of the KIT gene result in constitutive activation of receptor tyrosine kinase c-Kit, in enhanced mast cell proliferation and reduced apoptosis rates. Therefore, KIT is considered a proto-oncogene.
  • KIT mutation D816V is detected in virtually all adults with advanced systemic mastocytosis [11] [12]. Other KIT mutations are rarely identified. They may affect the same codon in the KIT gene activation loop, or other codons.
  • KIT mutations are not necessarily restricted to mast cells and their progenitors, but may also be found in other myeloid precursor cell populations. The presence of KIT mutations in non–mast cell-lineage precursors may represent an unfavorable prognostic factor and is more commonly seen in advanced systemic mastocytosis than in indolent cases [11].
  • Additional mutations identified in ASM patients comprise, but are not limited to, sequence anomalies of TET2, SRSF2, ASXL1, RUNX1, JAK2, and RAS [13].

All mutations described are somatic, acquired mutations.

Epidemiology

ASM is a rare form of systemic mastocytosis and accounts for less than 2% of all cases. In Denmark, the incidence of ASM has been estimated to 1 in 10,000,000 inhabitants per year and the prevalence of the disease was calculated to be 9 per 10,000,000 people [10].

ASM is generally diagnosed in adult patients. Their mean age at the time of diagnosis is 60 years, with the majority of individuals being diagnosed in their sixth or seventh decade of life [10]. In children, mastocytosis typically involves the skin and follows a benign, often self-limiting course. Nevertheless, ASM has occasionally been described in young patients, even in neonates [14]. Most studies reveal a slight predilection for females [10].

Sex distribution
Age distribution

Pathophysiology

Mast cell proliferation and differentiation is largely regulated by their main growth factor, namely mast cell growth factor or stem cell factor. This growth factor binds to tyrosine kinase c-Kit, a protein expressed in the membrane of hematopoietic stem cells. Ligand binding triggers tyrosine kinase phosphorylation and dimerization and ultimately activation. Through a variety of signaling cascades, c-Kit activation finally translates into an enhancement of mast cell proliferation. However, in the absence of its ligand, c-Kit remains inactive and doesn't stimulate mast cell propagation. This regulatory mechanism is invalidated in patients suffering from ASM. They present with gain-of-function mutations of the KIT gene, which encodes for receptor tyrosine kinase c-Kit. Such mutations are associated with constitutive activity of c-Kit, uncontrolled mast cell proliferation and reduced apoptosis rates.

The role of genes TET2, SRSF2, ASXL1, RUNX1, JAK2, and RAS in ASM pathogenesis is less clear. Most of them presumably affect the cell cycle, survival and death. In detail, TET2 has been related to an "increased self-renewal capacity of hematopoietic stem cells", while mutations of SRSF2 result in alterations of the spliceosome machinery and mutations of ASXL1 affect chromatin remodeling [13].

Prevention

No recommendations can be given to prevent ASM.

Summary

Mastocytosis is a general term referring to a heterogeneous group of diseases. According to the current classification of the World Health Organization, there are seven variants of mastocytosis [4]:

  • Cutaneous mastocytosis
  • Indolent systemic mastocytosis, including bone marrow mastocytosis and smouldering systemic mastocytosis
  • Systemic mastocytosis with associated clonal hematological non–mast cell-lineage disease
  • ASM, including lymphadenopathic mastocytosis with eosinophilia
  • Mast cell leukemia
  • Mast cell sarcoma
  • Extracutaneous mastocytoma

It becomes apparent from the list that there are several forms of systemic mastocytosis, with indolent systemic mastocytosis being the most benign variant of the disease and mast cell leukemia being the one with the poorest prognosis. Still, and as the name already suggests, ASM follows an aggressive course and affected individuals have mean survival times of less than 7 years [10].

Of note, the term advanced systemic mastocytosis refers to systemic mastocytosis with associated clonal hematological non–mast cell-lineage disease, ASM, and mast cell leukemia [13].

Patient Information

Mast cells are part of the immune system. They are white blood cells but may also be found in different tissues outside the bloodstream. Under physiological conditions, they account for a minor proportion of blood cells and immune cells to be found in distinct organs. Their proliferation is tightly regulated.

In patients suffering from aggressive systemic mastocytosis (ASM), those regulatory mechanisms are invalidated due to an acquired mutation of a gene called KIT. This gene encodes for c-Kit, a protein able to bind mast cell growth factor and undergo subsequent activation. ASM-associated mutations of the KIT gene may result in permanent activity of c-Kit, which provokes enhanced mast cell proliferation.

Consequently, abundant mast cells may be detected in the bone marrow - mast cells develop from hematopoietic stem cells in the bone marrow - and in virtually any organ that becomes infiltrated with mast cells. Degenerated mast cells interfere with organ function and therefore, ASM patients may develop bone marrow failure with subsequent anemia, susceptibility to infections, and bleeding diathesis, bone pain and pathological fractures, and dysfunction of liver, spleen, and intestines. The latter usually leads to significant weight loss. Because mast cells release histamine, ASM is also associated with histamine-mediated symptoms like flushing, skin itching, nausea, vomiting, diarrhea, and anaphylaxis.

ASM may be treated by means of pharmacotherapy or stem cell transplantation, but curative therapy is not yet available. Mean survival times are 3 to 7 years.

References

Article

  1. Valent P, Akin C, Sperr WR, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res. 2003; 27(7):635-641.
  2. Krauth MT, Födinger M, Rebuzzi L, Greul R, Chott A, Valent P. Aggressive systemic mastocytosis with sarcoma-like growth in the skeleton, leukemic progression, and partial loss of mast cell differentiation antigens. Haematologica. 2007; 92(12):e126-129.
  3. Sakane-Ishikawa E, Kodaka T, Tsunemine H, et al. Eosinophilia and bone lesion as clinical manifestations of aggressive systemic mastocytosis. J Clin Exp Hematop. 2013; 53(3):207-213.
  4. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 ed. Lyon, France: IARC Press; 2013.
  5. Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009; 113(23):5727-5736.
  6. Arock M, Sotlar K, Akin C, et al. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia. 2015; 29(6):1223-1232.
  7. Gotlib J, Kluin-Nelemans HC, George TI, et al. Midostaurin (PKC412) Demonstrates a High Rate of Durable Responses in Patients with Advanced Systemic Mastocytosis: Results from the Fully Accrued Global Phase 2 CPKC412D2201 Trial. Blood. 2014; 636–636.
  8. Molderings GJ, Haenisch B, Brettner S, et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol. 2016; 389(7):671-694.
  9. Ustun C, Reiter A, Scott BL, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014; 32(29):3264-3274.
  10. Cohen SS, Skovbo S, Vestergaard H, et al. Epidemiology of systemic mastocytosis in Denmark. Br J Haematol. 2014; 166(4):521-528.
  11. Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006; 108(7):2366-2372.
  12. Kristensen T, Vestergaard H, Bindslev-Jensen C, Moller MB, Broesby-Olsen S. Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis. Am J Hematol. 2014; 89(5):493-498.
  13. Ustun C, Arock M, Kluin-Nelemans HC, et al. Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice. Haematologica. 2016; 101(10):1133-1143.
  14. Huang A, Fiadorchanka N, Brar K, Balderacchi JL, Glick SA. In utero presentation of aggressive systemic mastocytosis in a neonate. Br J Dermatol. 2017; 177(5):1439-1441.

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Last updated: 2019-07-11 20:04