A Vertebral Fracture Unmasking Systemic Mastocytosis in a 29-Year-Old Man

A 29-year-old man presented to the endocrinology clinic after sustaining a T3 vertebral burst fracture from a ground-level fall. MRI revealed a T3 burst fracture deformity, compression deformities of four other vertebral bodies, and multilevel diffuse marrow enhancement (Figure 1). DXA scan showed both T- and Z-scores of -4.2 lumbar spine, -2.5 femoral neck, -1.8 total hip and -1.6 distal forearm. His medical history was significant for reflux, headaches, irritable bowel syndrome, and severe allergic reactions to tilapia and crab manifested as syncope. He denied fatigue, weight gain, cold intolerance, gluten sensitivity, kidney stones, nausea, and glucocorticoid use. The physical examination was unremarkable without rash. Laboratory evaluations revealed normal TSH, celiac panel, blood counts, CMP, PTH, 25-OH vitamin D, and 24-hour urine calcium. Basal serum tryptase was 16.5 ng/mL (reference range <11.5 ng/mL) and tryptase genotype was normal (2 alpha 2 beta). A bone marrow biopsy was obtained (Figure 2). What is the diagnosis?Figure 2Wright-Giemsa staining of the aspirate demonstrates atypical, spindled mast cells (original magnification 1000x). B, Hematoxylin and Eosin staining with aggregates of greater than 15 spindled mast cells (original magnification 400x). C, Reticulin special staining highlights increased reticulin around the spindled mast cells (original magnification 400x). D, Immunohistochemical staining for Tryptase highlights the spindled mast cells (original magnification 400x). E, Immunohistochemical staining for CD117 highlights spindled mast cells and CD117 positive precursor cells (original magnification 400x). F, Immunohistochemical staining for CD25 shows aberrant expression in the atypical mast cells (original magnification 400x).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Bone marrow biopsy revealed numerous aggregates of spindled mast cells (MCs) that demonstrated positive immunohistochemical staining for CD117, tryptase, and CD25 (Figure 2). The KIT p.D816V mutation was detected in the aspirate at 0.07% variant allele frequency. Therefore, this patient met the 2017 WHO criteria for systemic mastocytosis (SM) (1Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017;129(11):1420–1427.Google Scholar). Mastocytosis is a group of rare myeloid neoplasms that results in abnormal accumulation and expansion of neoplastic MCs within one or more organs. There are three types of mastocytosis including cutaneous mastocytosis, MC sarcoma, and SM. SM subtypes indolent SM (ISM), smoldering SM, aggressive SM, SM with an associated myeloid neoplasm, and MC leukemia. Patients with all subtypes of SM are at risk of osteoporosis and low-trauma fractures (2van der Veer E. van der Goot W. de Monchy J.G.R. Kluin-Nelemans H.C. van Doormaal J.J. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis.Allergy. 2012; 67: 431-438Crossref PubMed Scopus (101) Google Scholar). Patients who present with diffuse reddish-brown macules (termed mastocytosis-in-the-skin), anaphylaxis associated with cardiovascular collapse (3Alvarez-Twose I. González de Olano D. Sánchez-Muñoz L. et al.Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.The Journal of Allergy and Clinical Immunology. 2010; 125: 1269-1278.e1262Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), pathologic fracture, or a combination of these should be screened for SM. The pathophysiology of mastocytosis bone disease is poorly understood but may occur via activation of osteoclasts from MC mediators including histamine, tryptase, IL-6, IL-1, and TNF- α. The patient was started on a recently FDA-approved KIT p.D816V selective tyrosine kinase inhibitor (TKI) called avapritinib for ISM. He also began infusions of zoledronic acid for osteoporosis. There is little data to guide how to prevent or manage osteoporosis in SM. It is also not known whether TKIs might prevent or reverse bone damage. This case highlights SM in the differential for pathologic fracture and the need to study bone health in these patients.