Disease correlates and clinical relevance of hereditary α-tryptasemia in patients with systemic mastocytosis.

BACKGROUND: Systemic mastocytosis (SM) encompasses a heterogeneous group of clonal disorders characterized by abnormal expansion of mast cells (MCs). Beyond KIT and other genes recurrently mutated in myeloid neoplasms, several genetic variants have been described as predisposing to the development of the disease and influencing its clinical phenotype. Increased copy number variants of the TPSAB1 gene were identified as a cause of nonclonal elevated tryptasemia and defined as hereditary α-tryptasemia (HαT). Moreover, HαT is enriched in patients with SM, where it can affect the incidence of mediator-related symptoms. OBJECTIVE: In a multicenter data set of 444 patients with MC disorders, we aimed to investigate the clinical correlates of germline TPSAB1 copy number gains. METHODS: Droplet digital PCR was performed in all cases to ascertain the presence of HαT. Clinical history along with blood values and bone marrow examination were analyzed. RESULTS: We confirmed a higher incidence of HαT+ cases (n = 59, 13.3%) in patients diagnosed with mastocytosis with respect to the general population (approximately 5%). HαT+ patients were characterized by a lower MC-associated disease burden and higher levels of tryptase. Several disease variables were coherent with this pattern, from bone marrow MC infiltration to MC-related histopathologic traits, which also accounted for a significantly higher incidence of clonal MC activation syndrome in HαT+ (10.2%) compared to HαT- (3.4%, P = .029) patients. We also confirmed that HαT+ carriers had a significantly higher frequency of anaphylaxis, without relevant differences for other clinical manifestations. CONCLUSION: These findings on a large patient series support and extend previous data, and suggest that knowledge of HαT status may be useful for personalized management of patients with SM.

Advances in bone turnover markers.

Bone fragility fractures remain an important worldwide health and economic problem due to increased morbidity and mortality. The current methods for predicting fractures are largely based on the measurement of bone mineral density and the utilization of mathematical risk calculators based on clinical risk factors for bone fragility. Despite these approaches, many bone fractures remain undiagnosed. Therefore, current research is focused on the identification of new factors such as bone turnover markers (BTM) for risk calculation. BTM are a group of proteins and peptides released during bone remodeling that can be found in serum or urine. They derive from bone resorptive and formative processes mediated by osteoclasts and osteoblasts, respectively. Potential use of BTM in monitoring these phenomenon and therefore bone fracture risk is limited by physiologic and pathophysiologic factors that influence BTM. These limitations in predicting fractures explain why their inclusion in clinical guidelines remains limited despite the large number of studies examining BTM.