Whole-genome sequencing suggests a role of MIF in the pathophysiology of TEMPI syndrome

Abstract

TEMPI syndrome (telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting) is a newly defined multisystemic disease with its pathophysiology largely unknown. Here, we report the whole-genome sequencing (WGS) analysis on the tumor-normal paired cells from a patient with TEMPI syndrome. WGS revealed somatic nonsynonymous single-nucleotide variants, including SLC7A8, NRP2, and AQP7. Complex structural variants of chromosome 2 were found, particularly within regions where some putative oncogenes reside. Of potential clinical relevance, duplication of 22q11.23 was identified, and the expression of the located gene macrophage migration inhibitory factor (MIF) was significantly upregulated in 3 patients with TEMPI syndrome. Importantly, the level of serum MIF in one patient with TEMPI syndrome was significantly decreased in accordance with the downtrend of plasma cells, M-protein, hemoglobin, and erythropoietin and the improvement of telangiectasias, perinephric fluid collections, and intrapulmonary shunting after treatment with plasma cell–directed therapy. In conclusion, our study provides insights into the genomic landscape and suggests a role of MIF in the pathophysiology of TEMPI syndrome.

TEMPI Syndrome: Update on Clinical Features, Management, and Pathogenesis

“…Nail change included clubbing ( 23 ). Cyanosis due to intrapulmonary shunt could also occur ( 22 ). Cutaneous ulcers located at bilateral lower legs were found in three patients ( 13 , 23 ).…”

“…The rapid healing of ulcerations after treatment of bortezomib suggested a potential role of monoclonal gammopathy in the pathogenesis of cutaneous ulcers ( 23 ). The incidence of serous cavity effusions other than perinephric fluid collections was relatively common in TEMPI patients ( 22 ). Of the 29 patients, ten suffered from serous effusion ( 7 , 11 , 15 , 22 , 26 ).…”

“…The incidence of serous cavity effusions other than perinephric fluid collections was relatively common in TEMPI patients ( 22 ). Of the 29 patients, ten suffered from serous effusion ( 7 , 11 , 15 , 22 , 26 ). It often affected more than one cavity (6/10).…”

“…In the case of three patients reported by our group ( Table 1 ) ( 22 ), patient 25, a 56-year-old woman, received six cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a very good partial response. She has remained progression-free for over 3 years since her last cycle of VCD.…”

“…Macrophage migration inhibitory factor (MIF) is of interest for it can explain most of the constellation of symptoms in TEMPI syndrome and has been identified elevated in 3 patients. In addition, the level of serum MIF significantly decreased following effective treatment with the bortezomib-based regimen ( 22 ). The disturbance of TGF-β signaling pathway may also be an intriguing explanation for its pivotal role in neoangiogenesis, vessel maturation and stabilization ( 39 ).…”