HAEM4Backup:TEMPI Syndrome
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Primary Author(s)*
Sohini Anand, MBBS
Cancer Category/Type
Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome
Cancer Sub-Classification / Subtype
Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome
Definition / Description of Disease
TEMPI syndrome is an extremely rare blood disorder which involves multiple systems of the body. TEMPI syndrome stands for Telangiectasias, Erythropoiesis and elevated erythropoietin levels, Monoclonal gammopathy, Perinephric fluid collection and Intrapulmonary shunting.[1]
Synonyms / Terminology
TEMPI Syndrome
Epidemiology / Prevalence
TEMPI syndrome is a new disease entity. This term was coined in the year 2011. Prevalence is <1/106. The disease commonly occurs in 4th-5th decade of life. There is no sex, ethnic or geographical predilection[2]. Only 22[2] cases have been reported as of 2019 and only 10 cases have been included in the literature. TEMPI syndrome has been reported in 11 countries so far including USA, Sweden, Pakistan, Afghanistan, Germany.
Clinical Features
Renal manifestations- Nausea, flank pain, uncontrolled hypertension, fatigue, weight loss, hematuria, abdominal pain, hydronephrosis, hydroureter[3] and chronic renal insufficiency.[4]
Skin manifestations- Telangiectasias can lead to "web like appearance" of skin. "Red facies" because of increased RBCs[1]. Clubbing of fingernails[5]
Polycythemia- Fatigue, blurred vision, excessive sweating, headache.
Respiratory Failure- Presence of intrapulmonary shunting in TEMPI syndrome initially presents as dyspnea, hypoxia/hypoxemia leading to continuous oxygen requirement and ultimately respiratory failure.[6]
Thrombosis and intracranial bleeding- Spontaneous bleeding has been reported in some patients in absence of new blood vessel formations.[7]
Sites of Involvement
- Kidney
- Skin
- Blood/lymph nodes- It has been reported that <10% of plasma cells are present in bone marrow, unlike MM. Erythropoietin levels are markedly increased in TEMPI syndrome patients.
- Lung
Morphologic Features
Bone marrow biopsy- Plasma cell levels were approximately 10%. IgG κ is the most common monoclonal immunoglobulin reported in 6 out of 8 patients.[8] Erythroid hyperplasia with atypia and nuclear blebing. Vacuolization of plasma cells along with frayed of cytoplasm was noted. Lymphoid aggregates present without plasma cell rimming was reported.
Skin Biopsy for telangiectasia- dilated venules in histopathologic examination.
Erythropoietin levels- The titer can vary from 78mU/ml to 8144mU/ml. It is important to mention that hypoxemia driven erythropoiesis causes not more than 30mU/ml increase in erythropoietin levels.[8]
Kidney- Macroscopically, CT scan showed perinephric fluid collection between renal capsule and the kidney leading to compression of bilateral kidneys. No parenchymal cysts were reported.[9]
Pulmonary shunting- The extent of pulmonary shunting can be quantified using 99mTc macro-aggregated albumin scintigraphy. This is associated with decrease in resting oxygen saturation. This progresses to hypoxia and ultimately leading to use of supplemental oxygen.[2]
| clear, serous[9] and sterile fluid | + |
|---|---|
| Proteins | - |
| cells | - |
| Lymphatic fluids/chyle | - |
| Eletrolytes (Na+/K+/Cl-) | same as serum |
Immunophenotype
Loss of CD19 in plasma cells is one of the consistent findings while immunophenotyping the monoclonal PCs.
POSITIVE[10]
- CD56+
- CD38+,
- CD138+,
- IgG kappa+
- IgG κ
NEGATIVE[10]
- CD19
- CD20
- JAK2V617F
- JAK2 exon 12
- CALR
- MFL
- IGH (14q32)
- RB1 (13q14) deletion
- 1q gain
- hyperdiploidy
- 17p deletion
Chromosomal Rearrangements (Gene Fusions)
Somatic Structural variants of translocation:
| Chromosomal Rearrangement | Breaking Genes | Pathogenic Derivative | Prevalence |
|---|---|---|---|
| t(2;3) (2p22.3;q11.2) | |||
| t(2;4) (2p22.3;p1531) | |||
| t(2;5)(2p22.3/p15.3) | |||
| t(2;5)(2p22.3/q21.1) | |||
| t(2;6)(2p22.3/p12.1) | |||
| t(2;6)(2p22.3/q13) | |||
| t(2;8)(2p22.3/p21.2) | |||
| t(2;9)(2q13/p24.3) | |||
| t(2;9)(2p22.3/21.1) | |||
| t(2;10)(2p22.3/p11.21) | |||
| t(2;11)(2p22.3/p14.2) | |||
| t(2;11)(2p22.3/q22.3) | |||
| t(2;13)(2p22.3/q14.2) | |||
| t(2;13)(2p22.3/q21.31) | |||
| t(2;15)(2p22.3/q13.1) | |||
| t(2;19)(2q24.13/p13.2) | |||
| t(2;20)(2p22.3/12.1) | |||
| t(2;20)(p22.3/q11.21) | |||
| t(2,x)(p22.3/p22.12) | |||
| t(2;x)(p22.3/13.1) | |||
| t(2;x)(p22.3/q21.2) | |||
[10]Characteristic Chromosomal Aberrations / Patterns
TEMPI syndrome is a newly discovered disorder; therefore, nothing much is known about pathophysiology of the same. Supplemental pdf file attached in this research paper[10] demonstrates the involvement of possible genomic aberrations leading to development of TEMPI syndrome.
Genomic Gain/Loss/LOH
Put your text here and/or fill in the table
| Chromosome Number | Gain/Loss/Amp/LOH | Region | Cytoband |
|---|---|---|---|
| 2 | deletion | 33141401-62435304 | 2p22.3-p15 |
| 7 | deletion | 72788842-72789445 | 7q11.23 |
| 13 | deletion | 113518013-113519239 | 13q34 |
| 2 | duplication | 3925437-33141405 | 2p25.3-p22.3 |
| 10 | duplication | 53984356-54034064 | 10q21.1 |
| 15 | duplication | 23103187-231041416 | 15q11.2 |
| 22 | duplication | 23686256-25070295 | 22q11.23 |
| 2 | inversion | 14091693-33141660 | 2p24.3-p22.3 |
| 2 | inversion | 33141401-126175986 | 2q21.1 |
| 6 | inversion | 19429630-19430529 | 6p22.3 |
| 7 | inversion | 5943362-6861029 | 7p22.1 |
| 13 | inversion | 111736773-112875947 | 13q34 |
| 19 | inversion | 14508801-14876285 | 19p13.12 |
Gene Mutations (SNV/INDEL)
Molecular basis of TEMPI syndrome was studied using WES (Whole-Exome Sequencing). 25 somatic exonic SNVs( Single Nucleotide Variations) were reported. 18 out of 25 SNVs were non-synonymous. These 18 SNVs resides on the following 17 genes.[10]
| Chromosome | Gene | Mutation |
|---|---|---|
| 1 | SZT2 | Missense |
| 1 | IGSF3 | Missense |
| 1 | NBPF10 | Missense |
| 2 | POTEE | Misense |
| 2 | NRP2 | Missense |
| 6 | HIST1H2BM | Missense |
| 9 | AQP7 | Missense |
| 9 | AQP7 | Missense |
| 9 | TMEM245 | Missense |
| 11 | PGA3 | Missense |
| 12 | TAS2R43 | Missense |
| 14 | SLC7A8 | Missense |
| 15 | MCTP2 | Missense |
| 17 | PLCD3 | Missense |
| 17 | LRRC37A3 | Missense |
| 18 | CLUL1 | Missense |
| 18 | LOXHD1 | Missense |
| 21 | KRTAP10-4 | Missense |
| X | ATG4A | Missense |
| Chromosome | Gene | Mutation |
|---|---|---|
| 1 | OR2T2 | Synonymous |
| 6 | MDF1 | Synonymous |
| 7 | MUC12 | Synonymous |
| 14 | RBM23 | Synonymous |
| 22 | IGLL5 | Synonymous |
| 7 | IQCA1L | Unknown |
Other Mutations
Epigenomics (Methylation)
Molecular analysis in TEMPI syndrome showed involvement of chromosome2 and associated mutations. For example- deletion of 2p22.3-p15, duplication of 2p25.3-p22.3, inversion of 2p24.3-p22.3, 2q21.1. Chromosome 2 harbors important tumor genes as well. Therefore, it has be hypothesized that proximity of tumor associated genes and SVs can play a major role in the pathophysiology of TEMPI syndrome.
| Tumor associated genes | Location |
|---|---|
| MYCN | 2p24.3 |
| REL | 2p16.1 |
| BCL11A | 2p16.1 |
| BCL2L11 | 2q13 |
| MAPK4 | 2p22.1 |
| TP53I3 | 2p23.3 |
Genes and Main Pathways Involved
Macrophage MIF (Migratory Inhibitory Factor)- Gene synthesizing MIF is located at 22q11.23. Duplication of 22q11.23 which has been demonstrated by TEMPI syndrome which may lead to increased expression of MIF mRNA by CD138+ PCs and MIF proteins in the bone marrow of patients of TEMPI syndrome.[10]
MIF Function- MIF is a proinflammatory cytokine which can act as an intracellular signaling molecule as well[11]. It plays a major role in neovascularization by inducing erythropoietin, VEGFs and hypoxia-inducible factor1a. The pathogenesis of intrapulmonary shunting and telangiectasias are considered to be vascular dilations and neovascularization which can be explained by secretion of MIF from monoclonal plasma cells.
Diagnostic Testing Methods
Monoclonal plasma cells from TEMPI syndrome and healthy donors(control) collected for WGS (Whole Genome Sequence) and PCR (Polymerase Chain Reaction)
using Ficoll density gradient centrifugation. Following that, tumor cells can be isolated using CD138+ magnetic bead selection.
| Sample Preservation- | Preserved as dry pellets at -80o C | ||
|---|---|---|---|
| Extraction of DNA genome | TIANamp Genomic DNA Kit (Tiangen) | ||
| Quality of DNA | Nanophotometer | ||
| Quantity of DNA | Qubit 3.0 flourometer |
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications) using
| MAJOR CRITERIA |
|
|---|---|
| MINOR CRITERIA |
|
| OTHERS |
|
MANAGEMENT: It is important to mention here that because of rarity of TEMPI syndrome, most patients are treated empirically for Polycythemia Vera with phlebotomy, which ultimately leads to Iron deficiency anemia.
- Proteasome Inhibitors- example- Bortezomib (8 cycles, 4 doses of 1.3 mg/m2BSA/cycle) was tried in one of the patients with TEMPI syndrome showed marked improvement in clinical presentations- with resolution of telangiectasias, improvement in intrapulmonary shunting and perinephric fat, normalization of erythropoietin levels as well. Drastic response with use of bortezomib indicates the pathophysiological role of IgG κ paraproteins in development of TEMPI syndrome.
- No improvement was seen when other immunomodulators were used such as- Thalidomide, anti-VEGF (Bevacizumab) and immunosuppressants- Sirolimus.[9]
Familial Forms
Other Information
Differential Diagnosis of TEMPI Syndrome[12]
- Polycythemia Vera- TEMPI syndrome's patients and PV patients both have increased RBC concentration. PV have + JAK2 V617F contrary to TEMPI syndrome which is negative for the JAK2 V617F.
- POEMS syndrome- EPO levels are decreased in POEMS syndrome along with constellation of clinical features which are different from TEMPI syndrome. POEMS Syndrome
- Multiple myeloma- Monoclonal plasma cells concentration in BM are much higher in MM (>10%) compared to TEMPI syndrome along with absence of CRAB(hypercalcemia, renal insufficiency, anemia, bony lesions) features in TEMPI syndrome.
- Schnitzler syndrome- This disorder is characterized by urticarial eruptions and neutrophilic urticarial dermatoses. Also, Plasma cells concentration in Bm aspirate is restricted to <5%.
- Generalized essential telangiectasia
Links
Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome
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References
(use "Cite" icon at top of page)
- ↑ 1.0 1.1 RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Clinical Signs and Symptoms".
- ↑ 2.0 2.1 2.2 2.3 Sykes, David B.; et al. (2020-04-09). "The TEMPI syndrome". Blood. 135 (15): 1199–1203. doi:10.1182/blood.2019004216. ISSN 0006-4971.
- ↑ Mohammadi, F.; et al. (2012-11-01). "A new case of TEMPI syndrome". Clinical Kidney Journal. 5 (6): 556–558. doi:10.1093/ckj/sfs139. ISSN 2048-8505. PMC 4400562. PMID 26069800.CS1 maint: PMC format (link)
- ↑ Viglietti, D.; et al. (2011-08-02). "Perirenal fluid collections and monoclonal gammopathy". Nephrology Dialysis Transplantation. 27 (1): 448–449. doi:10.1093/ndt/gfr433. ISSN 0931-0509.
- ↑ Khan, Javed; et al. (2014-07-22). "Case report: a 37-year-old male with telangiectasias, polycythemia vera, perinephric fluid collections, and intrapulmonary shunting". BMC Hematology. 14 (1): 11. doi:10.1186/2052-1839-14-11. ISSN 2052-1839.
- ↑ Oljira, Robera; et al. (2020-10). "TEMPI SYNDROME: DISEASE PROGRESSION AND RESPONSE TO TREATMENT". Chest. 158 (4): A2046. doi:10.1016/j.chest.2020.08.1772. ISSN 0012-3692. Check date values in:
|date=(help) - ↑ Sykes, David B.; et al. (2011-08-04). "The TEMPI syndrome--a novel multisystem disease". The New England Journal of Medicine. 365 (5): 475–477. doi:10.1056/NEJMc1106670. ISSN 1533-4406. PMID 21812700.
- ↑ 8.0 8.1 Rosado, Flavia G; et al. (2014-09-12). "Bone marrow findings of the newly described TEMPI syndrome: when erythrocytosis and plasma cell dyscrasia coexist". Modern Pathology. 28 (3): 367–372. doi:10.1038/modpathol.2014.117. ISSN 0893-3952.
- ↑ 9.0 9.1 9.2 Sykes, David Brian; et al. (2011). "The TEMPI Syndrome — A Novel Multisystem Disease". New England Journal of Medicine. doi:10.1056/NEJMc1106670. ISSN 0028-4793.
- ↑ 10.0 10.1 10.2 10.3 10.4 10.5 Sun, Chunyan; et al. (2021-06-22). "Whole-genome sequencing suggests a role of MIF in the pathophysiology of TEMPI syndrome". Blood Advances. 5 (12): 2563–2568. doi:10.1182/bloodadvances.2020003783. ISSN 2473-9537. PMC 8270661 Check
|pmc=value (help). PMID 34129019 Check|pmid=value (help). - ↑ Oda, Seiko; et al. (2008-05-21). "Macrophage Migration Inhibitory Factor Activates Hypoxia-Inducible Factor in a p53-Dependent Manner". PLoS ONE. 3 (5). doi:10.1371/journal.pone.0002215. ISSN 1932-6203. PMC 2375051. PMID 18493321.
- ↑ "VisualDx Cookie Check".
EXAMPLE Book
- Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
Notes
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