Telangiectasias: When is it TEMPI time?

By Warren R. Heymann, MD, FAAD
Oct. 19, 2022
Vol. 4, No. 42

For the medical dermatologist, telangiectasis requires a thoughtful approach to diagnosis. Where are the lesions distributed (generalized, mucosal, periungual)? Are they linear or mat-like? Are they associated with other lesions (pigmented macules, spider angiomas)? Is the patient symptomatic (flushing, diarrhea, shortness of breath, arthralgias, etc.)? The differential diagnosis is long and depends on the answers to these questions. Generalized telangiectasias without any symptoms may be essential telangiectasias or cutaneous collagenous vasculopathy. Periungual telangiectasias are characteristic of autoimmune diseases (lupus, dermatomyositis, and scleroderma). When mat-like and mucosal, CREST syndrome and hereditary hemorrhagic telangiectasia are the two main differential diagnoses. When seen with spider angiomas, high estrogen states such as liver disease or pregnancy must be considered. An association with pulmonary or gastrointestinal symptoms may suggest carcinoid syndrome or mastocytosis (telangiectasia macularis eruptiva perstans).

A new disorder has been added to this list — the TEMPI syndrome. Although rare, it may be underrecognized. As of this writing only 27 cases have been reported, but the tempo of TEMPI manuscripts is increasing. Securing the diagnosis of TEMPI is vital, as it is a potentially life-threatening disease.

Every week I play a game when I receive my copy of the New England Journal of Medicine. I look at the title of the Case Records of the Massachusetts General Hospital and see if I can guess the diagnosis. Every so often I do, eliciting the same exhilaration as getting final Jeopardy right — most typically I am clueless. I do not recall reading “Case 23-2010: A 49-year-old man with erythrocytosis, perinephric fluid collections, and renal failure” but assume I had no idea and would have gone directly to the diagnoses of “renal lymphangiectasis, polycythemia secondary to renal lymphangiectasis, and monoclonal gammopathy of undetermined significance.” Within the detailed case presentation, the following was noted: “During the previous 5 years, telangiectasis had developed in the skin and the oropharynx.” (1)

Dr. David Sykes, a hematologist-oncologist, presented the case. He and his colleagues subsequently wrote a letter to the editor: “The description of a man with erythrocytosis and perinephric fluid collections recently appeared in the Case Records of the Massachusetts General Hospital…and the authors of that article appealed to readers to share similar cases. Two additional patients were identified...a review of the literature identified three more patients with similar findings...These six patients shared five characteristics — telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric-fluid collections, and intrapulmonary shunting — defining a syndrome that we have termed the TEMPI syndrome.” (2)

In 2020, these authors reviewed the TEMPI syndrome, which is now recognized by the World Health Organization as a monoclonal gammopathy of clinical significance, alongside POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormalities) as “plasma cell neoplasms with associated paraneoplastic syndrome.”

The TEMPI syndrome is an acquired disease and develops most commonly in the 3rd through 5th decades of life. Though numbers are small, men and women appear to be equally likely to be affected. Patients have been described across the globe, not pointing to any geographic bias or racial selectivity.

Patients with TEMPI characteristically present with a marked erythrocytosis and telangiectasias and are often mistakenly diagnosed with polycythemia vera. The telangiectasias are mostly distributed on the face, upper chest, and back, while sparing the legs (the reason for this is not known). Histologically, the telangiectasias show no unusual features. The telangiectasias appear to be temporally correlated with elevated serum erythropoietin levels, and the serum EPO progressively increases over time, in some cases to 500 times the upper limit of normal. The concentration of the monoclonal gammopathy on serum protein electrophoresis (in terms of mg/dL) may be quite small and the bone marrow typically has fewer than 10% plasma cells at presentation. The patients do not meet any clinical criteria for myeloma. Perinephric fluid collections occur in some patients and the fluid has the electrolyte composition of serum; the etiology of these fluid collections remains obscure. The pulmonary shunting is described as “microscopic” in that high resolution CT scans of the chest are normal. Regardless, over many years, patients may become hypoxic and require supplemental oxygen as the degree of shunted blood increases. Venous thromboses have been described in a small number of patients. The authors propose the following diagnostic criteria: Major (telangiectasia, elevated erythropoietin and erythrocytosis, monoclonal gammopathy), minor (perinephric fluid), and other (venous thrombosis). (3)

Therapeutically, myeloma regimens based on plasma cell-directed therapies have proven effective. Bortezomib, daratumumab, lenalidomide, high-dose melphalan, and autologous stem cell transplantation (ASCT) have led to partial and to complete responses with excellent outcomes. The small number of patients have not permitted defining an optimal treatment regimen. Fatal cases of TEMPI syndrome, for example, in a 56-year-old woman refractory to proteasome inhibitors and ASCT, have been described. (4)

Several cases of TEMPI syndrome have recently been reported in the dermatologic literature. Lor et al detailed the case of a 50-year-old man with lip lesions resembling venous lakes and cutaneous telangiectasias described as spider angiomas. Despite aggressive therapy with lenalidomide and daratumumab, he succumbed to respiratory failure. (5) Ruan et al described a 75-year-old woman truncal telangiectasias and “hemangioma-like lesions on the face and red macules on the mucosa” with an excellent response to bortezomib and dexamethasone; her diffuse truncal telangiectasias (which appeared more mat-like to my eye) disappeared with therapy. (6) Strobl et al reported a case of a 66-year-old man with recalcitrant, bizarrely shaped leg ulcers. Aside from elevated erythropoietin levels, his VEGF and IL-6 levels were increased. The leg ulcers and telangiectasias resolved following treatment with bortezomib and rivaroxaban. (7)

The etiology of TEMPI is unknown, although it is conjectured that the monoclonal gammopathy is instrumental in the pathogenesis of the disorder. Supporting this hypothesis is the recognition that the telangiectasias, erythrocytosis, perinephric fluid, and intrapulmonary shunting are rapidly and completely reversible in those patients where therapy is successful in eradicating the MGUS and plasma cells.

It has been suggested that the MGUS may be involved in increasing hypoxia-inducible factor-1, VEGF, and nitric oxide via macrophage migration inhibitory factor (MIF). (7,8) Sun et al, by using whole-genome sequencing of TEMPI patient bone marrow samples, identified duplication of chromosome 22q11.23, where the gene MIF is located. The protein expression of MIF also appeared to be significantly upregulated in 3 patients with TEMPI syndrome (8), though this upregulation of MIF has not been seen in other patients outside of this case series.

For dermatologists, when is it time to assess for TEMPI? In the patient presenting with unexplained telangiectasias, the first step may involve the simple task of checking a complete blood count (CBC) to look for evidence of erythrocytosis (elevated RBC, hemoglobin, hematocrit). Until we learn more, I think Ruan et al are correct in stating: “Even though the TEMPI syndrome is a newly named rare disorder, telangiectasia and monoclonal gammopathy are not rare in clinical practice. Therefore, for patients with diffuse telangiectasia and erythrocytosis, the clinician should measure serum erythropoietin levels and recommend serum protein electrophoresis as well as screening for TEMPI syndrome.” (6)

Point to Remember: TEMPI syndrome is a newly recognized syndrome where dermatologists may be instrumental in securing the diagnosis. The diagnosis may be easily confirmed by measuring a CBC, serum erythropoietin, and by checking a serum protein electrophoresis for a monoclonal gammopathy. Early recognition may be lifesaving.

Our expert’s viewpoint

David B. Sykes, MD, PhD
Assistant Professor, Medicine, Harvard Medical School
Principal Investigator, The Sykes Lab, Massachusetts General Hospital

TEMPI syndrome is a fascinating disease. Since our description of the syndrome in 2011, we have continued to hear about 2-3 new patients each year, mostly via emails from interested physicians across the world. Internet search engines have been remarkably helpful, and a Google search in 2021 for “telangiectasia AND erythrocytosis” immediately points to the TEMPI syndrome as the most likely cause. Our progress with the TEMPI syndrome has also been a success story of international collaboration, and we have welcomed and enjoyed meeting and discussing with colleagues across the globe.

Many of our patients’ stories are strikingly similar. They describe the initial development of these “strange spots” (telangiectasias). Somewhere along the way a CBC is checked with identification of a very robust or maybe slightly elevated hemoglobin and hematocrit. Some of our patients felt otherwise perfectly normal in the early stages of the disease while others have described non-specific symptoms such as fatigue and intermittent abdominal pain. At this stage, many of the early patients were simply followed and monitored for many years. As mentioned above, with the rising red blood cell count, many were mis-diagnosed as polycythemia vera (PV has a very LOW serum erythropoietin level) and initiated on courses of therapeutic phlebotomy. It is not common to check a serum erythropoietin level and a serum protein electrophoresis on young patients with unexplained telangiectasias, but we would encourage this practice! The serum erythropoietin level in patients with TEMPI syndrome is often astronomically elevated. In some cases, the serum erythropoietin level is even higher that one might see in the context of an erythropoietin producing tumor. And while the presence of an MGUS is quite common in patients over the age of 60 and 70, the presence of an MGUS is very uncommon (<1%) in patients in their 30s-50s and therefore should raise eyebrows.

Continued progress in understanding the pathophysiology of the TEMPI syndrome is going to depend on continued international collaboration and on the generosity of colleagues and patients across the globe! We have a small, but growing, collection of patient serum samples and bone marrow samples. Our research is focused on the single cell sequencing and antibody identification from bone marrow plasma cells, and we will only be successful if we can collect samples from as many patients as possible regardless of their geography.

Please reach out!

David B. Sykes, MD, PhD
dbsykes@mgh.harvard.edu
https://www.hematopia.com/tempi

1. Bazari H, Attar EC, Dahl DM, Uppot RN, Colvin RB. Case records of the Massachusetts General Hospital. Case 23-2010. A 49-year-old man with erythrocytosis, perinephric fluid collections, and renal failure. N Engl J Med. 2010 Jul 29;363(5):463-75. doi: 10.1056/NEJMcpc1004086. PMID: 20818867.

2. Sykes DB, Schroyens W, O'Connell C. The TEMPI syndrome--a novel multisystem disease. N Engl J Med. 2011 Aug 4;365(5):475-7. doi: 10.1056/NEJMc1106670. PMID: 21812700.

3. Sykes DB, O'Connell C, Schroyens W. The TEMPI syndrome. Blood. 2020 Apr 9;135(15):1199-1203. doi: 10.1182/blood.2019004216. PMID: 32108223.

4. Diral E, Parma M, Renso R, Pezzatti S, Terruzzi E, Perfetti P, D'Aliberti D, Gambacorti-Passerini C, Piazza R, Elli EM. A fatal case of TEMPI syndrome, refractory to proteasome inhibitors and autologous stem cell transplantation. Leuk Res. 2020 Oct;97:106441. doi: 10.1016/j.leukres.2020.106441. Epub 2020 Aug 22. PMID: 32861019.

5. Lor M, Cheng M, Liang B, Cheng CE. TEMPI Syndrome With Progressive Telangiectasias Associated With Pulmonary Deterioration. JAMA Dermatol. 2020 Dec 1;156(12):1379-1380. doi: 10.1001/jamadermatol.2020.2668. PMID: 32845290.

6. Ruan Y, Zhao X, Pan M. Diffuse telangiectasia: A clue to the TEMPI syndrome. JAAD Case Rep. 2021 Feb 27;10:99-101. doi: 10.1016/j.jdcr.2021.02.022. PMID: 33816736; PMCID: PMC8008156.

7. Strobl J, Sinz C, Heil PM, Stary G, Weninger W. Cutaneous ulceration as primary presentation of TEMPI syndrome. J Eur Acad Dermatol Venereol. 2021 Dec;35(12):e891-e894. doi: 10.1111/jdv.17539. Epub 2021 Aug 4. PMID: 34310769.

8. Sun C, Xu J, Zhang B, Huang H, Chen L, Yan H, Xu A, Zhao F, Huang D, Liu L, Li J, Hu Y. Whole-genome sequencing suggests a role of MIF in the pathophysiology of TEMPI syndrome. Blood Adv. 2021 Jun 22;5(12):2563-2568. doi: 10.1182/bloodadvances.2020003783. PMID: 34129019; PMCID: PMC8270661.

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