Calciphylaxis In A Patient With POEMS Syndrome Without

Calciphylaxis in a patient with POEMS syndrome
without renal failure and/or hyperparathyroidism.
A case report
Ileana De Roma, Raffaele Filotico*, Michele Cea, Pasquale Procaccio, Federico Perosa
POEMS (Crow-Fukase) syndrome is a rare plasma cell lymphoproliferative disorder associated
with polyneuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal (M) gammopathy
and skin (S) abnormalities. The latter are usually not specific and include hyperpigmentation, hypertrichosis, cutaneous angioma and skin-thickening. A 45-year-old Italian woman was admitted to
hospital because of muscle weakness, marked fatigue and paresthesia of the upper and lower extremities. Two and a half years earlier, a POEMS syndrome had been diagnosed on the basis of a history of organomegaly and mild lymphadenopathy, IgAλ monoclonal gammopathy, hypothyroidism, severe lower and upper limb sensory-motor peripheral neuropathy and a single osteosclerotic lesion in the left humerus. Eight weeks later, she developed skin lesions bioptically shown
to be due to calciphylaxis-induced cutaneous vasculitis. To our knowledge, this is the first case
of POEMS syndrome with this peculiar type of vasculitis. The absence of predisposing conditions,
namely renal failure, hyperparathyroidism or clotting disorders renders the pathogenetic mechanism(s) of this severe type of vasculitis more intriguing.
(Ann Ital Med Int 2004; 19: 283-287)
Key words: Calciphylaxis; Monoclonal gammopathy; POEMS syndrome; Vasculitis.
Introduction
Case report
POEMS (Crow-Fukase) syndrome1 is a rare plasma
cell lymphoproliferative disorder presenting as osteosclerotic myeloma associated with polyneuropathy (P),
organomegaly (O), endocrinopathy (E), monoclonal (M)
gammopathy and skin (S) abnormalities2. The latter are
usually not specific and include hyperpigmentation, hypertrichosis, cutaneous angioma and a sclerodermiform-like
skin thickening. Additional skin abnormalities have also
been observed as the result of cutaneous vasculitis and may
vary in their clinical presentation from small-vessel hypersensitivity to necrotizing vasculitis2.
Calciphylaxis is a vasculitis characterized by a systemic deposition of calcium salts in the small and medium-size vessels of end-renal stage patients3 or patients with
hyperparathyroidism4. We here report a unique case of a
patient with POEMS syndrome who developed calciphylaxis in the absence of predisposing conditions. The
possible pathogenetic role of inflammatory cytokines,
believed to be responsible for many signs and symptoms
of POEMS syndrome, is briefly discussed.
A 45-year-old Italian woman was admitted to our hospital in October 2003 with a 3-year history of autoimmune
thyroiditis and hypothyroidism, weakness, fatigue, night
sweats and weight loss in addition to a 1-year history of
pleural effusion, ascites and sensory-motor neuropathy.
In February 2001, a POEMS syndrome had been diagnosed on the basis of the following features: hepatosplenomegaly with ascites, a sensory-motor neuropathy
defined both clinically and by sural nerve biopsy, IgAλ
monoclonal gammopathy, a single osteosclerotic lesion and
mild lymphadenopathy. At discharge, she was prescribed
75 mg/day prednisone that she continued until May 2002,
when she spontaneously discontinued this therapy because
of a worsening of her neurological symptoms. In
September 2003, the onset of peripheral edema, ascites,
dyspnea and renal failure led to her admission to an emergency department where she was treated with dopaminergics, plasma expanders and diuretics.
After 3 weeks, her clinical picture and renal function
improved and she was discharged on low doses of corticosteroids as maintenance therapy. However, because of
continued worsening of her neurological symptoms and
weight loss, she was admitted to our department in October
2003. Her history was negative for alcohol consumption
and she was a non-smoker. She was cachectic, though not
completely anorexic. She complained of marked asthenia.
Her skin was brownish throughout and she also had severe
Dipartimento di Scienze Biomediche e Oncologia Umana (Direttore:
Prof. Franco Dammacco), *Dipartimento di Dermatologia (Direttore:
Prof. Luigi Vena), Università degli Studi di Bari
This work was supported by grants from the “Associazione Italiana
per la Ricerca sul Cancro”, Milan, Italy and by a research grant from the
University of Bari Medical School.
© 2004 CEPI Srl
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Ann Ital Med Int Vol 19, N 4 Ottobre-Dicembre 2004
muscle atrophy. A pitting lower limb edema (+-) was
present. In addition, a mild systemic lymphadenopathy was
detected with only one palpable 2-cm, left-supraclavicular lymph node, which was subsequently excised for biopsy. Her blood pressure was 110/80 mmHg on both arms.
A grade 2 systolic murmur was audible on the aortic and
pulmonary auscultation sites. The lungs were clear. The
liver was palpable 2 cm below the right costal margin on
the midclavicular line, and the spleen was enlarged to
3.5 cm below the left costal margin. Neurological examination confirmed the presence of paresthesia and a marked
decrease of muscle strength rated as 4 of 5 for the lower
and 2 of 5 for the upper extremities.
The laboratory findings are summarized in table I. The
hemoglobin level was 12 g/dL. The creatinine level was
normal and the urea nitrogen was slightly increased. The erythrocyte sedimentation rate, conjugated and total bilirubin,
aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, serum calcium and phosphate were within normal limits. The fasting plasma glucose was 104 mg/dL
and an oral glucose tolerance test was normal. The patient was
negative for HBsAg and anti-hepatitis C virus. The prothrombin time was slightly prolonged, while the activated partial thromboplastin time was normal. Thyrotropin was
increased, FT3 decreased, and FT4 in the normal range.
Estrone levels were below the normal range. Calcitonin and
parathyroid hormone levels were normal (Table I).
Serum protein electrophoresis confirmed the presence
of a monoclonal component characterized as IgAλ at
immunoelectrophoresis. The serum IgA concentration
was 523 mg/dL, whereas that of serum IgG was 487
mg/dL and the IgM levels were within the normal range.
The levels of beta-2-microglobulin were increased.
Urinalysis for proteinuria and free-light chains was
unremarkable. Nested polymerase chain reaction (PCR)
for human herpes virus 85 and qualitative PCR for hepatitis C virus were negative. Abdominal ultrasound revealed
enlargement of liver and spleen without focal lesions,
while the abdominal lymph nodes were of normal size.
Systemic skeletal X-ray confirmed the presence of an
osteosclerotic lesion in the proximal portion of the humerus.
The rectal mucosa, on the other hand, was Congo red negative, though a widespread infiltration of plasma cells (λ
60% and κ 40%) was found. A similar (mostly λ) pattern
was seen on a left latero-cervical lymph node biopsy,
which also served to rule out Castleman’s disease.
Eight weeks after our first observation, symmetrical
livedo reticularis-like skin changes on the inner upper
part of the thighs rapidly and locally extended to become
painful and tender (Fig. 1 A and B). These lesions were
initially cyanotic. After 1 week they became necrotic and
TABLE I. Hematological, serum chemistry and hormone laboratory
values on admission in October 2003.
Variable
Hemoglobin (g/dL)
Hematocrit (%)
White blood cells (mm3)
Differential count (%)
Neutrophils
Lymphocytes
Monocytes
Platelets (mm3)
MCV (µm3)
Serum iron (µmol/L)
Ferritin (µg/L)
ESR (mm/h)
PT (INR)
aPTT (INR)
Beta-2-microglobulin (mg/L)
Total protein (g/L)
Albumin
Sodium (mmol/L)
Potassium (mmol/L)
Calcium (mmol/L)
Phosphate (mmol/L)
Creatinine (µmol/L)
Urea nitrogen (mmol/L)
Fasting plasma glucose (mg/dL)
Thyrotropin (mUI/L)
Free triiodothyronine (ng/L)
Free thyroxine (ng/L)
PTH (ng/L)
Calcitonin (ng/L)
Estrone (ng/L)
Value (normal range)
12 (13-16.5)
36 (38-48)
8890 (4000-10 000)
70 (49-84)
24 (12-42)
6 (≤ 12)
357 000 (150 000-500 000)
83 (82-98)
4.83 (6.26-26.85)
55 (11-120)
14 (1-20)
1.4 (≤ 1.2)
0.94 (≤ 1.2)
5.2 (0.8-2)
50 (64-82)
32 (34-36)
138 (136-145)
4.7 (3.5-5.1)
2 (2-2.62)
0.96 (2.4-4.7)
70.72 (53.04-97.24)
31.48 (3.57-17.85)
104 (70-110)
6.06 (0.34-4.82)
0.89 (2.2-4.2)
10.3 (8.1-17.1)
11 (10-65)
4 (< 10)
< 13 (14-103)
aPTT = activated partial thromboplastin time; ESR = erythrocyte sedimentation rate; MCV = mean corpuscular volume; PT = prothrombin
time; PTH = parathyroid hormone.
resembled dry gangrene. Similar cyanotic lesions later
developed above the pubis and on the back (Fig. 2), but
did not progress to dry gangrene. Laboratory tests were performed, with particular emphasis on coagulation studies,
proteins C and S and homocysteine, calcium/phosphate
homeostasis as well as parathyroid hormone and calcitonin
(Table II). All values were within the normal range apart
from a slight homocysteine and creatinine increase.
Biopsy, performed early following the appearance of the
lesions, revealed occlusive vasculitis mostly involving
the medium- and small-size vessels, with microthrombi and
an impressively widespread calcification of the mediumand small-size vessel walls (Fig. 2), suggesting a calciphylaxis-induced cutaneous vasculitis. Mammography
performed because of the appearance of pseudo-nodules
in both breasts showed vascular calcification with an
arborization-like pattern (Fig. 3). Indirect evidence of
widespread calcification of the subcutaneous vessels was
also observed at ultrasound in the form of hyperechogenic
spots in the abdominal wall.
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Ileana De Roma et al.
FIGURE 1. Calciphylaxis-induced skin changes of the thighs (panels A and B) and dorsum
(panel C). The thigh lesions evolved to dry gangrene.
FIGURE 2. Histology of the skin biopsy specimen from the thighs taken soon after the
appearance of the lesions. Periodic Acid-Schiff reagent (PAS) staining showing the presence
of microthrombi in the small- (A) and medium-size vessels and calcium salt deposition in
their walls (original magnification 200) (A and B). Recanalization of the occluded vessels may also be observed (arrows).
case described here met the two major criteria (plasma cell
dyscrasia and sensory-motor peripheral neuropathy) and
more than one minor criterion (dark skin, hypothyroidism,
osteosclerotic lesion, pleural effusion and/or ascites).
The clinical spectrum of vasculitis described in this
syndrome2,6-8 ranges from asymptomatic, small-vessel
hypersensitivity-type vasculitis with complement and
immune complex deposits disclosed by muscle and nerve
biopsy6 to systemic necrotizing vasculitis8,9. In one report,
however, vasculitis occurred in a POEMS patient with
renal carcinoma7, which is known to be associated with
paraneoplastic vasculitis.
Calciphylaxis-induced cutaneous vasculitis is a rare
disorder which mainly manifests in patients with endstage renal disease (1 to 4%)3 and is associated with a mortality of 60 to 80%. Proximal lesions (thighs and trunk)
occur more often than distal ones (below the knee) and
have a worse prognosis. Indeed, septicemia from infected lesions is the most frequent cause of death. Since the
patient had only mild renal insufficiency, we explored addi-
TABLE II. Reevaluation of the coagulation status and calcium-phosphate homeostasis following the development of calciphylaxis.
Variable
Value (normal range)
Sodium (mmol/L)
Potassium (mmol/L)
Calcium (mg/dL)
Phosphate (mg/dL)
Creatinine (µmol/L)
Urea nitrogen (mmol/L)
PT (INR)
aPTT (INR)
C protein (%)
S protein (%)
Homocysteine (µmol/L)
PTH (ng/L)
Calcitonin (ng/L)
135 (136-145)
4.3 (3.5-5.1)
8.6 (8-10.5)
3.6 (2.5-4.9)
106.08 (53.04-97.24)
37.84 (3.57-17.85)
1.25 (≤ 1.2)
1.2 (≤ 1.2)
122 (67-140)
99 (62-145)
20.84 (5-15)
10 (10-65)
1.5 (< 10)
Abbreviations as in table I.
Discussion
The major and minor criteria for the definition of
POEMS syndrome have been previously outlined2 and the
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Ann Ital Med Int Vol 19, N 4 Ottobre-Dicembre 2004
Riassunto
La sindrome di POEMS (sindrome di Crow-Fukase) è
un raro disordine linfoproliferativo associato a polineuropatia (P), organomegalia (O), endocrinopatia (E), gammopatia monoclonale (M) e manifestazioni cutanee (S).
Queste ultime sono in genere aspecifiche e includono un
ispessimento della cute con iperpigmentazione, ipertricosi
ed angiomi cutanei. Una donna di 45 anni con sindrome
di POEMS si ricovera nel nostro reparto per una rivalutazione della sua patologia e per una persistente debolezza muscolare associata a parestesie riferite alle estremità
degli arti superiori ed inferiori. La sindrome di POEMS
le era stata diagnosticata 30 mesi prima sulla base di un
epatosplenomegalia, linfoadenomegalia, la presenza di
una gammopatia IgAλ, ipotiroidismo, una marcata polineuropatia sensitivo-motoria ed una lesione osteosclerotica solitaria all’omero di sinistra. Otto settimane dopo la
nostra prima osservazione, comparvero delle lesioni cutanee molto dolenti e ben delimitate che una biopsia rivelò
essere dovute a calcifilassi. Questo rappresenta il primo
caso di sindrome di POEMS associata a questo tipo di vasculite. L’assenza di condizioni predisponenti la calcifilassi quali l’insufficienza renale, l’iperparatiroidismo o disordini della coagulazione, sottolineano la complessità
della patogenesi di questa vasculite a decorso infausto.
FIGURE 3. X-ray of the mammary glands showing widespread calcification of the small- and
medium-size vessels.
tional factors reported to trigger or be associated with
this vasculitis. Hypercoagulability10-12 was excluded
because, apart from the prolongation of the prothrombin
time and a slight increase in homocysteine levels, the
activated partial thromboplastin time and the levels of
the S and C proteins were normal. We also excluded calcium-phosphate dysfunction4,13,14 as the serum levels of
parathyroid hormone, calcium and phosphate were normal.
Finally, reports describing the onset of calciphylaxis in
a patient with rheumatoid arthritis receiving immunosuppressive drugs for long periods of time15, suggest that
the previous assumption of corticosteroids by our patient
might have contributed to her calciphylaxis.
Dysregulation of the secretion of pro-inflammatory
cytokines, namely tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β and vascular endothelial growth factor (VEGF), has been suggested to explain many signs and
symptoms related to POEMS syndrome16-18. Notably,
increased levels of TNF-α and IL-6 with their osteoclastogenic properties may account for the osteolysis sometimes observed in this syndrome16. Increased levels of
VEGF18 may account for the ascites, pleural effusion or
cutaneous angioma often observed in these patients17.
VEGF also displays osteoblastogenic properties19,20 and
may be involved in the formation of osteosclerotic
lesions17. Inasmuch as we found none of the known calciphylaxis-inducing conditions in our patient, we propose that a disequilibrium between TNF-α/IL-616 and
VEGF20 levels, respectively with their osteoclastogenic and
osteoblastogenic properties, may have induced calcium
mobilization and calciphylaxis.
Parole chiave: Calcifilassi; Gammopatia monoclonale;
Sindorme di POEMS; Vasculite.
Acknowledgments
The authors are grateful to Mr. Vito Iacovizzi for his
excellent secretarial assistance.
References
01. Crow RS. Peripheral neuritis in myelomatosis. BMJ 1956; 12:
802-4.
02. Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome:
definitions and long-term outcome. Blood 2003; 101: 2496-506.
03. Mazhar AR, Johnson RJ, Gillen D, et al. Risk factors and mortality associated with calciphylaxis in end-stage renal disease.
Kidney Int 2001; 60: 324-32.
04. Khafif RA, DeLima C, Silverberg A, et al. Acute hyperparathyroidism with systemic calcinosis. Report of a case. Arch
Intern Med 1989; 149: 681-4.
05. Belec L, Mohamed AS, Authier FJ, et al. Human herpesvirus
8 infection in patients with POEMS syndrome-associated multicentric Castleman’s disease. Blood 1999; 93: 3643-53.
06. Gherardi RK, Amiel H, Martin-Mondiere C, et al. Solitary
plasmacytoma of the skull revealed by a mononeuritis multiplex
associated with immune complex vasculitis. Arthritis Rheum
1989; 32: 1470-3.
07. Pasqui AL, Bova G, Saletti M, et al. POEMS syndrome with vascular lesions and renal carcinoma - possible role of cytokines.
Eur J Med Res 1998; 3: 304-6.
286
Ileana De Roma et al.
08. Shibata M, Yamada T, Tanahashi N, et al. POEMS syndrome
with necrotizing vasculitis: a novel feature of vascular abnormalities. Neurology 2000; 54: 772-3.
15. Korkmaz C, Dundar E, Zubaroglu I. Calciphylaxis in a patient
with rheumatoid arthritis without renal failure and hyperparathyroidism: the possible role of long-term steroid use and
protein S deficiency. Clin Rheumatol 2002; 21: 66-9.
09. Melikoglu M, Apaydin S, Hamuryudan V, et al. Calciphylaxis:
a condition mimicking necrotizing vasculitis. Clin Rheumatol
1996; 15: 498-500.
16. Gherardi RK, Belec L, Soubrier M, et al. Overproduction of
proinflammatory cytokines imbalanced by their antagonists in
POEMS syndrome. Blood 1996; 87: 1458-65.
10. Mehta RL, Scott G, Sloand JA, et al. Skin necrosis associated
with acquired protein C deficiency in patients with renal failure and calciphylaxis. Am J Med 1990; 88: 252-7.
17. Watanabe O, Arimura K, Kitajima I, et al. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome.
Lancet 1996; 347: 702.
11. Rostaing L, el Feki S, Delisle MB, et al. Calciphylaxis in a chronic hemodialysis patient with protein S deficiency. Am J Nephrol
1995; 15: 524-7.
18. Soubrier M, Dubost JJ, Serre AF, et al. Growth factors in
POEMS syndrome: evidence for a marked increase in circulating vascular endothelial growth factor. Arthritis Rheum 1997;
40: 786-7.
12. Perez-Mijares R, Guzman-Zamudio JL, Payan-Lopez J, et al.
Calciphylaxis in a haemodialysis patient: functional protein S
deficiency? Nephrol Dial Transplant 1996; 11: 1856-9.
19. Midy V, Plouet J. Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem
Biophys Res Commun 1994; 199: 380-6.
13. Ahmed S, O’Neill KD, Hood AF, et al. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin
expression by vascular smooth muscle cells. Am J Kidney Dis
2001; 37: 1267-76.
20. Furumatsu T, Shen ZN, Kawai A, et al. Vascular endothelial
growth factor principally acts as the main angiogenic factor in
the early stage of human osteoblastogenesis. J Biochem (Tokyo)
2003; 133: 633-9.
14. Levin NW, Hoenich NA. Consequences of hyperphosphatemia
and elevated levels of the calcium-phosphorus product in dialysis patients. Curr Opin Nephrol Hypertens 2001; 10: 563-8.
Manuscript received on 15.10.2004; accepted on 26.10.2004.
Address for correspondence:
Prof. Federico Perosa, Sezione di Medicina Interna, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi, Piazza
Giulio Cesare 11, 70124 Bari. E-mail: [email protected]
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