eMedicine Specialties > Dermatology > Internal Medicine

POEMS Syndrome

Author: Joanna L Chan, MD, Resident Physician, Department of Dermatology, University of Texas Southwestern Medical Center
Coauthor(s): Wingfield Rehmus, MD, MPH, Co-Director of Clinical Trials, Clinical Instructor, Department of Dermatology, Stanford University Medical Center; Alexa F Boer Kimball, MD, MPH, Associate Professor of Dermatology, Harvard University School of Medicine; Vice Chair, Department of Dermatology, Massachusetts General Hospital; Director of Clinical Unit for Research Trials in Skin (CURTIS), Department of Dermatology, Massachusetts General Hospital and Brigham and Women's Hospital
Contributor Information and Disclosures

Updated: Jun 17, 2008

Introduction

Background

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystemic disease that occurs in the setting of a plasma cell dyscrasia. The pathophysiologic link between the constellation of symptoms and the underlying disease is not well understood, but the link may be related to changes in the levels of a cytokine or a growth factor. POEMS syndrome was first described by Crow in 1956 and then by Fukase in 1968. The syndrome was termed Crow-Fukase syndrome (by which it is known in Japan) by Nakanishi in a study of 102 cases in Japan.

In 1980, the acronym POEMS was coined by Bardwick et al based on the 5 main features of the disease, namely, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.

No specific case definition exists for POEMS syndrome; however, most authors agree that patients with POEMS syndrome should have 3 or more of the 5 features. Some authors have proposed that the presence of 2 major criteria, including a monoclonal plasma-proliferative disorder and polyneuropathy, in addition to the existence of 1 minor criterion, is sufficient for diagnosis. The suggested minor criteria include sclerotic bone lesions, organomegaly, edema, endocrinopathy, papilledema, and skin changes. However, the findings of a retrospective analysis of 629 patients using these criteria suggest that this approach may be inadequate for excluding other disease processes that may account for symptoms and that atypical presentations of POEMS may be misdiagnosed.^1,2

The polyneuropathy associated with POEMS syndrome is a bilateral symmetric disturbance. It involves both motor and sensory nerves, begins distally, and has a progressive proximal spread. Associated cranial or autonomic nerves are not involved. Both demyelination and axonal degeneration are noted.

The liver, the lymph nodes, and the spleen are the organs most frequently involved. Enlargement of the lymph nodes and spleen is secondary to changes consistent with Castleman disease (giant angiofollicular hyperplasia, multicentric plasma cell variant) in most patients. Approximately 15% of patients with POEMS syndrome have concomitant evidence of Castleman disease. Hepatomegaly is not associated with any defined histologic or pathophysiologic changes.

Multiple endocrinopathies have been associated with POEMS syndrome, and most patients have more than 1 endocrine abnormality. Many of the abnormalities noted can be explained by elevations in estrogen levels. Impotence and gynecomastia are common among men. Amenorrhea is common among women. Diabetes mellitus and glucose intolerance are also noted in many patients. Other associated endocrinopathies include hypothyroidism, hyperprolactinemia, and hypoparathyroidism.

POEMS syndrome is seen in the setting of a plasma cell dyscrasia. Although many plasma cell disorders have been reported in patients with POEMS syndrome, most patients are seen with osteosclerotic myeloma or monoclonal gammopathy of unknown significance.

The M proteins most frequently found are the immunoglobulin A (IgA)–gamma and immunoglobulin G (IgG)–gamma light chains. In a case report of one patient with POEMS syndrome,³ serum electrophoresis demonstrated an M-band with isolated IgA heavy chain but no abnormal light chain, which could suggest abnormal secretion of monoclonal protein or the rare possibility of coincidental heavy-chain disease in association with POEMS syndrome. A single case of POEMS syndrome in association with Waldenström macroglobulinemia,⁴ characterized by immunoglobulin M–kappa paraproteinemia, has been reported. Classic multiple myeloma has not been associated with the disease. The type of plasma cell disorder has not been shown to be correlated with the constellation of symptoms noted in patients with POEMS syndrome.

Multiple dermatologic changes have been associated with POEMS syndrome. The most common changes include hyperpigmentation, skin thickening, sclerodermoid changes, and hypertrichosis. Other skin changes, including whitening of the proximal nail (Terry nails), peripheral edema, hyperhidrosis, clubbing of the fingers, Raynaud phenomenon, and angiomas, have been observed.

Other signs and symptoms associated with POEMS syndrome include papilledema, anasarca, pleural effusions, ascites, fever, thrombosis, renal insufficiency, and diarrhea.

Pathophysiology

The pathophysiology of POEMS syndrome is not well understood. In all patients, a plasma cell disorder underlies the development of the syndrome; however, the mechanism by which this occurs is unknown. Elevations of cytokines, such as interleukin (IL)–1beta, IL-6, and tumor necrosis factor (TNF)–alpha, have all been noted.

Most recently,⁵ significant elevations in vascular endothelial growth factor (VEGF) levels have been noted. Increases in VEGF levels have been postulated to lead to enhanced vascular permeability, leading to the associated edema, increased endoneural pressure, and deposition of plasma cell–derived material. As myelin is exposed to serum cytokines and complement, demyelination can occur. In one case report of a patient with POEMS syndrome and bilateral cystoid macular edema, macular thickness varied with serum VEGF levels. After vitrectomy and an intraocular triamcinolone injection, decreased macular thickness was associated with lower intraocular VEGF levels. The authors proposed that elevated VEGF levels may be causally related to cystoid macular edema in persons with POEMS syndrome. Stimulated vascular proliferation has also been postulated to result in some of the skin changes associated with the disease.

VEGF may also play a role in bone metabolism, as suggested by a study of 2 patients who received high-dose therapy (HDT) with autologous stem cell transplantation. In this study by Kastritis et al,⁶ decreasing VEGF levels corresponded with both clinical improvement and the normalization of bone metabolism as measured by multiple remodeling indices.

In a study of 22 patients with POEMS, hyperalgesia was correlated with an elevation of proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), in addition to the electrophysiologic reduction of sensory nerve action potentials and the histopathologic loss of myelinated fibers.⁷ Serum levels of other growth factors, including epidermal growth factor, fibroblast growth factor, and platelet-derived growth factor, are not increased in patients with POEMS syndrome. Because POEMS syndrome is associated with Castleman disease and angioma formation, a role for human herpesvirus 8 (HHV-8) has been postulated; however, early studies have not demonstrated an association.

Frequency

International

POEMS syndrome is rare. Several hundred cases have been described in the literature; however, the incidence may be underreported because the syndrome may go unrecognized.

Mortality/Morbidity

The morbidity associated with POEMS syndrome depends on the systems involved and ranges from skin pigment alteration to debilitating weakness and loss of function. The median survival period for patients with POEMS syndrome is 8 years. The natural course of POEMS syndrome is chronic, with a reported median survival of approximately a decade (8-13.8 y). In their review, Miralles and colleagues⁸ reported a 5-year survival rate of 60%.

Overall shorter survival has been associated with extravascular volume overload (eg, effusions, edema, ascites) and fingernail clubbing. Cardiorespiratory failure, renal failure, infection, and progressive inanition are among the most common causes of death. The neurologic sequelae of POEMS syndrome cause approximately 50% of the patients with POEMS syndrome to become bedridden. Death may also occur as a consequence of decubitus ulcers and thromboses due to inactivity, organomegaly, and endocrinopathy, rather than as a consequence of the aggressiveness of the monoclonal protein.

Race

No specific racial association has been identified, although a preponderance of cases have been reported in the Japanese literature.

Sex

POEMS syndrome is slightly more prevalent among men than women, with a male-to-female ratio of 2.5:1.

Age

The onset of POEMS syndrome occurs most frequently in the fifth or sixth decade of life, with a mean patient age at onset of 48 years for men and 59 years for women.  In 2007 and 2008, however, POEMS syndrome has been reported to occur in two 15-year old patients.^9,10

Clinical

History

Presenting symptoms vary based on the organ systems involved.

• Frequent presentations include the following:
  • Symmetric distal weakness and paresthesia
  • Painful diarrhea
  • Peripheral edema
• Patients may also report the following:
  • Impotence
  • Gynecomastia
  • Amenorrhea
  • Shortness of breath
  • Hypertrichosis
  • Hyperpigmentation
  • Hyperhidrosis
  • Raynaud phenomenon
  • Loss of function because of skin tightening
  • Edema
  • Diarrhea
  • Rarely, bone pain and fractures

Physical

• Skin manifestations
  • Diffuse hyperpigmentation and lower extremity edema are seen in more than 90% of patients.
  • Hypertrichosis is seen in 80% of patients and can be diffuse but is usually most pronounced over the face, the limbs, and the chest.
  • Skin thickening with sclerodermoid changes and tightening, which can limit function, is seen in approximately 77% of patients.
  • Angiomas are often present and may progress rapidly.
  • Nail changes are noted, with whitening of the proximal nails and possible clubbing.
  • Many other skin changes have also been observed in persons with POEMS syndrome; these changes include alopecia, flushing, ichthyosis, Sweetlike lesions, and vasculitis.
  • Mucous membrane involvement has not been reported.
• Neurologic manifestations
  • Motor deficiency follows decreased perception of pinprick and vibration sensation.
  • Both motor and sensory deficits are reported and are characterized by distal, symmetric, and progressive involvement associated with gradual proximal spread.
  • Some loss of temperature sensation and nociception has been reported.
  • Deep tendon reflexes are diminished, but cranial nerve examination results are normal.
• Cardiovascular manifestations
  • Rarely, macroangiopathy affecting coronary and lower limb arteries may be associated with POEMS syndrome, which has resulted in reported cases of cerebrovascular manifestations in the absence of vascular risk factors.
  • Acute ischemic stroke has been reported rarely in patients with POEMS syndrome, and one case series of such patients described a particular association with end artery border-zone infarctions and elevated fibrinogen levels, which may be implicated in the pathogenesis of cerebrovascular events.⁷
  • Other authors suggest that patients with POEMS syndrome who had ischemic stroke had elevated fibrinogen levels in the absence of increased acute-phase reactants.⁸ This counterpoint suggests that increased fibrinogen may be more a consequence of the chronic release of proinflammatory cytokines characteristic of POEMS syndrome and of the inflammatory response following a stroke, rather than to its actual pathogenesis.
• Endocrine manifestations
  • In a series of 170 patients, 84% had a recognized endocrinopathy, the most common of which was hypogonadism associated with depressed testosterone levels, gynecomastia, or elevated prolactin levels.
  • Other abnormalities included hypothyroidism, abnormal glucose metabolism, adrenal insufficiency, hypocalcemia
  • Many patients may exhibit evidence of multiple endocrinopathies in the 4 major endocrine axes (ie, gonadal, thyroid, adrenal, and glucose).¹¹
• Pulmonary manifestations
  • Approximately a quarter of patients will develop respiratory symptoms within 2 years of diagnosis.
  • Patients may develop restrictive lung disease, pulmonary hypertension, respiratory muscle weakness, and an isolated diminished diffusing capacity.
  • Radiographic findings such as pleural effusions and diaphragm elevation may be seen in nearly a quarter of patients.¹²
• Other extracutaneous manifestations
  • Hepatomegaly, splenomegaly, and lymphadenopathy occur in patients with organomegaly.
  • Patients with endocrine involvement may have gynecomastia.
  • Strokes have been reported rarely in patients with POEMS syndrome, which is postulated to result from an intracranial vasculopathic process.¹³
  • Patients with POEMS syndrome have been shown to have bilateral optic disc edema and bilateral cystoid macular edema. Authors suggest that these findings may reflect increased vascular permeability.^14,15

Causes

• All cases of POEMS syndrome are associated with a plasma cell disorder.
• The syndrome has been seen in association with osteosclerotic myeloma, monoclonal gammopathy of unknown significance, and Waldenström macroglobulinemia, but not with classic multiple myeloma.
• The reason plasma cells in some dyscrasias produce factors that cause POEMS syndrome while others do not is not clear.
• The mechanism by which plasma cells lead to POEMS syndrome is not understood; however, elevations in IL-1beta, IL-6, TNF-alpha, and VEGF levels have been implicated.

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