POEMS Syndrome: Paraproteinemic neuropathies, Organomegaly, Endocrinopathy, M-protein and Skin changes
The POEMS syndrome, also known as Crow-Fukase syndrome, is a rare multi organ disorder characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein spike and skin changes. Other associated features, such as sclerotic bone lesions, edema, ascites, hematological disorÂders and Castleman disease can also be present. We report a case of POEMS syndrome who presented with insidious onset, progressive sensorimotor polyneuropathy, pedal edema, ascites, hepatomegaly along with skin changes. X-ray pelvis showed osteosclerotic lesions. Thyroid function tests showed hypothyroidism. M-protein (IgG) monoclonal band was seen on immunoelectrophoresis. The patient was started on melphalan and corticosteroid combination therapy. We emphasis on the importance of recognizing a challenging diagnosis of a rare disease, which is shown to be treatment responsive.
POEMS syndrome is a rare paraneoplastic disorder of plasma cell dyscrasias, which was first described in 1956 by Crow and then in 1968 by Fukase . The name POEMS was given to it by Bardwick and co-workers in 1980 based on five salient features: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes . It is more prevalent in men, with male to female ratio of 2.5:1. It usually manifests in 5th and 6th decades of life. Its inheritance is uncertain and its pathophysiology is still not well understood.
A 40-year-old male presented with progressive weakness, tingling and numbness sensation in both lower limbs for two years. He had swelling of lower limbs, abdominal distention and dermatologic changes in form of discoloration and thickening of skin over the cheeks, nose, hands and feet for one year. He had also gave history of erectile dysfunction and loss of libido for six months. There was no history of syncope, bony pain or drug abuse. He had no previous history of hypertension, diabetes or tuberculosis.
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On physical examination, the patient had bilateral pedal edema [Figure 1.c] and abdominal distention [Figure 2.a]. Skin was thickened and hyperpigmented over the face, fingers of the hands and shin (Figure.1a,b,c). Bilateral gynecomastia and testicular atrophy were present. Abdominal examination showed hepatomegaly and ascites. Higher mental functions and speech were normal. Fundus examination showed papilledema on both side and rest of the cranial nerves examination were normal. Motor power in upper limbs was normal and in lower limbs showed predominant distal weakness [Medical Research Council (MRC) 4/5 at hip joint and 4-/5 at ankle joint). Deep tendon reflexes in upper limb were diminished (+1) including biceps, triceps and supinator and absent in lower limbs. There was 30% loss in pain, touch and temperature sense in both lower limbs below knees. Posterior column sensations (joint position and vibration sense) were also impaired in lower limbs below the anterior superior iliac spine. Romberg sign was positive.
Hemogram, liver and renal function tests, muscle enzymes (creatine phosphokinase), serum ferritin and vitamin B12 level were normal. Serum total protein was 7.1 gm/dL, albumin 3 gm/dL, globulin 4.1 gm/dl, and A:G ratio 1:1.3. Fasting and postprandial blood sugar level were normal. Thyroid function test showed raised TSH level (16.62 μ/ml). Luteinizing hormone (LH) and testosterone levels were 15 IU/L (1.8-8.6 IU/L) and 111 ng/L (300-1,000 ng/dL), respectively. Antinuclear antibody (ANA), Rheumatoid factor (RF), serum human immunodeficiency virus (HIV) ELISA test, hepatitis B and C markers were negative. Ultrasonography of abdomen showed hepatomegaly (16 cm), moderate ascites and enlargement of multiple lymph nodes along the iliac vessels. Fine needle aspiration cytology of mesenteric lymph node was inconclusive. Ascitic fluid examination revealed exudative nature (SAAG <1.1). Ascitic fluid adenosine deaminase (ADA) and malignant cells were negative. Nerve conduction study showed sensorimotor demyelinating and axonal type neuropathy in both upper and lower limbs including bilateral median, ulnar, peroneal, tibial and sural nerves [Figure 3]. Cerebrospinal fluid examination was normal. X-ray pelvic bone showed multiple osteosclerotic lesions involving head of left femur and right iliac crest [Figure. 2.b]. X-ray skull and spine were normal. The serum protein electrophoresis showed gamma globulinemia with no monoclonal M spike. Immunoelectrophoresis using immunofixation method revealed monoclonal IgG lambda band. The bone marrow biopsy showed large atypical plasma cells in the range of 8%-10% [Figure. 4]. The patient was diagnosed as POEMS syndrome and was given melphalan (16 mg/m2) and corticosteroid combination therapy. The patient is still in follow up.
POEMS syndrome is a rare, multiple system disorder, characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal or M-protein band and skin changes. Any three of the five features may be present to establish diagnosis . However, some authors have proposed clinical criteria for diagnosis in which includes two major criteria, which can be either presence of polyneuropathy or plasma cell proliferative disorder. Minor criteria include sclerotic bone lesions, organomegaly, edema, endocrinopathy, papilledema or skin changes .
Polyneuropathy is a predominant feature of POEMS syndrome and is found in >90% of the cases. It is usually a sensorimotor, axonal and demyelinating type polyneuropathy . As in our patient, both axonal and demyelinating polyneuropathy are seen on electrodiagnostic studies. The mechanism of neuropathy is not known but the recent evidence of the presence of anti-neural antibodies points to an immunological mechanism . Endocrinopathies occur with a frequency of 60%-80% and the most common are gonadal failure (70%) and glucose intolerance/diabetes mellitus (50%).
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Hypo or hyperthyroidism, hyperprolactinemia and adrenal insufficiency have also been reported. The mechanism of endocrinopathy is also not obvious; however, involvement of direct acting antibodies against hypothalamo-hypophyseal-axis and endocrine end organs has been hypothesized . In our patient, impotence, loss of libido and testicular atrophy and hypothyroidism on ancillary laboratory investigation were present.
Increased levels of vascular endothelial growth factor (VEGF) are found in POEMS syndrome. VEGF increases microvascular permeability, thereby inducing edema, ascites and pleural effusions as were present in our patient [6,7]. However, measurement of VEGF level in ascites was not available in our patient. Papilledema may be seen in approximately 37% of patients and is not associated with the increase in intracranial pressure. The real cause of papilledema is not still known. Hepatomegaly may be seen in up to 50% of patients with splenomegaly and lymphadenopathy occurring less often. The hyperpigmentation over the face, legs and hands was also observed in our case. The skin changes usually observed in POEMS syndrome are hyperpigmentation, lichenification, hypertrichosis, sclerodermoid changes and glomeruloid hemangiomas. Skin biopsy may show inflammation, fibrosis, or nonspecific changes. Monoclonal protein is detected in more than 90% of patients and may become positive in the follow-up of patients who have no monoclonal gammopathy initially .
Nearly all cases reported in the literature show lambda positivity as in our patient. It may be rarely found in urine and cerebrospinal fluid (CSF). The natural course of POEMS syndrome is chronic, with a reported median survival for a decade (8-13.8ys). The morbidity depends on the extent and number of systems involved. The cause of POEMS syndrome is still unknown. It is tempting to incriminate the presence of lambda light chains in the pathogenesis because of their unexpected frequency (more than 95% of patients), but histopathologic review of affected organs and nerves does not support that it is a form of deposition disorder. Increased levels of cytokines IL-1ß, TNF-á and IL-6, more specifically VEGF, appear to play a pathogenic role in the disorder [9,10].
In view of the constellation of a mixed polyneuropathy, monoclonal gammopathy, osteosclerotic myeloma, extravascular volume overload, bilateral papilledema, skin changes and endocrinopathies, our patient was diagnosed as POEMS syndrome. However, other close differential diagnosis like tuberculosis and hemochromatosis were ruled out with appropriate investigations. Patient was treated with combination of alkylating agent melphalan and corticosteroid. To conclude, when a patient present with unexplained sensorimotor polyneuropathy, signs of extravascular volume overload and evidence of other system involvement, a high index of suspicion should be kept for a diagnosis of POEMS syndrome, to avoid missing this rare syndrome, which is amenable to treatment.
Figure 1. Photographs of patient showing skin hyperpigmentation over the face, hand and limbs (thin arrows). Thick arrow showing pitting edema over the left leg.
Figure 2. Photograph of patient (a) showing abdominal distention (free fluid was confirmed by ultrasonography). X-ray pelvic bone (b) showing multiple sclerotic lesion over right iliac crest (thin arrow) and one large osteosclerotic lesion (thick arrow) over the neck of left femur (b).
Figure 3. Nerve conduction study showing axonal and demyelinating neuropathy in right median nerve.
Figure 4. Bone marrow smear in centre reveals one large atypical plasma cell, which has prominent nucleoli and abundant cytoplasm. There is loss of normal nuclear configuration with fraying border.
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