J Neurol (1992) 239 : 49-52
Neurology © Springer-Verlag1992
Polyneuropathy with osteosclerotic myeloma - POEMS syndrome A case report Aleksandra Vidakovi~ 1, Petar Simi~2, Neboj~a Stojisavljevi~ 1, Ivo Eiezovi~ 3, Rajko Triki~ 1, and Slobodan Apostolski 1 1Department of Neurology, 2Department of Orthopaedic Surgery, and 3Department of Haematology, University Clinical Center, Dr. Subotida 6, YU-t 1000 Belgrade, Yugoslavia Received February 15, 1991 / Received in revised form April 26, 1991 / Accepted May 2, 1991
Summary. A rare form of plasma cell dyscrasia characterized by associated polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes has been termed the P O E M S syndrome. The pathophysiology is unknown; plasma cell dyscrasia is essential; secondary manifestations are unexplained. We report a 67-year-old m a n with a 7-month history of progressive weakness and numbness of the legs. Clinical examination revealed sensorimotor polyneuropathy, predominantly affecting the lower extremities, hepatomegaly, and skin haemangiomas. Additional investigations disclosed I g G - l a m b d a monoclonal serum protein, endocrine abnormalities, elevated cerebrospinal fluid protein level and an osteoblastic lesion of the lumbar vertebra. Biopsy of the osteosclerotic vertebra showed a m a r k e d lymphoplasmocytic infiltrate. M R I of the liver disclosed two haemangiomas; this association has not been reported previously.
Key words: M y e l o m a - Osteosclerosis - Polyneuropathy - M protein - H a e m a n g i o m a
Introduction Peripheral neuropathy, organomegaly, endocrinopathy, monoclonal g a m m o p a t h y and skin changes ( P O E M S ) or Crow-Fukase syndrome  is a rare multisystem disorder often associated with osteosclerotic myeloma. The acronym P O E M S , suggested by Bardwick et al. , refers to the m a j o r features of this syndrome; however, patients also typically have papilloedema, intracranial hypertension, high cerebrospinal fluid protein level, osteosclerotic bone lesion, lymphadenopathy and peripheral o e d e m a [2-4, 11, 17]. Since most of the early cases were reported from Japan [8, 14], it was felt that the syndrome was mainly limited to that country. During the last decade m a n y cases have also been recognized in the CaucaOffprint requests to: S. Apostolski
sian population [6, 10, 12, 16]. The pathogenesis of this syndrome has not been explained. The M protein seems to be the crucial factor because symptoms diminish or even disappear after adequate treatment of paraproteinaemia [10, 11]. We present the first case of P O E M S syndrome in this part of Europe.
Case report In a 67-year-old male patient the first symptoms appeared in January 1990, with numbness and weakness in both legs, swelling of the ankles and difficulty in walking. At the same time he noticed development of multiple skin changes over his chest, abdomen and, to a lesser extent, both arms. During the next 7 months, the numbness spread proximally in a symmetrical fashion involving both legs up to the knees. The weakness also progressed and the patient became unable to walk on his toes and heels. He had also become impotent. His previous history included peptic ulcer disease and episodic prostatitis in the last 10 years. In August 1990, neurological examination revealed a sensorimotor polyneuropathy, involving predominantly the lower extremities. A distal distribution of muscle atrophy and moderate weakness of tibial anterior and calf muscles was noted. The patient was areflexic. There was hyperaesthesia in a stocking-glove distribution and loss of vibratrion sense below the iliac crest. There were no autonomic findings and papilloedema was not present. In addition to neurological findings, the patient had hepatomegaly (2 cm below the right costal margin), multiple "wine-red" coloured polypoid and sessile cutaneous changes and skin hyperpigmentation over his shoulders (Fig. 1). EMG showed decreased median and peroneal motor nerve conduction velocities (30 and 21 m/s, respectively). Sensory evoked potentials of the peroneal nerve were not obtainable. Needle EMG revealed denervation of distal, predominantly lower limb muscles, with signs of reinnervation. We did not obtain the patient's agreement to perform nerve biopsy. Laboratory examination disclosed mild hypochromic anaemia (haemoglobin 132g/1, red blood cells 3.9 × 1012/1), white blood cells 5.6 × 109/1, with a normal differential; platelets 230 × 109/i and erythrocyte sedimentation rate (Westergren) 7 mich. There was also mild proteinuria, while urine sediment, serum electrolytes, cholesterol, triglicerides, bilirubin, alkaline and acid phosphatase, BUN, SGOT, SGPT, CK, LDH and creatinine were within normal limits. A fasting blood glucose was 4.48mol/1, and a 2-h post-
Fig. 1. Multiple skin haemangiomas on the chest Fig. 2. Agarose gel isoelectric focusing and immunofixation with anti-IgG of the serum (S) and cerebrospinal fluid (CSF), showing parallel monoclonal bands Fig. 3. Radiography of the lumbar spine: ivory sclerotic L2 vertebra Fig. 4. MRI shows hyperintense focus in the L2 vertebral body which corresponds to the osteosclerotic lesion seen on radiographs; another is localised in the posterior aspect of the L1 vertebral body Fig. 5. Proliferation of lymphocytes, including large numbers of plasma cells in the narrow adjacent to a sclerotic area Fig. 6. Biopsy of the skin showing capillary haemangiomas
Fig. 7. MRI revealed two hyperintense loci in the liver. Angiomatous nature of the lesion was proved by multi echo technique
prandial glucose was 7.89mmol/1, revealing abnormal glucose tolerance (GTT). Compared with the range of normal values in our laboratory for males of this age, testosterone and oestradiol concentrations were decreased (2.1nmol/l and less than 54.0 pmol/1, respectively), while FSH, LH, T4, TSH, cortisol, aldosterone, androstendione, growth hormone, and parathyroid hormone remained normal. Serum Nelson and VDRL tests were negative. The Shilling test showed normal absorption of vitamin B 12. Serum protein immunoelectrophoresis revealed a small peak of monoclonal IgG lambda paraprotein. Concentrations of serum immunoglobulins IgA (3.97 g/l); IgM (2.37 g/l) and IgG (9.01g/1) were within normal limits. Immunoelectrophoresis of the urine was normal, and there was no Bence-Jones proteinuria. Examination of the bone marrow aspirate and biopsy (sternum, anterior and posterior illiac crest) disclosed hypercellularity with less than 2% plasma cells clustered into scanty microfocal infiltrates. A lumbar puncture was performed; the total CSF protein content was increased (1.03g/1), only 2 lymphocytes/mm3 were found, while agarose gel isoelectric focusing and immunofixation of the CSF revealed a monoclonal IgG bind (Fig. 2). Radiographic examination disclosed an osteosclerotic lesion of the L2 vertebral body (Fig. 3) and MRI confirmed this abnormality and discovered another similar, but much smaller lesion in the posterior portion of the L1 vertebral body (Fig. 4). No signs of osteolytic destruction of the skeleton were observed. In an open bone biopsy specimen from L2 vertebra, osteosclerosis and lymphoplasmocytic infiltrations were noted. Plasma cell infiltration surrounded by extensive sclerotic bone with multiple cement lines were discovered (Fig. 5). The lesion was considered to be an osteosclerotic myeloma. Skin biopsy confirmed the presence of cutaneous haemangiomas (Fig. 6). Ultrasonographic examination of the abdomen revealed an enlarged liver with two irregular parenchymal cystic formations. MRI proved these lesions to be haemangiomata (Fig. 7).
Osteosclerotic myeloma is a rare variant of multiple myeloma ( 1 - 2 % ) [5, 21]. Diagnosis is usually made during the evaluation of a cryptogenic peripheral polyneuropathy which occurs in approximately 50% of patients with osteosclerotic myeloma [5, 8, 21], compared with 3 - 5 % in multiple myeloma . The bone marrow is rarely infiltrated with plasma cells and serum M-components (almost exclusively containing lambda light chain) are low and infrequently found in the urine. Peripheral neuropathy, as a major feature of P O E M S syndrome, is predominantly of motor or sensorimotor type . It usually begins in the legs, progresses to the arms and, eventually, if not treated, produces severe disability. Sural nerve biopsy specimens show either pure axonal degeneration, or both axonal degeneration and segmental demyelination [1, 14], without localized deposits of immunoglobulins or amyloid and no signs of vasculopathy. Bardwick et al.  could not demonstrate any antineuronal or antiglial activity of the monoclonal protein, while Reulecke et al.  reported that IgG lambda protein in one patient with P O E M S syndrome reacted with pituitary gland tissue. It was therefore suggested that the pituitary gland and perhaps related structures of the hypophyseo-hypothalamic axis may be the pimary target for pathogenic antibodies, producing secondary endocrinopathy and skin changes. According to these findings, the occurrence of polyneuropathy remains unclear. Endocrine abnormalities have been found in 60-80% of patients with P O E M S [1, 14] with gonadal failure and glucose intolerance or obvious diabetes mellitus being the most frequent (70% and 50%, respectively) . Low plasma testosterone concentration in males with gynaecomastia, atrophic testes and impotence, as well as hyperprolactinaemia, hypothyroidism, hyperthyroidism and adrenal insufficiency have also been reported . Observed increased oestrogen levels have been explained by accelerated conversion of androgen to oestrogen in some patients with P O E M S . In addition to more frequent hyperpigmentation, skin thickening and hypertrychosis [15, 19], several authors have also reported haemangiomatous proliferation of small skin blood vessels in the skin . The same has been observed in kidneys, brain and lymph nodes [2, 11]. Hepatomegaly has been found in up to 68% patients with P O E M S , with only non-specific changes seen on biopsy and autopsy specimens . This is the first report of a patient with fully developed P O E M S syndrome in our population. Liver haemangiomas, as found in our patient, have not been reported previously. It is uncertain whether this finding is just coincidential or a result of a common pathogenic mechanism which leads to the formation of haemangiomas in the skin and other organs.
Discussion The presented case shows all the features of P O E M S syndrome with polyneuropathy, hepatomegaly, oedema, endocrine disturbances, monoclonal IgG lambda gammopathy, solitary osteosclerotic myeloma and skin and liver haemangiomas.
References 1. Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL (1980) Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, m-protein, and skin
4. 5. 6. 7. 8.
9. 10. 11.
changes: the POEMS syndrome; report of two cases and a review of the literature. Medicine (Baltimore) 59:311-322 Bitter MA, Komaiko W, Franklin W A (1985) Giant lymph node hyperplasia with osteoblastic bone lesion and the POEMS (Takatsuki's) syndrome. Cancer 56 : 188-194 Bolling JP, Brazis PW (1990) Optic disc swelling with peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS syndrome). Am J Ophthalmol 109 : 503-510 Bourdette DN, Rosenberg NL (1984) Infiltrative orbitopathy, optic disc edema, and POEMS. Neurology 34 : 532-533 Driedger H, Pruzanski W (1979) Plasma cell neoplasia with osteosclerotic lesions: a study of five cases and a review of the literature. Arch Intern Med 139 : 892-896 Driedger H, Pruzanski W (1980) Plasma cell neoplasia with peripheral polyneuropathy: a study of five cases and a review of the literature. Medicine (Baltimore) 59 : 301-310 Ishikawa O, Nihei Y, Ishikawa H (1987) The skin changes of POEMS syndrome. Br J Dermatol 117 : 523-526 Iwashita H, Ohnishi A, Asada M, Kanazawa Y, Juroiwa Y (1977) Polyneuropathy, skin hyperpigmentation, edema and hypertrychosis in localised osteosclerotic myeloma. Neurology 27 : 675-681 Kelly JJ, Kyle RA, Miles JM, O'Brien PC, Dyck PJ (1981) The spectrum of peripheral neuropathy in myeloma. Neurology 31 : 31-34 Kelly JJ, Kyle RA, Miles JM, Dyck PJ (1983) Osteosclerotic myeloma and peripheral neuropathy. Neurology 33:202-210 Kyle RA (1987) Osteosclerotic myeloma. In: Kelly JJ, Kyle RA, Latov N (eds) Polyneuropathies associated with plasma cell dyscrasia. Nijhoff, Boston Dordrecht Lancaster, pp 91103
12. Libeert P, Van Hoof A, Louwagie A, Marchau M, Dehaene I (1987) The POEMS-syndrome: an unusual form of plasma cell dyscrasia. Acta Clin Belg 42:188-192 13. Matsumine H (1985) Accelerated conversion of androgen to estrogen in plasma cell dyscrasia associated with polyneuropathy, anasarca, and skin pigmentation. N Engl J Med 313: 1025-1026 14. Nakanishi T, Sobue I, Toyokura Y, Nishitani H, Kuroiwa Y, Satoyoshi E, Tsubaki T, Igata A, Ozaki Y (1984) The CrowFukase syndrome: a study of 102 cases in Japan. Neurology 34: 712-720 15. Piette WW (1986) Myeloma, paraproteinemias, and the skin. Med Clin North Am 70 : 155-176 16. Reitan JB, Pape E, Fossa SD, Julsrud OJ, Slettens ON, Solhelm OP (1980) Osteosclerotic myeloma with polyneuropathy. Acta Med Scand 208 : 137-144 17. Resnick D, Greenway GD, Bardwick PA, Zvaifler NJ, Gill GN, Newman DR (1981) Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, m-protein, and skin changes: the POEMS syndrome: distinctive radiographic abnormalities. Radiology 140 : 17-22 18. Reulecke M, Dumas M, Meier C (1988) Specific antibody activity against neuroendocrine tissue in a case of POEMS syndrome with IgG gammopathy. Neurology 38: 614-616 19. Shelley WB, Shelley ED (1987) The skin changes in the CrowFukase (POEMS) syndrome. Arch Dermatol 123 : 85-87 20. Takatsuki K, Sanada Z (1983) Plasma cell dyscrasia with polyneuropathy and endocrine disorder: clinical and laboratory features of 109 reported cases. Jpn J Clin Oncol 13 : 543-556 21. WaldenstrOm JG, Adner A, Gydell K, Zettervall O (1978) Osteosclerotic "plasmocytoma" with polyneuropathy, hypertrichosis, and diabetes. Acta Med Scand 203 : 297-303