Crow-Fukase syndrome
(POEMS syndrome)

Article written and reviewed by Dr Luca Moretti

Crow-Fukase syndrome is not a disease distinct from POEMS syndrome. It is a historical synonym, used mainly in Japanese literature, for the same multisystem paraneoplastic syndrome associated with a monoclonal plasma cell disorder. The terms Takatsuki syndrome and PEP syndrome have also been used in the past.

The definition of a specific “atypical Crow-Fukase syndrome” as an incomplete variant is not standardized. Incomplete or early presentations of POEMS are possible, but they must be evaluated using recognized diagnostic criteria and by investigating alternative diagnoses.

Etiology, pathogenesis and pathophysiology

The disease arises from a monoclonal plasma cell clone, almost always characterized by lambda restriction. The monoclonal component may be small and is not always evident on electrophoresis alone. Increased VEGF plays a central role in increased vascular permeability, edema, effusions and microvascular abnormalities. Other cytokines contribute to neuropathy, endocrinopathies and hematologic and cutaneous manifestations.

Clinical manifestations

The dominant manifestation is a progressive sensorimotor polyneuropathy, predominantly demyelinating and often initially distal and symmetric. Associated findings may include organomegaly, endocrinopathies, hyperpigmentation, glomeruloid hemangiomas, hypertrichosis, peripheral edema, ascites, pleural effusions, papilledema, thrombocytosis or polycythemia and osteosclerotic bone lesions. The clinical picture is variable, and not all letters of the acronym need to be present simultaneously.

Investigations and Diagnosis

Evaluation includes neurologic examination, electromyography, investigation of the monoclonal component with serum and urine immunofixation, free light chains, VEGF measurement, skeletal imaging with CT or PET-CT, bone marrow biopsy and assessment of endocrine, cardiopulmonary and ocular manifestations. In incomplete presentations, it is essential to exclude CIDP, AL amyloidosis, IgM-associated neuropathy, multiple myeloma, Castleman disease and other causes of systemic neuropathy.

The diagnosis of POEMS requires:

• both mandatory criteria: polyneuropathy and a monoclonal plasma cell disorder;
• at least one additional major criterion: Castleman disease, osteosclerotic bone lesions or increased VEGF;
• at least one minor criterion: organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema or thrombocytosis or polycythemia.

A partial presentation should be defined as suspected or incomplete POEMS only after specialist assessment; the term Crow-Fukase does not itself identify an atypical form.

Treatment and Prognosis

Treatment depends on the extent of the plasma cell clone. One or a few osteosclerotic lesions without diffuse bone marrow involvement may be treated with radiotherapy. Systemic disease requires clone-directed therapy, frequently with lenalidomide and dexamethasone or other appropriate regimens, while autologous stem cell transplantation is an option in eligible patients. Supportive therapies are required for neuropathy, endocrinopathies, edema and cardiopulmonary complications.

Bevacizumab is not recommended in clinical practice for POEMS because lowering VEGF has not translated into reliable benefit and clinical deterioration and deaths have been reported.

Complications

Complications include severe neurologic disability, neuropathic pain, falls, respiratory failure, pulmonary hypertension, effusions, anasarca, thrombosis, endocrine dysfunction and infections related to general impairment or treatment. Prognosis is influenced mainly by cardiopulmonary involvement, timeliness of diagnosis and response to treatment of the plasma cell clone.

References
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