Hypergammaglobulinemic purpura of Waldenström
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York
We report a case of a 33-year-old-woman with a one-year history of bilateral lower extremity vasculitis and laboratory evidence of hypergammaglobulinemia with otherwise unremarkable routine laboratory and rheumatologic studies. Her clinical picture, together with histopathologic evidence of leukocytoclastic vasculitis, favor a diagnosis of hypergammaglobulinemic purpura of Waldenström.
A 33-year-old woman was referred to the Charles C. Harris Skin and Cancer Pavilion for evaluation and a treatment of an intermittent eruption on her lower extremities that had been present for one year. The lesions began after an upper respiratory tract infection. She was taking neither prescription nor over-the-counter medications at the time of the eruption. She denied constitutional symptoms, which include fever, chills, arthralgias, or weight loss. She also denied headache, abdominal pain, and photosensitivity. The patient saw a dermatologist in her home state shortly after the eruption began and a biopsy was performed.
On the lower extremities below the knees there were scattered, hyperpigmented macules, some approaching 1 to 2 cm in size, and few, palpable purpuric lesions that extended to the dorsal aspects of the feet and toes. There was no cervical, supraclavicular, inguinal, or axillary lymphadenopathy and no hepatosplenomegaly.
A serum protein electrophoresis initially showed hypergammaglobulinemia. The erythrocyte sedimentation rate was 20mm/hr, and the following labs were negative or normal: rheumatoid factor, ANA, anti-double stranded DNA, RNP, anti-smooth muscle antibody, Scl-70, SSA/SSB, La, Jo-1, antichromatin, anticentromere antibody, anti-cardiolipin antibody, complement, cryoglobulins, lupus anticoagulant (PTT-LA, drVVT), C-ANCA, P-ANCA, hepatitis B serologies, hepatitis C serologies, HIV ELISA, and anti-CMV antibodies. Subsequent serum protein electrophoresis was normal.
There is a perivascular infiltrate that is composed predominantly of neutrophils with associated nuclear dust, extravasated erythrocytes, and fibrin deposits in the vessel walls.
Hypergammaglobulinemic purpura of Waldenström, which is sometimes called benign hypergammaglobulinemic purpura, was first described by the Swedish physician Jan Gosta Waldenström in 1943 . He reported three cases of women with chronic relapsing purpura, hypergammaglobulinemia, an elevated erythrocyte sedimentation rate (ESR), and mild anemia.
Clinically this entity is characterized by recurrent crops of petechiae and larger purpuric macules on the lower extremities, which often burn or sting and may be fleeting. The purpura is usually preceded by pruritus, tingling, or pain and is often exacerbated by tight-fitting garments, prolonged immobilization, and heat [2, 3]. There is general consistency among reports of this rare entity in the literature with more than 80 percent of reported cases occurring in women between the ages of eighteen and forty years at the onset of petechiae [4, 5]. A skin biopsy specimen from one of these lesions may show a range of histopathologic findings: simple hemorrhage, a mild perivascular lymphocytic infiltrate, or leukocytoclastic vasculitis .
The differential diagnosis for lower extremity purpura is vast. However, in this patient, two of the more likely considerations include cryoglobulinemic purpura, which can be associated with internal organ involvement and necrosis of the skin, and thrombocytopenic purpura. Both of these diseases were ruled out with normal coagulation studies, platelet count, and serum cryoglobulins.
The pathogenesis of hypergammaglobulinemic purpura of Waldenström remains incompletely understood. Whereas this condition has been associated with hypergammaglobulinemia, authors have argued that perhaps a more specific feature of this condition is the presence of small circulating immune complexes that contain IgG or IgA rheumatoid factor. These small complexes have been isolated in individuals with a clinical presentation that fits this syndrome but who lacked polyclonal hypergammaglobulinemia [7, 8]. IgG and IgA rheumatoid factors are highly soluble, which has been posited to explain the rapidity with which lesions appear and resolve. The presence of monoclonal rheumatoid factor early in the disease in some patients as well as the tendency of affected individuals to develop autoimmune and (less often) lymphoproliferative disorders supports the presence of a mild immune dysregulation syndrome. However, in this patient rheumatoid factor was tested and repeatedly negative.
Hypergammaglobulinemic purpura of Waldenström can be primary or secondary . In younger patients it is usually primary, but over time some patients develop evidence of an autoimmune connective-tissue disease, most frequently Sjögren's syndrome and occasionally rheumatoid arthritis or lupus erythematosus. Hence justifying the extensive autoimmune serologic work-up our patient underwent. It has been reported that much less often, a monoclonal gammopathy or, very rarely, a lymphoma or multiple myeloma develops. Because no clear underlying trigger other than a preceding viral syndrome has been identified as the cause for this patient's condition, she is considered to have primary hypergammaglobulinemic purpura of Waldenström.
Waldenström observed one of his original patients for at least 35 years and, although she displayed persistent gammopathy and recurring purpura, he concluded that life expectancy was not diminished . Treatment for this disease has been varied but overall is unsatisfactory. Owing to the benign nature of this condition, aggressive therapy is unnecessary and should be avoided. In some cases plasmapheresis has resulted in decreased levels of circulating immune complexes and transient improvement in cutaneous lesions [5, 7]. Other agents used to treat this syndrome include aspirin and dipyridamole; support stockings are helpful.
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