Cryoglobulinemia in a child.

Cryoglobulinemia is a rare condition. We report a case of cryoglobulinemia in 1.5-year-old boy, who presented with bluish black discoloration of hands and feet. Serum was positive for cryoglobulins. The serum cryoglobulin level was 70 μg/ml (normal <20 μg). Serum protein electrophoresis revealed the presence of M-spike. Serum immunofixation and assessment of clonality could not be done as these specialized investigations are not available here. Investigations did not reveal any systemic involvement. He was treated with anticoagulants, broad-spectrum antibiotics, and systemic steroids with which he recovered completely.

Introduction

Cryoglobulins are circulating immunoglobulins complexed with other immunoglobulins or other proteins that reversibly precipitate in cold.[1] Cryoglobulins were first described by Wintrobe and Buell in 1933 in a patient with Multiple myeloma .The classification initially proposed by Brouet et al defined simple cryoglobulinemia as type 1 and subdivides mixed cryoglobulinemia as type 2, in which case the antiglobulin is typically monoclonal and type 3 in which the antiglobulin is polyclonal.[2] Type 1 cryoglobulinemia accounts for 10 to 15% of people with Cryoglobulinemia. It is mainly found in patients with lymphoproliferative disorders it is frequently asymptomatic. Type 2 mixed cryoglobulinemia accounts for 50 to 60% of patients. Type 3 mixed Cryoglobulinemia (30 to 40%). The term essential cryoglobulinemia describes cryoglobulinemia with no clinical signs of underlying disease.[23]

Case Report

A 2-year-old boy was brought to the department of dermatology with a history of progressive bluish black discoloration of the skin involving hands, feet, legs, and arms of 20-day duration, associated with low-grade fever. There was a history of injury to right heel 15 days back. There was no history of drug intake. The boy was febrile and a single lymphnode was enlarged in the right inguinal region. Cutaneous examination revealed bluish black gangrenous patches involving both knees [Figure 1], legs, feet, and left hand. Vasculitic purpuric patches were seen on both palms and soles. Acral cyanosis was present. Dorsalis pedis artery on the right side was absent. Oral examination revealed small ulceration on the palate. It was provisionally diagnosed as purpura fulminans. However, antiphospholipid syndrome and acute hemorrhagic edema of infancy were also considered. He was investigated. count blood count was within normal limits. The platelet count was 3.5 lacs. Blood sugar was 105 mg%, blood urea was 17 mg%. The coagulation profile was normal. The blood culture was sterile. The urine culture showed no growth. ANA was negative. The rheumatoid factor was positive. Anticardiolipin antibodies IgG, IgM, and IgA were negative. HbsAg was negative. HCV antibody was negative. VDRL, HIV 1, and 2 were nonreactive. Serum electrolytes were normal. The Shilling test and C-reactive protein were negative.

Figure 1

Both knees showing gangrenous patches

Echocardiogram revealed a normal study. The color Doppler study showed mild narrowing of the right anterior tibial artery and dorsalis pedis artery. Serum cryoglobulin was positive. The serum cryoglobulin level was 70 μg/ml. Serum protein electrophoresis showed the presence of M-spike. The detailed characterization and typing of cryoglobulins by immunofixation analysis could not be done as it is not available here. Skin biopsy showed features of vasculitis [Figure 2]. Direct immunofluorescence did not reveal immune deposits. The diagnosis of cryoglobulinemia was established but the type of cryoglobulinemia could not be determined and the child was treated with broad-spectrum antibiotics, anticoagulants, and systemic steroids with which the child recovered completely.

Figure 2

Histopathology of skin H&E stain 40× showing features of Vasculitis

Discussion

Cryoglobulins were first described by Wintrobe and Buell in 1933 in a patient with multiple myeloma.[1] The detailed characterization and typing of the cryoglobulins require specialized investigations like immunofixation, immunoblotting, two-dimensional gel electrophoresis, and capillary zone electrophoresis which are available in advanced centers.

The clinical presentation of patients with cryoglobulinemia includes purpura, arthralgia, and fatigue. Purpura is usually located distally, most typically on the lower extremities. Showers of these lesions may occur spontaneously, may be provoked by cold exposure, and may be induced by long periods of standing or sitting. Synovitis, serositis, digital ulceration and gangrene, urticaria, urticarial vasculitis, and cold urticaria may also occur in association with cyoglobulinemia.[4] Raynaud's phenomena and ulceration of lower extremities have also been reported.[25] A minority of patients present with vasculitis affecting kidneys, skin, liver, brain, or abdominal organs.[3] A total of 30-60% of patients develop renal involvement which is predominantly membranoglomerulonephritis.[6] However, the reported case did not have renal involvement. Wing et al. (2004) from China have reported eight cases of cryoglobulinemia.[7] Two of his cases were associated with adenocarcinoma and one was associated with lymphocytic leukemia. All the three cases were found to have structural abnormalities including multiple dissection, aneurism, and congenital aortic abnormalities. They attributed these unusual vascular changes peculiar to this ethnic (Chinese) group. Patients with mixed essential cryoglobulinemia tend to have interstitial lung disease possibly related to immune complex deposition.[8] There was no lung involvement in the reported case. Neurologic symptoms may occur in a small percentage of patients and typically consists of peripheral sensory and motor polyneuropathy, which may present as paresthesia or foot drop.[5] Hepatic signs consist of hepatomegaly with the elevation of alkaline phosphatase levels. Serological studies for hepatitis B and C may be positive. Other manifestations of vaso-occlusive phenomena or immune complex disease may affect the eyes and gastrointestinal system. Dermatological and articular manifestations may be improved by nonsteroidal anti-inflammatory agents. A more severe visceral involvement may require glucocorticoid therapy in conjunction with cytotoxic agents, melphelan, chlorambucil, or cyclophosphamide. Plasmapheresis has been used to treat patients with rapidly progressive disease. Cryofilteration has been recently used to treat patients refractory to conventional therapy. Cakir et al. (2005) have reported a case of type 3 mixed cryoglobulinemia with digital necrosis which was successfully treated with intermittent IV pulse cyclophosphomide.[9] The reported case was successfully treated with broad-spectrum antibiotics, anticoagulants, and systemic steroids.