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Crystallizing thoughts about crystalglobulinemia

DII small banner By Warren R. Heymann, MD
Dec. 14, 2017

A, Necrotic purpuric lesions on the dorsum of the foot in a patient with crystalglobulinemia. The thumb had been previously amputated because of necrotic gangrene secondary to occluded vessels. B, Histopathologic features in cutaneous lesions of crystalglobulinemia. Scanning power showing a subepidermal blister and dilated and congestive blood vessels in the dermis. C, Higher magnification showing elongated eosinophilic crystals of immunoglobulins within the vessel lumen. D, Direct immunofluorescence showing IgG positivity of the intravascular crystals. Additional immunofluorescence findings consisted of positivity for κ and negativity for λ light chains (B and C, Hematoxylin-eosin stain; original magnifications: B, ×10; C, ×400; D, Direct immunofluorescence for IgG; original magnification: ×200).
Credit: JAAD
Every resident asks me if and when they will become confident about their level of knowledge. My answer is simple and consistent — never. This perception was reinforced by perusing the outstanding review of cutaneous paraprotein deposits by Alegría-Landa et al, that included a discussion of “crystalglobulinemia” (1); I was unaware this diagnosis and decided to learn more about it.

The term “crystalglobulinemia” (CG) was coined by Grossman et al in 1972. The authors found a cryoprotein consisting of spontaneously formed crystals of gamma globulin (IgG3K) in the serum of a 54-year-old woman who had repeated episodes of widespread purpura and necrotic cutaneous ulcerations. No renal disease or involvement of other organ systems was observed. Analyses of the patient’s serum showed microscopic crystals of gamma globulin comprising almost 50% of her serum volume when cooled to 4 °C. Treatment with steroids and plasmapheresis was successful in controlling the manifestations of her disease. In their discussion, they note that in 1938, a spontaneously crystallizable human immunoglobulin was first described in a patient with myeloma. (2)
The crystalglobulinemia syndrome (CS) is rare; approximately 40 cases have been reported. (3) Although occasionally associated with non–plasma cell malignancies such as B-cell chronic lymphocytic leukemia (1), according to Ball et al, CS usually occurs as a paraneoplastic syndrome associated with multiple myeloma (MM). The demographics of CS are similar to those of MM. It occurs more often in male patients (male: female ratio, 2.4:1), at a median age of 55 years (range, 26-82 years).The syndrome may be the initial manifestation of underlying MM typically presenting as a systemic necrotizing vasculitis with rapidly progressive renal failure, polyarthropathy, peripheral neuropathy, cutaneous ulcerations, petechiae, and ecchymoses. Although CS usually is associated with MM at the time of diagnosis, in 26% of patients, it occurs as essential crystalglobulinemia, unassociated with a lymphoreticular malignancy.(4). CG has been reported in a 61 year-old man with a mononclonal gammopathy of undetermined significance (MGUS) manifesting as chronic arthralgia and recurrent acute arterial occlusion. (5)
Although CG and the CS characteristically affect small vessels, large vessels may also be affected, as illustrated by the fatal case of a 44 year-old man with CG and MM, presenting with numbness, pain, and swelling of his left leg, in addition to visual impairment. His autopsy revealed laminar crystal deposition in the aorta and its first-degree tributaries. (6)

The underlying mechanism of vascular injury is an IgG, or occasionally a light chain paraprotein, spontaneously crystallizing in the microvasculature, where there is relative stasis or cooling. Intravascular crystals damage the vascular endothelium, which initiates the coagulation cascade to produce thrombosis and local ischemia. (4) Unlike cryoglobulins, CGs are not dissolved by rewarming. The pathogenesis of irreversible cryoprecipitation involves aggregation of the M-proteins as insoluble extracellular crystals. This phenomenon is reportedly associated with structural characteristics such as abnormal N-glycosylation on the IgG κ chain, which is not observed in immunoglobulins from multiple myeloma patients without crystalglobulinemia. (5)

The CS is treated with plasmapheresis to reduce CGs; steroids and chemotherapy [cyclophosphamide, melphalan] for an underlying MM; and supportive measures, including hemodialysis for those with renal failure. Therapies with novel agents, such as thalidomide and bortezomib, lessen the risks associated with other treatments, and high response rates have reported for patients with a monoclonal gammopathy of renal significance. (3)

There are multiple etiologies of occlusive nonvasculitic vasculopathic disorders characterized by retiform pupura and necrosis. These have been reviewed by Llamas-Velasco, et al (7) and categorically include embolization, platelet plugging, vessel-invasive microorganisms, systemic coagulopathies, vascular coagulopathies, red cell occlusion syndromes, miscellaneous disorders, and cold-related gelling or agglutination processes — cryofibrinogenemia, cryoglobulinemia, cold agglutinin syndrome, and crystalglobulinemia.

In conclusion, the CS should primarily be considered in patients with MM or MGUS presenting with retiform purpura and/or cutaneous necrosis. I hope this point is crystal clear.

1. Alegría-Landa V, et al. Paraprotein deposits in the skin. J Am Acad Dermatol 2017; 77: 1145-58.
2. Grossman J, et al. Crystalglobulinemia. Ann Intern Med 1972; 77: 395-400.
3. Tsuji T, et al Crystalglobulinemia syndrome due to monoclonal gammopathy of renal significance. QJ Med 2015; 108: 417-8.
4. Ball NJ, et al. Crystalglobulinemia syndrome: A manifestation of multiple myeloma.
5. Abe N, et al. Crystalglobulinemia manifesting as chronic arthralgia and acute limb ische Medicine (Baltimore) 2017; 96(16):e6643
6. Shintani-Domoto Y, et al. Laminar crystal deposition in large vessels in a patient with crystalglobulinemia. Pathol Int 2017; 67: 269-72.
7. Llamas-Velasco M, et al. Occlusive nonvasculitic vasculopathy. Am J Dermatopathol. 2017; 39(9):637-662.

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