Crystalglobulinemia manifesting as chronic arthralgia and acute limb ischemia

Abstract

Rationale:Crystalglobulinemia is a rare disease caused by monoclonal immunoglobulins, characterized by irreversible crystallization on refrigeration. It causes systemic symptoms including purpura, arthralgia, and vessel occlusive conditions to be exacerbated by exposure to cold. We report a patient with crystalglobulinemia associated with monoclonal gammopathy of undetermined significance (MGUS) manifesting as chronic arthralgia and recurrent acute arterial occlusion.Presenting concerns:A 61-year-old man, who had been diagnosed with MGUS and who had arthralgia of unknown origin, presented with recurrent acute limb ischemia after surgical thromboembolectomy. Refrigeration of his serum formed precipitates that looked like needle-shaped crystals. These crystals did not dissolve with warming, which is not a characteristic of cryoglobulins. Skin biopsy results showed crystal-liked eosinophilic bodies in small vessels and we diagnosed crystalglobulinemia.Intervention and outcomes:Although he underwent above-knee amputation, he was treated with a bortezomib and dexamethasone-based chemotherapeutic regimen, following lenalidomide maintenance therapy. Finally, he achieved complete remission and serum crystalglobulins diminished.Lessons:Monoclonal gammopathy, previously diagnosed as MGUS, can cause systemic symptoms and thrombotic conditions by producing pathologic immunoglobulins, such as crystalglobulins. In such situations, MGUS, even when it has not progressed to multiple myeloma, can be a target of aggressive chemotherapy. Crystalglobulinemia should be considered for patients with monoclonal gammopathy manifesting as systemic and thrombotic symptoms exacerbated by cooling.

Crystalglobulin-Induced Nephropathy and Keratopathy

“…13 Crystalglobulinemia is reportedly associated with in vivo formation of monoclonal antibodies against albumin, as well as abnormal N-glycosylation of oligosaccharides on the κ chain of crystalglobulins, leading to protein misfolding and insolubility of immunoglobulins. 12,14 Clinical manifestations are a result of small-vessel inflammation and thrombosis leading to end-organ injury. 9,11 A proposed mechanism of injury is the extracellular deposition of these crystalline structures within the microvasculature and subsequent damage to the vascular epithelium, leading to increased vascular permeability and recruitment of inflammatory mediators with activation of the clotting cascade, culminating in thrombosis with subsequent fibrosis of the vessel and surrounding tissue.…”

“…15 Patients can present with acute kidney injury, renal artery thrombosis, skin rash/ulcerations, neurologic manifestations, neuropathy, polyarthritis, and blurry vision. [3][4][5][6][7][8][9][13][14][15][16][17][18] The latter symptom is a result of crystalline keratopathy that develops as a result of precipitation of these immunoglobulin crystals in the cornea. [3][4][5] Crystalline keratopathy has been reported in <1% of patients with myeloma-related disorders.…”

“…Although some crystalglobulins cryoprecipitate, not all are easily detectable and they do not resolubilize at warmer temperatures. 9,11,14,18 Histology is crucial in establishing the diagnosis. On light microscopy, the presence of hypereosinophilic extracellular crystals within the glomerular capillary loops and/or surrounding vasculature warrants further investigation.…”

“… 13 Crystalglobulinemia is reportedly associated with in vivo formation of monoclonal antibodies against albumin, as well as abnormal N -glycosylation of oligosaccharides on the κ chain of crystalglobulins, leading to protein misfolding and insolubility of immunoglobulins. 12 , 14 …”

“… 15 Patients can present with acute kidney injury, renal artery thrombosis, skin rash/ulcerations, neurologic manifestations, neuropathy, polyarthritis, and blurry vision. 3 , 4 , 5 , 6 , 7 , 8 , 9 , 13 , 14 , 15 , 16 , 17 , 18 …”