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 .
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 .
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 .
although he underwent above - knee amputation , he was treated with a bortezomib and dexamethasone - based chemotherapeutic regimen , following lenalidomide maintenance therapy .
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 .
monoclonal gammopathy of undetermined significance ( mgus ) is a premalignant condition without end - organ damage ; treatment is not recommended unless there is progression to multiple myeloma .
however , paraproteins due to monoclonal gammopathy , including mgus , can be pathogenic when the monoclonal protein ( m - protein ) has autoantibody activity or altered conformation leading to improper aggregation .
m - protein - related disease caused by pathological immunoglobulins and light chains , such as cryoglobulinemia , poems ( polyneuropathy , organomegaly , endocrinopathy , monoclonal gammopathy , and skin changes ) syndrome , al amyloidosis , and light - chain deposition disease , can have diverse symptoms such as pyrexia , arthralgia , skin rash , peripheral neuropathy , thrombosis , and renal involvement , which mimic systemic rheumatic diseases . although m - protein - related diseases can cause fulminant end - organ damage , indications for aggressive treatment of mgus causing m - protein - related disease
we report a case of crystalglobulinemia , which is a rare form of m - protein - related disease , characterized by irreversible cryoprecipitation , and it is caused by monoclonal gammopathy that was previously diagnosed as mgus . in this case ,
crystalglobulinemia manifested as chronic arthralgia and acute limb ischemia , and the patient was treated with a chemotherapeutic regimen for multiple myeloma .
a 61-year - old man presented to our unit in february 2014 with right femoral pain , pallor , paraesthesia , and poikilothermia .
five years previously , he had fever , arthralgia , and pain in the extremities that worsened with cold exposure . at another hospital , immunoglobulin g ( igg ) mgus was diagnosed and confirmed by bone marrow aspiration . however , because of negative cryoglobulin test results , his symptoms did not appear to be related to igg mgus .
treatment with prednisolone , methotrexate , and infliximab for presumed autoimmune disease manifesting as polyarthritis did not result in appreciable clinical improvement . on examination , he had widespread , nonpalpable , painful purpura covering his extremities , and his right leg was particularly cool and pale ( fig .
1 ) . ultrasonography revealed absence of doppler signals on the right superficial femoral artery and acute arterial occlusion was diagnosed .
this recurrent thrombotic arterial obstruction was thought to be caused by extensive venous thromboembolism , which was not unresponsive to thrombolytic treatment .
blood test results showed increased igg ( 3262  mg / dl ; reference range , 8701700  mg / dl ) , normal immunoglobulin a ( 134  mg / dl ) , decreased immunoglobulin m ( 28  mg / dl ; reference range , 33190  mg / dl ) , and skewed free light - chain / ratio ( 152 ; reference range , 0.261.65 ) .
other blood test results revealed that serum complement components , total hemolytic complement level , antinuclear antibodies , antineutrophil cytoplasmic antibodies , lupus anticoagulants , protein s and c activity , antithrombin iii activity , and hepatitis b and c serology were normal .
serum cryoglobulin and plasma cryofibrinogen results were negative again in routine study , but refrigeration of the serum and plasma samples at 4  c for up to 72  hours led to the formation of microscopic needle - shaped precipitates . warming the samples to 37 
skin biopsy of the purpura revealed crystal - like eosinophilic bodies in small vessels ( fig .
2 ) . immunofluorescence showed crystal - like bodies stained with anti - igg antiserum and anti- light - chain antiserum ( fig .
we diagnosed crystalglobulinemia caused by underlying plasma cell dyscrasia ( previously diagnosed as mgus ) .
( a ) crystal - like eosinophilic bodies in small vessels ( arrows ) and surrounding sweat glands , with lymphocytic infiltration .
( b ) multiple eccrine gland necrosis ( arrows ) . hematoxylin and eosin stain .
crystal - like bodies ( arrows ) were stained for ( a ) anti - immunoglobulin g ( igg ) heavy - chain antiserum and ( b ) anti- light - chain antiserum , but not for ( c ) anti - immunoglobulin m ( igm ) antiserum or ( d ) anti- light - chain antiserum .
magnification 400. in march , the patient presented with exacerbation of pain , pallor , and sensory loss below the right knee .
the limb appeared marble white , and no pulse was palpable over the right popliteal artery .
acute limb ischemia developed rapidly and caused gangrene , leading to oliguria , creatine kinase elevation , hyperkalemia , and myoglobinuria with acute renal failure .
he was admitted to the intensive care unit for the treatment of sepsis due to staphylococcus aureus bacteremia , which originated from the necrotizing soft tissue of the ischemic limb .
the patient 's condition improved substantially , but his right lower extremity was not viable .
an above - knee amputation was necessary ; therefore , he was transferred to a high - volume center for orthopedic surgery .
bone marrow aspiration performed postoperatively revealed 17.5% plasmacytosis , which led to the final diagnosis of multiple myeloma .
he was treated with 4 cycles of a bortezomib and dexamethasone - based chemotherapeutic regimen .
although the patient 's m - protein level decreased , his systemic symptoms exacerbated by cold exposure persisted .
he was administered lenalidomide to diminish m - protein and achieved complete remission . during subsequent follow - up
the case presented here showed that crystalglobulins , caused by monoclonal gammopathy , previously thought to be mgus , cause chronic arthralgia and extensive venous thromboembolism , which is insensitive to thrombolytic agents , following acute arterial occlusion .
therefore , crystalglobulinemia can mimic systemic rheumatic disease , vasculitic syndrome , and thrombotic conditions .
in addition , when end - organ damage is caused by pathogenic m - proteins , the underlying monoclonal gammopathy , despite being categorized as mgus because of the limitations of the current diagnostic system , can be a therapeutic objective .
crystalglobulinemia is a rare condition resulting from monoclonal gammopathy associated with multiple myeloma , mgus , and other plasma cell disorders .
crystalglobulins , characterized by irreversible crystallization on cooling , are deposited in blood vessel walls and lead to vascular endothelial injury , thrombosis , and vessel occlusion , thereby causing ischemic damage to various organs .
crystalglobulinemia manifests as recurrent purpura , skin ulceration , arthralgia , and thrombotic conditions such as renal arterial occlusion and limb ischemia , which are exacerbated by cold exposure .
symptoms of crystalglobulinemia are similar to those of cryoglobulinemia . however , unlike cryoglobulins , crystalglobulins are not dissolved by rewarming .
the pathogenesis of irreversible cryoprecipitation in cryoglobulinemia 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  chain , which is not observed in immunoglobulins from multiple myeloma patients without crystalglobulinemia .
nonfucosylated oligosaccharides on the  chain of crystalglobulins , which lead to protein misfolding and insolubility of immunoglobulin , have been suggested . in cases of crystalglobulinemia , despite negative findings of cryoglobulins and cryofibrinogens according to routine laboratory studies , cryoprecipitates can be observed grossly in blood collection tubes or microscopically in blood smears .
microscopic detection of irreversible cryoprecipitation and the presence of intravascular crystalized bodies in affected tissues in pathological specimens are critical for the diagnosis of crystalglobulinemia . in our case , at the time of admission , mgus may have already progressed to multiple myeloma . however , based on the unitarian theory known as ockham 's razor , the early presentation of arthralgia exacerbated by cold exposure , which had persisted for several years , was thought to be caused by crystalglobulins from mgus .
patients with mgus generally require only watchful waiting because clinical trials of early therapeutic interventions with standard chemotherapy have yielded negative results .
therefore , there is no standard treatment indication or chemotherapy for mgus with m - protein - related disease in which m - proteins have autoantibody activity or altered conformation with aggregating improperly .
aggressive treatment for symptomatic monoclonal gammopathy due to pathogenic paraproteinemia , even without progression to multiple myeloma , would be required because m - protein - related diseases can cause irreversible organ damage because of a delay in treatment .
chemotherapy for plasma cell dyscrasia and plasmapheresis to remove pathogenic immunoglobulins are presumed to be beneficial for symptomatic relief .
therapeutic strategies should be established to prevent fulminant end - organ damage caused by pathogenic m - proteins , including crystalglobulins .
crystalglobulinemia and al amyloidosis have similar characteristics in paraproteins forming irreversible and insoluble structures , and they have similar clinical symptoms caused by aggregated paraproteins . in al amyloidosis , one of the m - protein - related diseases , fibrilization of paraproteins has been observed .
an abnormal monoclonal light chain characterized by protein misfolding , aggregation , and deposition in tissues causes multisystem involvement , such as macroglossia , purpura , nephrotic syndrome , hepatosplenomegaly , restrictive cardiomyopathy , and peripheral neuropathy . like crystalglobulinemia , n - glycosylation of amyloidogenic  light chains has also been reported . however , the treatment strategy for al amyloidosis is clearer than that for crystalglobulinemia .
al amyloidosis with organ dysfunction should be treated with high - dose melphalan followed by autologous hematopoietic cell transplantation or chemotherapeutic agents for multiple myeloma , depending on the patient 's transplant eligibility .
the chemotherapeutic regimen includes melphalan and dexamethasone , a bortezomib - based regimen , or immunomodulatory derivatives , such as a lenalidomide - based regimen . as evidenced from this case
, crystalglobulinemia can mimic rheumatic and thrombotic diseases ; therefore , monoclonal gammopathy , although diagnosed as mgus by definition , may be symptomatic because of the effects of pathogenic paraproteins .
therefore , early recognition and appropriate treatment can prevent end - organ damage and improve prognosis .
various physicians ( eg , rheumatologists , nephrologists , neurologists , and dermatologists ) should remember that systemic symptoms of unknown cause for patients with mgus may require further testing and differential diagnosis for m - protein - related diseases , including crystalglobulinemia .
it is critical to detect the presence of crystalglobulins so that the chemotherapeutic regimen targeting the responsible clone plasma cells may improve the symptoms . in this case
however , the clinical course and treatment efficacy highly indicated crystalglobulinemia due to monoclonal gammopathy .
further reports are required to establish clinical practice for crystalglobulinemia and to formulate a treatment strategy for monoclonal gammopathy with pathological m - protein that has not progressed to multiple myeloma .
 abstractrationale : 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 . 
Rationale:
Presenting concerns:
Intervention and outcomes:
Lessons:
Introduction
Case report
Discussion
Acknowledgments