Patient. 7-year-old previously healthy male.
Chief Complaint. The patient presented with a 2-week history of low-grade intermittent fever and pain in multiple joints including the wrists, shoulders, and ankles.
History of Present Illness. The patient initially developed a fever of 102°F 2 weeks prior to admission accompanied by headache and eye pain. His primary care physician performed a strep test and throat culture, both of which were negative. The patient later developed periumbilical abdominal pain and presented to his local emergency room where a urinalysis was performed and was within normal limits. His fever subsided for 3 days after this visit, subsequently returning to approximately 104°F. He began experiencing wrist pain and shoulder pain and edema of his lower extremities. He was admitted to a local hospital, found to be pancytopenic, and subsequently transferred to our facility for further workup.
Past Medical History. The patient was born at term, demonstrated normal growth and development patterns, and had no history of surgeries or prior hospitalizations.
Social History. The patient lives with his mother (a smoker), 1 sibling, and 2 cats.
Family History. The patient's mother has a history of rheumatoid arthritis and the removal of cervical lymph nodes for unknown reasons. His maternal grandmother had a history of Grave's disease and hepatitis C. His maternal grandfather had a history of diabetes.
Physical Examination Findings. On physical exam, an annular rash of the chest, face, abdomen, and thighs was identified along with mild conjunctivitis and bilateral periorbital and lower extremity edema.
Principal Laboratory Findings. Table 1
Additional Laboratory and Clinical Studies
An MRI of the abdomen demonstrated hepatosplenomegaly, portal hepatitis lymphadenopathy, periportal edema and gallbladder wall thickening, pulmonary interstitial edema, and small left pleural effusion. Whole body fluorodeoxyglucose positron emission tomography (FDG-PET) scan to look for cancers such as lymphoma using labeled glucose was performed, and no foci suspicious for malignancy were identified suggesting no underlying neoplastic process was present. A bone marrow biopsy identified non-specific changes such as a slightly hypocellular bone marrow (70%), increased megakaryocytes, and a mildly left-shifted granulopoiesis with < 5% blasts. Bone marrow cytogenetics were normal. Renal biopsy (after 2 weeks of hospitalization) demonstrated ultrastructural changes consistent with type I membranoglomerulonephritis (Figure 1). Serum protein electrophoresis (SPE) identified 2 monoclonal proteins that were immunophenotyped by immunofixation electrophoresis (IFE) as IgG lambda (≈0.7 g/dL) and IgM lambda (too low to quantify) (Figure 2). Serum IgM concentration was elevated (701 mg/dL; reference range: 35–290 mg/dL) while the IgG concentration was high, although in the normal range (1,375 mg/dL; reference range: 490–1,400 mg/dL). Urine protein electrophoresis (UPE) on a random urine sample revealed a selective glomerular proteinuria with excretion of moderate amounts of albumin and small amounts of alpha- and beta-globulins (total protein concentration, 184 mg/dL). Urine IFE demonstrated the presence of monoclonal IgG lambda, a kappa free light chain (FLC), and 2 monoclonal bands of lambda FLCs. Cryoglobulin analysis revealed 3 monoclonal components corresponding to IgG lambda, IgM lambda, and kappa FLCs within a polyclonal IgM background (data not shown).
Transmission electron microscopy of tissue from the patient's renal biopsy illustrating A) electron dense membrane deposits reflecting the deposition of circulating immune complexes (arrows); B) endocapillary mononuclear cell hypercellularity indicative of the proliferative aspects of membranoprolieferative disease; and, C) the presence of large phagolysosomes in many of the mononuclear cell elements containing black, presumably proteinaceous, material indicative of phagocytosed paraproteins (ie, cryoglobulins).
Monoclonal antibodies identified in this 7-year-old patient's serum (A) by SPE (IgM lambda and IgG lambda monoclonal proteins [arrowheads]) and urine (B) by UPE (IgG lambda, as well as kappa and lambda free light chains [arrowheads]).
What are this patient's most striking clinical and laboratory findings?
How do you explain this patient's most striking clinical and laboratory findings?
What is this patient's most likely diagnosis?
What conditions are most often associated with this patient's diagnosis?
What age groups does this disease normally affect?
Are urinary M-spikes a common finding in this patient's disease?
What is the composition of cryoglobulins?
What is the pathogenesis of this disease?
How is this patient's condition typically treated?
1. The most striking clinical findings include fever, migrating arthralgias, erythematous rash, and periorbital and peripheral edema. The most striking laboratory findings at presentation were pancyopenia, the presence of monoclonal proteins in serum and urine, subsequently identified as cyroglobulins, elevated liver aminotransferases (AST and ALT), elevated renal function tests (BUN and creatinine), decreased complement components (C3 and C4), low serum phosphorous and albumin concentrations, and elevated erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) concentration.
2. In a patient with pancytopenia, elevated liver aminotransferases, elevated BUN and creatinine, and decreased complement the differential diagnosis includes: 1) a neoplastic process; 2) bacterial or viral infection with bone marrow suppression; 3) post-streptococcal glomerulonephritis or minimal change disease; or 4) a rheumatological disorder. Because of this patient's profound pancytopenia, a series of additional laboratory tests were performed to determine if an underlying neoplastic process was present in the bone marrow. A bone marrow biopsy identified nonspecific changes including a slightly hypocellular bone marrow (70%), increased megakaryocytes, and a mildly left-shifted granulopoiesis with < 5% blasts. Bone marrow cytogenetics did not detect any abnormalities. Clinically, a positron emission tomography (PET) scan to look for cancers such as lymphoma was performed, and no foci suspicious for malignancy were identified. Taken together, these findings suggest that an underlying neoplastic process was not responsible for his clinical presentation. To investigate underlying bacterial and viral causes of illness, both serological assays and polymerase chain reaction (PCR) methods were used. Pertinent positive results include the presence of an anti-Epstein-Barr virus (EBV) IgG and a positive IgG anti-EBV viral capsid antigen; however, no IgM anti-EBV viral capsid antigen was detected, indicating that this was not an acute illness. Moreover, EBV viral load by quantitative PCR was performed and revealed a low positive result (< 250 copies of EBV genome/mL), consistent with the serological findings. Since quantitative EBV viral load correlates well with severity of illness in pediatric patients, a recent, but non-acute, EBV infection was likely present in this patient. The patient was HIV negative by IFA and pooled PCR. Serologic testing for Ehrlichia, Rickettsia rickettsii, Parvovirus B19, CMV, Leptospiridia, Bartonella quintana, Francisella tularensis, Brucella, and Arboviruses was negative. Anti-streptolysin O and anti-DNase B were also negative indicating that a recent streptococcal infection was unlikely. Blood, urine, and fecal cultures were negative. These findings suggest that an infectious etiology to his clinical presentation was not likely. Studies were undertaken to determine the underlying cause of this patient's renal disease. Upon admission, urinalysis demonstrated urine sediment including red cell casts and proteinuria (3+). Abnormally-elevated serum creatinine and BUN were identified at admission (1.4 mg/dL and 26 mg/dL, respectively, Table 1 ) which spiked sharply at day 12 of hospitalization to 2.6 mg/dL and 34 mg/dL, respectively. A needle biopsy of the kidney was performed during this spike, which detected ultrastructural changes consistent with type I membranoglomerulonephritis and having features suggestive, but not diagnostic, of cryoglobulinemia (Figure 1). No morphologic evidence of a thrombotic microangiopathy was identified, consistent with the lack of schistocytes on multiple blood smears. This made either hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP) an unlikely cause of this patient's renal disease. To evaluate the possibility of an underlying rheumatological disorder, tests to detect autoantibodies were performed. Pertinent positive tests included a positive (1:80) antinuclear antibody (ANA) which had a speckled pattern ( Table 2 ). This ANA was undetectable 6 weeks after admission. Tests for rheumatoid factor, double-stranded deoxyribosenucleic acid (dsDNA), extractable nuclear antigen (ENA), and anti-neutrophilic cytoplasmic antibodies (ANCA) (including myeloperoxidase [MPO] and proteinase-3 [PR3]) were negative during his hospitalization ( Table 2 ).
3. What is this patient's most likely diagnosis? Type II cryoglobulinemia of unknown etiology.
Cryoglobulinemia indicates the presence of 1 or more immunoglobulin types in the blood that precipitate in serum below 37°C and redissolve upon warming. Cryoglobulins form secondary to the intrinsic characteristics of the immunoglobulins. These characteristics include the subclass of IgG antibody formed and post-translational modification of the antibodies themselves. The underlying pathogenesis of cryoglobulinemia can be classified by characterizing the immunoglobulins in the precipitate according to the Brouet classification ( Table 3 ). The Brouet classification has been used widely for the past 30 years and subdivides cryoglobulinemia into 3 types: type I, type II, and type III. Type I cryoglobulinemia is associated with lymphoproliferative disorders, while types II and III are associated with infections and autoimmune diseases. The patient in the present case demonstrated a biclonal cryoglobulin, which may be found in both types I and II cryoglobulinemia. The fact that his bone marrow biopsy and PET scan did not reveal a lymphoproliferative disorder, and because his cryoglobulins occurred in a polyclonal background, a diagnosis of type II cryoglobulinemia was made.
4. Type II cryoglobulinemia is primarily associated with viral infections in adults. Up to 90% of patients with type II cryoglobulins have serologic evidence of HCV infection. Epstein-Barr virus, HIV, and HBV infections can result in type II cryoglobulins. While the most common cause of type II cryoglobulinemia is hepatitis C infection, this patient's serology and qualitative PCR for HCV were negative. Similarly, hepatitis B serologic tests (HBsAg, HBsAb, and HBcAb) were negative. Clinical findings of type II cryoglobulinemia include Raynaud's phenomenon, arthralgias, lower extremity purpura, liver disease, abdominal pain, and leukocytoclastic vasculitis of the dermis. Renal involvement occurs in up to 50% of cases, and isolated proteinuria or hematuria are the most common presentations. Mesangial expansion and hypercellularity with electron-dense deposits (Figure 1A) between the basal lamina and endothelial cells were visible on ultrastructural examination of renal biopsy tissue. However, the most common light microscopy finding in renal biopsy tissue from patients with type II cryoglobulinemia is membranoproliferative glomerulonephritis (corresponding to the electron microscopy identified in Figure 1B). Immunofluorescent staining of this tissue shows glomerular deposits with immunoglobulins and variable amounts of complement. Electron microscopy may show phagocytosed cryogloblins in monocytes which appear as dark, membrane-bound bodies in lysosomes (Figure 1C). While the patient falls well below the median age for type II cryoglobulimia, his clinical presentation is consistent with this diagnosis based on his clinical findings, including arthralgia, transaminitis, abdominal pain, proteinuria, and the histopathology findings indicated above.
5. Type II cryoglobulinemia usually presents in patients in their 40s and 50s, with a female predominance (2:1). This is consistent with the underlying diseases that are responsible for cryoglobulinemia, such as multiple myeloma (average age of onset, 65 years), mixed connective tissue diseases (systemic lupus erythematosus [SLE], 15 to 40 years; Sjögren's, 30 to 40 years; systemic sclerosis, 30 to 50 years), and hepatitis C (65% of those infected with HCV are between 40 to 49 years).[6,7,8] These demographics indicate that cryoglobulinemia in a pediatric patient is not common. Cryoglobulins have been sparsely reported in pediatric patients over the past 4 decades. We have been able to identify 5 single case studies of pediatric patients with cryoglobulins and concomitant: 1) pulmonary cirrhosis and psoriasis (1961); 2) Mononucleosis and hepatitis B (1993); 3) streptococcal infection with evidence of a vasculitic process (1978); 4) sickle cell disease with cold agglutinins (1963); and, 5) IgA nephropathy (2003). However, these studies do little to elucidate the associations between various diseases and cryoglobulins. Additionally, we were able to identify 3 larger studies (n = 30 to 250 patients) that shed light on the association between cryoglobulins and pediatric disease processes ( Table 4 ). Specifically, Schistosoma infection, Schölein-Henoch purpura, and autoimmune diseases have been associated with an increased prevalence of cryoglobulins in pediatric patients.[14,15,16] Schölein-Henoch purpura, Schistosoma infections, and autoimmune diseases such as systemic lupus erythematosus are rare in the United States. While no screening tests for SLE to determine its prevalence in pediatric patients have been performed, it is estimated that 5,000 to 10,000 children in the United States are affected. Yang and colleagues investigated 250 patients suspected of having immune complex-mediated disorders and found that 50% of them were positive for cryoglobulins. Significant correlations exist between the presence of cryoglobulins, serum hypocomplementemia, and C1q activity (evidence of immune complexes) in patients with SLE; however, only 60% of patients with cryoglobulins had immune complexes demonstrable by a positive test for C1q activity. The patient in the present case did have a positive (1:80 titer) ANA antibody with a speckled pattern ( Table 2 ) and hypocomplementemia (decreased C3 and C4), but no other autoantibodies were identified. The possibility of an underlying autoimmune disease with immune complex deposition would explain many of his clinical and laboratory findings; however, no definitive diagnosis can be made at this time.
6. It is rare to identify urinary Bence Jones proteins with cryoglobulin properties. One of the earliest reports was by Alper in 1966 on a patient with multiple myeloma. While we did not test specifically for cryoglobulins in the urine, IFE of the patient's urine detected an IgG lambda monoclonal antibody. This antibody isotype is the same as that in the cryoglobulin fraction of serum (cf, Figure 2A versus 2B). Therefore, it is likely that we identified a cryoglobulin in our patient's urine.
7. Cryoglobulins are unique immunoglobulins that precipitate at temperatures < 37°C (mostly at 0°C to 4°C) and re- dissolve upon warming. Approximately 95% of cryoglobulins are immune complexes that have a rheumatoid factor (RF) component (anti-IgG). These can be referred to as mixed cryoglobulins, which are differentiated from monoclonal bands without RF or antigen-antibody complexes. The remaining fraction (≈5%) comprise the monoclonal proteins observed in patients with monoclonal gammopathies. These proteins have unique amino acid sequences that cause poor solubility at low temperatures (ie, increased precipitation in the cold). Other proteins precipitate in the cold such as fibrinogen in plasma (cryofibrinogen) and fibronectin. Cyroprecipitate is made up of antibodies (including RF), albumin, fibronectin, fibrinogen, viruses, and bacteria.[19,20] In type I cyroglobulinemia, only antibodies are found. In mixed cryoglobulinemias (types II and III), many components are found including RF. The RF-immunoglobulin complex can cause rheumatoid factor and immune-complex vasculitis in skin, nerves, kidney, joints, and liver. This may account for several of the laboratory findings in the present patient, including elevated liver enzymes. Low affinity rheumatoid factor antibodies (anti-IgG) are antibodies that form naturally and likely play a role in clearing immune complexes by activating complement. Rhematoid factor can react with other antigens, such as microorganisms coated with IgG antibodies, leading to complement activation and agglutination. It is hypothesized that HCV stimulates B cells, inducing a polyclonal IgM rheumatoid factor, although other factors play a role in the IgM RF factor found in Type II cryoglobulinemia associated with HCV infection.
8. The cryoglobulins in mixed cryoglobulinemias (type II and type III) tend to precipitate in the small vessels of multiple types of tissues due to their decreased solubility in plasma. Histologically, a leukocytoclastic vasculitis is observed which results from immune complex deposition, complement activation, and leukocyte infiltrates. Arterioles, venules, and capillaries are particularly vulnerable to this deposition, and this vasculitis can lead to ischemia, infarction, and purpura. However, not all patients with mixed cryoglobulins develop vasculitis symptoms.[19,20,23]
9. Therapy is based on the underlying cause of the disease, which can be guided by the classification of cryoglobulins. The mainstay of therapy includes immunosuppression and may require plasmapheresis and antiviral therapy depending on the underlying cause of the patient's cryoglobulinemia. Organ failure secondary to vasculitis in HCV warrants plasmapheresis and therapies against B cells (Rituximab) or TNF (Infliximab) and may be applicable to other causes of type II cryoglobulinemia.[24,25,26,27]
The patient was treated symptomatically for his edema with lasix. His hypertension was treated using amlodipine (calcium channel blocker), and his elevated phosphate was treated using Renagel, a polymeric phosphate binder. Fresh frozen plasma (FFP), packed red blood cells (RBCs), and platelet concentrates were given periodically as needed for this patient's hypocomplementemia, anemia, and thrombocytopenia, respectively. Serial serum protein electrophoresis patterns (SPEPs) showed a gradual decrease in monoclonal protein, consistent with his gradual clinical improvement. Two weeks after the initial detection of the patient's monoclonal antibodies by SPE, his IgG lambda peaked at 1.0 g/dL (up from 0.7 g/dL), and at 6 weeks after the initial detection his IgG lambda M-protein concentration had decreased to 0.9 g/dL. The patient is currently being followed by the Pediatric Rheumatology and Nephrology Services to monitor his disease progression. Three months after his initial hospitalization he reported occasional bouts of an erythematous/flushing rash of the cheeks, which is also known to occur on other parts of the body. While there has been no fever, the patient remains very susceptible to exercise-induced tachycardia and is still experiencing easy fatigability, although no fever or major intercurrent illness has been experienced. His pancytopenia and hypergammaglobulinemia have improved, although he has a mild anemia and his ESR is still elevated.
Lab Med. 2007;38(6):347-351. © 2007 American Society for Clinical Pathology
Cite this: Biclonal M-Spike in a 7-Year-Old Child - Medscape - Jun 01, 2007.