hereditary periodic fevers syndromes definition: recurrent attacks of inflammation with genetic...
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Hereditary periodic fevers syndromes
Definition: recurrent attacks of inflammation with genetic molecular basis for which no infectious or
auto-immune cause can be identified
Familial Mediterranean Fever (FMF) 88%
TNF-R-associated periodic syndrome (TRAPS) (55-kd TNFRSF1A gene mutation: C70R, P46L)
Hyper IgD periodic fever syndrome (HIDS) (MVK gene mutation--> mevalonate kinase deficiency)
Muckle-Wells syndrome (MWS)
Familial cold urticaria (FCU)
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Familial Mediterranean Fever (FMF)
Autosomal recessive inherited periodic disease Sephardic, North African Jews, Armenians, Arabs, Druze and Turks are affected
Major criteria: Fever attacks >38
Serositis (peritoneum, pleura, pericardium)
Monoarthritis (hip, knee, ankle)
Minor criteria: Incomplete attacks:
Exertional leg pain
Colchicine efficiency (1-2mg/day)
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12-72hr typical
incomplete wk6hr
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FMF. Supportive criteria:
1. Family history of FMF / parents consanguinity
2. Appropriate ethnic origin
3. Age <20 years at disease onset
4. Severe, requiring bed rest
5. Spontaneous remission
6. Acute phase reaction: ESR, SAP, fibrinogen
7. Appendectomy
8. Episodic proteinuria / hematuria
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FMF. The requirements for diagnosis:
•= or > 1 major criteria
•= or > 2 minor criteria
•1 minor plus 5 supportive criteria
1 minor plus 4 of the first 5 supportive criteria
Typical attacks:
recurrent: = or > 3 of the same type
febrile >38
short (12hr-3 days)
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Familial Mediterranean Fever
Genetic
FMF gene is mapped to short arm of chromosome 16p (The International FMF Consortium. Cell 1997. The French FMF consortium. Nat Genet 1997)
FMF gene mutations (25) ---> transcription factor deficit (pyrin) -----> cytoskeleton mobility----> granulocyte activation ----> inflammation
Common FMF mutations:
M694V(3/52%), M680I(5/9%), V726A(2/3%), M694I(0/0.4%), E148Q(1.2/4%)
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Familial Mediterranean FeverCommon MEFV (FMF gene) mutations among Jewish ethnic groups in Israel:M694V, 726A, M680I, E148QCarrier frequency of at least two mutations: Ashkenazi 14%, Iraqi 29%, Moroccan Jews 21%Ashkenazi carrier / non-carrier : no difference in morbidityV726A or E148Q: excess of febrile episodesThe frequency of MEFV mutation exceeds overt FMF rate (phenotype III) by 40-240 fold.Conclusions (MEFV mutations in Israel): high carrier rate among Jews most subjects are unaffected
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Familial Mediterranean Fever
Elevated pro-inflammatory cytokine expression in circulating leukocytes:
TNF-alpha
IL-1beta
IL-6
IL-8
is found during attacks and in attack-free FMF patients and supports subclinical inflammation between attacks.
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Familial Mediterranean Fever
Corticosteroid failure
Colchicine:
Daily administration
Life-long treatment
Dose:1-2mg/day
Reduces the frequency of attacks
Reduces the severity of attacks
Prevents amyloidosis
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Amyloidosis
•Amyloid - extracellular fibrillar insoluble protein deposition affecting organ structure and function.
•Amyloid has blue staining with iodine (Virchow 1854). Cellulose (amylum) has the same staining.
•Diagnose is established by demonstration of amyloid in tissue:
Congo red staining in polarized light(apple-green birefringence): + in 1/3 AL and 2/3 AA
Tissue biopsy is positive: abdominal fat 85% AL, gingival, rectal 1/3-2/3, kidney,bone 30%,CTS 90%
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Amyloidosis. Light-Chain Amyloid (AL)
Primary (non-tumor type): derived from small population of non-tumor plasma cells
Multiple myeloma (MM) (tumor-type): derived from malignant clone of plasma cells
Pathology: monoclonal Ig light-chain deposits
Bence-Jones (light-chains) proteinuria is common
1/3 of light-chain amyloidosis show MM
15% of MM are complicated with Amyloidosis
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Amyloidosis AL. Clinical features:
•One organ shows predominant involvement
•Cardiovascular - in almost all cases, CHF 25%
•Proteinuria and azotemia - in most cases. AL should be ruled out:>30 yrs+nephrotic syndrome
•Tongue enlargement (macroglossia) 20%
•Peripheral neuropathy 16%. CNS is not involved
•Carpal tunnel syndrome 20%
•GI tract: malabsorbtion, hepatomegaly, diarrhea
•Autonomic dysfunction: ortostatism, constipation..
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Amyloidosis AL. Clinical features:
• Rare splenomegaly. Functional hyposplenism (Howell-Jolly bodies: blood cells remnants, CBC)
•Cutaneous echymoses (periorbital: “raccoon eye”)
•Nail dystrophy
•Alopecia
•Arthropathy: cold non-inflammatory effusion, pad-like shoulders enlargement, DD hypothyroid
•Lung AL is usual. Decreased function is rare.
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Amyloidosis AL. Laboratory abnormalities.
1. Serum protein electrophoresis: Ig monoclonal spike 45%, hypogammaglobulinemia 25%
2. Immunoelectrophoresis/immunofixation: monoclonal protein 90%, Bence-Jones proteinemia (Light chain) 25%. Lambda light chains 65%. kappa 35% (in contrast to MM).
3. Urine: Bence-Jones 75%. Low level<200mg/24hr - occult malignancy:LY,CLL,MM, may be N serum
4. Monoclonality is not found in other amyloidosis
5. Renal failure 50%, Cr > 1.3 - shorter survival
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Amyloidosis AL. Laboratory abnormalities.
6. Anemia 50%
7.Thrombocytosis 10%, functional hyposplenism
8. Leucocytosis
9. Increased ESR
10. Bone marrow: >5% plasma cells in 50% cases
7. Multiple myeloma laboratory abnormalities due to infections, pancytopenia, hypercalcemia, hypoIg, hypoalbuminemia
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Amyloidosis AL. Treatment.
Survival of AL without treatment -few months only
Multiple myeloma - VAD
Primary AL:
1. Cyclic oral therapy -mild efficacy. Melphalan 0.2 mg/d + prednison 1mg/kg for 4 days every 6 weeks
2. High dose of melphalan (200mg/m2+prednison 1mg/kg for 2 days) + autologic stem cells + GCSF harvesting. Normal cardiac function is requested. Efficacy 50 %. Heart, liver, kidney disease reverse.
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Amyloidosis AL. Treatment.
Primary AL:
3. Intermediate melphalan+autologic stem cells are given at compromise cardio-renal function patients with response 25%.
4. Organ transplantation + aggressive 2 schedule
5. IDOX (resorbtion of amyloid) +dexamethasone+alkalating agent
6. Supportive: nutrition, pacemaker, dialysis, transplantation
7. Contraindicated: digitalis, beta-, Ca-blockade
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Amyloidosis AA Reactive Systemic (secondary)
Amyloid A Protein (acute phase reactant) deposits
Bence Jones proteinuria is absent. Signs resemble AL. Better survival: 10 years, less due to infection.
Due To: Autoimmune dis.:RA, JRA, AS, IBD
Neoplasm: Hodgkin dis., adenocarcinoma
Chronic infections: osteomyelitis, TB
Heredofamilial: FMF
Neuropathic I-IV types
Diagnosis: tissue immuno-staining for AA protein
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Amyloidosis AA. Treatment.
Therapy for underlying disease: RA, TB, FMF
Colchicine 1.5-2mg/d, Chlorambucyle 2-8mg/d 2yrs
Other amyloidosis types ( no Bence Jones protein)
SSA senile cardiac amyloid: 24% >70yrs old, CHF
AF or ATTR familial: heart, renal, neuropathic
CAA cerebral, CNS plaques of Alzheimer disease
Beta 2-microglobulinemic amyloid due to dialysis
IAPP islet polypeptid amyloid of DM type II
AE amyloid:thyroid medullary cancer (Calcitonin)
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FMF. ARTHRITIS.
THREE FORMS OF ARTHRITIS IN FMF:
1. Asymmetrical non-destructive acute (75%). Knees, ankle, wrist. One-two joints. Large effusion. Resolution.
2. Chronic destructive including sacroiliitis (2-5%). Hips, knees. One protracted.Repeated short attacks Sacroiliitis 0.4%. HLA B27neg. Free lumbar spine.
3. Migratory, rheumatic fever-like.
Erysipelas-like erythema (7-40%). Unilateral. Dorsum of ankle or foot. Fades away within 2-3ds
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FMF.
RARE MANIFESTATIONS
Mollaret’s meningitis
Fundoscopy: retinal colloid bodies
Splenomegaly, 30-50%. Nonamyloid.
Acute orchitis
Phenotype II: renal family amyloidosis+non history of FMF + positive genetic for FMF
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