際際滷

際際滷Share a Scribd company logo

Fmf

Download as PPTX, PDF
N
naeim1370

Familial Mediterranean Fever (FMF) is an autosomal recessive disease characterized by recurrent fevers and inflammation of the abdomen, lungs, or joints. It is caused by mutations in the MEFV gene and predominantly affects populations around the Mediterranean. Diagnosis is based on clinical criteria including fever with abdominal, chest, or joint pain. Treatment is with the drug colchicine, which prevents inflammation and secondary amyloidosis. Genetic testing can confirm a diagnosis and guide treatment in atypical or resistant cases.

1 of 22
Downloaded 88 times
Familial Mediterranean Fever Naeim Ehtesham
Disease characteristics (Clinical Description) Common manifestations Recurrent fever during early childhood may be the only manifestation of FMF Abdominal attacks Articular attacks Pleural attacks Pericarditis
Rash
Amyloidosis
Molecular Genetics Gene Symbol Chromosomal Locus Protein Name MEFV 16p13.3 Pyrin
Simplified view of the pathogenesis
Inheritance FMF is an autosomal recessive disease A patient with only one mutation is a carrier and should not display the disease phenotype MEFV heterozygous genotypes produce a phenotype intermediate between that of homozygous affected individuals and homozygous wild-type unaffected individuals How a genetic carrier can express the phenotype? Ruled out several possible explanations, such as loss of expression of one allele A single mutation can cause unexpected inflammation in the setting of a number of polymorphisms in genes encoding relevant proinflammatory cytokines
Cont Although disease severity, are influenced by the MEFV pathogenic variants themselves, intra- and interfamilial clinical differences suggest that these parameters are also influenced by other genes (outside the MEFV locus) However, in these individuals, detection of a single pathogenic variant appears to be sufficient in the presence of clinical symptoms for the diagnosis of FMF and the initiation of a trial of colchicine
Prevalence FMF predominantly affects populations living in the Mediterranean region, especially North African Jews, Armenians, Turks, and Arabs 1 in 5 Mediterranean descent have FMF gene , but 1 in 200 have FMF The pathogenic variant c.2080A>G(p.Met694Val) is found in more than 90% of affected Jewish persons of North African origin. FMF is also seen (although in much lower numbers) in many other countries, where it shows considerable variability in severity and type of manifestations
Differential Diagnosis
Fmf
Differential diagnosis in a child referred with fever
Diagnosis/testing The minimal (and most current) criteria for diagnosis of FMF are the Tel Hashomer clinical criteria: Fever plus Either: One or more major signs and one minor sign; OR Two minor signs
Cont Major signs Abdominal pain Chest pain Joint pain Skin eruption
cont Minor signs Increased erythrocyte sedimentation rate (ESR) Normal values: Men age <50 years: <15 mm/h Men age 50-85 years: <20 mm/h Women age <50 years: <20 mm/h Women age 50-85 years: <30 mm/h Leukocytosis Normal values: 4.5 to 11.0 times 103袖L (4.5-11.0 x 10-9L) Elevated serum concentration of fibrinogen Normal values: 200-400 mg/dL (2.00-4.00 g/L)
Flowchart to guide requests for MEFV mutation analysis
Algorithm to guide diagnosis and treatment decisions after MEFV genotype analysis
Treatment and management The treatment of patients with FMF is aimed at suppressing the inflammation, as indicated by laboratory measures such as CRP levels, and providing an acceptable quality of life colchicine is efficient in preventing the development of amyloidosis in the majority of the patients who are compliant with the drug Indeed, the mainstay of treatment for FMF is colchicine, which is effective not only in controlling the attacks but also in preventing secondary amyloidosis
Cont The follow up of patients with FMF should include the management of possible complications that arise from chronic inflammation For example, quality of life will be impaired in patients with frequent attacks, and thus depression might ensue In untreated patients, uncontrolled inflammation can result in splenomegaly, growth retardation, decreased bone density, premature atherosclerosis and, ultimately, secondary amyloidosis Frequent attacks might also lead to female or male infertility owing to adhesions in reproductive organs
Cont Patients with FMF are considered to be resistant to colchicine if they continue to have >1 attack per month and have elevated CRP and SAA levels in between the attacks (during the attack-free period). In patients resistant to colchicine, anti-IL-1 treatment has proven beneficial in suppressing clinical and laboratory measures of inflammation
Genetic counseling For autosomal recessive FMF: In general, both parents of an affected individual with biallelic MEFV pathogenic variants are unaffected heterozygotes. However, in populations with a high carrier rate and/or a high rate of consanguineous marriages, it is possible that one or both parents have biallelic pathogenic variants and are affected Symptomatic heterozygotes have also been reported. Thus, it is appropriate to consider molecular genetic testing of the parents of the proband to establish their genetic status. If both parents are heterozygotes, the risk to sibs of inheriting two pathogenic variants and being affected is 25% Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the MEFV pathogenic variants in the family are known
Refrences A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin , Ozen, S. & Bilginer, Y. Nat. Rev. Rheumatol. 10, 135147 (2014) http://www.ncbi.nlm.nih.gov/gtr/ http://www.ncbi.nlm.nih.gov/omim/ http://www.ncbi.nlm.nih.gov/books/NBK1116/

More Related Content

Fmf

  • 2. Disease characteristics (Clinical Description) Common manifestations Recurrent fever during early childhood may be the only manifestation of FMF Abdominal attacks Articular attacks Pleural attacks Pericarditis
  • 5. Molecular Genetics Gene Symbol Chromosomal Locus Protein Name MEFV 16p13.3 Pyrin
  • 6. Simplified view of the pathogenesis
  • 7. Inheritance FMF is an autosomal recessive disease A patient with only one mutation is a carrier and should not display the disease phenotype MEFV heterozygous genotypes produce a phenotype intermediate between that of homozygous affected individuals and homozygous wild-type unaffected individuals How a genetic carrier can express the phenotype? Ruled out several possible explanations, such as loss of expression of one allele A single mutation can cause unexpected inflammation in the setting of a number of polymorphisms in genes encoding relevant proinflammatory cytokines
  • 8. Cont Although disease severity, are influenced by the MEFV pathogenic variants themselves, intra- and interfamilial clinical differences suggest that these parameters are also influenced by other genes (outside the MEFV locus) However, in these individuals, detection of a single pathogenic variant appears to be sufficient in the presence of clinical symptoms for the diagnosis of FMF and the initiation of a trial of colchicine
  • 9. Prevalence FMF predominantly affects populations living in the Mediterranean region, especially North African Jews, Armenians, Turks, and Arabs 1 in 5 Mediterranean descent have FMF gene , but 1 in 200 have FMF The pathogenic variant c.2080A>G(p.Met694Val) is found in more than 90% of affected Jewish persons of North African origin. FMF is also seen (although in much lower numbers) in many other countries, where it shows considerable variability in severity and type of manifestations
  • 12. Differential diagnosis in a child referred with fever
  • 13. Diagnosis/testing The minimal (and most current) criteria for diagnosis of FMF are the Tel Hashomer clinical criteria: Fever plus Either: One or more major signs and one minor sign; OR Two minor signs
  • 14. Cont Major signs Abdominal pain Chest pain Joint pain Skin eruption
  • 15. cont Minor signs Increased erythrocyte sedimentation rate (ESR) Normal values: Men age <50 years: <15 mm/h Men age 50-85 years: <20 mm/h Women age <50 years: <20 mm/h Women age 50-85 years: <30 mm/h Leukocytosis Normal values: 4.5 to 11.0 times 103袖L (4.5-11.0 x 10-9L) Elevated serum concentration of fibrinogen Normal values: 200-400 mg/dL (2.00-4.00 g/L)
  • 16. Flowchart to guide requests for MEFV mutation analysis
  • 17. Algorithm to guide diagnosis and treatment decisions after MEFV genotype analysis
  • 18. Treatment and management The treatment of patients with FMF is aimed at suppressing the inflammation, as indicated by laboratory measures such as CRP levels, and providing an acceptable quality of life colchicine is efficient in preventing the development of amyloidosis in the majority of the patients who are compliant with the drug Indeed, the mainstay of treatment for FMF is colchicine, which is effective not only in controlling the attacks but also in preventing secondary amyloidosis
  • 19. Cont The follow up of patients with FMF should include the management of possible complications that arise from chronic inflammation For example, quality of life will be impaired in patients with frequent attacks, and thus depression might ensue In untreated patients, uncontrolled inflammation can result in splenomegaly, growth retardation, decreased bone density, premature atherosclerosis and, ultimately, secondary amyloidosis Frequent attacks might also lead to female or male infertility owing to adhesions in reproductive organs
  • 20. Cont Patients with FMF are considered to be resistant to colchicine if they continue to have >1 attack per month and have elevated CRP and SAA levels in between the attacks (during the attack-free period). In patients resistant to colchicine, anti-IL-1 treatment has proven beneficial in suppressing clinical and laboratory measures of inflammation
  • 21. Genetic counseling For autosomal recessive FMF: In general, both parents of an affected individual with biallelic MEFV pathogenic variants are unaffected heterozygotes. However, in populations with a high carrier rate and/or a high rate of consanguineous marriages, it is possible that one or both parents have biallelic pathogenic variants and are affected Symptomatic heterozygotes have also been reported. Thus, it is appropriate to consider molecular genetic testing of the parents of the proband to establish their genetic status. If both parents are heterozygotes, the risk to sibs of inheriting two pathogenic variants and being affected is 25% Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the MEFV pathogenic variants in the family are known
  • 22. Refrences A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin , Ozen, S. & Bilginer, Y. Nat. Rev. Rheumatol. 10, 135147 (2014) http://www.ncbi.nlm.nih.gov/gtr/ http://www.ncbi.nlm.nih.gov/omim/ http://www.ncbi.nlm.nih.gov/books/NBK1116/