A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder?
Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurring short attacks of fever and serositis. Secondary AA amyloidosis is the worst complication of the disease and often determines the prognosis. The MEFV gene, on chromosome 16p13.3, is responsible for the disease and around 30 mutations have been reported to date. Colchicine is the standard FMF treatment today, and prevents both attacks and amyloid deposition in 95% of patients. Here we describe a three-generation Spanish kindred with five family members affected by a severe periodic inflammatory disorder associated with renal AA amyloidosis and colchicine unresponsiveness. Clinical diagnosis of definite FMF disease was made based on the Tel-Hashomer criteria set. Genetic analyses revealed that all subjects were heterozygous for the new H478Y MEFV variant, segregating with the disease. In addition, mutations in the TNFRSF1A and CIAS1/PYPAF1/NALP3 genes, related to the dominantly inherited autoinflammatory periodic syndromes, were ruled out. However, the dominant inheritance of the disease, the long fever episodes with a predominant joint involvement, and the resistance to colchicine in these patients raise the question of whether the periodic syndrome seen in this kindred is a true FMF disease with unusual manifestations or rather another MEFV-associated periodic syndrome. We conclude that the new H478Y MEFV mutation is the dominant pathological variant causing the inflammatory periodic syndrome in this kindred and that full-length analyses of the MEFV gene are needed to obtain an adequate diagnosis of patients with clinical suspicion of a hereditary periodic fever syndrome, especially those from non-ancestral populations.
Aldea
Anna
A
Servei d'Immunologia, Institut Clínic d'Infeccions i Immunologia (ICII), c/Villaroel 170, 08036 Barcelona, Spain.
Campistol
Josep M
JM
Arostegui
Juan I
JI
Rius
Josefa
J
Maso
Montserrat
M
Vives
Jordi
J
Yagüe
Jordi
J
D000328:Adult; D028226:Amyloidosis, Familial / Q000235:genetics* / Q000473:pathology; D003078:Colchicine / Q000627:therapeutic use; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000473:pathology; D005260:Female; D006074:Gout Suppressants / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010507:Periodicity; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D000071198:Pyrin; D013030:Spain
D003598:Cytoskeletal Proteins; D006074:Gout Suppressants; C000604192:MEFV protein, human; D011506:Proteins; D000071198:Pyrin; D003078:Colchicine