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ObjectiveRecurrent attacks of peritonitis due to familial Mediterranean fever (FMF) may lead to peritoneal adhesions and fallopian tube obstruction. Colchicine, which is the treatment of choice for FMF, may disturb cell division. Secondary amyloidosis, a complication of untreated FMF, may involve the testes and ovaries. Thus, FMF and colchicine may potentially affect fertility and pregnancy in patients with FMF. The aims of the study are to evaluate the causes of infertility and pregnancy outcome in FMF patients and to compare them with 2 groups: non-FMF patients with peritoneal female genital tuberculosis (FGTB) and normal healthy controls.MethodsThis is a retrospective study in which FMF patients with reproductive disorders were recruited from the National Center of Medical Genetics and Primary Health Care in Yerevan, Armenia. The patients with FGTB and the healthy controls with reproductive problems were recruited successively from a large gynecology clinic in Yerevan. Genetic analyses for FMF were performed using ViennaLab StripAssay.ResultsThe FMF group (211 patients) resembles the FGTB group (127 patients) regarding etiologies of infertility. However, in vitro fertilization (IVF) success rate and pregnancy outcome were comparable between the FMF patients and the control group (162 patients). Infertility in patients with FMF was clearly associated with a more severe disease and a lack of adequate colchicine treatment.ConclusionsColchicine medication and controlled FMF disease do not adversely affect the reproductive system and pregnancy outcome. However, a lack of an appropriate colchicine treatment may cause infertility and poor pregnancy outcome.

Objectives FMF shows considerable variability in severity and type of clinical manifestations by geographic region, which are attributed to Mediterranean fever (MEFV) gene allelic heterogeneity, additional genetic modifiers and environmental factors. Considering the severe impact of MEFV mutation M694V on the FMF phenotype, this work aimed at investigating a possible disease modifying role of the serum amyloid A1 (SAA1) genotype in a cohort of 386 Armenian FMF patients homozygous for MEFV mutation M694V. Methods A cohort of 386 Armenian patients diagnosed with FMF based on the Tel-Hashomer criteria and carrying two MEFV M694V mutant alleles were included in this study. Fifty-two (13.40%) of these patients experienced their first attack at the age of ≥20 years (i.e. adult-onset FMF). MEFV and SAA1 analyses were performed by a commercial reverse-hybridization assay, and resulting genotypes were matched against the patients’ clinicodemographic profiles. Results Genotypic distribution of SAA1 alleles was significantly different between patients with an age of onset Conclusion We have identified a significant relationship between the SAA1β/β genotype and the age of disease onset in M694V homozygous FMF patients.

Hereditary breast and ovarian cancer (HBOC) can be identified by genetic testing of cancer-causing genes. In this study, we identified a spectrum of genetic variations among 76 individuals of Armenian descent either with a family history of cancer or breast cancer before the age of 40. We screened 76 suspected HBOC patients and family members as well as four healthy controls using a targeted and hereditary comprehensive cancer panel (127 genes). We found 26 pathogenic (path) and 6 likely pathogenic (LPath)variants in 6 genes in 44 patients (58%); these variants were found in BRCA1 (17), BRCA2 (19), CHEK2 (4), PALB2 (2), and NBN (1). A few different variants were found in unrelated individuals; most notably, variant p.Trp1815Ter in the BRCA1 gene occurred in four unrelated patients. We did not find any known significant variants in five patients. Comprehensive cancer panel testing revealed pathogenic variants in cancer genes other than BRCA1 and BRCA2, suggesting that testing only BRCA1 and BRCA2 would have missed 8 out of 44 suspected HBOC patients (18%). These data also confirm that a comprehensive cancer panel testing approach could be an appropriate way to identify most of the variants associated with hereditary breast cancer., Breast cancer: The spectrum of mutations in Armenian patients Genetic variants associated with hereditary breast cancer have been identified by a comprehensive analysis of Armenian patients, highlighting the need for testing panels to be tailored to the population being screened. A team led by Mike Moradian and Davit Babikyan of Yerevan State University Medical School, screened samples from 76 breast cancer patients of Armenian descent. Using a panel including 127 genes, they identified 32 pathogenic variants in 44 patients, mostly in BRCA1 or BRCA2. However, testing only BRCA1 and BRCA2 would have missed 8 of these 44 patients. The analysis also found variants of unknown significance in 32 patients which might be involved in hereditary breast cancer. Based on this analysis, the researchers argue that it is important to screen with comprehensive gene panels to increase the chance of detecting variants associated with cancer.

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.

Background Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential. Methods The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting. Results In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease. Conclusions These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.

This work aimed at investigating demographic, clinical, and genetic characteristics of individuals experiencing their first familial Mediterranean fever (FMF) attack at age ≥40 years in a very large cohort of Armenian FMF patients. In total, 10,370 Armenian patients diagnosed with FMF based on the Tel Hashomer criteria and carrying at least one MEFV mutant allele were included in this study. A total of 354 (3.40%) patients had late-onset FMF. Of these, 194 (54.80%) were female and 160 (45.20%) were male. The following genotypes were significantly associated with the late-onset variant: M680I/E148Q (P = 0.004), M694V/E148Q (P

Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disease in the group of Hereditary periodic fever syndromes (HPFS), characterized by recurrent, self-limited attacks of fever and polyserositis, which last 2-4 days. It manifests mainly in childhood and often has early onset, resolve without sequels. Genetic testing of FMF is efficient and allows diagnosing of atypical cases. FMF is a significant health care problem in Armenia because of high frequency of carriers of MEFV mutations 1:3 - 4 (0.21) and marked FMF prevalence 54.7 per 10`000 of the total population. Articular symptoms are found in about 45% of cases. They usually manifest as acute recurrent arthritis (ARA) or arthralgia, but more rarely also chronic arthritis can be found. We aimed to investigate clinical and genetic characteristics of the joint manifestations in Armenian children with FMF. The charts of all 715 patients with proven diagnosis of FMF at the National Pediatric Center (NPC) for FMF were reviewed for joint manifestations. The diagnosis of FMF and disease severity were determined according to the Tel-Hashomer criteria and molecular-genetic detection of 12 MEFV mutations common for Armenians. The characteristics of joint manifestations and overall FMF disease were then compared to MEFV mutation analysis. There were 438 boys and 277 girls with an age at diagnosis between 3 months and 17 years (mean age: 8.64±0.17). Joint involvement was observed in 56.4% of all 715 cases. The manifestation was ARA in 30.5%, arthralgia in 21.2% and chronic arthritis (CA) in 4.7%, which would also qualify for a diagnosis of JIA. The frequency of ARA was associated with M694V mutation, mainly M694V homozygous and M694V heterozygous genotypes. The risk of CA depended on MEFV genotype of the FMF patients and was the highest in M694Vheterozygotes and M694Vhomozygotes. M694V heterozygous genotype was noticed significantly more frequently among FMF patients with spondyloarthritis in comparison to those without it. The probability of the development of CA among FMF patients without M694V mutation was significantly higher also in heterozygotes in comparison to compound-heterozygotes. We concluded, that the frequency of joint involvement among Armenian pediatric FMF patients was high - 56.4%, especially for CA. Chronic arthritis may be the first manifestation of FMF and occurred usually in patients with severe M694V mutations. Patients of Armenian origin with refractory arthritis should be asked for isolated febrile attacks, hemorrhagic vasculitis, episodes of pleuritis and family history to rule out FMF.

Background Familial Mediterranean Fever (FMF) is an autoinflammatory disorder caused by mutations in the MEFV gene. These mutations appear in different populations with different frequencies and their caused symptom severities vary from mild to moderate to severe depending on the mutation type. Methods In this study, we analyzed the mutations that have been reported in the MEFV gene from symptomatic FMF patients and compared their frequencies in different populations from the 1000 Genome and the Exome databases, using statistical clustering. We also analyzed the nucleotide and amino acid substitution patterns across the MEFV gene. Results We found 16 (8%) nonsynonymous mutations outside exon 10 that did not cluster with known disease-causing mutations (DCMs), due to their high frequencies in other populations. We also studied the substitution patterns for nucleotides and amino acids to determine the conserved and variable regions in the MEFV gene. In general more nonsynonymous substitutions were reported in exons 2, 3, and 10 from the FMF database (symptomatic FMF patients) compared to the 1000 Genome and the Exome databases. The same was true for amino acid (AA) substitutions where there were 1.5 times more radical (RAD) to conservative (CON) changes. However, when it came to AA substitutions exon 10 was quite conserved with a RAD/CON ratio of 0.9. In fact, we report that the most severe FMF symptoms are caused by conservative mutations in two highly conserved exon 10 regions. Conclusion We found presumptive FMF-causing mutations that did not cluster with DCMs based on their allele frequencies. We also observed that the type of mutation is less likely to determine the severity of the FMF symptoms; rather it was the location of the mutations that was the determining factor.

In this study, we present clinical data from 16,000 familial Mediterranean fever patients. We also discuss the clinical manifestation of a subset of these patients and their potential symptom associations with other disorders.Familial Mediterranean fever patients were confirmed using Tel-Hashomer criteria and were tested for the 12 most common mutations using the familial Mediterranean fever StripAssay. A total of 100 samples were selected, and their MEFV gene exons and intron junctions were completely sequenced.We observed that in children severe phenotypes with polyserositis, erysipelas-like erythema, splenomegaly, and vasculitis are associated with high penetrance of exon 10 mutations, particularly M694V. Several forms of arthritis were associated with familial Mediterranean fever, including acute mono/oligoarthritis in the lower extremities, destructive arthritis, ankylosing spondylitis, sacroiliitis, arthritis of the hip joint, and juvenile chronic arthritis. Severe life-threatening complications, such as adhesive intestinal obstruction, renal amyloidosis, and uncommon/rare symptoms were sometimes the only form of familial Mediterranean fever manifestation.We suggest performing familial Mediterranean fever genetic testing for patients presenting with rare/uncommon symptoms also common in other disorders, to prevent misdiagnosis or delayed diagnosis. In our experience, the most effective patient management for familial Mediterranean fever was its rapid diagnosis through genetic testing, initiation of colchicine therapy, and promotion of attack prevention through counseling.

Objective To gain insight into the molecular bases of genetically unexplained periodic fever syndromes (PFS) by screening NLRP12, a gene in which only a nonsense and a splice site mutation have so far been identified, and to assess the functional consequences of the identified missense variation. Methods NLRP12 was screened for mutations by direct sequencing. Functional assays were performed in HEK 293T cells stably expressing the proapoptotic protein ASC and procaspase 1, in order to determine the effects of normal and mutated NLRP12 proteins on speck formation, caspase 1 signaling, and NF-κB activation. Results A heterozygous NLRP12 missense mutation involving a CpG site (c.1054C>T; p.Arg352Cys) was identified in exon 3, which encodes the nucleotide-binding site (NBS) of the protein, in 2 patients from different countries and carrying different NLRP12 haplotypes. The mutation, which does not alter the inhibitory effect of NLRP12 on NF-κB activation, increases speck formation and activates caspase 1 signaling. To define this new class of PFS, we propose the term NLRP12-associated disorders (NLRP12AD). Conclusion Given the rarity of known NLRP12-associated disorders, the identification of this NLRP12 molecular defect contributes to the delineation of the clinical spectrum associated with mutations in this gene and highlights the importance of screening NLRP12 in patients presenting with unexplained PFS. This study also demonstrates, by means of functional assays, the deleterious effect of this recurrent missense mutation; the gain of function for speck formation and caspase 1 signaling associated with this NBS mutation is consistent with the inflammatory phenotype of PFS.

Familial Mediterranean fever (FMF) is an autoinflammatory disorder generally caused by recessively inherited mutations in the MEFV gene. FMF is quite prevalent in Armenian population in which majority of patients have two mutated alleles, yet in 18% of symptomatic patients just one mutation has been detected. To explain this finding, we analyzed the symptoms and genotypes of 1,299 patients, including 236 affected heterozygous patients with definite diagnosis of FMF. We selected a subset of 63 heterozygous, homozygous and asymptomatic normal individuals and completely sequenced their MEFV genes (exons) to discover any other mutations potentially missed by currently used screening method. Besides four synonymous polymorphisms in exon two and five, we found a T267I mutation in one heterozygous patient with a severe case of FMF who should have been designated as compound heterozygous, yet the other genotypes were all accurate. We used binomial probability distribution of symptoms in homozygous FMF patients to estimate the likelihood of their occurrences in heterozygous patients and demonstrated the assemblage of patients into groups with similar clinical criteria using statistical clustering. We found extremely high probabilities for the presence of FMF symptoms in heterozygous individuals and determined that symptoms were equally likely to occur in both analyzed genotypes. Therefore, our study supports the rising evidence that a single MEFV mutation could be associated with mild FMF symptoms. However, heterozygous patients presenting with severe phenotype should be further analyzed for less common second MEFV mutation using gene sequencing.

Objective: To determine whether or not the use of colchicine decreases the risk of amyloidosis among Armenian patients with familial Mediterranean fever (FMF). Subjects and Methods: The study included 99 Armenian patients from the Center of Medical Genetics database with genetically ascertained FMF; 33 had renal amyloidosis and 66 were randomly selected control patients without renal amyloidosis. Self- reported colchicine use was assessed by interviewer-based questionnaire. Results: The patients with incident amyloidosis were more likely to be older men, but younger at the time of disease onset, and more likely to have had a family history of amyloidosis and M694F mutation in the MEFV gene compared to patients without amyloidosis. The risk of amyloidosis decreased with adequate colchicine use rather than nonadequate use (adjusted odds ratio, OR, 0.48, 95% confidence interval, CI, 0.16–1.43), continuous colchicine use rather than interrupted use (adjusted OR 0.15, 95% CI 0.04–0.53), earlier rather than later initiation age of colchicine treatment (adjusted OR 0.95, 95% CI 0.90–1.01), current colchicine rather than ever/never colchicine use (adjusted OR 0.20, 95% CI 0.05–0.89). Conclusion: The study demonstrated that colchicine treatment is effective in preventing amyloidosis among Armenian patients with FMF and that earlier initiation and continuous therapy at an adequate dose of 1.2–1.8 mg/day may be associated with a decreased amyloidosis risk among Armenian patients with FMF.

Objective To gain insight into the pathophysiology of an unusual autoinflammatory syndrome, in a patient of Armenian origin, that mimicked familial Mediterranean fever (FMF) but with episodes triggered by generalized exposure to cold, and to further elucidate the controversial function of the protein encoded by PYPAF1, whose mutations (exclusively missense to date) have been identified in 3 hereditary recurrent fever syndromes. Methods The patient's DNA was screened for mutations in both MEFV, the gene responsible for FMF, and PYPAF1. The ability of different recombinant PYPAF1 isoforms, expressed in HEK 293 cells, to regulate NF-κB signaling was subsequently assessed. Results No disease-causing mutation was found in MEFV. However, a nonsense mutation (p.Arg554X) was identified in PYPAF1; this defect resulted in a truncated protein lacking all leucine-rich repeats. Study of the wild-type and mutant PYPAF1 recombinant proteins revealed that PYPAF1 inhibited NF-κB proinflammatory pathways, and that the identified nonsense mutation impaired this property. Conclusion These molecular and clinical findings, together with the clinical manifestations in the patient, which call into question the current nosology of the hereditary recurrent fever syndromes, are consistent with the hypothesis that PYPAF1 acts as an inhibitor of NF-κB signaling. They also provide a clear elucidation of the functional consequences of this nonsense PYPAF1 mutation not previously described in the literature, which result in a partial loss of function and may thereby explain the pathophysiology of the autoinflammatory syndrome observed in this patient.

Objective Familial Mediterranean fever (FMF) is an autosomal-recessive disorder that is common in Armenian, Turkish, Arab, and Sephardic Jewish populations. Its clinical diagnosis is one of exclusion, with the patients displaying nonspecific symptoms related to serosal inflammation. MEFV gene analysis has provided the first objective diagnostic criterion for FMF. However, in the absence of an identified mutation (NI/NI genotype), both the sensitivity of the molecular analyses and the involvement of the MEFV gene in FMF are called into question. The present study was designed to further evaluate the diagnostic value of MEFV analysis in another population of Mediterranean extraction. Methods The MEFV gene was screened for mutations in 50 patients living in Karabakh (near Armenia) who fulfilled the established criteria for FMF. In addition, we analyzed published series of patients from the above-mentioned at-risk populations. Results The mutation spectrum in Karabakhian patients, which consisted of only 6 mutations (with 26% of NI alleles), differed from that reported in Armenian patients. Strikingly, among patients from Karabakh and among all classically affected populations, the distribution of genotypes differed dramatically from Hardy-Weinberg equilibrium (P = 0.0016 and P < 0.00001, respectively). These results, combined with other population genetics–based data, revealed the existence of an FMF-like condition that, depending on the patients' ancestry, was shown to affect 85–99% of those with the NI/NI genotype. Conclusion These data illuminate the meaning of negative results of MEFV analyses and show that in all populations evaluated, most patients with the NI/NI genotype had disease that mimicked FMF and was unrelated to the MEFV gene. Our findings also demonstrate the high sensitivity of a search for very few mutations in order to perform a molecular diagnosis of MEFV-related FMF.

Streszczenie Rodzinna gorączka środziemnomorska jest chorobą dziedziczoną autosomalnie recesywnie, wystepującą u ludności wokol basenu Morza Środziemnego. Charakteryzuje sie epizodami gorączki, zapaleniem blon surowiczych i wysypką. Objawy ustepują samoistnie, a miedzy kolejnymi rzutami dziecko jest zdrowe. Najpowazniejszym powiklaniem jest amyloidoza. Opisano przypadek 8-letniego chlopca, syna armenskich emigrantow, z nawracającym zapaleniem oplucnej.

Familial Mediterranean fever (FMF) is a recessively inherited disorder predisposing to renal amyloidosis and associated with mutations in MEFV, a gene encoding a protein of unknown function. Differences in clinical expression have been attributed to MEFV -allelic heterogeneity, with the M694V/M694V genotype associated with a high prevalence of renal amyloidosis. However, the variable risk for patients with identical MEFV mutations to develop this severe complication, prevented by lifelong administration of colchicine, strongly suggests a role for other genetic and/or environmental factors. To overcome the well-known difficulties in the identification of modifying genetic factors, we investigated a relatively homogeneous population sample consisting of 137 Armenian patients with FMF from 127 independent families living in Armenia. We selected the SAA1, SAA2, and APOE genes—encoding serum amyloid proteins and apolipoprotein E, respectively—as well as the patients' sex, as candidate modifiers for renal amyloidosis. A stepwise logistic-regression analysis showed that the SAA1 α/α genotype was associated with a sevenfold increased risk for renal amyloidosis, compared with other SAA1 genotypes (odds ratio [OR] 6.9; 95% confidence interval [CI] 2.5–19.0). This association, which was present whatever the MEFV genotype, was extremely marked in patients homozygous for M694V (11/11). The risk for male patients of developing renal amyloidosis was fourfold higher than that for female patients ( OR =4.0; 95% CI =1.5–10.8). This association, particularly marked in patients who were not homozygous for M694V (34.0% vs. 11.6%), was independent of SAA1 -allelic variations. Polymorphisms in the SAA2 or APOE gene did not appear to influence susceptibility to renal amyloidosis. Overall, these data, which provide new insights into the pathophysiology of FMF, demonstrate that susceptibility to renal amyloidosis in this Mendelian disorder is influenced by at least two MEFV -independent factors of genetic origin— SAA1 and sex—that act independently of each other.

SummaryFamilial Mediterranean fever (FMF) is a recessively inherited disorder that is common in patients of Armenian ancestry. To date, its diagnosis, which can be made only retrospectively, is one of exclusion, based entirely on nonspecific clinical signs that result from serosal inflammation and that may lead to unnecessary surgery. Renal amyloidosis, prevented by colchicine, is the most severe complication of FMF, a disorder associated with mutations in the MEFV gene. To evaluate the diagnostic and prognostic value of MEFV-gene analysis, we investigated 90 Armenian FMF patients from 77 unrelated families that were not selected through genetic-linkage analysis. Eight mutations, one of which (R408Q) is new, were found to account for 93% of the 163 independent FMF alleles, with both FMF alleles identified in 89% of the patients. In several instances, family studies provided molecular evidence for pseudodominant transmission and incomplete penetrance of the disease phenotype. The M694V homozygous genotype was found to be associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes (P=.0002 and P=.006, respectively). The demonstration of both the diagnostic and prognostic value of MEFV analysis and particular modes of inheritance should lead to new ways for management of FMF—including genetic counseling and therapeutic decisions in affected families.

Analysis of various symptoms from 20000 FMF patients indicates that several issues, including the clinical manifestation in a variety of combinations and the genotype penetrance, make FMF diagnosis and management challenging. Severe phenotypes with development of serositis, ELE, splenomegaly, and vasculitis are associated with high penetrance mutations of exon 10, mainly M694V allele.

International audience; Background: Identification of modifier genes and characterization of their effects represent major challenges in human genetics. SAA1 is one of the few modifiers identified in humans: this gene influences the risk of renal amyloidosis (RA) in patients with familial Mediterranean fever (FMF), a Mendelian autoinflammatory disorder associated with mutations in MEFV. Indeed, the SAA1 alpha homozygous genotype and the p.Met694Val homozygous genotype at the MEFV locus are two main risk factors for RA.Methodology/principal findings: HERE, WE INVESTIGATED ARMENIAN FMF PATIENTS AND CONTROLS FROM TWO NEIGHBORING COUNTRIES: Armenia, where RA is frequent (24%), and Karabakh, where RA is rare (2.5%). Sequencing of MEFV revealed similar frequencies of p.Met694Val homozygotes in the two groups of patients. However, a major deficit of SAA1 alpha homozygotes was found among Karabakhian patients (4%) as compared to Armenian patients (24%) (p = 5.10(-5)). Most importantly, we observed deviations from Hardy-Weinberg equilibrium (HWE) in the two groups of patients, and unexpectedly, in opposite directions, whereas, in the two control populations, genotype distributions at this locus were similar and complied with (HWE).Conclusions/significance: The excess of SAA1alpha homozygotes among Armenian patients could be explained by the recruitment of patients with severe phenotypes. In contrast, a population-based study revealed that the deficit of alpha/alpha among Karabakhian patients would result from a negative selection against carriers of this genotype. This study, which provides new insights into the role of SAA1 in the pathophysiology of FMF, represents the first example of deviations from HWE and selection involving the modifier gene of a Mendelian disorder.

NALP proteins, also known as NLRPs, belong to the CATERPILLER protein family involved, like Toll-like receptors, in the recognition of microbial molecules and the subsequent activation of inflammatory and immune responses. Current advances in the function of NALPs support the recently proposed model of a disease continuum bridging autoimmune and autoinflammatory disorders. Among these diseases, hereditary periodic fevers (HPFs) are Mendelian disorders associated with sequence variations in very few genes; these variations are mostly missense mutations whose deleterious effect, which is particularly difficult to assess, is often questionable. The growing number of identified sporadic cases of periodic fever syndrome, together with the lack of discriminatory clinical criteria, has greatly hampered the identification of new disease-causing genes, a step that is, however, essential for appropriate management of these disorders. Using a candidate gene approach, we identified nonambiguous mutations in NALP12 (i.e., nonsense and splice site) in two families with periodic fever syndromes. As shown by means of functional studies, these two NALP12 mutations have a deleterious effect on NF-κB signaling. Overall, these data identify a group of HPFs defined by molecular defects in NALP12 , opening up new ways to manage these disorders. The identification of these first NALP12 mutations in patients with autoinflammatory disorder also clearly demonstrates the crucial role of NALP12 in inflammatory signaling pathways, thereby assigning a precise function to this particular member of an emerging family of proteins whose putative biological properties are currently inferred essentially through in vitro means.

Objective Familial Mediterranean fever (FMF), the prototype of autoinflammatory disorders, is caused by recessive mutations in the MEFV gene. Some FMF patients develop renal amyloidosis, a potentially fatal condition. This complication has mainly been associated with the M694V mutation, although the different study designs, small numbers of patients, and/or evaluation of few or no covariables calls this association into question. The aim of this study was to examine the controversial issue of amyloidosis susceptibility in FMF by determining the relative contributions of MEFV and numerous epidemiologic factors to the risk of renal amyloidosis. Methods Online questionnaires were completed at the MetaFMF database by patients at 35 centers in 14 countries. Using a standardized mode of data collection, we retrieved crude initial data from over half of the genetically confirmed FMF patients referred worldwide until May 2003 (2,482 cases, including 260 patients who developed renal amyloidosis). Results Amyloid nephropathy was present in 11.4% of the cases. In the total study population, country of recruitment was the leading risk factor for this manifestation (odds ratio 3.2 [95% confidence interval 1.8–5.9]), followed by M694V homozygosity, proband status, and disease duration. Differing results were found when countries were stratified. Conclusion Country of recruitment, rather than MEFV genotype, is the key risk factor for renal amyloidosis in FMF. This risk, which parallels infant mortality rates, indicates a possible environmental origin of amyloidosis susceptibility. The patient's country should be considered in addition to MEFV genotype as an indication for prophylactic colchicine, a treatment suggested for asymptomatic individuals who are incidentally discovered to be M694V homozygous.

We recently heard about the case of an 8-year-old Arabic patient who, following the recent article by Milledge et al,[1][1] was offered a bone marrow transplantation (BMT) by a private institution to cure his familial Mediterranean fever (FMF). This boy has a very good general constitution but is

The "pigmented xerodermoid" was previously defined on the basis of mild clinical symptoms that suggested it might be similar to but distinct from xeroderma pigmentosum (XP). XP and pigmented xerodermoid cell cultures were irradiated with ultraviolet light and unscheduled DNA synthesis, strand breakage during repair, chain growth during semiconservative DNA replication with or without caffeine, and the recovery of DNA replication were determined. It is concluded that a pigmented xerodermoid cell culture is indistinguishable from the XP variant and the former term is therefore redundant. The defect common to these cell types appears to be the loss of a gene product that permits normal cells to replicate DNA without interruption at damaged sites (u.v.-induced pyrimidine dimers). The consequence of this loss is that replication forks are blocked more frequently and at lower doses in XP variant cells. The correlation between this defect and high levels of actinic carcinogenesis in these patients points to an important role for perturbations in DNA replication in human carcinogenesis.

Familial Mediterranean Fever (FMF) is the most common hereditary disorder among Armenians. The establishment of clinical and genetic testing of FMF in the Center of Medical Genetics and Primary Health Care (CMG) was mostly forced by the high social and public health problems concerning a huge cohort of patients.

FMF is considered an autosomal recessive autoinflammatory syndrome caused by single gene (MEFV) mutations. Recently, it has been known that also heterozygous mutation carriers can suffer from a mild or incomplete form of FMF, named FMF-like disease. Among Armenians, who have relatively high carrier rate of MEFV mutations, single mutation has been detected in about 1/5 of symptomatic cases. Thus, one cannot exclude the influence of other modifier genes and/or environmental factors which can contribute to the variable penetrance and to the phenotypic variability of FMF-like disease.