FMF is an autoinflammatory disease common in eastern Mediterranean populations. It is characterized by febrile episodes of serosal and synovial inflammation causing marked increase in the acute phase response . FMF is more prevalent in males, with a male to female ratio of 1.5-2:1 .
In the current study, a male preponderance was noted in all the study population, with an overall M:F ratio of 1.3:1. Male to female ratios of 1.5:1, 1.1:1, and 2.3:1 were reported among homozygotes, heterozygotes, and the uncharacterized group respectively. A male preponderance was noted in different other studies. El-Garf et al. , who studied 136 Egyptian patients in the period between January, 2005 and July, 2008 recruited from the rheumatology clinic, Pediatric Hospital, Cairo University, as well as three referral centers (a general rheumatology, pediatric rheumatology and general pediatric clinics), also reported a M:F ratio of 1.9:1. Similarly, Settin et al. , who studied 66 Egyptian patients who were referred from various hospitals to Genetics Department, Mansoura University, Children’s Hospital for confirmation of diagnosis through molecular analysis also reported a M:F ratio of 1.3:1. Another retrospective study done by Booty et al.  reported that out of 28 FMF patients with only one identified MEFV mutation, and who were seen at the National Institutes of Health, Bethesda MD - USA, 15 were males and 13 were females with M:F ratio of 1.15:1.
However, Duşunsel et al.  who reviewed the medical records of 102 Turkish patients, documented a M:F ratio of 1:1.3 (a slight female preponderance), but these results are not statistically significant and do not support the suggestion that FMF may have incomplete penetrance in female subjects . Although a male predominance among FMF patients has been documented in several ethnic groups, most studies have reported that FMF affects both genders in a similar ratio [18, 19].
The onset of clinical manifestations in FMF occurs before 5 years of age in 63–68% of cases and before 20 years of age in 90% of cases. The onset may be as early as 6 months of age . In our study, the mean age of onset, mean age at diagnosis, and mean time interval between disease onset and diagnosis of all study population, were 4.86 ± 2.56, 7.14 ± 2.89, and 2.31 ± 1.57 years respectively. The mean age at diagnosis was significantly higher in heterozygous group than homozygous group and the mean duration of follow-up was significantly lower in the heterozygous patients. Our study populations had age of onset much earlier than reported. In a retrospective study done by Ebru  that was carried out on 415 clinically diagnosed FMF Turkish patients; the mean age of onset was 13.9 ± 9.8 years. Duşunsel et al.  also reported a mean age of onset, a mean age at diagnosis, and a median time interval between disease onset and diagnosis of 6.8 ± 3.7, 9.7 ± 3.7 and 2 (0.5–11) years respectively. This earlier age of onset that was observed in our study may be explained by the early detection of FMF patients in our rheumatology pediatric unit by clinical suspicion before confirmation by genetic analysis.
FMF is considered as an autosomal recessive hereditary disease, associated with a single gene named MEFV . However, about one-third of FMF patients bear a single mutation on one allele, suggesting that the disease might be transferred as an autosomal dominant trait with partial penetration. Alternatively, an additional gene—yet to be identified—might be responsible for the disease in these cases with single allele mutation .
The inherited pattern of FMF which is mostly recessive was supported on the basis of consanguinity and positive family history. Regarding consanguinity of the study population; 37.14% of patients had consanguineous parents, all of them were homozygotes and heterozygotes except one patient who was gene-negative. A positive family history of FMF was recorded in 14 patients (20%), of whom 7 patients were homozygotes and 7 patients were heterozygotes. Family history of amyloidosis was noted in 4 patients (5.7%) all of them were heterozygous. Consanguinity in our study is nearly similar to Duşunsel et al.  who reported that 30.4% of their patients had consanguineous parents, a positive family history of FMF was recorded in 26.5% of patients and a family history of amyloidosis was noted in 5.9% of patients. El-Garf et al.  reported that, out of their 136 patients, a positive consanguinity was present in 32 (23.5%) patients and a positive family history in 45 (33.1%) patients. Settin et al.  showed that 21.2% of their patients had a positive family history for FMF; however parental consanguinity was positive in 63.3% of these cases which was more than that in our results. These differences may due to familial predisposition of FMF in certain populations and the impact of cultural traditions.
Regarding clinical presentations among our study groups; fever was a prevalent feature in all groups, and was documented in 90%, 97.5%, and 100% of homozygtes, heterozygotes, and the uncharacterized group respectively. Abdominal pain was a constant feature in both homozygotes and the uncharacterized group and was documented in all patients. Arthritis was a common feature in both heterozygotes and the uncharacterized group and was documented in 87.5%, and 90% of patients respectively. Variation in clinical picture of FMF patients with positive gene mutation was in agreement with many reports but differ from each other in the frequency of each clinical picture; this difference may be due to the difference in racial group and geographic region, and may be due to the difference in predominant gene mutation in different populations (phenotype genotype correlation) [24, 25].
Based on the Tel Hashomer Severity Score , severity score of the disease was calculated. The mean severity score was 8.27 ± 2.03. Mild to moderate disease severity scores were detected in a significantly higher proportion of heterozygotes and the uncharacterized group than homozygotes.
Attacks of FMF can be prevented by prophylactic colchicine (0.02-0.03 mg/kg/day; maximum: 2 mg/day) in 1 to 2 divided doses. Colchicine therapy reduces the frequency of acute attacks, but also greatly decreases the probability of development of amyloidosis; it may produce partial regression of existing amyloidosis . In our study all patients received colchicine therapy (dose 0.5 - 2 mg/day); only 22.9% of them showed complete response, 74.3% showed incomplete response and 2.9% showed no response. Although incomplete response to colchicine was documented in a significant proportion of patients, the mean number of attacks per year was significantly lower after treatment than before initiation of therapy. Colchicine dose needed to control attacks was significantly lower in heterozygotes than homozygotes. Also response to colchicine therapy was significantly better in the heterozygous group. Contrary to our results, Al-Wahdneh and Dahabreh  reported that prescribing colchicine to all of their patients, in doses ranged between 0.5 mg and 2 mg daily according to age and response, resulted in disappearance of the attacks completely in 68% of cases, a significant decrease in the number and severity of attacks in 29% and no response to treatment in 3% of patients. Similarly, Duşunsel et al.  reported that 77.5% of their patients had complete response, 13.7% had some attacks despite colchicine, and 2% were unresponsive. Booty et al.  also reported that among their 28 heterozygous patients, information on colchicine responsiveness was unavailable for 3 patients, colchicine response was either complete or partial in 84% of patients (21/25), and 4 patients did not respond at all. Fourteen patients (56%) had a complete response, while 7 patients (28%) had periodic attacks of inflammation although less frequently while on treatment. The reasons for lacking response to colchicine could be explained by knowing the fact that colchicine has to go through several stages on its way to controlling inflammation, therefore its efficacy may be affected at various points. Theoretically, problems with its absorption in the intestine can change the therapeutic plasma levels. Problems with the functioning of the human multidrug resistance (MDR1 gene) (P-glycoprotein pump) in white blood cells or serous membrane cells can also affect colchicine function [27, 28]. Modulation of colchicine metabolism by different factors (erythromycin, clarithromycyn, lovastatin, simvastatin, cyclosporin, grapefruit juice, etc.) at the level of cytochrome 3A4 can also influence the effect of colchicine .
In our study, out of 70 patients, 5 patients (7.1%) underwent surgery; appendectomy was performed in 4 patients and herniotomy was done in only one patient. Our results are nearly similar to Al-Wahadneh and Dahabreh  who reported that only 2 out of 56 patients (3.7%) underwent appendectomy. Duşunsel et al.  also reported that 4 out of 102 patients (3.4%) underwent surgery, and all of them had appendectomy. Settin et al.,  reported a higher percent of patients who underwent surgery; 15 out of 66 patients (22.7%) underwent laparotomy during severe abdominal pain either for exploration or for appendectomy. This high percent could be a result of the severe abdominal pain that forced the patients to be bed ridden and that was documented in 66.7% of their patients.
In our study, the most frequent mutations in all patients were E148Q, M680I, and V726A and were detected in 20%, 15.7%, and 14.3% of patients respectively. In an Egyptian study, among 66 patients, M694V was the most common allelic mutation found followed by V726A then M680I (18.8%, 17.42% 12.1% respectively) . In another Egyptian study, among 136 patients, it was found that the most frequent gene mutations were V726A, M694V, M680I, E148Q and M694I in 41.2, 32.4, 29.4, 25 and 20.6% of patients respectively . This differences in the allelic mutations found among patients could indicate the mutational heterogeneity of FMF in the Egyptian population. This mutational heterogeneity appears to be less obvious among other ethnic populations. M694V mutation was found in 97% of the North African Jews in Israel , while M694I mutation was present in 80% of Algerian Arabs . In the studies by Touitou et al. , and by the Turkish FMF study group , the most common MEFV mutation in Turkey is M694V (57.0 and 51.4%, respectively), followed by M680I (16.5 and 14.4%, respectively), and V726A (13.9 and 8.6%, respectively). Possible explanation is that having only one MEFV mutation may give rise to a FMF phenotype in the presence of one or more modifying alleles in other related genes, or other environmental factors like a stress. Asymptomatic carriers for one FMF mutation have biochemical evidence for subclinical inflammation [7, 32] and a more recent study found a higher frequency of carriers for highly penetrant FMF mutations among patients with systemic inflammatory response syndrome (SIRS) and sepsis . Therefore, modifying alleles could contribute to an inflammation dosage threshold, which is necessary to develop systemic inflammation and symptomatic FMF.
HSP and polyarteritis nodosa (PAN) are more common in FMF patients than in the general population . In our study, HSP was determined in 4.3% of patients and this in agreement with a high prevalence of vasculitis found in FMF patients but PAN was not found. Duşunsel et al.  also reported HSP in 6.8% of their patients.