HLA-B27-negative sacroiliitis: a manifestation of familial Mediterranean fever in childhood.

Familial Mediterranean fever is a polysystemic disease seen most frequently in persons of Mediterranean ancestry. Arthritis is one of the common manifestations. Both symptomatic and asymptomatic sacroiliitis have been reported in adults. We report on two children with familial Mediterranean fever with radiographic abnormalities similar to those described in adults. Although sacroiliitis is strongly correlated with the presence of HLA-B27 in most arthropathies, these children were HLA-B27-negative. The diagnosis of familial Mediterranean fever was delayed in both patients because the association of sacroiliitis with familial Mediterranean fever in childhood was not recognized.

Ornithine metabolism in normal subjects and patients with cancer.

The metabolism of L-(1-14C)ornithine monohydrochloride was monitored in patients with histologically proven cancer and in normal volunteers. Following i.v. injection of 8 microCi C-14 ornithine (160 nmoles), the decarboxylation of ornithine--yielding 14CO2--was monitored for a 2.5-hr period using the ionization chamber and vibrating-reed electrometer of Tolbert, as modified by Davidson and Schwabe. Twelve normal subjects exhaled 7.3-15.7% of the administered C-14 (mean 12.6% s.d. 3.11%). In ten patients tested before initiation of therapy, recovery ranged from 18.2-32.1% (mean 23.02%, s.d. 4.52%). A t-test indicates a confidence level of > 99.5% that a significant difference exists between the two means. Re-testing of two normal volunteers showed little or no change in ornithine metabolism over a 2-5-mo period. Results from testing three cancer patients before and after therapy correlate well with clinical evidence of the presence of tumor burden.

Hypothesis: familial Mediterranean fever--a genetic disorder of the lipocortin family?

Familial Mediterranean fever is an autosomal recessively inherited disorder of unknown cause characterized by recurrent attacks of inflammation, involving mainly the peritoneum, pleura, synovia, and skin. Based on a phenotype analysis, we propose that its manifestations may be related to a genetic defect in one of the family of lipocortin proteins. Evidence is presented supporting an abnormality in the first step of prostaglandin/leukotriene synthesis.

Familial Mediterranean fever in Armenians: autosomal recessive inheritance with high gene frequency.

Familial Mediterranean fever (FMF) is a recurrent episodic inflammatory disorder of unknown pathogenesis that occurs with high frequency in non-Ashkenazi Jews and Armenians. However, there are some differences in the clinical manifestations of FMF in these ethnic groups. FMF has been reported to be an autosomal recessive disease in non-Ashkenazi Jews, with a male/female ratio of 1.7, indicating reduced penetrance in females. However, the inheritance is less clear for Armenians. To resolve this problem, we studied prospectively families of 64 Armenian index cases randomly ascertained at the UCLA FMF clinic. Fifty-three families containing 176 sibs in addition to the probands were analyzed by genetic segregation analysis (exclusions included: six single-child families, four families in which one of the parents was also affected, and a family with incomplete information). Upper and lower bounds of the segregation ratio were estimated, and ranged from .10 +/- .03 to .18 +/- .05 when only definitely affected sibs were classified as affected; .17 +/- .04 to .27 +/- .05 when considering "possibly affected" sibs as affected; and .19 +/- .04 to .30 +/- .05 when incomplete penetrance in females was corrected. A value of .25 is the expected segregation ratio for autosomal recessive inheritance, and our data are consistent with this mode of inheritance. We can reject autosomal dominant inheritance, where the expected segregation ratio is .5. Using extended pedigree data, we calculated an FMF gene frequency of 0.073 and a carrier rate of 1/7, which is about four times the frequency in non-Ashkenazi Jews.(ABSTRACT TRUNCATED AT 250 WORDS)

Pericardial disease in familial Mediterranean fever: an echocardiographic study.

We studied 30 randomly selected patients with familial Mediterranean fever (FMF) by M mode echocardiography to determine the frequency of pericardial involvement. There was no evidence of congestive heart failure, uremia, or any other illness known to be associated with pericardial disease in the study population. Eight of the 30 patients (27 percent) had echocardiographic evidence of pericardial disease. Two had pericardial effusions, two had pericardial thickening, and four either or both. Patients with pericardial involvement had a mean duration of FMF of 28.9 +/- 12.2 (SD) years vs 18.5 +/- 10.6 (SD) years for those without pericardial disease (P less than .02). We concluded that pericardial involvement is common in FMF and that its occurrence as detected by echocardiography increases with duration of illness.

Microtubules in PMNs from patients with familial Mediterranean fever.

Polymorphonuclear (PMN) cells derived from patients with Familial Mediterranean Fever (FMF) were evaluated in vitro for the function and concentration of their microtubules. Using the time-decay colchicine binding assay to determine the tubulin concentration in PMN cells, no difference was found in PMN cells derived from FMF patients in comparison with those from normal healthy subjects. Colchicine treatment had no effect on the detectable tubulin concentration in the cells. The mobility of fluorescent con A(F-con A)-receptor complexes on PMN membranes was used to test the function of the microtubules. PMNs from untreated FMF patients showed the same pattern of con A cap formation as seen in normal cells. PMNs derived from colchicine treated patients, however, showed 22-32% spontaneous cap formation. These cells also showed 10-30% more capping in comparison with normal or untreated FMF cells, for any given in vitro colchicine concentration, suggesting that at therapeutic doses, the colchicine does accumulate in the PMNs in vivo. We were unable to demonstrate a microtubule defect in the neutrophils from FMF patients in these studies.

Recurrent polyserositis (familial Mediterranean fever) in a Japanese.

A 36-year-old male of pure Japanese ancestry presented with a classical 20-year history of Recurrent Polyserositis manifested by self-limited attacks of fever plus pleuritis, peritonitis or arthritis. These attacks were completely suppressed by daily prophylactic colchicine, but recurred when the drug was briefly discontinued. For the past 10 years he has been on 1.2 mg of colchicine daily and has had no further febrile attacks. Although several cases of periodic or cyclic febrile disorders in patients of Japanese ancestry have been cited in the literature, the patient described here appears to satisfy the required criteria for a diagnosis of Recurrent Polyserositis in a Japanese.

Disseminated cytomegalovirus infection with gastrointestinal involvement. The role of altered immunity in the elderly.

Disseminated cytomegalovirus (CMV) infections seem to occur in patients with impaired immunity. The evidence for the altered immunity and the predisposing factors in elderly patients are summarized and illustrated by a report of a 75-year old patient with CMV colitis. The clinical and pathologic features of CMV infections involving the gastrointestinal tract in noncompromised hosts are reviewed.

Chronic destructive arthritis in familial Mediterranean fever: the predominance of hip involvement and its management.

Chronic destructive arthritis is a rare complication of Familial Mediterranean Fever (FMF). The hip joints are most commonly involved, but destructive changes may also occur in the knees, ankles, sacroiliac spine, shoulder, or temporomandibular joints. A 28-year-old man with bilateral advanced coxitis and FMF was successfully treated by total hip arthroplasty.

Colchicine use for familial Mediterranean fever. Observations associated with long-term treatment.

Of 85 patients with familial Mediterranean fever receiving continuous prophylactic colchicine therapy, 62 (73 percent) have had a significant reduction in the severity and frequency of their attacks. All 62 have been observed for three years or more, for a total of 4,680 patient-months and a mean duration of 75.5 months. Of the 85 patients, 23 (27 percent) did not complete three years of treatment for a variety of reasons. Diarrhea was the most common side effect, necessitating reduction of colchicine dosage in 12 patients, but discontinuation of treatment in only one. No other significant side effects were observed. Continuous, prophylactic colchicine therapy is effective in preventing the recurrent febrile paroxysms of familial Mediterranean fever and is indicated in those patients who are incapacitated by frequent attacks or who are at risk for amyloidosis developing.

Anorexia nervosa.

The clinical and physiologic features of anorexia nervosa seem to be consequences of a complex interaction among psychologic abnormalities, endocrine disturbances, and malnutrition. Although a spectrum of psychologic disorders has been observed, distortion of body image, weight phobia, disordered perception of hunger and satiety, and a sense of ineffectiveness are encountered most frequently. The impaired secretion of luteinizing hormone-releasing factor, release of gonadotropins, and production of estrogens reflect a defect in the hypothalamic-anterior pituitary-gonadal axis. Because most of the endocrine abnormalities are reversible with improved nutrition, they are probably secondary to malnutrition rather than to hypothalamic dysfunction. Hypercarotenemia observed in 16 of 21 patients studied recently seems useful in differentiating anorexia nervosa from other forms of malnutrition and weight loss. A combined medical and psychiatric approach has been successful in drastically reducing the mortality of this disorder.

A neutrophil lysozyme leak in patients with familial Mediterranean fever.

Polymorphonuclear cells derived from the peripheral blood of patients with Familial Mediterranean Fever release more lysozyme in response to high temperature (42 degrees, 46 degrees C) than do control cells. No differences between the FMF and control cells were observed in the release of acid phosphatase, beta-glucuronidase, or lactoferrin. Colchicine treatment had no effect on the measurable release of the enzyme from PMNs derived from FMF patients. The increased release of lysozyme in response to high temperatures appears to be specific to FMF neutrophils, and was not found in PMNs from non-FMF patients with febrile or inflammatory diseases, nor was it seen in monocytes derived from the FMF patients. It is suggested that the increased release of lysozyme from the neutrophils may be of importance in the pathogenesis of FMF.

Effect of long-term colchicine therapy on jejunal mucosa.

Colchicine is recommended as daily prophylactic therapy in patients with familial Mediterranean fever (FMF) to prevent febrile paroxysms. The drug is known to be a potent inhibitor of mitotic activity and might therefore be expected to have a significant adverse effect on tissues that undergo rapid turnover. We studied small bowel biopsies from nine patients with FMF who were receiving daily low-dose oral colchicine therapy. In each patient the lengths of 20 crypts and villi were measured and the number of mitotic figures in 20 crypts were counted. The data were compared with similar measurements from histologically normal-appearing biopsies obtained from 14 patients with a variety of mild gastrointestinal complaints. The mean crypt length was found to be significantly greater (0.197 mm vs 0.186 mm, P < 0.0001) and the mean villous length significantly smaller (0.369 mm vs. 0.442 mm, P < 0.0001) in the FMF patients than in the control population. In addition, the mean number of mitotic figures per crypt was significantly higher in the FMF patients (2.58 vs 1.00, P < 0.001). The data reveal a pattern of mucosal injury in the colchicine-treated FMF patients characterized by a hyperplastic crypt-villous atrophy pattern with increased mitotic rate, which is indicative of an increase in cell turnover and opposite to what we anticipated based on colchicine's known effect on mitotic activity.

Enhanced neutrophil chemiluminescence in familial Mediterranean fever.

Familial Mediterranean Fever is a disorder of unknown cause characterized by recurrent, self-limited paroxysms of serosal inflammation. Although the neutrophil is the predominant cell involved, no cellular abnormalities are known. Chemiluminescence was studied in neutrophils from 20 asymptomatic patients with this disease and 21 healthy controls to evaluate the oxidative response to formyl-methionyl-leucyl-phenylalanine (f-met-leu-phe). In a subset of patients with familial Mediterranean fever, neutrophils but not monocytes were shown to have significantly enhanced chemiluminescence compared to controls. The enhanced responsiveness of neutrophils to f-met-leu-phe in this disease was found to occur at a postreceptor level. Receptor binding assays demonstrated no differences in binding affinity and receptor number between patients and controls. In addition, a similar enhancement in chemiluminescence was observed with an alternative stimulus (zymosan). In contrast to chemiluminescence, chemotaxis induced by f-met-leu-phe was not enhanced in patients with familial Mediterranean fever. The enhanced neutrophil chemiluminescence may identify a subclinical inflammatory state in attack-free patients with familial Mediterranean fever, as enhanced chemiluminescence is also observed in chronic inflammatory diseases with active inflammation.

Familial Mediterranean fever--linkage studies with genetic markers on chromosome 6.

Familial Mediterranean Fever (FMF) is an autosomal recessive disease manifested by recurrent short episodes of fever associated with polyserositis. Although the biochemical defect is unknown, there are several immunologic abnormalities which have been described in this disease. To examine critically whether there is linkage between FMF and the immunogenetic region (major histocompatibility complex-MHC) on chromosome 6, including the HLA, BF, and GLO1 loci, blood samples from members of 13 nuclear Armenian families were tested for these genetic markers. These 13 families included 28 affected and 42 unaffected family members. Linkage could be excluded at 7.5% recombination with the HLA ABC and D loci. Linkage could be excluded at 2.5% recombination for GLO1. Linkage could not be excluded with BF individually, but can be rejected based on the haplotype data. No association was found with either BF, GLO1, and HLA DQ alleles. HLA DR4 was found more often in affected cases than in controls; however, after adjusting for the number of antigens tested this was not significant. Our results would appear to exclude the immunogenetic region on chromosome 6 from linkage with FMF in the Armenian population.