Necmiye Tümer

MEFV mutations in Turkish patients suffering from familial Mediterranean fever

Familial Mediterranean fever (FMF) is a recessive inherited disorder affecting Sephardic Jews, Arabs, Armenians and Turks. The gene responsible for FMF was recently cloned and several disease‐associated mutations have been described. We have evaluated seven MEFV mutations in 460 chromosomes of 230 unrelated patients with FMF living in Turkey, using PCR methods. The M694V allele accounted for 43.5% of the alleles studied and 19.1% of the patients were homozygous. The M680I, V726A and M694I mutations were responsible for 12.0%, 11.1% and 2.8% of the patients respectively. R761H, K695R and E148Q were rarely encountered. Two thirds of the disease alleles were attributed to three common mutations: M694V, M680V and V726A, but only 54% of the patients carried one or two of the three mutations. Adding the four rarer mutations increased these figures to 72% and 60%, respectively. Altogether, 79.6% of the patients bore at least one of the main mutations, and 84.3% carried at least one of the seven mutations studied. The 28 patients suffering also from amyloidosis carried at least one of five mutations, M694V being the most common. These results suggest that the origin of FMF in Turkey is heterogenous, all common mutations are associated with amyloidosis. Further, rapid and accurate molecular diagnosis of FMF is feasible in most cases. Hum Mutat 15:118–119, 2000.

Blood pressure nomograms for children and adolescents in Turkey

Abstract In order to obtain data on blood pressure (BP) distribution in Turkish children, a total of 5,599 Turkish children from birth to 18 years were studied. BP rises with age, and both systolic and diastolic BP showed a positive correlation with height and weight in both sexes. As the sampling was representative of Turkish children at different ages, the mean systolic and diastolic BP levels were compared for each age with the results reported in the study of the Second Task Force. The mean systolic and diastolic BP of Turkish children and the increase with growth and development were different from the Second Task Force study. Genetic, ethnic, and environmental factors were suggested to be responsible for this variation. In conclusion, normal BP curves should be applied with caution in childhood, and every population should use their own normal standards to define a measured BP level in children.

CLINICAL, LABORATORY AND MOLECULAR CHARACTERISTICS OF CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER-ASSOCIATED VASCULITIS

Familial Mediterranean Fever (FMF) is an autosomal recessive disease characterized by recurrent self‐limited attacks of fever accompanied by peritonitis, pleuritis and arthritis. Approximately 5% of individuals with FMF have been reported to have Henoch‐Schonlein purpura (HSP) and about 1% have polyarteritis nodosa (PAN). Protracted febrile myalgia is another vasculitis‐associated clinical entity among patients with FMF. Recently, the gene responsible for FMF, MEFV, has been cloned and four missense mutations (M680I, M694V, V726A and M694I) have been described. In this report, we present clinical and laboratory findings and mutation results of 23 children with FMF‐associated vasculitis. HSP, PAN and protracted febrile attacks have been diagnosed in 11, 2 and 10 children, respectively. Mutation analysis shows that 3 children are homozygotes for the M694V mutation and 11 are compound heterozygotes for 2 of the studied mutations. M694V/V726A mutations were identified in 8, M694V/M694I in 2 and M680I/M694V in 1 of these children. In six children only one mutation was found and in three none of the studied mutations were identified. This study confirms that most children with FMF‐associated vasculitis have identifiable mutations in the MEFV gene. Environmental and/or other genetic factors are possibly involved in the pathogenesis of vasculitis in FMF; elucidation of these mechanisms will help to understand pathogenesis of childhood vasculitides. ?Children, Familial Mediterranean Fever, MEFV mutations, vasculitis

MEFV mutations in multiplex families with familial Mediterranean fever : is a particular genotype necessary for amyloidosis?

Familial Mediterranean fever (FMF) is an autosomal recessive disease. It is characterized by recurrent febrile episodes in association with peritonitis, pleuritis, and arthritis. Progressive systemic amyloidosis is the most important complication of FMF that inevitably leads to chronic renal failure. Recently, the gene for FMF, MEFV, has been cloned and four missense mutations have been described: M694V, M680I, V726A, and M694I. Initial studies have suggested that the presence of the M694V mutation carries a significant risk for the development of amyloidosis. In this study, we present seven families, in which at least two individuals have been diagnosed with FMF and at least one with amyloidosis. Among 18 individuals, in whom molecular testing was performed for the four aforementioned mutations, ten had amyloidosis. None of these ten individuals was found to be homozygous for the M694V mutation. In three families, there were two sibs with amyloidosis. None of the sib‐pairs with amyloidosis was found to have the same genotype. There were two or more sibs with the same genotype in four families. Only one sib from each family developed amyloidosis in these families. These results provide evidence that FMF patients without the M694V mutation are also at risk for the development of amyloidosis. Particular mutations themselves do not appear to be sufficient to explain the occurrence of amyloidosis in all cases with FMF.

Antistreptococcal Response is Exaggerated in Children with Familial Mediterranean Fever

Abstract: Familial Mediterranean fever (FMF) is an autosomal recessive disorder. Although the pathogenesis of the disease is not yet completely understood, enhanced acute-phase responsiveness is considered to be one of the most important mechanisms. The presence of high levels of antistreptolysin O (ASO) antibodies and streptococcus-associated diseases, such as acute poststreptococcal glomerulonephritis (AGN) and acute rheumatic fever (ARF), has been reported in patients with FMF. In order to better understand the effect of FMF on antistreptococcal antibody response, we measured ASO and antideoxyribonuclease B (anti-DNAse B) levels in patients with FMF and compared them with those in healthy controls. The study consisted of two parts. In the first step, antistreptococcal antibody levels were analysed in 44 patients with FMF and 165 healthy children who had no history or clinical evidence of upper respiratory tract infection (URTI) for the last 4 months. In the second step, antistreptococcal antibody levels were measured in 15 patients with FMF and 22 healthy controls in response to documented group A β-haemolytic streptococcal pharyngitis. In the first part of the study, ASO and anti-DNAse B levels in patients with FMF were found to be significantly higher than those in healthy controls (P<0.001). In the second part, ASO and anti-DNAse B titres were found to be significantly higher in patients with FMF than in controls (P<0.001 and <0.05, respectively) 4 weeks after a positive throat culture. We concluded that patients with FMF have an exaggerated response to streptococcal antigens and might be prone to poststreptococcal non-suppurative complications, such as ARF.

Familial mediterranean fever and acute rheumatic fever: A pathogenetic relationship?

Abstract: The frequency of acute rheumatic fever (ARF) in patients with familial Mediterranean fever (FMF) was documented and the effects of preceding streptococcal infections on the exacerbation of FMF were determined. In the first part of the study, 162 individuals with FMF were investigated for a history of ARF in a retrospective study. In the second part of the study, antistreptolysin-O (ASO) titres were measured in 130 individuals with FMF. Thirty-six patients had an arthritic attack (group A1), 55 patients had a typical FMF attack without arthritis (group A2) and 39 patients were in the attack-free interval (group B) during the investigation. Nine patients with FMF (5.5%) were considered to have ARF and three of them (1.85%) also had rheumatic heart disease. This prevalence of rheumatic heart disease in FMF is higher than that of the normal population (0.65%) reported in Turkey. Elevated ASO titres were found in 75%, 42% and 38% of the patients in groups A1, A2 and B, respectively. These percentages were found to be significantly higher in group A1 than in both groups A2 (p<0.01) and B (p<0.01). We concluded that patients with FMF might be more prone to the late complications of streptococcal infections.

Pseudoxanthoma elasticum: a rare cause of hypertension in children.

Abstract. We describe an 11-year-old girl with severe renin-dependent hypertension. She had characteristic cutaneous, ocular, and vascular signs of pseudoxanthoma elasticum (PXE), and the diagnosis was confirmed histologically. Because PXE is a heterogeneous heritable disorder, the family was evaluated for this condition. Since the patient’s mother and brother showed some manifestations of PXE, autosomal dominant inheritance is the most likely inheritance pattern in this family.

Tuberculosis in children undergoing continuous ambulatory peritoneal dialysis

Abstract The incidence of tuberculosis (TB) is increasing worldwide. Due to an impairment of cellular immunity, patients with chronic renal failure are susceptible to reactivation of TB. Seventy patients were treated by continuous ambulatory peritoneal dialysis (CAPD) in our pediatric nephrology department during the years 1989–1997. TB was diagnosed in 4 patients, representing 5.7% of all CAPD patients in our department. One patient had extrapulmonary (TB osteomyelitis) and the others had pulmonary TB. All patients were treated with antituberculous drugs.Two patients with pulmonary TB were cured. Symptoms improved in the other 2 patients but they died at home for unknown reasons. We recommend that all children in regions of high prevalence of TB should be investigated for TB, especially if they have a cough or fever of unknown etiology.

Spectrum of renal osteodystrophy in children on continuous ambulatory peritoneal dialysis

Abstract Background: The prevalence of different types of bone disease in chronic renal failure (CRF) has changed significantly during the last decade. The aim of the present study is to evaluate the spectrum of bone disease in children with CRF undergoing continuous ambulatory peritoneal dialysis (CAPD).

Low-dose erythropoietin is effective and safe in children on continuous ambulatory peritoneal dialysis.

Abstract. Hypertension is one of the most important complications of erythropoietin (rHuEPO) therapy in dialysis patients. In this study, the effect of two different dosage regiments of subcutaneous rHuEPO on blood pressure [BP] was evaluated in 20 anemic children on continuous ambulatory peritoneal dialysis (CAPD). Patients were randomized to receive rHuEPO 50 U/kg, either once a week (group 1, 50 U/kg per week) or three times a week (group 2, 150 U/kg per week). At the beginning of the study, 8 patients in group 1 and 8 patients in group 2 were on antihypertensive therapy. In group 1, the hematocrit increased gradually and significantly from 18.98%±1.79% to 30.1%±1.62% after 6 months, while in group 2 it rapidly increased from 19.53%±1.86% to 32.4%±1.11% after 3 months. A significant increase in the mean arterial BP was observed in group 2. Antihypertensive therapy had to be increased in all of the 8 previously hypertensive patients and had to be initiated in 1 of the 2 originally normotensive patients in the same group. None of the patients in group 1 required a change in antihypertensive medication. We conclude that during treatment with rHuEPO pre-existing hypertension and the dose of rHuEPO are the most important risk factors for the development or worsening of hypertension in children on CAPD, and gradual elevation of hematocrit by low-dose rHuEPO avoids the development of severe hypertension.