Clinical features and disease severity of Turkish FMF children carrying E148Q mutation.

BACKGROUND: Familial Mediterranean fever (FMF) is the most common hereditary monogenic autoinflammatory disease caused by mutations in the MEFV gene. It is controversial whether E148Q alteration is an insignificant variant or a disease-causing mutation. The aim of this study was to evaluate the clinical features and disease severity of FMF patients carrying E148Q mutation. METHODS: Files of FMF patients were retrospectively evaluated. Patients with at least one E148Q mutation were included to the study. The clinical characteristics and disease severity of the patients who were carrying only E148Q mutation were compared with the patients who were compound heterozygous for E148Q and homozygous for M694V mutation. RESULTS: The study group comprised 33 patients who were homozygous or heterozygous for E148Q; 34 with compound heterozygous E148Q mutations and 86 patients who had homozygous M694V mutation. Patients who had only E148Q mutation were found to have the oldest mean age of disease onset and lowest mean disease severity score. Attack frequency and colchicine doses were lower in patients with only E148Q mutation as compared with the other two groups. The frequency of clinical findings such as fever, abdominal pain, arthralgia, and arthritis among the three groups was similar. CONCLUSION: Familial Mediterranean fever patients with only E148Q mutation are presenting with late-onset and milder disease course despite having similar clinical findings as compared with patients who had other mutations. Finally, we imply that E148Q is a mutation and colchicine treatment should be given.

Sacroiliitis in Children With Familial Mediterranean Fever.

BACKGROUND/OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent, self-limited attacks of fever with serositis. Various diseases were reported to be associated with FMF. The aim of this study was to investigate the frequency and characteristics of sacroiliitis in children with FMF. METHODS: Files of FMF patients who had been seen in 2 reference hospitals in Ankara were retrospectively evaluated. Patients with FMF and concomitant sacroiliitis were included to the study. All patients had magnetic resonance imaging evidence of sacroiliitis. RESULTS: Among 650 FMF patients, 17 (11 females, 6 males; mean age, 13.32 ± 4.24 years) (2.6%) of them were found to have sacroiliitis. Familial Mediterranean fever diagnosis was done prior to sacroiliitis diagnosis in 11 patients (65%) and concurrently or afterward in 6 patients (35%). Ten patients had isolated sacroiliitis, and 7 had associated diseases (5 enthesitis-related arthritis, 1 psoriatic arthritis, and 1 ulcerative colitis). Arthritis (59%), arthralgia (77%), leg pain (71%), heel pain (41%), and enthesitis (29%) were common complaints. Sacroiliac tenderness was detected in 77%, and M694V mutation in almost 90% of the patients. All patients received colchicine therapy. Additionally, 14 of them were treated with nonsteroidal anti-inflammatory drugs, 10 were on sulfasalazine treatment, and 7 of them were on biological agents. CONCLUSIONS: Sacroiliitis can be seen in patients with FMF during childhood, and M694V mutation seems to be a susceptibility factor for its development. Inflammatory low-back pain and leg and heel pain could suggest sacroiliitis.

C3 glomerulopathy in NLRP12-related autoinflammatory disorder: case-based review.

Autoinflammatory diseases (AIDs) are a recently described group of conditions caused by mutations in multiple genes that code for proteins of the innate immune system. Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory diseases comprising three clinically overlapping disorders: familial cold urticarial syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). CAPS have been associated with gain-of-function variations in NLRP3 (NOD-like receptor family, pyrin containing domain-3). However, a new class of autoinflammatory disease resembling FCAS or MWS has been described in patients with NLRP12 mutations. Here, we report a 6-year-old boy diagnosed with AID who developed an unexpected C3 glomerulopathy during attacks and carried a novel variation in NLRP12. Following treatment with IL (interleukin) 1 targeting agents, all symptoms and inflammation resolved. This is the first case in the literature affected by both autoinflammatory disease and C3 glomerulopathy.

Effects of whole blood viscosity and plasma NOx on cardiac function and cerebral blood flow in children with chronic kidney disease

Background/aim: The aim of the study was to investigate the effects of whole blood viscosity and plasma nitric oxide on cerebral and cardiovascular risks associated with chronic kidney disease. Materials and methods: The study group consisted of 40 pediatric patients and 21 healthy control subjects. Hematologic and biochemical variables, viscosity and plasma nitric oxide levels, echocardiographic findings, and middle cerebral artery blood flow velocity were examined. Results: Viscosity values of patients were significantly lower than those of the control group. Lower values of hematocrit, total protein, and albumin and higher values of ferritin in all patient groups resulted in significantly low viscosity levels. Plasma nitric oxide levels were higher in all patient groups than those in the controls. No statistically significant difference was present in middle cerebral artery blood flow velocity between the patient and control groups. Even when systolic functions were normal, the patient group had significant deterioration in diastolic functions, suggesting morbidity and mortality risks. Conclusions: Cerebral blood flow velocities were not affected by viscosity and nitric oxide levels, suggesting that cerebral circulation has the ability to make adaptive modulation. The metabolism of nitric oxide levels needs further investigation and studies in patients with chronic renal disease.

Assessment of neutrophil to lymphocyte ratio and mean platelet volume in pediatric familial Mediterranean fever patients.

BACKGROUND: Blood neutrophil to lymphocyte ratio (NLR) and mean platelet volume (MPV) both have been used as a simple marker of inflammation in many disorders. Here, we aimed to investigate the relationship between NLR, MPV, and familial Mediterranean fever (FMF). MATERIALS AND METHODS: In this retrospective study, the files of FMF patients in pediatric rheumatology outpatient clinic were reviewed. There were 160 participants (68.4%) in the FMF patient group and 74 participants (31.6%) in the control group. Ninety of patients were in attack-free period, and 70 were in attack period. RESULTS: The highest values of NLR were found in the patients at attack period. Patients in attack-free period and the participants in control group had similar levels of NLR (1.71 ± 0.83 and 1.91 ± 1.86 respectively) (P = 0.457), and they had lower ratios than the patients did at attack period (4.10 ± 3.11) (P < 0.001 for both). There was no significant difference between MPV values of attack patients (8.35 ± 4.91) and attack-free patients (8.43 ± 1.15) (P = 0.074). MPV values of attack patients and attack-free patients were significantly higher than control group (7.99 ± 0.81) (P < 0.001 for both). CONCLUSION: NLR ratio may indicate FMF attack period. Since there was no significant difference between attack-free patients and control groups, NLR ratio cannot be used as a subclinical inflammation marker. However, NLR could be a useful predictor of inflammation in FMF patients. On the other hand, since our attack and attack-free patients have similar MPV values and both had greater MPV values than control group, we suggest that MPV may be used to show subclinical inflammation.

Hemophagocytic lymphohistiocytosis secondary to Varicella zoster infection in a child with Henoch-Schönlein purpura.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal, hyper-inflammatory syndrome that is characterized by untimely activation of macrophages, and manifests as cytopenia, organ dysfunction, and coagulopathy. Secondary HLH can be associated with infection, drugs, malignancy, and transplantation, and is mostly triggered by infection. Herein, we report the case of a patient with Henoch-Schönlein purpura (HSP) who developed severe HLH secondary to Varicella zoster infection.

Interleukin-1 targeting treatment in familial Mediterranean fever: an experience of pediatric patients.

OBJECTIVES: The aim of this report was to evaluate and discuss treatment of pediatric familial Mediterranean fever (FMF) patients with anti-interleukin1 (IL-1) agents. METHODS: Refractory or colchicine unresponsive FMF was described as severe and frequent attacks and/or having high acute phase reactance levels despite having a maximum dose of colchicine (2 mg/day). Disease course, adverse effects, duration of follow-up, treatment protocols, responses to the therapies were discussed. RESULTS: Eight patients (6 male, 2 female) having refractory FMF were identified. Mediterranean fever (MEFV) gene analyses revealed homozygous M694V mutations in six patients and heterozygote M694V mutations in one patient and no mutation in one patient. They were all treated with anakinra and/or canakinumab. The use of anti-IL-1 drugs was beneficial to all patients. None of them had any severe adverse effects due to the therapy. CONCLUSIONS: Anakinra and canakinumab were effective in patient refractory to colchicine treatment as shown both in our series and in the literature. Therefore, controlled trials are needed to evaluate the safety and long-term efficacy of IL-1 targeting agents in colchicine resistant patients.

Clinical characteristics of paediatric neuro-Behçet's disease: a single tertiary centre experience.

OBJECTIVES: To investigate the demographic and neurological features and treatment modalities of neuro-Behçet's disease (NBD) in children, to share our experiences and to summarise the literature. METHODS: We retrospectively reviewed the medical records of Behçet's disease (BD) patients who attended our paediatric rheumatology department between December 2005 and October 2013. Five patients had the diagnosis of NBD. Initial neurological presentation, clinical BD presentation, magnetic resonance imaging pictures of those five patients was recorded. RESULTS: A total of 18 patients were diagnosed with BD. Among BD patients five of them were identified with NBD (27.8%). The mean age of NBD patients at the time of diagnosis was 12.4 years (range 5.5-15 years). The mean follow-up time after the neurological involvement was 5.2 years (range 0.5-14). In two cases neurological involvement occurred at the same time with the onset of other clinical findings of BD (40%). Both of these patients had parenchymal involvement. Three patients were admitted with headache as the initial neurological symptom. They revealed benign intracranial hypertension. One of them had cerebral venous sinus thrombosis (CVST). The other two had normal cranial magnetic resonance imagines. All patients received colchicine and steroid, two of them who had parenchymal involvement received also cytotoxic drugs. CONCLUSIONS: This study has shown that neurological symptoms can be the first manifestations of BD in children. Clinicians should be aware of this possibility and when a patient presents with neurological manifestations, it would be valuable to query the patient for the clinical features of Behçet's disease.

Utility of peritoneal dialysis in neonates affected by inborn errors of metabolism.

AIM: Some inborn errors of metabolism induce metabolic encephalopathy through accumulation of neurotoxic metabolites. Rapid elimination of these metabolites by peritoneal or extracorporeal dialysis is crucial to prevent neuronal damage or death. In this retrospective study, we evaluated the outcomes of nine neonates with metabolic crisis treated with peritoneal dialysis. METHOD: Six neonates with hyperammonemic coma (four with organic acidemias, two with urea cycle disorders) and three with leucine accumulation due to maple syrup urine disease (MSUD) were managed with peritoneal dialysis in conjunction with dietary and pharmacological therapy. RESULTS: Three patients with organic acidemia survived. One of the patients was normal; others had moderate and severe neurological impairments. One neonate with organic acidemia and both neonates with urea cycle disorders died. Two of the three patients with MSUD survived without neurological impairment; the other had severe neurological damage and died at 9 months of age due to sepsis. CONCLUSION: Theoretically, extracorporeal dialysis should be the first dialysis treatment of choice; however, this report demonstrates that peritoneal dialysis has a chance to prevent neurological damage in some patients. Therefore, in developing countries without extracorporeal dialysis opportunities, it can be still a life-saving procedure, if it is applied with skilled staff and standard procedures.

Cytomegalovirus-related hemorrhagic cystitis in an immunocompetent child.

Cytomegalovirus (CMV) infections are mostly seen in immunocompromised patients. However, unusual manifestations or complications of acquired CMV infections in immunocompetent patients are rarely reported. CMV-related hemorrhagic cystitis is extremely rare but should be considered even in immunocompetent patients. We present a case of a 3-year-old immunocompetent boy with intermittent, terminal gross hematuria lasting for 1 month. There was no history of genitourinary trauma or stone disease. Urine analysis revealed hematuria with eumorphic red blood cells and no proteinuria. Urine culture was negative. Ultrasonography showed increased bladder wall thickness and irregularity at inferior of bladder. Cystoscopy revealed hyperemia and edema. Histopathological examination was consistent with CMV infection, viral DNA by polymerase chain reaction in peripheral blood and urine were positive. Clinical, laboratory, and imaging features pointed towards hemorrhagic cystitis due to CMV. He was followed-up with no treatment. After 1 month, repeated investigations showed complete resolution of finding. This is a rare description of an immunocompetent child with CMV-induced cystitis.

Eculizumab therapy in a child with hemolytic uremic syndrome and CFI mutation.

BACKGROUND: Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in childhood. It usually occurs after a prodromal episode of diarrhea and it leads to significant morbidity and mortality during the acute phase. However, cases that start as diarrhea-positive HUS whose renal function fail to recover should be screened for genetic disorders of the complement system, which is called atypical HUS (aHUS). CASE-DIAGNOSIS/TREATMENT: We herein report a 10-year-old girl, who initially came with bloody diarrhea and had features of HUS with delayed renal and hematological recovery despite plasma therapy. Eculizumab (600 mg/week) was initiated on day 15 for atypical presentation and later a complement factor I (CFI) mutation was detected. The girl recovered diuresis within 24 h and after the third eculizumab infusion, hemoglobin, platelet, and C3 levels normalized; renal function improved; and proteinuria completely disappeared in 2 weeks. CONCLUSION: It is our belief that eculizumab can be the treatment of choice in children who have plasma exchange-refractory HUS with defective regulation of the alternative complement pathway.

Application of the new pediatric criteria and Tel Hashomer criteria in heterozygous patients with clinical features of FMF.

Recently, a new set of criteria was established for the diagnosis of familial Mediterranean fever (FMF) in childhood. The aim of this study is to validate the new criteria set among heterozygous patients with clinical features of FMF. The study group consisted of FMF patients, who had a mutation at a single allele, who were followed in four pediatric nephrology-rheumatology centers in Turkey. Patients were evaluated by the new criteria set and also by the Tel Hashomer criteria. According to the new criteria, the diagnosis of FMF was established by the presence of two or more of five criteria (fever, abdominal pain, chest pain, arthritis, family history of FMF). The study group consisted of 110 FMF (54 male, 56 female) patients. Majority of the patients had heterozygous pM694V mutation (65%). The sensitivity of the new criteria set and that of the Tel Hashomer criteria in our study group were found to be 93% and 100%, respectively. In conclusion, this study designates that sensitivity of the new criteria set is also high in patients who had a mutation at a single allele.

Etiology and outcome of acute kidney injury in children.

The aim of this prospective, multicenter study was to define the etiology and clinical features of acute kidney injury (AKI) in a pediatric patient cohort and to determine prognostic factors. Pediatric-modified RIFLE (pRIFLE) criteria were used to classify AKI. The patient cohort comprised 472 pediatric patients (264 males, 208 females), of whom 32.6% were newborns (median age 3 days, range 1-24 days), and 67.4% were children aged >1 month (median 2.99 years, range 1 month-18 years). The most common medical conditions were prematurity (42.2%) and congenital heart disease (CHD, 11.7%) in newborns, and malignancy (12.9%) and CHD (12.3%) in children aged >1 month. Hypoxic/ischemic injury and sepsis were the leading causes of AKI in both age groups. Dialysis was performed in 30.3% of newborns and 33.6% of children aged >1 month. Mortality was higher in the newborns (42.6 vs. 27.9%; p < 0.005). Stepwise multiple regression analysis revealed the major independent risk factors to be mechanical ventilation [relative risk (RR) 17.31, 95% confidence interval (95% CI) 4.88-61.42], hypervolemia (RR 12.90, 95% CI 1.97-84.37), CHD (RR 9.85, 95% CI 2.08-46.60), and metabolic acidosis (RR 7.64, 95% CI 2.90-20.15) in newborns and mechanical ventilation (RR 8.73, 95% CI 3.95-19.29), hypoxia (RR 5.35, 95% CI 2.26-12.67), and intrinsic AKI (RR 4.91, 95% CI 2.04-11.78) in children aged >1 month.

Primary peritonitis in children with nephrotic syndrome: results of a 5-year multicenter study.

Primary peritonitis is a well-described infectious complication of nephrotic syndrome. Current data on the true incidence of peritonitis and efficacy of preventive pneumococcal vaccination are not clear in this group of children. In this nationwide study, among a total of 268 patients with an initial diagnosis of steroid sensitive nephrotic syndrome, eight episodes of primary peritonitis were detected in seven patients during 5 years. All eight attacks of peritonitis occurred in the relapse period. Seven of these peritonitis episodes occurred in the first 2 years of nephrotic syndrome, three of them during the first attack. One patient had two attacks with a 6-month interval. Only two of the patients were steroid sensitive, while four of them were steroid dependent, and one was steroid resistant at the diagnosis of peritonitis. The causing microorganism was identified in three patients (Streptococcus hemolyticus, Streptococcus pneumoniae, and alpha-hemolytic Streptococcus). Incidence of peritonitis (2.6%) in our series was not high when compared with previous reports. None of the patients had been immunized against pneumococcus before or after the peritonitis attack. It raises the question if the vaccine is necessary for every child with steroid sensitive nephrotic syndrome. However, we suggest that immunization against pneumococcus is not indicated in children with steroid-responsive nephrotic syndrome (NS) and should be reserved for the small number of children who have steroid-dependent or steroid-resistant NS.

Effect of anti-interleukin-1 treatment on quality of life in children with colchicine-resistant familial Mediterranean fever: A single-center experience.

AIM: The aim of this study is to evaluate the clinical parameters, acute-phase reactants, side effects, genetic mutations among colchicine-resistant Familial Mediterranean fever (FMF) patients who received anti-interleukin-1 (anti-IL-1) treatment. We also evaluate the quality of life and school attendance among colchicine-resistant FMF patients, in relation to treatment with anti-IL-1. INTRODUCTION: Familial Mediterranean fever is the most common inherited autoinflammatory disorder. Although the main treatment of FMF is colchicine, a small group of patients are resistant to colchicine treatment. Anti-IL-1 treatment is promising in colchicine-resistant patients due to excessive IL-1ß production in pathogenesis. The aim of this study is to evaluate the quality of life and school attendance rates among colchicine-resistant FMF patients after anti-IL-1 treatment. METHODS: This is a single center retrospective study of 25 pediatric colchicine-resistant FMF patients treated with anti-IL-1 treatment. Autoinflammatory Disease Activity Index (AIDAI) was used for disease activity assessment. School attendance rates were evaluated before and after treatment. RESULTS: There were 25 patients with FMF (11 M/14 F) who were treated with anakinra or canakinumab for various indications (colchicine-resistant recurrent febrile attacks in 20, colchicine-related side effects in 2, subclinical inflammation in 3 patients). Only 3 patients developed side effects with anakinra (2 headache, 1 urticarial rash). There was a significant decrease in the frequency of attacks, acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein), AIDAI and physician's and patient's global assessment scores and improvement in school attendance rates. At the last follow-up, all patients were in remission, and only 3 had subclinical inflammation. CONCLUSION: Anti-IL-1 treatment is quite effective in children with colchicine-resistant FMF patients, proven with improved AIDAI scores and school attendance rates. In the long term by lowering disease activation even development of amyloidosis may be prevented.

Predictive role of neutrophil to lymphocyte ratio and mean platelet volume in Henoch-Schönlein purpura related gastrointestinal and renal involvement. / Función predictiva del índice de neutrófilos/linfocitos y del volumen plaquetario medio en la púrpura de Henoch-Schönlein relacionada con compromiso renal y gastrointestinal.

BACKGROUND: Henoch-Schönlein purpura (HSP) is a systemic small-vessel vasculitis that occurs mainly in children. The aim was to evaluate the blood neutrophil-to-lymphocyte ratio (NLR) and mean platelet volume (MPV) in patients with HSP and to investigate the relationship with gastrointestinal and renal involvement. METHODS: Children with HSP and healthy individuals as controls were included. Hemoglobin level, white blood cell count, platelet count, NLR, MPV erythrocyte sedimentation rate and C-reactive protein were evaluated. RESULTS: There were 71 HSP children and 74 controls. NLR was significantly higher in HSP patients with gastrointestinal bleeding than without gastrointestinal bleeding (p < 0,001). The optimal cutoff value of NLR for predicting gastrointestinal bleeding was 2.05, with 93 % sensitivity and 62 % specificity. MPV was significantly higher in HSP patients with renal involvement than without renal involvement (p = 0,027). CONCLUSIONS: Blood NLR and MPV may be useful markers to identify gastrointestinal and renal involvement in HSP patients.

Antecedentes: La púrpura de Henoch-Schönlein (PHS) es una vasculitis sistémica de vasos pequeños. El objetivo fue evaluar elíndicedeneutrófilos/linfocitos (INL) ensangreyelvolumen plaquetario medio (VPM) en la PHS e investigar la relación con el compromiso renal y gastrointestinal. Métodos: Se incluyeron niños con PHS y controles sanos. Se evaluaron concentración de hemoglobina, recuento de leucocitos, recuento de trombocitos, INL, VPM, velocidad de sedimentación globular y proteína C-reactiva. Resultados: El INL fue significativamente mayor en los pacientes con PHS con hemorragia gastrointestinal (p < 0,001). El valor ideal de corte del INL para predecir la hemorragia gastrointestinal fue 2,05, con 93 % de sensibilidad y 62 % de especificidad. El VPM fue significativamente mayor en los pacientes con PHS con compromiso renal (p = 0,027). Conclusiones: El INL en sangre y el VPM podrían ser útiles para identificar el compromiso renal y gastrointestinal en la PHS.

Takayasu Arteritis: A Case Presenting With Neurological Symptoms and Proteinuria.

In this article, we present an 18-year-old female patient who was initially diagnosed as central nervous system vasculitis and focal segmental glomerulosclerosis but later diagnosed as Takayasu arteritis.