Paraoxonase 1 polymorphisms (L55M and Q192R) as a genetic marker of diabetic nephropathy in youth with type 1 diabetes.

INTRODUCTION: Paraoxonase 1 (PON1) polymorphisms have been largely involved in diabetes complications. The aim of the study is to evaluate the effects of PON1 polymorphisms (L55M and Q192R) on diabetic nephropathy (DN). MATERIAL AND METHODS: The study involved 116 children and adolescents with type 1 diabetes (T1D) and 91 healthy subjects. Albumin excretion rate (AER) was determined by immunoturbidimetry. PON1 activity was measured by a spectrophotometric method, and genotyping of PON1 gene was assessed by multiplex PCR followed by RFLP. RESULTS: PON1 activity was inversely correlated to AER (r = -0.245, p = 0.008). A significant decrease (p = 0.037) in PON1 activity was shown between patients with nephropathy and those without (162 [57-618] vs. 316 [37-788] IU/L, respectively). The distribution of AER was, for L55M polymorphism MM > LM > LL (p = 0.002), and for Q192R polymorphism QQ > QR > RR (p < 0.001). The opposite distribution was noted for PON 1 activity (p < 0.001). LMQQ and MMQQ haplotypes seem to increase AER (p = 0.004, p = 0.003, respectively) and to reduce PON1 activity (p = 0.011, p = 0.052, respectively) in youths with T1D. However, LLRR haplotype seems to have the opposite effect. CONCLUSIONS: This study demonstrated that PON1 polymorphisms L55M and Q192R seem to be genetic markers involved in the development of DN in T1D. (Endokrynol Pol 2017; 68 (1): 35-41).

Osteoprotegerin as a marker of cardiovascular risk in children and adolescents with type 1 diabetes.

BACKGROUND: Elevated osteoprotegerin (OPG) levels have been reported in patients with diabetes complications. We investigated whether plasma OPG levels can be used as a marker of cardiovascular risk in children and adolescents with type 1 diabetes (T1D). METHODS: Plasma blood samples were obtained from 243 subjects (143 children and adolescents with T1D and 100 healthy controls). OPG concentrations were measured by enzyme-linked immunosorbent assay (ELISA) method. All data were analyzed by using PASW statistics 18. RESULTS: A significant higher plasma OPG level was found in children with T1D compared to controls (p < 0.001). A significant increase of OPG levels has been related to the glucose level ≥ 7 mmol/L (2.44 [0.01-6.22] vs. 2.16 [0.13-6.22] pmol/L, p = 0.019), microalbuminuria ≥ 30 mg/24 h (3.71 [0.160-6.03] vs. 2.26 [0.01-6.22] pmol/L, p < 0.001), and cystatin-C ≥ 0.789 mg/L (2.64 [0.37-6.22] vs. 2.11 [0.01-5.82] pmol/L, p < 0.001). We noted a significant higher frequency of children with increased cystatin-C levels in the group with elevated plasma level of OPG compared with those with normal levels (49 vs. 18%, respectively) with an odds ratio (OR) = 4.42 [1.41-13.84] (p = 0.006). We showed a significant increase of OPG levels when the number of cardiovascular risk factors exceeds 3 (p = 0.001). CONCLUSION: OPG may be a potential biomarker of cardiovascular risk in T1D. Implementation of OPG determination in the clinical laboratory setting would be useful in order to better stratify patients and to assess the most adequate treatment.

A Founder Effect of c.257 + 2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients.

Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients' clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families.

Enterovirus meningitis in Tunisia (Monastir, Mahdia, 2011-2013): identification of virus variants cocirculating in France.

Acute enterovirus (EV) meningitis is a frequent cause of hospitalisation, and over 100 EV serotypes may be involved. A total of 215 patients of all ages with meningitis signs were investigated in 2 Tunisian hospitals. Their cerebrospinal fluid (CSF) was analysed retrospectively for EVs with a TaqMan real-time RT-qPCR. The virus strains were typed, and their evolutionary relationships were determined by Bayesian phylogenetic methods. An EV genome was detected in 21/215 patients (9.8%). The CSF viral loads ranged from 3.27 to 5.63 log10 genome copies/mL. The strains were identified in 13/21 patients and assigned to EV-B types. Viruses identified in Tunisian patients were genetically related to variants detected in France. The viral loads were similar in Tunisian and French patients for most EV types. The phylogenetic data and viral loads determined in Tunisian and French patients suggest that close EV variants were involved in aseptic meningitis in the 2 countries over a same period.

Partial KCNQ1OT1 hypomethylation: A disguised familial Beckwith-Wiedemann syndrome as a sporadic adrenocortical tumor.

Beckwith-Wiedemann syndrome has a wide spectrum of complications such as embryonal tumors, namely adrenocortical tumor. Tumor predisposition is one of the most challenging manifestations of this syndrome. A 45-day old female with a family history of adrenocortical tumor presented with adrenocortical tumor. The case raised suspicion of a hereditary Beckwith-Wiedemann syndrome, therefore molecular analysis was undertaken. The results revealed partial KCNQ1OT1 hypomethylation in the infant's blood DNA which was associated with a complete loss of methylation in the infant's adrenocortical tumor tissue. It is unique for familial Beckwith-Wiedemann syndrome caused by KCNQ1OT1 partial hypomethylation to manifest solely through adrenocortical tumor. Incomplete penetrance and specific tissue mosaicism could provide explanations to this novel hereditary Beckwith-Wiedemann syndrome presentation.

Can paraoxonase 1 polymorphisms (L55 M and Q192 R) protect children with type 1 diabetes against lipid abnormalities?

BACKGROUND: Only a few studies have focused on the possible modulatory role of paraoxonase 1 (PON1) polymorphisms in lipid profiles, especially in children and in adolescents with type 1 diabetes (T1D). OBJECTIVE: We propose to study the association between PON1 polymorphisms (PON1-55 and PON1-192) and a lipid profile in a young Tunisian population with T1D. METHODS: The study compared 122 children and adolescents with T1D with 97 controls. Genomic DNA was collected from 116 patients and 91 controls. Lipid parameters were determined by automated methods. PON1 activity was measured by a spectrophotometric method and genotyping of the PON1 gene was assessed by multiplex polymerase chain reaction followed by restriction fragment-length polymorphism. RESULTS: A significant increase in total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (ApoB), and lipoprotein (a) (Lp(a)) and a significant decrease in apolipoprotein A1 (ApoA1), ApoA1/ApoB ratio, and PON1 activity/HDL-C ratio were observed in children with T1D compared with controls. In the LLQR haplotype, the group with diabetes showed significantly higher values of total cholesterol, LDL-C, apoB, Lp(a), and apoA1/apoB ratio compared with the control group. Those with diabetes with the LLQQ haplotype showed a significant decrease in LDL-C and Lp(a) compared with controls (P < .0001). CONCLUSION: PON1 polymorphisms (PON1-55 and PON1-192) seem to be involved in the altering the lipid profile in T1D. The LLQR haplotype provided an atherogenic lipid profile in children with T1D compared with controls. LLQQ haplotype seemed to have a protective effect against the increase in LDL-C and Lp(a) that are heavily involved in the development of cardiovascular diseases.

Congenital pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by pulmonary surfactant accumulation within the alveolar spaces. It occurs with a reported prevalence of 0.1 per 100,000 individuals. Two clinically different pediatric types have been defined as congenital PAP which is fatal and a late-onset PAP which is similar to the adult form and less severe. The clinical course of PAP is variable, ranging from spontaneous remission to respiratory failure. Whole-lung lavage is the current standard treatment for PAP patients. We report a new congenital case of PAP.

Detection of herpes simplex virus (1 and 2), varicella-zoster virus, cytomegalovirus, human herpesvirus 6 and enterovirus in immunocompetent Tunisian patients with acute neuromeningeal disorder.

Enteroviruses (EVs) and human herpesviruses (HHVs) are involved frequently in acute neurological disorders of viral etiology. This study aimed to investigate the incidence of herpes simplex virus types-1 (HSV-1) and 2 (HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6) and human enteroviruses (EVs) in cerebrospinal fluid (CSF) samples of Tunisian immunocompetent patients with neuromeningeal disorders. The patients had been hospitalized at the Fattouma Bourguiba University Hospital (Monastir, Tunisia) between September 2007 and June 2009. At least one viral genome was detected in 58 (46%) out of 126 CSF samples collected. Enterovirus was detected in 31 of the positive samples (53.4%), CMV in 20 (34.5%), HSV-1 in 3 (5.2%), HSV-2 in 6 (10.3%), VZV in 4 (6.9%), HHV-6 in 2 (3.4%). More than one viral genome was detected in seven CSF samples, including CMV DNA in six of the samples. The high frequency of enteroviral infections in aseptic meningitis was confirmed. The detection of CMV DNA only suggests a direct role of this virus in the etiology of acute neuromeningeal disorder.

[Idiopathic steroid-resistant nephrotic syndrome in child : study of 20 cases]. / Syndrome néphrotique idiopathique corticorésistant de l'enfant : Etude de 20 cas.

BACKGROUND: Idiopathic steroid-resistant nephrotic syndrome (ISRNS) is rare and represents a significant therapeutic dilemma for paediatricians and paediatric nephrologists. AIM: To analyze characteristics of the ISRNS in the child. METHODS: Retrospective study of 20 cases of ISRNS enrolled in paediatric department of nephrology in Sahloul hospital (Tunisia) between June 1993 and December 2007 (14 years period). RESULTS: There were eight girls and 12 boys (mean age: 5.8± 3.7 years) originating from the center or the south of Tunisia. Eight of them had a minimal-change disease (MCD), 11 a focal and segmental glomerulosclerosis (FSGS) and one a mesangioproliferative glomerulonephritis (MePGN). In this group, no family form could be identified. All patients were treated by cyclosporine associated with low dose of steroid. We noted a complete remission (CR) in nine cases, partial remission (PR) in three cases and no response to cyclosporine in eight cases. Among patients with CR, six presented MCD and three a FSGS. In this group, we observed relapse of nephrotic syndrome in six cases. End stage renal disease (ESRD) was noted in 10 patients of which five not responded to cyclosporine, two initially having presented a RC and three having since the beginning a PR. Among them, two only could be grafted; one relapses on transplant was observed with a single patient initially presenting a secondarily transformed MePGN in FSGS. CONCLUSION: Our study confirms the clinical, histological and evolutive heterogeneity of idiopathic steroid-resistant nephrotic syndrome. Although there is any therapeutic consensus in this domain, cyclosporine remains indicated in first intention in sporadic forms of ISRNS. On the other hand, renal transplantation constitutes the only therapeutic alternate in genetic forms that constantly evolve at ESRD.

Infantile scurvy: two case reports.

Background. Ascorbic acid (vitamin C) is necessary for the formation of collagen, reducing free radicals, and aiding in iron absorption. SCURVY, a disease of dietary ascorbic acid deficiency, is uncommon today. It still exists in high risk groups including economically disadvantaged populations with poor nutrition. The incidence of SCURVY in the pediatric population is very low. Cases Report. Here we report two cases of SCURVY revealed by subperiosteal hematoma in children with cerebral palsy and developmental delay. Conclusion. SCURVY is extremely rare in children. Musculoskeletal manifestations are prominent in pediatric SCURVY. Multiple subperiosteal hematomas are an important indicator for diagnosis.

Nail-patella syndrome associated with short stature: a case series.

Introduction. Nail-patella syndrome (NPS) is a rare genetic disorder that is characterized by a pleiotropic malformation affecting the nail, the skeleton, and occasionally the central nervous system and the kidneys. Case Presentation. We report two paediatric cases, which are of two sisters, who aged, respectively, two and five years. They are admitted to explore short stature. The initial clinical examination and radiologic findings confirmed the diagnosis of Nail-patella syndrome. Conclusion. Skeletal, ophthalmologic, and renal involvements were mostly associated with NPS. The association with short stature was exceptional.

Molecular epidemiology of human astrovirus and adenovirus serotypes 40/41 strains related to acute diarrhea in Tunisian children.

Human astrovirus (AstV) and adenovirus types 40 and 41 (AdV 40/41) are responsible for epidemic and endemic acute gastroenteritis in children and adults. The present study was designed to evaluate the prevalence and genetic diversity of enteric viruses in children in Tunisia. A total of 788 fecal samples were collected during a 4-year period in the region of Monastir, from children under 12 years old, hospitalized or presenting in dispensaries with symptoms of acute gastroenteritis. AstV and AdV40/41 were detected by immunoenzymatic methods and confirmed by PCR/RT-PCR and sequence analysis. Phylogenetic analyses were performed for nucleotide homology with reference strains. AstV and AdV40/41 were characterized as a causative agent in 28 (3.6%) and 18 (2.3%) of the fecal samples, respectively. Phylogenetic analysis showed that the AstVs belonged to the serotypes 3 (n = 4; 14.3%) and 1 (n = 24; 85.7%), and the enteric AdVs to the serotypes 40 (n = 1; 5.6%) and 41 (n = 17; 94.4%). This is the first report that describes the molecular epidemiology of AstV and AdV40/41 in Tunisian children. Their respective detection rate was very low, far below that of rotavirus and norovirus. The genetic diversity among these two viruses is relatively limited and varies depending on the area.

Detection and genomic characterization of Aichi viruses in stool samples from children in Monastir, Tunisia.

Aichi virus has been associated with acute gastroenteritis in adults and children. Stool samples were collected from 788 Tunisian children suffering from diarrhea. Aichi virus was found in 4.1% of the cases. The high proportion of monoinfections and the high frequency of hospitalizations support the role of Aichi virus in pediatric gastroenteritis.

Molecular epidemiology of norovirus gastroenteritis investigated using samples collected from children in Tunisia during a four-year period: detection of the norovirus variant GGII.4 Hunter as early as January 2003.

Human noroviruses (NoVs) cause epidemic and endemic acute gastroenteritis in children and adults. To study the prevalence and genetic diversity of NoV in children in Tunisia, a total of 788 fecal samples were collected during a 4-year period in the region of Monastir, from children 12 years of age or younger, hospitalized or presenting in dispensaries with symptoms of acute gastroenteritis. NoV was detected by reverse transcription-PCR and confirmed by sequence analysis. This is the first report that describes the molecular epidemiology of NoV in Tunisian children: NoVs were characterized as the causative agent in 128 (16.2%) of the samples. Fourteen samples contained a mixture of two NoVs, and 33 samples were coinfected with additional enteric viruses. Eight distinct NoV genotypes were detected (GGI.2, GGI.4, GGII.1, GGII.4, GGII.8, GGII.14, GGIIb/GGII.2, and GGIIb/GGII.3). GGII.4 was the most prevalent genotype, accounting for 83 (64.8%) cases. Interestingly the GGII.4 variant Hunter, described as spreading all over the world in 2004, was found in Tunisia as early as January 2003. The delay of 1 year between the isolation in Tunisia and the worldwide emergence is somewhat surprising, considering the importance of the contacts between North Africa and Europe particularly. Nevertheless, this illustrates the idea that sporadic gastroenteritis cases may be a reservoir for emerging epidemic NoV strains.

Acute infantile gastroenteritis associated with human enteric viruses in Tunisia.

This prospective study, conducted from January 2003 to June 2005, investigated the incidence and the clinical role of various enteric viruses responsible for infantile gastroenteritis in 632 Tunisian children presenting in dispensaries (380 children) or hospitalized (252 children) for acute diarrhea. At least one enteric virus was found in each of 276 samples (43.7%). A single pathogen was observed in 234 samples, and mixed infections were found in 42 samples. In terms of frequency, rotavirus and norovirus were detected in 22.5 and 17.4% of the samples, respectively, followed by astrovirus (4.1%), Aichi virus (3.5%), adenovirus types 40 and 41 (2.7%), and sapovirus (1.0%). The seasonal distribution of viral gastroenteritis showed a winter peak but also an unusual peak from May to September. The severity of the diarrhea was evaluated for hospitalized infants. No significant differences were observed between rotavirus and norovirus infections with regard to the incidence and the clinical severity of the disease, especially in dehydration.

Interplay of socio-economic factors, consanguinity, fertility, and offspring mortality in Monastir, Tunisia.

AIM: To assess the association among social status, prevalence of consanguineous marriages, and the effects of consanguinity on reproductive behavior and mortality in Tunisia. METHODS: The study included data on a total of 1741 live-births born from November 1989 to October 1990 in the maternity ward of the University-Hospital Fattouma Bourguiba of Monastir, Tunisia. After delivery, women filled out a questionnaire on the age of the parents at marriage, the number of pregnancies and abortions, the number of neonatal and post-neonatal deaths, and deaths of children under 5 years. Three categories of marriages were distinguished as follows: marriages between first cousins, marriages between cousins of other degree, and non consanguineous marriages. RESULTS: Consanguineous marriages represented 432 (24.81%) of the unions. Most consanguineous marriages were contracted between first cousins (n=303; 70.13%). Consanguineous couples had a lower age at marriage and a higher fertility index than non-consanguineous couples. The rates of spontaneous abortions and stillbirths were not correlated with consanguinity. However, higher rates of neonatal and post-neonatal deaths, and deaths of children younger than 5 years were observed in consanguineous couples. CONCLUSION: Fertility index and mortality, especially in the first year of life, were significantly higher in consanguineous marriages. This important socio-economical factor needs to be considered in assessing equity on health in specific social and cultural contexts.

[Profile of antimicrobial resistance of agents causing urinary tract infections in children]. / Sensibilite aux antibiotiques des germes responsables d'infections urinaires de l'enfant.

OBJECTIVE: The management of urinary tract infection in children faces the problem of the emergence of resistant strains to antibiotics. The aim of this study is to precise the frequency of the different germs and their susceptibility to antibiotics. METHODS: We report a retrospective study concerning 200 cases of urinary tract infection hospitalised in the paediatric department of Monastir between January 1995 and December 2000. There were 58 boys and 142 girls aged between two months and 14 years with a mean age of 5 years. The frequency of urinary tract infection is 1.85%. RESULTS: The most common causative agent is Escherichia coli in 75.5% of cases, followed by Proteus mirabilis (10%) then by Klebsiella pneumoniae (6%). Escherichia coli is predominant in girls, whereas Proteus mirabilis and Klebsiella pneumoniae are likely encountred in boys. Of all the strains, 96% are resistant to ampicillin, amoxicillin and cefalotin, 67% to amoxicillin + clavulanic acid and 34% to cotrimoxazole. A resistance to ampicillin, amoxicillin and cefalotin is noted in 96% of the germs. The resistance is of 67% for amoxicillin + clavulanic-acid and of 34% for cotrimoxazole. However, third generation cephalosporins and aminoglycosides remain usually active on the majority of strains incriminated in these infections a part from Pseudomonas.