Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith–Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

Beckwith–Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron–exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.     

Comparison of non-invasive liver fibrosis biomarkers in HIV/HCV co-infected patients: the fibrovic study--ANRS HC02

BACKGROUND/AIMS: To compare non-invasive biological liver fibrosis scores, as alternatives to liver biopsy, in HIV/HCV co-infected patients. METHODS: Two hundred and seventy-two HIV/HCV patients, nai ve for HCV treatment, underwent liver biopsy [197 (72%) men, 39.9 years, fibrosis stage (Metavir) F1 (25%), F2 (40%), F3 (25%), F4 (10%), median CD4 486/mm(3) and median HIV viral load 3.5log. Fibrotest (FT), Hepascore (HS), Fibrometer (FM), SHASTA, APRI, Forns index, and Fib-4 were tested in order to differentiate patients with mild to moderate fibrosis (F2) and those with advanced fibrosis (F3). The AUROC and the rate of well-classified patients were compared to liver biopsy. RESULTS: FT, HS, and FM were able to stage liver fibrosis in all patients with AUROCs of 0.78, 0.84 and 0.89 for the diagnosis of F2, respectively. The correlation coefficient indexes were 0.37, 0.46 and 0.48, respectively. The rates of well-classified patients were 62%, 68% and 71%, respectively. Fib-4, APRI and the Forn's index were only able to stage 37-61% of patients and showed lower accuracies. Using a combination of FT, HS and FM did not significantly increase the performance of each test. CONCLUSIONS: In HIV/HCV co-infected patients, Fibrometer, Hepascore and Fibrotest outperformed other non-invasive liver fibrosis biomarkers for the prediction of significant liver fibrosis.     

Treatment of hepatitis C virus in human immunodeficiency virus infected patients in "real life": modifications in two large surveys between 2004 and 2006

BACKGROUND/AIMS: To analyze the barriers to HCV treatment in HIV-HCV co-infected patients and their evolution between 2004 and 2006. METHODS: Three hundred and eighty HIV-HCV co-infected patients were prospectively included in surveys from November 22 to 29, 2004 (2004 survey), and 416 from April 3 to 10, 2006 (2006 survey). RESULTS: Patients in 2006 compared to those in 2004 had negative HCV RNA more often (24% vs. 12%). The rate of liver biopsy was similar (56% vs. 54%) while 24% had had a non-invasive liver damage assessment. The rate of previous treatment for HCV infection was higher (48% vs. 26%). The main reasons for HCV non-treatment have changed: HCV treatment deemed questionable (44% vs. 53%), lack of liver biopsy (18% vs. 33%), physicians' conviction of poor patient compliance (20% vs. 30%). In both surveys, HCV treated patients were more often of European origin, had better control of HIV infection, and had a liver damage assessment more often. CONCLUSIONS: The care of HIV-HCV co-infected patients has changed significantly in "real life". These results underline the importance of continuing efforts to educate physicians and patients in order to increase the access of co-infected patients to HCV treatment.     

Efficacy of sulfadoxine/pyrimethamine in the treatment of uncomplicated Plasmodium falciparum malaria in Republic of Congo

Congo is facing frequent failures of treatment of Plasmodium falciparum malaria with chloroquine (CQ), which is still recommended and used as a first-line drug. In Pointe-Noire and Brazzaville, the two largest cities that contain approximately 60% of the population of Congo, we compared the efficacy of CQ versus sulfadoxine/pyrimethamine (SP) for treatment of uncomplicated malaria in children 6-59 months old (mean = 33 months) using the standard World Health Organization (WHO) 14-day in vivo test in two phases between 1999 and 2002. Patients enrolled were randomly assigned to receive SP (25 mg/kg of sulfadoxine and 1.25 mg/kg of pyrimethamine) or CQ (25 mg/kg). In the first phase of the study, 46 patients were assigned to the CQ (n = 23) or SP (n = 23) groups in Pointe-Noire and 52 children were assigned to the CQ (n = 26) or to SP (n = 26) groups in Brazzaville. Results were interpreted according to the WHO lot quality assurance sampling method, and treatment failure rates for SP versus CQ were < 25% versus > 25% in both cities. In the second phase of the study, we accurately determined the actual proportion of treatment failures for SP in Brazzaville. Thus, in 75 of the 80 children enrolled and followed-up until day 14, no clinical or parasitologic failure was recorded and no serious adverse reaction was observed. Since the CQ treatment failure rate exceeds the unacceptable upper limit, SP seems well to be an appropriate alternative for the first-line treatment of uncomplicated P. falciparum malaria, at least in the settings of the present study.     

Irritable bowel syndrome in France: a common, debilitating and costly disorder

OBJECTIVE: This epidemiological investigation aims to measure the prevalence of irritable bowel syndrome (IBS) in the general population using the Rome II criteria and to evaluate the medical management including treatments and the impact of IBS on patient life. METHODS: A nationally representative sample of 20,000 French subjects, aged 18 years and over, were interviewed by SOFRES (French Public Opinion Poll Institute) in May 2001. In a second phase (June/July 2001), a 48-question self-administered questionnaire was given to the subjects who have been selected during the first phase as suffering from IBS (Rome II criteria). RESULTS: The prevalence of IBS was 4.7% (confidence interval, 4.36-5.04% with 5% risk) with a predominance in women (5.7% versus 3.7%, P < 0.01). The abdominal pain was often longstanding (> 5 years, 50%), intense (43%) and nocturnal (35%). During the most recent painful episode the levels of associated transit problems were almost equally divided between diarrhoea (36%), constipation (29%) and alternate episodes of both (31%). Apart from pain, bloating was given as the most frequent (73%) and most troublesome (24%) symptom. Since the onset, 80% of subjects with IBS had consulted a doctor (90% consulted a general physician, 57% a gastroenterologist, 50% both) and of these, 80% consulted within the previous 12 months. Sixty-seven per cent of subjects underwent additional investigations since the start of their illness (average of 3.4 examinations per patient examined: colonoscopy, 34.1%; laboratory tests, 34%; and abdominal ultrasound, 27.7%). Over the previous 12 months, 8% of the subjects had been admitted to hospital (average length of stay, 6.6 days), 11% of employed subjects had to take time off, 93% of subjects had taken prescribed medication (87%), but 43% of people thought it was ineffective. The effect on daily life was considerable (score, 6.2/10; close to the score for flu, 7/10). Two-thirds of the individuals changed their diet; 54% said it affected their social life and 29% their professional life. Seventy-four per cent of patients trusted their doctor, with a satisfaction index of 63%, but 45% of patients would like to have more information on IBS. CONCLUSION: This study confirmed that the Rome II criteria detected IBS with a prevalence of 4.7%. The recruited subjects had severe symptoms (frequency, intensity and duration) that had a considerable effect on their daily life. The high level of referrals and initial consultations in all categories and the patient's attitudes towards the illness and its treatment emphasize the relative ineffectiveness of care for patients suffering from IBS.     

Molecular genetic characterization and urinary excretion pattern of metabolites in two families with MCAD deficiency due to compound heterozygosity with a 13 base pair insertion in one allele

Summary Two families with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency due to compound heterozygosity are described. All patients have a 13 bp insertion in exon 11 of one allele at the MCAD gene locus. In the other allele patients in one of the families harbour the prevalent G985 mutation, and the other family possess an unidentified mutation causing reduced levels of MCAD mRNA. We demonstrate that the disease in these families is inherited as an autosomal recessive trait. Individuals heterozygous for the mutations show heterozygous/control levels of -oxidation activities in cultured fibroblasts (9.1–16.3 pmol/min per mg protein; control 10–17 pmol/min per mg protein), and in the excretion of the -oxidation metabolites, hexanoylglycine (<2 µmol/mmol creatinine), suberylglycine (<2 µmol/mmol creatinine) and phenylpropionylglycine (<2 µmol/mmol creatinine). This shows that there is no negative dominance from the mutant monomeric protein onto the normal ones, in accordance with the finding of low levels of MCAD mRNA from the allele harbouring the 13 bp insertion as well as the allele with the unidentified mutation, and the low steady-state level of enzyme protein expressed from the G985-bearing allele. In the family possessing the G985 and the 13 bp insertion mutations, two asymptomatic compound heterozygous individuals were detected. They exhibited elevated excretion of hexanoylglycine (5–15 µmol/mmol creatinine) and suberylglycine (4–13 µmol/mmol creatinine), together with -oxidation activity in fibroblasts in the homozygous range (2.9 pmol/min per mg protein), showing a lack of correlation between the genotype, some biochemical parameters and the clinical phenotype.