Assessment of fetal head engagement with transperineal ultrasound: Searching for the cutoff level.

PURPOSE: Engagement of the fetal head is a determinant element when deciding on operative vaginal delivery. In routine practice, engagement is a clinical diagnosis based on transvaginal digital examination. Transperineal ultrasound might provide complementary information useful for measuring the fetal head-perineum distance (HPD). The purpose of this work was to determine the cutoff HPD distinguishing engagement from non-engagement. MATERIALS AND METHODS: This single-center prospective study approved by the institutional review board was conducted between December 25, 2012 and August 31, 2015 in 411 nulliparous women; 20 did not provide informed consent and were excluded; analysis concerned 391 patients. Clinical diagnosis - engagement or non-engagement depending on results of the transvaginal digital examination (Farabeuf's and Demelin's signs) - was compared with the ultrasound HPD measurement. RESULTS: The clinical diagnosis was non-engagement at complete dilatation in 96 patients (24.6%). The cutoff HPD distinguishing between engagement and non-engagement was 57mm (AUC 83.5% [95%CI 79.3-87.8]), with 75.0% [65.5-82.6] sensitivity, 75.9% [70.7-80.5] specificity, 50.3% [42.2-58.4] positive predictive value, and 90.3% [86.0-93.4] negative predictive value. CONCLUSIONS: In this series, the HPD cutoff distinguishing between engagement and non-engagement was 57mm. Below this cutoff level, the head should be considered engaged, beyond non-engaged. Nevertheless, the pertinence of this cutoff level is hampered by the imprecision of the gold standard used for the clinical diagnosis (transvaginal digital examination). In case of doubt, we recommend, in addition to considering the obstetrical setting, to combine transperineal ultrasound with transvaginal digital examination to avoid deleterious failure of operative vaginal delivery.

The first mutations in the MYH gene reported in Moroccan colon cancer patients.

BACKGROUND: Biallelic germline mutations in the MYH gene cause MYH-associated polyposis (MAP) disease, an autosomal recessive form of inherited colorectal cancer. People with MAP tend to develop attenuated multiple adenomatous colon polyps during their lifetime and will have an increased risk of colorectal cancer. Contrary to familial adenomatous polyposis, the number of adenomas is often lower in MAP (from 5 to 100), and even some patients have recently been reported with no identified adenomas. There have been many investigations into MAP that have been conducted in many different countries. Currently there is limited data on MAP in Morocco, and it is reasonable to think, that the prevalence of this form of genetic predisposition is as high as other autosomal recessive genetic diseases found in countries with high rates of consanguinity. The aim of this study is to examine the frequency of MYH mutations in colorectal cancer and/or attenuated polyposis in Moroccan patients. PATIENTS AND METHODS: The study population consisted of 62 patients; 52 with colorectal cancer, three of them had attenuated polyposis (2 to 99 adenomatous polyps). 10 other patients were referred to our department for polyposis without colorectal cancer. We carried out DNA analysis in 62 patients to screen for the three recurrent mutations c.494A>G (p.Tyr165Cys), c.1145G>A (p.Gly382Asp) and c.1185_1186dup, p.Glu396GlyfsX43, whereas 40 subjects were screened for germline MYH mutations in the whole coding sequence of the MYH gene by direct DNA sequencing. All these 40 patients, except two, had colorectal cancer without polyposis. RESULTS: Three patients with colorectal cancer and attenuated polyposis carried biallelic mutations in the MUTYH gene one with the c.494 A>G mutation, one with the c.1105delC mutation, one with the c.1145G>A mutation. One patient with 25 adenomas without colorectal cancer carried the c.1145G>A mutation at a homozygote state and one patient with 3 polyps was heterozygote for the mutation c.1145G>A. No biallelic mutations of MYH gene were detected in colorectal cancer patients and in patients with small number (<5) of polyps without colorectal cancer. CONCLUSION: We report the first biallelic MYH mutations in four Moroccan patients with clinical criteria of MAP; three of them had colorectal cancer with attenuated polyposis. No MYH mutations were found in colorectal patients without polyposis. Despite the relatively small sample size of the current study, our findings suggest that the MAP is not a frequent cause of colon cancer in Morocco as we had expected, and the molecular analysis of MYH gene should be restricted to patients displaying the classical phenotype of MAP.

Frequent mutation in North African patients with MUTYH-associated polyposis.

MUTYH-associated polyposis (MAP) has been characterized as an autosomal recessive disease predisposing to a variable number of colorectal adenomas with a high risk of cancer. Numerous studies have indicated that two missense mutations (Y179C and G396D) account for about 80% of MUTYH allelic variants in Europeans. Ethnic and geographic differences in the mutation spectrum have been observed. The aim of this study was to report mutations in patients from North Africa, determine the incidence of the c.1227_1228dup mutation in our cohort of MUTYH patients and to evaluate the existence of a founder effect. Within a group of 36 families with MAP, 11 were shown to have a homozygous c.1227_1228dup mutation. These families came from Algeria (n = 5), Tunisia (n = 4), Morocco (n = 1) and Portugal (n = 1). Probands belonging to families of North African origin showed a significantly higher frequency of c.1227_1228dup (78.6% vs 4.5%, p < 0.0001). Haplotype analyses were performed using 10 microsatellite markers surrounding the MUTYH gene spanning a region of 4.4 cM. We identified a common haplotype of at least 1.3 cM in all families suggesting a founder effect for this mutation.

Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families.

We have performed an extensive analysis of TP53 in 474 French families suggestive of Li-Fraumeni syndrome (LFS), including 232 families fulfilling the Chompret criteria. We identified a germline alteration of TP53 in 82 families (17%), in 67/232 of the families fulfilling the Chompret criteria (29%) and in 15/242 which did not fulfil these criteria (6%). Most of the alterations corresponded to missense mutations (67%), and we identified in four families genomic deletions removing the entire TP53 locus, the promoter and the non-coding exon 1, or exons 2-10. These results represent a definitive argument demonstrating that LFS results from TP53 haplodeficiency. The mean ages of tumour onset were significantly different between patients harbouring TP53 missense mutations and other types of alterations, missense mutations being associated with a 9 year earlier tumour onset. These results confirm that missense mutations not only inactivate p53 but also have an additional oncogenic effect. Germline alterations of TP53 that lead exclusively to loss of function are therefore associated with a later age of tumour onset and the presence of such mutations should be considered in atypical LFS families with tumours diagnosed after 40 years.

Non-Hodgkin lymphoma related to hereditary nonpolyposis colorectal cancer in a patient with a novel heterozygous complex deletion in the MSH2 gene.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal disorder caused by mutations in DNA mismatch repair (MMR) genes. Tumors of the HNPCC-spectrum are associated with microsatellite instability (MSI) and loss of MMR protein expression. Lymphomas are not considered to be HNPCC-related tumors. We report and analyze a case of an HNPCC patient with three colorectal cancers and a B-cell non-Hodgkin lymphoma. Quantitative multiplex PCR of short fluorescent fragments detected a novel MSH2 rearrangement involving exons 9 and 10, which proved to be the pathogenic cause of the disease in the family. Tumor tissues including the lymphoma showed MSI and loss of MSH2 expression. Multiplex ligation-dependent probe amplification analysis revealed a somatic loss of the wild-type MSH2 allele in the lymphoma. These results support the fact that the total loss of a MMR gene can lead to lymphomagenesis, as seen in biallelic MMR-deficient families and knockout mice. Moreover, this is the first report of a B-cell non-Hodgkin lymphoma with a loss of the MSH2 protein expression, linked to a heterozygous germline MSH2 mutation in an HNPCC family.

Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome.

Li-Fraumeni syndrome, resulting from p53 (TP53) germline mutations, represents one of the most devastating genetic predispositions to cancer. Recently, the MDM2 SNP309 (T-->G variation) was shown to be associated with accelerated tumour formation in p53 mutation carriers. The impact of the common p53 codon 72 polymorphism on cancer risk remains controversial. We therefore investigated the effect of these two polymorphisms in 61 French carriers of the p53 germline mutation. The mean age of tumour onset in MDMD2 SNP309 G allele carriers (19.6 years) was significantly different from that observed in patients homozygous for the T allele (29.9 years, p<0.05). For the p53 codon 72 polymorphism, the mean age of tumour onset in Arg allele carriers (21.8 years) was also different from that of Pro/Pro patients (34.4 years, p<0.05). We observed a cumulative effect of both polymorphisms because the mean ages of tumour onset in carriers of the MDM2G and p53Arg alleles (16.9 years) and those with the MDM2T/T and p53Pro/Pro genotypes (43 years) were clearly different (p<0.02). Therefore, our results confirm the impact of the MDM2 SNP309 G allele on the age of tumour onset in germline p53 mutation carriers, and suggest that this effect may be amplified by the p53 72Arg allele. Polymorphisms affecting p53 degradation therefore represent one of the rare examples of modifier genetic factors identified to date in mendelian predispositions to cancer.

Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer.

We report the association of CDH1/E-cadherin mutations with cleft lip, with or without cleft palate (CLP), in two families with hereditary diffuse gastric cancer (HDGC). In each family, the CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing the extracellular cadherin repeat domains involved in cell-cell adhesion. Such transcripts might encode mutant proteins with trans-dominant negative effects. We found that CDH1 is highly expressed at 4 and 5 weeks in the frontonasal prominence, and at 6 weeks in the lateral and medial nasal prominences of human embryos, and is therefore expressed during the critical stages of lip and palate development. These findings suggest that alteration of the E-cadherin pathway can contribute to human clefting.

[Maternal diaphragmatic hernia during pregnancy: report of two cases]. / Hernie diaphragmatique maternelle pendant la grossesse: a propos de 2 cas.

We report two cases of maternal diaphragmatic hernia during pregnancy. Diaphragmatic hernia is an unusual and severe disease. Maternal and fetal prognosis are threatened. Diagnosis is uncertain when confronted to respiratory and digestive symptoms without any specificity. The chest X ray is the first exam to perform. The objective of this work is to discuss the management of such a pathology in terms of ways of delivery and surgical cure of hernia.

[Recurrent edema of the face and neck in a chronically hemodialyzed patient]. / Oedèmes récidivants de la face et du cou chez un hémodialysé chronique.

We report the case of a patient undergoing long-term hemodialysis admitted to hospital for diagnosis of recurrent face and neck edema influenced by dialysis sessions with paroxysmal dyspnea. We considered the possible role of allergy to ethylene oxide and to formaldehyde without diagnostic confirmation. Dialyzer complement activation was suspected but changing the dialyzer did not improve the symptoms. Anti-histaminic and corticosteroid therapy did not modify symptoms. A mild hemithoracic collateral circulation occurred and led to the discovery of a superior vena cava syndrome. Computed tomography and bilateral upper limb contrast venography visualized a thrombus in the superior vena cava extending into the right venous brachiocephalic arm from the central vein catheter. A stent was inserted into the superior vena cava which, together with anticoagulant therapy, led to rapid resolution of the symptoms. Superior vena cava syndrome related to a central catheter and hypersensitivity reactions should always be considered as possible causes of recurrent face and neck edema in patients on long-term hemodialysis.

CC chemokines and interleukin-5 in bronchial lavage fluid from patients with status asthmaticus. Potential implication in eosinophil recruitment.

In status asthmaticus (SA), severe bronchial inflammation is associated with acute respiratory failure. Neutrophils are the prominent cells found in bronchi from SA patients, but eosinophils are also recruited within the first 48 h after the beginning of mechanical ventilation (MV). Interleukin (IL)-5 and CC chemokines have been directly implicated in the pathophysiology of allergic asthma. However, their involvement in SA had not been determined. The aim of this study was to evaluate the production of CC chemokines and of IL-5 in airways from ventilated patients with SA as compared with mild asthma (A), and to assess the role of these mediators in eosinophil recruitment. We measured levels of the chemokines monocyte chemotactic proteins (MCPs)-1 and -3; regulated on activation, normal T-cell expressed and secreted (RANTES); macrophage inflammatory peptide (MIP)-1alpha; and eotaxin; and of the cytokine IL-5 in bronchial lavage fluid (BLF) from 10 SA patients, four patients without respiratory disease but undergoing ventilation (V) who were receiving MV, 11 patients with A, and eight healthy volunteers (C). We further evaluated in vitro eosinophil chemotactic activity of BLF from the various groups. Levels of MCP-1, MIP-1alpha, RANTES, and IL-5 were significantly higher in the SA than in the V, A, and C groups. MCP-3 and eotaxin values were not significantly different in the SA and other groups; however, their levels, as well as those of MIP-1alpha, RANTES, and IL-5 correlated with eosinophil influx. Eosinophil chemotactic activity in BLF was increased in asthmatic subjects (A and SA groups) as compared with the other groups, and in SA patients as compared with A patients. Addition of neutralizing anti-IL-5, anti-MCP-3, anti-eotaxin, and anti-RANTES antibodies significantly inhibited the eosinophil chemotactic activity as compared with that of native BLF. This study shows that the levels of various CC chemokines and IL-5 are increased in airways of SA patients, and are potentially involved in eosinophil recruitment.

Effects of itraconazole therapy in allergic bronchopulmonary aspergillosis.

STUDY OBJECTIVES: Allergic bronchopulmonary aspergillosis (ABPA) is the result of an immune reaction to antigens of Aspergillus fumigatus, which colonizes the bronchial lumen of affected individuals. Presently, the recommended treatment of ABPA, mainly for acute episodes of exacerbations, is administration of glucocorticoids. We initiated this study to analyze the effects of itraconazole on the clinical, biological, and functional parameters in patients with ABPA. PATIENTS: in this report, we describe the follow-up of 14 asthmatic patients who presented with ABPA. During the 2-year reference period (a 2-year period before the introduction of itraconazole), 14 patients were treated with inhaled corticosteroids and 12 of the 14 received oral glucocorticoids. During the itraconazole treatment period, the patients were treated with oral itraconazole, 200 mg/d, for at least 12 months. RESULTS: During the 2-year reference period, no significant clinical, immunologic, and functional improvement was observed on a long-term basis. During the itraconazole treatment period, a clinical improvement was observed. Blood eosinophilia, serum total IgE levels, and serum precipitating antibodies against A fumigatus antigen significantly decreased. No decrease of specific IgE against A fumigatus spp was observed. All patients experienced a partial improvement in pulmonary function tests: FEV(1) significantly increased from 1,433 +/- 185 to 1,785 +/- 246 mL/s (p < 0.01). All patients successfully lowered oral glucocorticoid dose when receiving itraconazole. In 7 of 14 patients receiving itraconazole, the removal of oral glucocorticoids was possible. CONCLUSION: These results demonstrate the efficacy of itraconazole in ABPA in reducing or eliminating the need for glucocorticoid therapy, along with clinical, biological, and functional improvement.

[Treatment of pulmonary lymphangioleiomyomatosis using a GnRH agonist]. / Traitement de la lymphangioléiomyomatose pulmonaire par un agoniste du GnRH.

Pulmonary lymphangioleiomyomatosis is a rare and exclusively female disease which is oestrogen dependent and has a serious prognosis. We present two cases of young women aged 30 and 33 with the same clinical history of renal angiomyolipomas and recurring pneumothoraces. The computerised tomographic scans of the lung were strongly suggestive of LAM (there were fine wall cysts which were disseminated throughout both lung fields). The histological proof was provided by lung biopsy which was carried out during a thoracotomy for pleurectomies. The first patient who is currently asymptomatic and in excellent general health, was treated for three months with tamoxifen (Nolvadex), then for 20 months with 3.75 mg per month of triptoline (Decapeptyl), an agonist of GnRH. The second patient received triptoline in the same dose. After 40 months of treatment this patient was asymptomatic with satisfactory lung function tests. Agonists of GnRH (gonadotropic release hormone) seem to provide a useful alternative in the treatment of LAM.