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J Feingold

Publications and source records attributed to J Feingold.

At least 19 recordsLinked to original sources
PubMed2006

[Identification and management of HNPCC syndrome (hereditary non polyposis colon cancer), hereditary predisposition to colorectal and endometrial adenocarcinomas].

BACKGROUND: The HNPCC syndrome (hereditary nonpolyposis colon cancer) is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for small intestine, urothelial, ovary, stomach and biliary tract carcinomas. HNPCC syndrome is responsible for 5% of colorectal cancers. Identification and management of this disease are part of a multidisciplinary procedure. METHODS: Twelve experts have been mandated by the French Health Ministry to analyze and synthesize their consensus position, and the resulting document has been reviewed by an additional group of 4 independent experts. MAIN RECOMMENDATIONS: The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a 2-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks, but other organs being at low lifetime risk, no specific surveillance will be proposed.

Adenocarcinoma↗
PubMed2006

Mutations of the RET gene in isolated and syndromic Hirschsprung's disease in human disclose major and modifier alleles at a single locus.

BACKGROUND: In Hirschsprung's disease (HSCR), a hypomorphic allele of a major gene, RET, accounts for most isolated (non-syndromic) cases, along with other autosomal susceptibility loci under a multiplicative model. However, some syndromic forms of HSCR are monogenic entities, for which the disease causing gene is known. OBJECTIVE: To determine whether RET could be considered a modifier gene for the enteric phenotype on the background of a monogenic trait. METHODS: The syndromic HSCR entities studied were congenital central hypoventilation (CCHS) and Mowat-Wilson syndrome (MWS), caused by PHOX2B and ZFHX1B gene mutations, respectively. The RET locus was genotyped in 143 CCHS patients, among whom 44 had HSCR, and in 30 MWS patients, among whom 20 had HSCR. The distribution of alleles, genotypes, and haplotypes was compared within the different groups. To test the interaction in vivo, heterozygous mice were bred for a null allele of Phox2b and Ret genes. RESULTS: RET was shown to act as a modifier gene for the HSCR phenotype in patients with CCHS but not with MWS. The intestine of double heterozygote mice was indistinguishable from their littermates. A loss of over 50% of each gene function seemed necessary in the mouse model for an enteric phenotype to occur. CONCLUSIONS: In CCHS patients, the weak predisposing haplotype of the RET gene can be regarded as a quantitative trait, being a risk factor for the HSCR phenotype, while in MWS, for which the HSCR penetrance is high, the role of the RET predisposing haplotype is not significant. It seems likely that there are both RET dependent and RET independent HSCR cases.

Alleles↗
PubMed2005

[HNPCC syndrome (hereditary non polyposis colon cancer): identification and management].

BACKGROUND: The hereditary non-polyposis colon cancer (HNPCC) syndrome is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for other organs tumors. HNPCC syndrome is responsible for 5% of colorectal cancers. MAJOR ASPECTS: The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a two-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. FURTHER DEVELOPMENTS: The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks; other organs being at low lifetime risk, no specific surveillance will be proposed.

Adolescent↗
PubMed2005

A postmarketing surveillance study of the safety and efficacy of ReFacto (St Louis-derived active substance) in patients with haemophilia A.

This clinical trial evaluated the safety and efficacy of ReFacto (St Louis-derived active substance) in patients with severe or moderately severe haemophilia A over a period of 6 months or 50 exposure days (EDs), whichever occurred first. Sixty patients, 58 previously treated and two previously untreated, were enrolled into this study. This was an open-label, multicentre, postmarketing surveillance study in which patients received prophylaxis or on-demand treatment as determined by their doctor. Surgical prophylaxis was evaluated in seven patients requiring elective surgery. Thirty-two patients aged <1 to 66 years (median 19.5) received prophylaxis and 28 patients, aged 1-71 years (median 33.5), received on-demand treatment. The majority of patients had severe haemophilia A (FVIII:C < 2%): 84.4% in the prophylaxis group and 85.7% in the on-demand group. Prophylaxis with ReFacto was associated with a median of 6.7 bleeds per year (range: 0-37). The investigator's assessment of final outcome for prophylactic treatment was excellent or effective for 93.1% of patients. ReFacto resolved 92.8% of bleeds with one or two infusions. The investigator's assessment was excellent or good for 98.2% of bleeds treated with ReFacto. Haemostasis was achieved for all seven surgical cases and ReFacto gave an excellent or good response for each. The nature and incidence of adverse events was as expected and no new safety concerns emerged. One previously treated patient (PTP) developed a high-titre inhibitor (maximum 75 BU) and one minimally treated patient (MTP) developed a low-titre inhibitor while on the study but eventually achieved high titres (maximum 30 BU) after immune tolerance therapy was initiated with a plasma-derived FVIII product. One previously untreated patient (PUP) developed a transient low-titre inhibitor (0.4 BU). Other serious adverse events (SAEs) were unrelated to study treatment. There were no allergic events. The results of this study are consistent with the previously published ReFacto pivotal studies.

Adolescent↗
PubMed2004

Do parents and grandparents of patients with achondroplasia have a higher cancer risk?

Several studies, performed according to hypotheses based on teratogenesis and carcinogenesis have tried to answer the question: Do parents of children with congenital anomalies have a higher cancer risk? If the general answer is no, however, a higher risk for cancer was reported in the parents of children with cleft lip/palate (Zhu et al. [2002: Br J Cancer 87:524-528]). In achondroplasia, the neo-mutations are from paternal origin raising the hypothesis of the existence of a "mutator" gene acting in male meiosis and in somatic, mitotic cells in both sexes which may favor also the occurrence of cancer. In order to test this hypothesis, a questionnaire was sent to people with non-familial achondroplasia, asking for cancer, lymphoma, and leukemia in their parents and grandparents. In the hypothesis tested, the maternal lineage was the control. One hundred forty eight answers were obtained from 76 males and 72 females with achondroplasia. Out of them 68 had parents and/or grandparents with cancer. Among the grandparents of people with achondroplasia there were 36 cancers including two lymphomas in the paternal grandparents, 20 cancers including two chronic myeloid leukemia (CML) in the paternal grandmothers, 22 cancers including two CML in the maternal grandfathers, and two cancers in the maternal grandmothers. Paternal grandfathers and grandmothers had significantly more cancers (56) than maternal grandfathers and grandmothers (24) (chi(2)-test = 14.80, P < 0.001). In conclusion, paternal grandfathers and grandmothers of people with achondroplasia had significantly more cancers than maternal grandfathers and grandmothers. This result raises hypotheses in relationship with the paternal origin of neo-mutations in achondroplasia.

Achondroplasia↗
PubMed2004

[Parent's information and prenatal diagnosis of cerebral malformation with an uncertain prognosis].

UNLABELLED: Fetal ultrasounds examinations allow identification of brain malformations; announce of diagnosis and information about prognosis may be difficult when malformation is rare and prognosis uncertain. OBJECTIVES: In this study we tried to analyze how fetal imaging for prenatal screening was organized and how couples were managed and supported. METHODS: We focused on the procedures used to inform couples: content, method of delivery and consequences. A referent physician in each large multidisciplinary center for prenatal diagnosis in Paris area was questioned by semi-directed interview. RESULTS: Our study showed that it is difficult to standardize the way in which information is supplied before and after fetal ultrasounds examination; uncertainty about prognosis led more often to abortion. CONCLUSION: Thus, couples should have clear and complete information provided by a multidisciplinary team including specialists particularly concerned by the malformation (neuropediatrician and/or neurosurgeon)--moreover when prognosis is uncertain, in order to support them, and to accompany their decision concerning pregnancy.

Adult↗
PubMed2003

Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C.

Autosomal recessive forms of axonal Charcot-Marie-Tooth (ARCMT2) disease are frequent in some areas, such as North Africa and the Middle East, since consanguineous marriages are still common there. Recently, a unique homozygous mutation in LMNA, which encodes lamin A/C, a component of the nuclear envelope, was identified in members of three Algerian families with ARCMT2 linked to chromosome 1q21.2-q21.3. In the present study we describe a group of 21 ARCMT2 patients from seven unrelated Algerian families with the same R298C mutation in the lamin A/C gene and marked variability of the clinical phenotype. There is a wide range of age of onset, from 6 to 27 years, with a mean of 14.4 +/- 4.6 years. The course of the disease varies considerably from one patient to another. Twelve patients with a disease duration of 10-15 years had a severe CMT phenotype with distal wasting and weakness of all four limbs and areflexia associated with involvement of the proximal lower limb muscles. In contrast, nine patients had the classical CMT phenotype with mild functional disability without proximal lower limb involvement after a disease duration of 5-18 years. Electrophysiological studies showed a median motor nerve conduction velocity (MNCV) in the normal range in almost all the patients. MNCV and compound muscle action potential (CMAP) values were inversely correlated with the disease duration and the MNCV was strictly related to the CMAP, strongly supporting a pure axonal process without a demyelinating component. Six patients had a nerve biopsy, which revealed severe rarefaction of myelinated fibres in all cases and an increased density of unmyelinated fibres in the majority of cases. In conclusion, the ARCMT2 associated with the R298C mutation differs from other types of ARCMT2. The variability among patients in the age of onset and the course of the disease strongly suggests the action of modifying genes, which remain to be identified.

Adolescent↗
PubMed2003

[Towards an improved antenatal screening for cystic fibrosis].

BACKGROUND: Cystic Fibrosis is an autosomal and recessive lethal disease which affects in France one newborn in 3.000. New technologies may afford quite a cheap and efficient screening for a large set of mutations within the same assay in order to test their presence or absence. These procedures are very valuable for prenatal diagnosis for further pregnancies when couples at risk have been identified through a first affected newborn. But, for carriers or couples at risk before the birth of a first child, these antenatal screening methods remain of limited efficacy. However carrier screening would be the only way, on a public health standpoint, to decrease the disease frequency as no therapy seems to emerge till now. Recently hyperechogenic fetal bowel at routine ultrasound in the second trimester has been recognized to be associated with various deleterious conditions, especially cystic fibrosis. These observations lead praticians to investigate for parent CFTRmutations screening and subsequent prenatal diagnosis if the two parents are carriers. METHODS: Through data issued from two prospective investigations, our study aimed at the estimation of both the sensibility and efficiency of the screening for cystic fibrosis using ultrasound foetal bowel examination. RESULTS: Using the frequency of the disease in the population and the number of affected fetuses within the hyperechoic sample (20 in 641 in a recent study), our analysis may lead to the conclusion that fetal echogenic bowel may concern about 0.75% of fetuses. CONCLUSION: Orders of magnitude of the sensibility and efficiency of cystic fibrosis screening through fetal echogenic bowel are calculated and lead to the conclusion that sonographic screening might decrease the number of affected newborn more than two time less.

Cystic Fibrosis↗
PubMed2002

Genetic testing and genetic counselling in hypertrophic cardiomyopathy: the French experience.

AIMS: A major breakthrough in the molecular genetics of hypertrophic cardiomyopathy (HCM) has made genetic testing now available in clinical practice, raising new questions about its implications, potential benefits, and the organisation of the procedure. The aim of this work was (1) to discuss the different questions related to genetic testing in HCM, and propose guidelines for the different situations, (2) to report our preliminary experience with a specific procedure. METHODS AND RESULTS: The main questions asked by patients and relatives concern presymptomatic diagnosis and prenatal counselling/diagnosis, while clinicians sometimes discuss diagnostic and prognostic testing. To take into account the complex medical and psychological implications of this new approach, we developed a specific, multidisciplinary, and multiple step procedure, including a cardiologist, a geneticist, and a psychologist. Seventy subjects were examined, including (1) 29 adults for presymptomatic diagnosis (of whom 10 left the procedure after the first visit and 19 continued, among whom six had a mutation and two experienced negative psychological impact, observed during follow up), (2) nine couples of parents for presymptomatic diagnosis in their children (the procedure was stopped after the first visit in eight and continued in one), (3) 22 couples for prenatal counselling (no prenatal genetic testing was asked for after the first visit), and (4) 10 subjects for diagnostic testing. We decided to perform no prognostic testing. CONCLUSION: Our preliminary experience confirms the complexity of the situation and suggests the necessity for a specific procedure to ensure good practice in genetic testing of HCM.

Adolescent↗
PubMed2001

Genotype analysis of the NF1 gene in the French Canadians from the Québec population.

We genotyped 19 NF1 families from the French Canadians of the Québec population with six intragenic polymorphic markers including 2 RFLPs (EcoRI and RsaI) and 4 microsatellites (IVS26-2.3, IVS27AC28.4, IVS27AC33.1, and IVS38GT53.0). Genotype analysis indicated families 7610 and 7473 bear deletions. In Family 7610 the deletion removed the entire NF1 gene except exons 1 to 4b. The breakpoint of the deletion is located between exons 4a and 4b. The deletion 7473 was derived from the maternal chromosome and exons 1 to 5 were deleted. The breakpoint of the deletion is located between exons 7 and 13. Their phenotypes are reported. The allele frequencies of microsatellites IVS27AC28.4 and IVS38GT53.0 are compared to previously reported data from Caucasians, including Spanish and Italians. The difference is statistically significant (P < 0.0036) for marker IVS27AC28.4 between the Québec French Canadian and the Italian population.

Alleles↗
PubMed2001

Phenotypic variability at the TGF-beta1 locus in Camurati-Engelmann disease.

Camurati-Engelmann disease (CED) [OMIM 131300] is an autosomal dominant sclerosing bone dysplasia recently ascribed to mutations of the transforming growth factor (TGF-beta1) gene on chromosome 19q13.1-q13.3. Five mutations consistently located in the TGF-beta1 propeptide have been hitherto identified in 21 families. Here, we report on TGF-beta1 mutations in one Australian and six European families. Three distinct mutations were identified among seven families: namely, R218H (family 1), R218C (families 2, 6, 7) and C225R (families 3, 4, 5). The three mutations identified in our pedigrees have been previously observed in families of Japanese and Israeli origin and the R218C appears to be the most prevalent mutation worldwide (17/28 reported families). No obvious correlation between the nature of the mutations and the severity of the clinical manifestations could be established, but a marked intrafamilial clinical variability was observed, supporting incomplete penetrance of CED. Interestingly, the polymorphisms in the TGF-beta1 gene showed no correlation with the severity of the disease. We conclude that CED is a clinically variable condition and that this clinical variability is not accounted for by polymorphisms at the TGF-beta1 locus.

Australia↗
PubMed2001

Evidence for digenic inheritance in a family with both febrile convulsions and temporal lobe epilepsy implicating chromosomes 18qter and 1q25-q31.

We report a clinical and genetic study of a French family among whom febrile convulsions (FC) are associated with subsequent temporal lobe epilepsy (TLE) in the same individual, without magnetic resonance imaging-identifiable hippocampal abnormalities. Linkage analyses excluded the loci FEB1 and FEB2, previously implicated in FC; the GEFS+1 locus responsible for generalized epilepsy with febrile seizures plus; and the locus implicated in lateral temporal lobe epilepsy. After scanning the entire genome, significant lod scores (>3) for markers on 18qter and suggestive lod scores (>2) for markers on 1q25-q31 were obtained. An analysis of the haplotypes at these two loci supported the hypothesis that two genes segregated with the phenotype. All patients shared common haplotypes for both 1q25-q31 and 18qter chromosomes. All but one unaffected at-risk individuals carried only one, or none, of the disease haplotypes. Under the assumption of digenic inheritance, haplotype reconstruction defined a 26 cM interval on chromosome 1 and a 10 cM interval on chromosome 18. This family suggests that the association between FC and TLE may be observed in the absence of hippocampal structural abnormalities and that they may have, in some cases, a common genetic basis.

Adolescent↗
PubMed2001

[Contribution of genetics to knowledge and management of hereditary kidney diseases progressing to renal failure].

Genes of most of the hereditary renal diseases progressing to renal insufficiency are now identified. In the first part of this paper we describe their multi-faceted genetics. Genetic heterogeneity has been demonstrated in many of these diseases, such as Alport's syndrome and nephronophtisis. In some of them an allelic heterogeneity is present as in the X-linked form of Alport's syndrome (more than 300 different mutations have been described along the COL4A5 gene). Besides these classical mendelian diseases, mendelian subentities have been isolated within common diseases such as cortico-resistant nephrosis. Many diseases also demonstrate a variability of their phenotype resulting from allelic and/or genetic heterogeneity, or from modifier genes. In the second part of the paper we discuss the consequences of this explosion of knowledge with respect to epidemiology, genetic diagnosis, prenatal diagnosis and treatment.

Adrenal Cortex Hormones↗