[Show abstract][Hide abstract] ABSTRACT: Severe osteoarthritis and thoracic aortic aneurysms have recently been associated with mutations in the SMAD3 gene, but the full clinical spectrum is incompletely defined.
All SMAD3 gene mutation carriers coming to our centre and their families were investigated prospectively with a structured panel including standardized clinical workup, blood tests, total body computed tomography, joint X-rays. Electroneuromyography was performed in selected cases.
Thirty-four SMAD3 gene mutation carriers coming to our centre were identified and 16 relatives were considered affected because of aortic surgery or sudden death (total 50 subjects). Aortic disease was present in 72%, complicated with aortic dissection, surgery or sudden death in 56% at a mean age of 45 years. Aneurysm or tortuosity of the neck arteries was present in 78%, other arteries were affected in 44%, including dissection of coronary artery. Overall, 95% of mutation carriers displayed either aortic or extra-aortic arterial disease. Acrocyanosis was also present in the majority of patients. Osteoarticular manifestations were recorded in all patients. Joint involvement could be severe requiring surgery in young patients, of unusual localization such as tarsus or shoulder, or mimicking crystalline arthropathy with fibrocartilage calcifications. Sixty eight percent of patients displayed neurological symptoms, and 9 suffered peripheral neuropathy. Electroneuromyography revealed an axonal motor and sensory neuropathy in 3 different families, very evocative of type II Charcot-Marie-Tooth (CMT2) disease, although none had mutations in the known CMT2 genes. Autoimmune features including Sjogren's disease, rheumatoid arthritis, Hashimoto's disease, or isolated autoantibodies- were found in 36% of patients.
SMAD3 gene mutations are associated with aortic dilatation and osteoarthritis, but also autoimmunity and peripheral neuropathy which mimics type II Charcot-Marie-Tooth.
PLoS ONE 01/2014; 9(5):e96387. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.
[Show abstract][Hide abstract] ABSTRACT: The optimal strategy for identifying patients with Lynch syndrome among patients with newly diagnosed colorectal cancer (CRC) is still debated. Several predictive models (e.g., MMRpredict, PREMM1,2 and MMRpro) combining personal and familial data have recently been developed to quantify the risk that a given patient with CRC carries a Lynch syndrome-causing mutation. Their clinical applicability to patients with CRC from the general population requires evaluation. We studied a consecutive series of 214 patients with newly diagnosed CRC characterized for tumor microsatellite instability (MSI), somatic BRAF mutation, MLH1 promoter methylation and mismatch repair (MMR) gene germline mutation status. The performances of the models for identifying MMR mutation carriers (8/214, 3.7%) were evaluated and compared to the revised Bethesda guidelines and a molecular strategy based on MSI testing in all patients followed by the exclusion of MSI-positive sporadic cases from mutational testing by screening for BRAF mutation and MLH1 promoter methylation. The sensitivities of the three models, at the lowest thresholds proposed, were identical (75%), with similar numbers of probands eligible for further MSI testing (almost half the patients). In our dataset, the prediction models gave no better discrimination than the revised Bethesda guidelines. Both approaches failed to identify two of the eight mutation carriers (the same two patients, aged 67 and 81 years, both with no family history). Thus, like the revised Bethesda guidelines, predictive models did not identify all patients with Lynch syndrome in our series of consecutive CRC. Our results support systematic screening for MMR deficiency in all new CRC cases.
International Journal of Cancer 04/2011; 130(6):1367-77. · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Evaluate the risk of aortic complications (aortic dissection or prophylactic aortic surgical replacement) associated with pregnancy in Marfan syndrome in the absence of specific care.
Data are scarce on aortic complications during pregnancy in Marfan syndrome.
Retrospective study on a large population (415 patients) followed up in our multidisciplinary out-patient clinic devoted to Marfan syndrome. Women over 18 years of age were divided into 2 groups: 85 had been pregnant (MFSP+) giving birth to 136 children through 160 pregnancies; 68 had not been pregnant (MFSP-). The occurrence of aortic complication was compared between the 2 groups using a piecewise discrete-time model.
In MFSP+, 7 aortic complications occurred during 160 pregnancies (4.4%) and 17 aortic complications occurred during 1870 years of follow-up out of pregnancy. In MFSP-, 14 aortic complications occurred over 940 years of follow-up. Pregnancy was associated with a 5 fold increase in risk of aortic complication, which did not translate into increased risk during life, suggesting that pregnancy may act as a revealer in women prone to aortic complication.
Pregnancy is associated with a transient increased risk of aortic complication in the absence of specific care.
International journal of cardiology 08/2009; 136(2):156-61. · 6.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations identified in the fibrillin-1 (FBN1) gene have been associated with Marfan syndrome (MFS). Molecular analysis of the gene is classically performed in probands with MFS to offer diagnosis for at-risk relatives and in children highly suspected of MFS. However, FBN1 gene mutations are found in an ill-defined group of diseases termed 'type I fibrillinopathies', which are associated with an increased risk of aortic dilatation and dissection. Thus, there is growing awareness of the need to identify these non-MFS probands, for which FBN1 gene screening should be performed. To answer this need we compiled the molecular data obtained from the screening of the FBN1 gene in 586 probands, which had been addressed to our laboratory for molecular diagnosis. In this group, the efficacy of FBN1 gene screening was high in classical MFS probands (72.5%,), low (58%) in those referred for incomplete MFS and only slight (14.3%) for patients referred as possible MFS. Using recursive partitioning, we found that the best predictor of the identification of a mutation in the FBN1 gene was the presence of features in at least three organ systems, combining one major, and various minor criteria. We also show that our original recommendation of two systems involved with at least one with major criterion represents the minimal criteria because in probands not meeting these criteria, the yield of mutation identification drastically falls. This recommendation should help clinicians and biologists in identifying probands with a high probability of carrying a FBN1 gene mutation, and thus optimize biological resources.
European journal of human genetics: EJHG 04/2009; 17(9):1121-8. · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TGFBR1 and TGFBR2 gene mutations have been associated with Marfan syndrome types 1 and 2, Loeys-Dietz syndrome and isolated familial thoracic aortic aneurysms or dissection. In order to investigate the molecular and clinical spectrum of TGFBR2 mutations we screened the gene in 457 probands suspected of being affected with Marfan syndrome or related disorders that had been referred to our laboratory for molecular diagnosis. We identified and report 23 mutations and 20 polymorphisms. Subsequently, we screened the TGFBR1 gene in the first 74 patients for whom no defect had been found, and identified 6 novel mutations and 12 polymorphisms. Mutation-carrying probands displayed at referral a large clinical spectrum ranging from the Loeys-Dietz syndrome and neonatal Marfan syndrome to isolated aortic aneurysm. Furthermore, a TGFBR1 gene mutation was found in a Shprintzen-Goldberg syndrome patient. Finally, we observed that the yield of mutation detection within the two genes was very low : 4.8% for classical MFS, 4.6% for incomplete MFS and 1% for TAAD in the TGFBR2 gene; 6.2%, 6.2% and 7% respectively in the TGFBR1 gene; in contrast to LDS, where the yield was exceptionally high (87.5%).
Human Mutation 10/2008; 29(11):E284-95. · 5.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The identification of individuals who should undergo hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing remains a critical issue. The Bethesda guidelines were developed to preselect patients for microsatellite instability (MSI) testing before germline mutation screening. These criteria have been revised, and a new set of recommendations, the revised Bethesda guidelines, has been proposed.
To evaluate the performance of these revised guidelines for identifying patients with HNPCC in a series of unselected consecutive patients and compare this revised guidelines-based approach with a molecular strategy (MSI testing for all tumors, followed by exclusion of MSI-positive sporadic cases from mutational testing).
The study included 214 patients with newly diagnosed colorectal cancer. The MSI analysis was performed for all tumors. Germline testing, guided by immunohistochemical staining for mismatch repair proteins, was performed for patients with MSI-positive tumors. Sporadic MSI-positive tumors were identified by screening for BRAF mutation and MLH1 promoter methylation.
Ninety patients (42.1%) met the revised guidelines. Twenty-one patients (9.8%) had MSI-positive tumors. Germline testing identified eight mutations (3.7%) (MSH2 N = 5, MLH1 N = 2, MSH6 N =1). The revised guidelines failed to identify 2 of the 8 probands (aged 67 and 81 yr, both with no family history). In contrast, the molecular strategy identified all patients requiring testing for germline mutation. The percentages of patients selected for germline testing by the revised guidelines and the molecular strategy were 4.2% and 5.1%, respectively.
The revised Bethesda guidelines did not identify all HNPCC cases in our series. The molecular approach identified all HNPCC patients with MSI-positive tumors, increasing the workload for germline testing only slightly.
The American Journal of Gastroenterology 09/2008; 103(11):2825-35; quiz 2836. · 7.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.
The American Journal of Human Genetics 10/2007; 81(3):454-66. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To measure bone mineral density (BMD) in a group of patients meeting Gand criteria for Marfan syndrome, comparatively with a group of healthy controls.
Dual-energy X-ray absorptiometry (DEXA) was used to measure BMD at the hip and wrist in 130 patients seen at the Multidisciplinary Marfan Clinic, Paris, France. Results were compared to values in the database of the absorptiometry machine (Hologic QDR100) and to values in 72 healthy height-matched controls including 35 whose body mass index (BMI) values were similar to those in the patients.
A history of fractures was noted in 32 (24.6%) patients. Z-score values were significantly decreased in the patients compared to the Hologic database values at the femoral neck (-1.190+/-0.098, P<0.0001) and wrist (-1.403+/-1.06; P < 0.001). Patients had significantly lower BMD values at the femoral neck compared to the height-matched controls (0.841+/-0.15 versus 1.010+/-0.017; P<0.0001). BMD values were also significantly lower in the patients compared to the controls of similar height and BMI. BMD values did not correlate with history of fractures or acetabular protrusion. In the patients, BMD values lower than -2.5 correlated with presence of dural ectasia.
Men and women with Marfan syndrome have significant osteopenia independent from BMI.
[Show abstract][Hide abstract] ABSTRACT: We investigated the possible role of chromosome 10q losses in colorectal cancer metastasis by carrying out an allelic imbalance study on a series of microsatellite instability-negative (MSI-) primary tumours (n=32) and metastases (n=36) from 49 patients. Our results demonstrate that 10q allelic losses are associated with a significant proportion (25%) of MSI- colorectal tumours, but are not involved in the metastatic process. PTEN and BMPR1A, two genes located in the common deleted region, were screened for mutations in samples with loss of heterozygosity. The absence or low frequency of mutations indicates that the inactivation of these genes by deletion of one allele and mutation of the other one plays only a minor role in MSI- tumours.
British Journal of Cancer 04/2004; 90(6):1230-4. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chimerism is the coexistence of more than one cell line in an individual, due to the fusion of originally separate zygotes. It has been very rarely described in humans. A 36-year-old woman referred for in vitro fertilization (IVF) had three embryos transferred leading to a monofetal pregnancy. Ultrasound examination at 17 weeks showed severe intrauterine growth retardation. Amniocentesis revealed a mixture of 46,XY and 46,XX clones. Histopathologic examination showed a dysmorphic fetus with female phenotype and severe growth retardation. Fusion of two of the three embryos (one male and one female) seems to be the most probable mechanism that could explain both cytogenetic and histopathologic observations.
[Show abstract][Hide abstract] ABSTRACT: Two new patients, mosaic for a small supernumerary ring chromosome 7 are described. There are only seven published reported concerning supernumerary ring chromosome 7 and we reviewed the previously reported cases in an attempt to establish genotype-phenotype correlations, which are particularly important for genetic counselling and clinical genetics. Our first case was a 20 months old girl who was referred for a mild motor developmental delay, an asymmetric facial appearance, a plagiocephaly and a short nose with anteverted nostrils. Our second case was a 9 years old boy who was referred for a IQ at the lower end of the normal range (? 80), obesity, hyperactivity and some dysmorphic features including hypertelorism and down slanting palpebral fissures. In both cases, chromosome analysis after G and R banding and FISH showed a small ring chromosome 7 in respectively 76% and 50% of consecutively scored metaphases. Both ring chromosomes were labelled by FISH using the Williams Syndrome locus probe (Elastin Gene D7S486). Comparison between these two cases and previously published cases allowed to delineate frequent clinical findings. A mild mental retardation was found in the majority of patients. which is an important data for genetic counselling.
[Show abstract][Hide abstract] ABSTRACT: Chimerism is the coexistence of more than one cell line in an individual, due to the fusion of originally separate zygotes. It has been very rarely described in humans.
A 36-year-old woman who was referred for in vitro fertilization (IVF) for unexplained infertility had three embryos transferred.
Four weeks and five days after the transfer, ultrasound examination detected a single fetus in the uterus. Ultrasound examination at 17 weeks for metrorrhagia showed severe intrauterine growth retardation. Amniocentesis revealed a mixture of 46,XY and 46,XX clones. Histopathologic examination showed a dysmorphic fetus with female phenotype and severe growth retardation.
Although demonstration by fingerprinting has not been possible, fusion of two of the three transferred embryos (one male and one female) seems to be the most probable mechanism that could explain both cytogenetic and histopathologic observations. No chimera has yet been described after IVF. It would be interesting to collect any such observations from other IVF centers.
[Show abstract][Hide abstract] ABSTRACT: The causal factors of aneurysm are not the same in the ascending and abdominal aorta. Atheroma is the dominant lesion in the abdominal aorta and genetic abnormalities predisposing to "mediacystic necrosis" are more frequently observed in ascending aortic aneurysms. The causal genetic abnormalities are multiple: abnormalities of fibrillin type I in Marfan's syndrome, collagen abnormalities in the Ehlers-Danlos syndrome, abnormalities of microfibrils, possible metallo-proteases, with many gene candidates. Finally, some ascending aortic aneurysms are associated with bicuspid aortic valves, some of which are familial. Familial factors are less evident in abdominal aortic aneurysms: genes favoring atheroma may be responsible but the factors which predispose to dilatation and non stenosis are not well known: they would seem to be general factors because the tendency to arterial dilatation is diffuse. In all cases, because of the high risk of disease in a close relative, a familial enquiry would seem to be justified with echocardiography for close relatives of affected subjects, especially when young and female.
Archives des maladies du coeur et des vaisseaux 12/2003; 96(11):1074-80. · 0.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Marfan syndrome is the second most common inherited connective tissue disorder after osteogenesis imperfecta. Musculoskeletal abnormalities are at the forefront of the clinical picture and count among the major diagnostic criteria for Marfan syndrome, together with cardiovascular and ocular system involvement. Early diagnosis is of the utmost importance since preventive measures significantly increase life expectancy and prevent the occurrence of impairments and disabilities. Marfan syndrome is due to mutations within the fibrillin-1 gene, which is the main protein of the microfibril network. Microfibrils play a crucial role in the trophicity and function of elastic tissue. Multidisciplinary management of the patients and their families is vital.
Joint Bone Spine 02/2000; 67(5):401-7. · 2.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Marfan’s syndrome is the second most common inherited connective tissue disorder, after osteogenesis imperfecta. The musculoskeletal abnormalities dominate the clinical presentation and produce a characteristic phenotype that is among the major diagnostic criteria, together with cardiac and ocular involvement. Early diagnosis is essential because appropriate preventive measures can significantly increase survival and reduce impairments and disabilities. Marfan’s syndrome is due to mutations within the gene encoding fibrillin 1, which is the main protein of the microfibril network. Fibrillin 1 influences elastic tissue nutrition and function. Multidisciplinary management of the patients and families is of the utmost importance.
Revue Du Rhumatisme - REV RHUM. 01/2000; 67(8):613-620.