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International audience; Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in LMNA gene encoding lamins A and C. The disease is characterized by early onset joint contractures during childhood associated with humero-peroneal muscular wasting and weakness, and by the development of a cardiac disease in adulthood. Important intra-familial variability characterized by a wide range of age at onset of myopathic symptoms (AOMS) has been recurrently reported, suggesting the contribution of a modifier gene. Our objective was to identify a modifier locus of AOMS in relation with the LMNA mutation. To map the modifier locus, we genotyped 291 microsatellite markers in 59 individuals of a large French family, where 19 patients carrying the same LMNA mutation, exhibited wide range of AOMS. We performed Bayesian Markov Chain Monte Carlo-based joint segregation and linkage methods implemented in the Loki software, and detected a strong linkage signal on chromosome 2 between markers D2S143 and D2S2244 (211 cM) with a Bayes factor of 28.7 (empirical p value = 0.0032). The linked region harbours two main candidate genes, DES and MYL1 encoding desmin and light chain of myosin. Importantly, the impact of the genotype on the phenotype for this locus showed an overdominant effect with AOMS 2 years earlier for the homozygotes of the rare allele and 37 years earlier for the heterozygotes than the homozygotes for the common allele. These results provide important highlights for the natural history and for the physiopathology of Emery-Dreifuss muscular dystrophy.

Resume Introduction La dystrophie musculaire des ceintures de type 1B (LGMD1B), due a des mutations du gene LMNA , associe une faiblesse musculaire des ceintures a une atteinte cardiaque caracterisee par des troubles de la conduction auriculo-ventriculaire et une cardiomyopathie dilatee. Elle reste une forme peu connue de dystrophie des ceintures, et seulement 7 mutations du gene LMNA ont ete decrites comme etant responsables d’une LGMD1B. Le diagnostic clinique et genetique de cette myopathie est essentiel pour assurer la prise en charge de l’atteinte cardiaque et le conseil genetique. Patients et methodes Nous decrivons l’atteinte musculaire et cardiaque de 14 patients appartenant a 8 familles chez qui ont ete identifiees 6 mutations differentes, dont 4 nouvelles, du gene LMNA . Resultats Onze patients avaient une LGMD1B avec une atteinte scapulo-humerale et pelvi-femorale. Treize patients avaient une atteinte cardiaque. Des troubles de la conduction etaient presents chez 12 patients, et des troubles du rythme chez 9 patients. Sept patients ont beneficie de l’implantation d’un pacemaker ou d’un defibrillateur. Une transplantation cardiaque fut pratiquee dans 2 cas. Conclusion Cette etude permet de preciser les principales caracteristiques cliniques de cette affection musculaire ainsi que les premieres relations phenotype/genotype resultant de ces nouvelles observations.

Background Sotos syndrome is one the most common overgrowth conditions, after Beckwith-Wiedemann syndrome. As with other overgrowth syndromes, Sotos syndrome can be associated with an increased risk of tumors. Case We describe a young girl with Sotos syndrome and ovarian fibromatosis with a new mutation not reported before in the literature. Summary and Conclusion Development of ovarian tumor in Sotos syndrome has been poorly documented. Ovarian fibromatosis is a very rare non neoplastic disease. Management is guided by the benignity of the lesion and consists of surgical excision of the fibroma.

Resume Les nephroblastomes ou numerus de Wilms, frequentes parmi les tumeurs de l'enfant, sont parfois associees a des malformations congenitales (7 a 10 % des cas), dont l'aniridie. Celle-ci est l'element le plus constant du syndrome WAGR qui comporte en outre des anomalies genito-urinaires, un retard mental, et dans un tiers des cas une tumeur de Wilms. Nous presentons deux cas d'enfants atteints d'aniridie avec nephroblastome fœtal rhabdomyomateux. Observations. Cas 1. Une enfant de 1 an est hospitalisee pour hematurie macroscopique ; elle est atteinte d'aniridie congenitale. L'echographie abdominale et la tomodensitometrie mettent en evidence une volumineuse tumeur sur chaque rein. Elle est traitee par actinomycine et vincristine sans que le volume tumoral ne diminue. Une tumorectomie bilaterale est realisee a 6 mois du diagnostic. L'examen anatomopathologique retrouve un nephroblastome fœtal rhabdomyomateux. L'enfant est en remission a 6 ans du diagnostic. Cas 2. Le deuxieme enfant est suivi lui aussi pour aniridie congenitale et le diagnostie de nephroblastome du rein droit est fait a l'âge de 2 ans. La chimiotherapie preoperatoire comporte actinomycine et vincristine selon le protocole SIOP no 9. La nephrectomie droite est effectuee apres 1 mois de traitement et met en evidence un nephroblastome fœtal rhabdomyomateux. L'enfant est toujours en remission a 5 ans. Conclusion. Ces deux observations de nephroblastome fœtal rhabdomyomateux semblent etre les premieres rapportees dans le cadre du syndrome WAGR.

Objectives The 22q11 microdeletion is a chromosomal disorder detected by fluorescence in situ hybridization (FISH). It has been known since the 80s, and is involved in many malformative syndromes (DiGeorge sequence, VCFS syndrome, etc.). Airway abnormalities are frequently localized in the larynx, as reported in the following series. Methods A retrospective chart review of laryngeal abnormalities and 22q11 deletion in a tertiary referral center. Results Five cases of laryngeal abnormalities associated to 22q11 deletion syndrome (DS) were found in a series of 35 cases. Abnormalities encountered were subglottic stenosis (3%), glottic web (9%), laryngeal paralysis (9%), vocal nodule (3%), laryngomalacia (3%) associated with bronchial malposition (3%). Conclusion Laryngeal abnormalities are relatively common (14% in this series) and important to recognize with the 22q11 deletion syndrome, especially if cardiac surgery is planed. Conversely, in case of laryngeal abnormalities associated to other malformation (like facial dysmorphia or cardiac malformation), the 22q11 deletion must be searched.

Sensorineural hearing defect and goiter are common features of Pendred's syndrome. The clinical diagnosis of Pendred's syndrome remains difficult because of the lack of sensitivity and specificity of the thyroid signs. The identification of PDS as the causative gene allowed molecular screening and enabled a re-evaluation of the syndrome to identify potential diagnostic characteristics. This report presents the clinical and genotypic findings of 30 French families, for whom a diagnosis of Pendred's syndrome had been made. Twenty-seven families had at least one mutated allele. Twenty-eight different mutations were identified, 11 of which had never been previously reported. The main clinical characteristics were: early hearing loss, fluctuation in terms of during deafness evolution, and the presence of an enlarged vestibular aqueduct.

Aims: Mutations in the lamin A/C gene (LMNA) have been reported to be involved in dilated cardiomyopathy (DCM) associated with conduction system disease and/or skeletal myopathy. The aim of this study was to perform a mutational analysis of LMNA in a large white population of patients affected by dilated cardiomyopathy with or without associated symptoms. Methods: We performed screening of the coding sequence of LMNA on DNA samples from 66 index cases, and carried out cell transfection experiments to examine the functional consequences of the mutations identified. Results: A new missense (E161K) mutation was identified in a family with early atrial fibrillation and a previously described (R377H) mutation in another family with a quadriceps myopathy associated with DCM. A new mutation (28insA) leading to a premature stop codon was identified in a family affected by DCM with conduction defects. No mutation in LMNA was found in cases with isolated dilated cardiomyopathy. Functional analyses have identified potential physiopathological mechanisms involving identified mutations, such as haploinsufficiency (28insA) or intermediate filament disorganisation (E161K, R377H). Conclusion: For the first time, a specific phenotype characterised by early atrial fibrillation is associated with LMNA mutation. Conversely, mutations in LMNA appear as a rare cause of isolated dilated cardiomyopathy. The variable phenotypes observed in LMNA-DCM might be explained by the variability of functional consequences of LMNA mutations.

Purpose: The mutations responsible for Best Vitelliform Macular Dystrophy (BVMD) are found in a gene called VMD2. The VMD2 gene encodes a transmembrane protein named bestrophin-1 (hBest1) which is a Ca2+-sensitive chloride channel. This study was performed to identify disease-specific mutations in 27 patients with BVMD. Because this disease is characterized by an alteration of the Cl- channel function, patch clamp analysis was used to test the hypothesis that one of the VMD2 mutated variant is indeed causing the disease. Methods: Direct sequencing analysis of the 11 VMD2 exons was performed to detect new abnormal sequences. The mutant of hBest1 was expressed in HEK-293 cells and the associated Cl- current was examined using whole-cell patch clamp. Results: We identified six new VMD2 mutations, located exclusively in exons four, six and eight. One of these mutations (Q293H) is particularly severe. Patch clamp analysis of HEK cells expressing the Q293H mutant shows that this mutant channel is non-functional. Furthermore, the Q293H mutant inhibits the function of wild-type bestrophin-1 channels in a dominant negative manner. Conclusions This study provides further support to the idea that mutations in VMD2 are a necessary factor for Best disease. However, because variable expressivity of VMD2 was observed in family C which carries the Q293H mutation, it is also clear that a disease-linked mutation in VMD2 is not sufficient to produce BVMD. Our finding that the Q293H mutant does not form functional channels in the membrane could be explained either by disruption of channel conductance or gating mechanisms or by improper trafficking of the protein to the plasma membrane.