Lopez E.,University of Burgundy |
Callier P.,University of Burgundy |
Cormier-Daire V.,Genetique Medicale |
Lacombe D.,Bordeaux University Hospital Center |
And 13 more authors.
American Journal of Medical Genetics, Part A | Year: 2012
Floating-Harbor syndrome (FHS) is characterized by characteristic facial dysmorphism, short stature with delayed bone age, and expressive language delay. To date, the gene(s) responsible for FHS is (are) unknown and the diagnosis is only made on the basis of the clinical phenotype. The majority of cases appeared to be sporadic but rare cases following autosomal dominant inheritance have been reported. We identified a 4.7Mb de novo 12q15-q21.1 microdeletion in a patient with FHS and intellectual deficiency. Pangenomic 244K array-CGH performed in a series of 12 patients with FHS failed to identify overlapping deletions. We hypothesized that FHS is caused by haploinsufficiency of one of the 19 genes or predictions located in the deletion found in our index patient. Since none of them appeared to be good candidate gene by their function, a high-throughput sequencing approach of the region of interest was used in eight FHS patients. No pathogenic mutation was found in these patients. This approach failed to identify the gene responsible for FHS, and this can be explained by at least four reasons: (i) our index patient could be a phenocopy of FHS; (ii) the disease may be clinically heterogeneous (since the diagnosis relies exclusively on clinical features), (iii) these could be genetic heterogeneity of the disease, (iv) the patient could carry a mutation in a gene located elsewhere. Recent descriptions of patients with 12q15-q21.1 microdeletions argue in favor of the phenocopy hypothesis. © 2012 Wiley Periodicals, Inc.
Functional assessment of non-metastatic paraganglioma and pheochromocytoma by 18F-FDopa PET: Impact of tumor localization and genetic status [évaluation fonctionnelle par TEP 18F-FDopa des paragangliomes et phéochromocytomes non métastatiques: Impact de la localisation lésionnelle et du statut génétique]
Cerdan F.,British Petroleum |
Gabriel S.,Center hospitalo University La Timone |
Sebag F.,Center hospitalo University La Timone |
Fakhry N.,Center hospitalo University La Timone |
And 5 more authors.
Medecine Nucleaire | Year: 2013
Objective: Paraganglioma (PGL) and pheochromocytoma (PCC) are neuroendocrine tumors most often benign associated with hereditary syndromes in about 30% of cases. This study aims to define the impact of tumor location and patient genotype on the clinical value of 18F-FDopa PET by assessing in detail the false negative occurrences. Patients and methods: A retrospective study was conducted on a cohort of 53 cases with non-metastatic sporadic or inherited PGL/PCC (SDHx or VHL related syndromes), investigated with 18F-FDopa PET. Results: Overall detection sensitivity of 18F-FDopa PET was 88%. Seventy-three lesions were found using this technique, including 49 head-and-neck PGL (HNP), two thoracic PGL (1 sympathetic and 1 parasympathetic), eight extra-adrenal retroperitoneal PGL and 15 PCC. The 10 missed lesions were seven extra-adrenal abdominal PGL (2 SDHB, 2 SDHD), two HNP (1 sporadic, 1 SDHD) and one PCC (1 SDHD). Conclusion: 18F-FDopa PET is a sensitive technique for the evaluation of non-metastatic head and neck and adrenal PGLs. Exploration of extra-adrenal retroperitoneal PGL associated with SDHB or SDHD syndrome is the main limitation of this technique, encouraging the use of alternative functional imaging modalities like FDG-PET. Negativity of 18F-FDopa PET in the initial assessment of a PGL should prompt to search for a SDHx mutation. © 2013 Elsevier Masson SAS.
Bahi-Buisson N.,University of Paris Descartes |
Bahi-Buisson N.,French Institute of Health and Medical Research |
Poirier K.,University of Paris Descartes |
Poirier K.,French Institute of Health and Medical Research |
And 17 more authors.
Brain | Year: 2014
Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5), 18 in TUBB2B (16.9), 11 in TUBB3 (10.4), three in TUBB5 (2.8), and three in TUBG1 (2.8). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75 of cases) and are present in 100 of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern. © 2014 The Author.
Vincent M.,Montpellier University Hospital Center |
Collet C.,Service de Biologie Moleculaire |
Verloes A.,University of Paris Pantheon Sorbonne |
Lambert L.,Service de Genetique Medicale |
And 8 more authors.
European Journal of Human Genetics | Year: 2014
Mandibulofacial dysostosis is part of a clinically and genetically heterogeneous group of disorders of craniofacial development, which lead to malar and mandibular hypoplasia. Treacher Collins syndrome is the major cause of mandibulofacial dysostosis and is due to mutations in the TCOF1 gene. Usually patients with Treacher Collins syndrome do not present with intellectual disability. Recently, the EFTUD2 gene was identified in patients with mandibulofacial dysostosis associated with microcephaly, intellectual disability and esophageal atresia. We report on two patients presenting with mandibulofacial dysostosis characteristic of Treacher Collins syndrome, but associated with unexpected intellectual disability, due to a large deletion encompassing several genes including the TCOF1 gene. We discuss the involvement of the other deleted genes such as CAMK2A or SLC6A7 in the cognitive development delay of the patients reported, and we propose the systematic investigation for 5q32 deletion when intellectual disability is associated with Treacher Collins syndrome. © 2014 Macmillan Publishers Limited.