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Le Touquet – Paris-Plage, France

Lehalle D.,Hopital Necker Enfants Malades | Gordon C.T.,University of Paris Descartes | Oufadem M.,University of Paris Descartes | Goudefroye G.,Hopital Necker Enfants Malades | And 39 more authors.
Human Mutation

Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle. We have delineated the clinical spectrum of Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) in a series of 36 patients with mutations in EFTUD2, which encodes a component of the spliceosome. Despite high phenotypic variability amongst MFDGA patients, a characteristic facial gestalt provides the most useful diagnostic handle. © 2014 WILEY PERIODICALS, INC. Source

Gordon C.T.,University of Paris Descartes | Petit F.,Service de Genetique Clinique | Oufadem M.,University of Paris Descartes | Decaestecker C.,Service de Genetique Clinique | And 25 more authors.
Journal of Medical Genetics

Background: Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated. Results: We report on 10 cases presenting with MFD, eight of whom had OA, either due to de novo 17q21.31 deletions encompassing EFTUD2 and neighbouring genes or de novo heterozygous EFTUD2 loss-of-function mutations. No EFTUD2 deletions or mutations were found in a series of patients with isolated OA or isolated oculoauriculovertebral spectrum (OAVS). Conclusions: These data exclude a contiguous gene syndrome for the association of MFD and OA, broaden the spectrum of clinical features ascribed to EFTUD2 haploinsufficiency, define a novel syndromic OA entity, and emphasise the necessity of mRNA maturation through the spliceosome complex for global growth and within specific regions of the embryo during development. Importantly, the majority of patients reported here with EFTUD2 lesions were previously diagnosed with Feingold or CHARGE syndromes or presented with OAVS plus OA, highlighting the variability of expression and the wide range of differential diagnoses. Source

Di Meglio C.,Marseille University Hospital Center | Cano A.,Marseille University Hospital Center | Milh M.,Marseille University Hospital Center | Girard N.,Marseille University Hospital Center | And 2 more authors.
Archives de Pediatrie

Acute necrotizing encephalopathy is a rare neurologic disease most often triggered by a febrile viral event affecting an otherwise healthy infant. The clinical course is characterized by rapid deterioration of the neurological condition that often leads to coma and requires intensive care. The diagnosis is usually suggested by MRI, which shows symmetrical and focal necrotic lesions of thalami. Acute necrotizing encephalopathy has been linked in recent studies to an autosomal-dominant mutation of the gene for the protein RAN-binding protein 2. Case report: We report three cases in siblings of Tunisian origin. Two of them presented with acute necrotizing encephalopathy at the age of 9 months in the immediate aftermath of a viral infection. The molecular study conducted in the family showed that both patients and their mother were carriers of the missense mutation gene RAN-binding protein 2. Comments: Although the role of Ran BP2 protein is incompletely known, mutation of the RANBP2 gene causes rare, reversible central neurologic disorders. Suspected diagnosis is facilitated by MRI, which shows specific lesions of multifocal, symmetric involvement of the thalami, brainstem tegmentum, supratentorial white matter, and cerebellum. Due to the low frequency of the disease and its non-specific clinical presentation, the diagnosis of acute necrotizing encephalopathy is a major challenge, while preventative measures can be proposed in familial mutation. © 2013 Elsevier Masson SAS. Source

Jeanson L.,University Pierre and Marie Curie | Copin B.,Service de Genetique et Embryologie Medicales | Papon J.-F.,University Paris Est Creteil | Dastot-Le Moal F.,Service de Genetique et Embryologie Medicales | And 21 more authors.
American Journal of Human Genetics

Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive condition resulting from structural and/or functional defects of the axoneme in motile cilia and sperm flagella. The great majority of mutations identified so far involve genes whose defects result in dynein-arm anomalies. By contrast, PCD due to CC/RS defects (those in the central complex [CC] and radial spokes [RSs]), which might be difficult to diagnose, remains mostly unexplained. We identified non-ambiguous RSPH3 mutations in 5 of 48 independent families affected by CC/RS defects. RSPH3, whose ortholog in the flagellated alga Chlamydomonas reinhardtii encodes a RS-stalk protein, is mainly expressed in respiratory and testicular cells. Its protein product, which localizes within the cilia of respiratory epithelial cells, was undetectable in airway cells from an individual with RSPH3 mutations and in whom RSPH23 (a RS-neck protein) and RSPH1 and RSPH4A (RS-head proteins) were found to be still present within cilia. In the case of RSPH3 mutations, high-speed-videomicroscopy analyses revealed the coexistence of immotile cilia and motile cilia with movements of reduced amplitude. A striking feature of the ultrastructural phenotype associated with RSPH3 mutations is the near absence of detectable RSs in all cilia in combination with a variable proportion of cilia with CC defects. Overall, this study shows that RSPH3 mutations contribute to disease in more than 10% of PCD-affected individuals with CC/RS defects, thereby allowing an accurate diagnosis to be made in such cases. It also unveils the key role of RSPH3 in the proper building of RSs and the CC in humans. © 2015 The American Society of Human Genetics. Source

Katorza E.,Service de radiologie | Nahama-Allouche C.,Service de radiologie | Castaigne V.,Service de gynecologie obstetrique | Gonzales M.,Service de Genetique et Embryologie Medicales | And 6 more authors.
Pediatric Radiology

Background: Analysis of the middle ear with fetal MRI has not been previously reported. Objective: To show the contribution of fetal MRI to middle ear imaging. Materials and methods: The tympanic cavity was evaluated in 108 fetal cerebral MRI examinations (facial and/or cerebral malformation excluded) and in two cases, one of Treacher Collins syndrome (case 1) and the other of oculo-auriculo-vertebral (OUV) spectrum (case 2) with middle ear hypoplasia identified by MRI at 27 and 36 weeks' gestation, respectively. Results: In all 108 fetuses (mean gestational age 32.5 weeks), the tympanic cavity and T2 hypointensity related to the ossicles were well visualised on both sides. Case 1 had micro/retrognathia and bilateral external ear deformity and case 2 had retrognathism with a left low-set and deformed ear. MRI made it possible to recognize the marked hypoplasia of the tympanic cavity, which was bilateral in case 1 and unilateral in case 2. Both syndromes are characterized by craniofacial abnormalities including middle ear hypoplasia, which cannot be diagnosed with US. Conclusion: The middle ear cavity can be visualized with fetal MRI. We emphasize the use of this imaging modality in the diagnosis of middle ear hypoplasia. © 2010 Springer-Verlag. Source

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