Université de Bordeaux, INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme, Bordeaux, France.
Published: August 2016
AI Article Synopsis
Article Abstract
Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.
Mutations in , which encodes the cytoskeletal protein FLNA, cause a spectrum of sclerosing skeletal dysplasias. Although many of these genetic variants are recurrent and cluster within the gene, the pathogenic mechanism that underpins the development of these skeletal phenotypes is unknown. To determine if the skeletal dysplasia in -related conditions is due to a cell-autonomous loss-of-function localising to osteoblasts and/or osteocytes, we utilised mouse models to conditionally remove from this cellular lineage.
Otopalatodigital spectrum disorder (OPDSD) is characterized by variable phenotypes, including skeletal dysplasia, and is caused by pathogenic variants in filamin A-encoding FLNA. FLNA variants associated with lethal OPDSD primarily alter the CH2 subdomain of the ABD of FLNA. Herein, we report a novel FLNA mutation in a fetus with severe skeletal dysplasia in a pregnant multigravida female with a history of repeated miscarriages and terminations.
Introduction: Frontometaphyseal dysplasia 1 (FMD1) is a rare X-linked craniofacial syndrome belonging in the otopalatodigital spectrum of disorders. Here we present a case with severe FMD1 that was caused by a mutation in the FLNA gene located on Xq28.
Methods: A diagnosis for FMD1 was clinically set for a 22-year-old male who presented with cranial hyperostosis with marked supraorbital ridge, hypertelorism, progressive mixed hearing loss, partial anodontia, scoliosis, generalized skeletal dysplasia, and muscle atrophy.
Frontometaphyseal dysplasia 1 (FMD1) is a rare otopalatodigital spectrum disorder (OPDSD) that is inherited as an X-linked trait and it is caused by gain-of-function mutations in the . It is characterized by generalized skeletal dysplasia, and craniofacial abnormalities including facial dysmorphism (supraorbital hyperostosis, hypertelorism, and down-slanting palpebral fissures). The involvement of the central nervous system in patients with OPDSD is rare.
Otopalatodigital syndrome spectrum disorders are caused by Filamin A (FLNA) gene mutations. Otopalatodigital syndrome spectrum disorders are a group of rare congenital skeletal dysplasia, with specific craniomaxillofacial features including otopalatodigital syndrome type 1 and type 2, Melnick-Needles syndrome, frontometaphyseal dysplasia, terminal osseous dysplasia with pigmentary defects. The authors describe cases of a young girl with Melnick-Needles syndrome and a young boy with frontometaphyseal dysplasia treated in the Oral and Maxillofacial Surgery Department.
