Prenatal diagnosis of Larsen syndrome caused by a mutation in the filamin B gene

Abstract

Larsen syndrome [OMIM 150 250] is an autosomal dominant skeletal dysplasia characterized by craniofacial features, large-joint dislocations and abnormalities of the extremities. Craniofacial anomalies include hypertelorism, prominence of the forehead, a depressed nasal bridge and a flattened midface. Dislocation of the large joints (knees, hips, elbows, tibio-tarsal) including anterior dislocation of at least one of the knees are the main features. The limb abnormalities include a very characteristic tapering aspect of the distal humerus. Other occasionally seen findings include short stature, cleft palate, and extraskeletal manifestations include bilateral testicular ectopy, retinal lesions and bilateral macular dysplasia, deafness, cardiac abnormalities (ventricular septal defect) and tracheomalacia.Heterozygosity for mutations in the gene encoding the filamin B (FLNB) located at chromosome 3p14.3 have been identified in a wide spectrum of osteochon-drodysplasias, including Larsen syndrome, atelosteogenesis type III (AOIII) and I, boomerang dysplasia and spondylocarpotarsal syndrome (Krakow et al., 2004). Filamin B is a cytoskeletal protein essential in modulation of the cellular cytoskeleton and has functions in signal transduction, cell division motility and transport of small molecules.Diagnosis of Larsen syndrome is usually made in the postnatal period. The prognosis is highly variable and occasionally lethal. Complications include multiple orthopedic abnormalities, instability of the cervical spine, pulmonary hypoplasia and neonatal tracheomalacia. Prenatal

Review of Cervical Spine Anomalies in Genetic Syndromes

“…2 This cytoskeletal protein allows for communication between the cell membrane and the cytoskeleton to control and guide proper skeletal development; mutation of the fi lamin B gene has been implicated in several osteochondrodysplasias. 2 Although prognosis is variable, clinical presentation typically includes multiple joint dislocations (elbows, hips, and knees), distinct facial anomalies (prominent and fl at forehead, depressed nasal bridge, fl at midface, widespread eyes, and round face), club foot, heart defects, cleft palate, and neonatal tracheomalacia. 1 -3 Patients with Larsen syndrome often develop abnormalities of the spine; however, deformities of the cervical spine are most dangerous because of the risk of cord compression leading to paralysis and death.…”

Arthrogryposis Multiplex Congenita and Pena-Shokeir Phenotype: Challenge of Prenatal Diagnosis – Report of 21 Cases, Antenatal Findings and Review

“…Restrictive dermopathy and Neu-Laxova syndrome are rare skin developmental disorders which reportedly result in fetal hypokinesia [22][23][24] . Other differential diagnosis are Freeman-Sheldon syndrome (= distal arthrogryposis type 2A), Sheldon-Hall syndrome (distal arthrogryposis type 2B), Marden-Walker syndrome and Larsen syndrome, characterized by craniofacial anomalies, kyphoscoliosis and arthrogryposis [10,[25][26][27] .…”

Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients

“…Mutations associated with AOI and AOIII are present in the CH2 domain and Ig repeats 2, 5, 6, 14, and 15 [ 1 , 4 , 24 ], while amino acid substitutions causing BD are exclusively located in the CH2 domain [ 6 , 24 ]. The missense mutations and small in-frame deletions found in LS have been detected both in the CH2 domain and the Ig repeats 2, 13, 14, 15, 17, and 23 [ 1 , 15 , 16 , 24 – 26 ]. Dominant FLNB mutations have been proposed to result in increased F-actin binding affinity of filamin B or dysregulation of the hinge region [ 24 , 27 ].…”