A molecular and clinical study of Larsen syndrome caused by mutations in FLNB

University of Groningen, Groningen, Groningen, Netherlands
Journal of Medical Genetics (Impact Factor: 6.34). 03/2007; 44(2):89-98. DOI: 10.1136/jmg.2006.043687
Source: PubMed


Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied.
Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated.
The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.

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Available from: Louise S Bicknell
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    • "Congenital bowing of the long bones is a hallmark feature of STWS [1], but it is not unique to STWS and manifests in other syndromes including type IX Ehlers-Danlos syndrome, Campomelic Displasia, Larsen syndrome and other conditions. [109-112]. Some have suggested that prenatal bowing of the long bones results from the mechanical forces of imbalanced muscles acting on structurally weak bones in utero[113-115]. "
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    • "Autosomal dominant mutations of FLNB (missense mutations, small in-frame deletions or insertions) cause a group of skeletal dysplasias, including Larsen syndrome (LS; OMIM 150250), atelosteogenesis I and III (AOI and AOIII; OMIM 108720 and 108721), and boomerang dysplasia (BD; OMIM 112310) [1], [2], [3]. LS features joint dislocations, cervical spine malformations, and supernumerary carpal and tarsal ossification centers [1]. AOI, AOIII, and BD exhibit more severe phenotypes including undermodeled bones or ossification initiation failure [2], [3], [4]. "
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