ClinVar

Stahl-Hallengren et al. (1994) described an unusual mutation in the FBN1 gene in a family with several members affected with an atypical form of Marfan syndrome (154700). The proband was 21 years old when he was referred to a rheumatologist because of pain in the hands during motion and episodes of knee joint effusions. There were no joint deformities, no scoliosis, and no cardiac symptoms. He had had spherophakia and lens dislocation since childhood. In his family, 8 members had lens dislocation and 7 of these underwent echocardiography with particular attention to aortic root dimensions and valvular function. No sign of aortic root dilatation, mitral valve prolapse, or other kind of cardiac involvement was observed either on physical examination or on echocardiography and there was no history of sudden deaths in the family. One or several episodes of knee joint effusion with moderate pain had occurred in 5 individuals. These episodes may have been related to moderate physical activity. Physical examination did not reveal ongoing joint effusion or other signs of synovitis in any of the family members. Five of the individuals with ectopia lentis had flexion contractures of the fifth proximal interphalangeal joint, whereas none of the other family members had this. The upper segment/lower segment ratio of the affected individuals was within the range characteristic of the Marfan syndrome. Linkage analysis with an informative marker in the vicinity of the fibrillin locus on chromosome 15, namely G113, revealed a lod score of 2.4 with no recombinations between the disorder and the marker. By using an automated sequenator in the screening of specific regions of FBN1 cDNA prepared from the cultured fibroblasts of the one affected family member, Stahl-Hallengren et al. (1994) identified a C-to-T transition at nucleotide 364. This mutation substituted a cysteine for arginine-122 (R122C). The mutation was confirmed in genomic DNA of the proband by use of the solid-phase minisequencing technique. This technique was also used to establish that all affected members of the family carried the same mutation, whereas unaffected members did not have the mutation. Furthermore, none of 60 Marfan patients or 60 healthy controls analyzed was shown to carry this mutation. The fibrillin polypeptide is made up of 47 repetitive EGF-like repeats interspersed by other motifs. Most of the EGF-like motifs have calcium-binding properties; however, 3 of them located close to the amino-terminal end of the fibrillin polypeptide exhibit the characteristic 6-cysteine pattern, but lack the putative calcium-binding consensus sequence. The R122C mutation in this family occurred in the second of these 3 non-calcium-binding EGF-like motifs and resulted in an extra cysteine just before the conserved second cysteine in this motif. Stevenson et al. (1982) gave the clinical description of 2 families with ectopia lentis in association with dolichostenomelia and joint stiffness.