Girl with Ectopia Lentis, and Possibly Marfan Syndrome, Caused by a FBN1 Gene Mutation

Background: Marfan syndrome (MFS) and Ectopia Lentis, which is part of the MFS spectrum of fibrillinopathies, are allelic autosomal-dominant connective tissue disorders caused by mutations in the Fibrillin 1 gene (FBN1). FBN1 enables normal development of ocular, cardiac and musculoskeletal structures. Almost inevitable, most severe complications of MFS include aortic root dilatation, aortic dissection and sudden cardiovascular death. To alleviate the clinical course, early diagnosis and monitoring are essential.

Objective: We performed molecular diagnostics in a 4-year-old girl with bilateral lens dislocation but no other signs of MFS.

Methods: The girl was the only affected in her family. Clinical examination revealed no skeletal, cutaneous, cardiovascular, or pulmonary abnormalities. According to the revised Ghent criteria (2010), patients without positive family history should demonstrate four different clinical abnormalities to establish a diagnosis of MFS (revised criteria give more weight to aortic aneurysm and lens dislocation than original criteria). This girl did not meet the Ghent criteria, but nevertheless we strongly suspected mild or incomplete MFS and performed molecular genetic analysis.

Results: Using next generation sequencing we identified a heterozygous base exchange c.4589G>C in FBN1. The variant was not reported previously. It was absent in the parents and thus likely originated de novo in the patient. We propose that it represents a novel pathological (disease-causing) mutation. Furthermore the girl demonstrated a heterozygous c.4645C>T variant (predicting p.Arg1549Cys) in MYLK (the gene for aortic thoracic aneurysm, type 7) inherited from the mother. This MYLK variant was also not described previously and was predicted to likely represent another pathological finding.

Conclusions: (1) Bilateral ectopia lentis represents an important diagnostic clue to MFS spectrum disorders. (2) Early diagnosis is crucial to delay complications. (3) Additionally we identified in the girl and her mother a MYLK gene variant that could possibly represent another genetic predisposition for aortic aneurysm.