Two-hit mechanism in cerebral cavernous malformation? A case of monozygotic twins with a CCM1/KRIT1 germline mutation.

ABSTRACT

Cerebral cavernous malformations are focal vascular abnormalities that show recurrent intralesional microhemorrhage and may cause focal deficits or seizures in affected patients. These lesions occur in both sporadic and inherited autosomal dominant form. Germline mutations in three different genes have been identified yet. One explanation for the unpredictable individual clinical course with wide variability of the number of developing cerebral cavernous malformations (CCMs) and their rate of progression within CCM families is thought to be based upon a "two-hit" mechanism. However, the direct influence of a heterozygous underlying germline mutation in combination with secondary somatic mutations on a patient's individual clinical course is hard to investigate in vivo. In this context, we present a rare and interesting case of monozygotic twins heterozygous for the CCM1 germline mutation c.730-1G>A and discuss their similar age and type of disease manifestation and their beginning divergent clinical course.