Anna Allavena

A unique MSH2 exon 8 deletion accounts for a major portion of all mismatch repair gene mutations in Lynch syndrome families of Sardinian origin

Lynch syndrome is an autosomal-dominant hereditary condition predisposing to the development of specific cancers, because of germline mutations in the DNA-mismatch repair (MMR) genes. Large genomic deletions represent a significant fraction of germline mutations, particularly among the MSH2 gene, in which they account for 20% of the mutational spectrum. In this study we analyzed 13 Italian families carrying MSH2 exon 8 deletions, 10 of which of ascertained Sardinian origin. The overrepresentation of Sardinians was unexpected, as families from Sardinia account for a small quota of MMR genes mutation tests performed in our laboratory. The hypothesis that such a result is owing to founder effects in Sardinia was tested by breakpoint junctions sequencing and haplotype analyses. Overall, five different exon eight deletions were identified, two of which recurrent in families, all apparently unrelated, of Sardinian origin (one in eight families, one in two families). The c.1277–1180_1386+2226del3516insCATTCTCTTTGAAAA deletion shares the same haplotype between all families and appears so far restricted to the population of South-West Sardinia, showing the typical features of a founder effect. The three non-Sardinian families showed three different breakpoint junctions and haplotypes, suggesting independent mutational events. This work has useful implications in genetic testing for Lynch syndrome. We developed a quick test for each of the identified deletions: this can be particularly useful in families of Sardinian origin, in which MSH2 exon 8 deletions may represent 50% of the overall mutational spectrum of the four MMR genes causing Lynch syndrome.

Juvenile Vertebrobasilar Ischaemic Stroke in a Patient with Camurati-Engelmann Disease

(652C 1 T; Arg 218Cys) in exon 4 (coding the TGF1 latency-associated peptide). Immunological and coagulation tests (namely protein C and S, homocysteine plasma levels, activated protein C resistance, prothrombin polymorphism, lupus anticoagulant, anticardiolipin antibodies) were unremarkable. Cranial CT showed a dramatic increase in the thickness of the skull bones, particularly in the lower half. Brain MRI revealed multiple small ischaemic lesions involving the cerebellar hemispheres ( fi g. 1 A), the left thalamus and the right occipital region and a T 1 hyperintensity on the course of the intracranial right vertebral artery ( fi g. 1 B). Duplex sonography revealed increased carotid wall thickness and reduced fl ow in both vertebral arteries. Digital subtraction angiography demonstrated that the right vertebral artery was occluded immediately after the origin of the postero-inferior cerebellar artery and the left vertebral artery had a reduced lumen between the origin of the postero-inferior cerebellar artery and the vertebrobasilar junction and furnished a normal basilar artery ( fi g. 1 C). Cranial CT revealed patent intravertebral foramina despite the huge thickness of the skull base bone ( fi g. 1 D). Transthoracic and transoesophageal echocardiography revealed only a slight increase in thickness of the endocardium and in the aortic valve. The patient was treated with low-molecular-weight heparin for 2 weeks followed by ticlopidine. No further ischaemic events occurred.