Familial gastrointestinal stromal tumor with hyperpigmentation: Association with a germline mutation of the c-kit gene

We describe 2 siblings with multiple gastrointestinal stromal tumors (GISTs ) and cutaneous hyperpigmentation. Both had a point mutation of the c-kit g ene. The patients were sisters who had exhibited cutaneous hyperpigmentatio n since their late teens, but the diagnosis of multiple gastrointestinal su bmucosal tumors was not made until they were 41 and 45 years old. Histolodi c examination showed that these tumors were GISTs expressing CD34 and Hit p rotein. Both patients died of GISTs, Single-strand conformation polymorphis m analysis showed a mutation of c-hit in tumor DNA extracted from paraffin- embedded specimens. Direct sequencing analysis showed that the point mutati on occurred at codon 559 of exon 11 (Val-->Ala). The same single-point muta tion was detected in DNA extracted from peripheral leukocytes obtained from the younger sister and her 2 children (who had similar general hyperpigmen tation) as well as in DNA from a skin biopsy specimen taken from the older sister. The germline mutation at codon 559 of the c-hit gene found in the p resent familial GISTs differed from that in a previously reported case of f amilial GISTs. We propose that GISTs caused by a germline mutation of the c -kit gene should be referred to as GIST-cutaneous hyperpigmentation disease .