Context: Isolated familial somatotropinoma (IFS) is a rare endocrine disease defined as the occurrence of at least two cases of acromegaly or gigantism in a family that does not exhibit features of Carney complex or multiple endocrine neoplasia type 1. Analysis of the multigenerational expression in families suggests that IFS is inherited as an autosomal dominant disease with incomplete penetrance. The association between the disease and loss of heterozygosity on chromosome 11q13 as well as its linkage to this region has been well established, but the IFS gene still remains unknown.
Objective: The aim of this report was to narrow the previously described chromosomal region (9.7 cM) to which the gene was previously localized and to evaluate potential candidates.
Design and setting: Using haplotyping and allelotyping techniques, we studied eight new families (total of 14 tumors) with IFS and 15 sporadic somatotropinomas. Eighteen polymorphic markers spanning an approximately 9-Mb region on chromosome 11q12.2-11q13.3 were used.
Main outcome and results: Loss of heterozygosity was found in all families and in 40% of sporadic tumors. Although multiple and frequently discontinuous, the presence of allelic loss limited by retentions at their boundaries suggests a new interval of approximately 2.21 Mb on chromosome 11q13.3. Three potential candidate genes (DOC-1R, LOC 399919, and LOC 440049) in this region were sequenced, although no mutations were found.
Conclusions: Identification of the IFS gene is still necessary because it will not only provide insight into the molecular basis of IFS but may also elucidate the pathogenesis of sporadic somatotropinomas.