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Absence of PTEN/MMAC1 Germ-Line Mutations in Sporadic Bannayan-Riley-Ruvalcaba Syndrome¹

Departments of Medicine [J. M. C., H-J. S. H., D. P. C., C. L. C., W. K. C., C. R. B.], Surgery [A. F. Z., H. T. H.], and Pediatrics [J. E. L.]; Cancer Center [J. M. C., W. K. C., C. R. B.]; Ludwig Institute for Cancer Research [F. B. F., H-J. S. H., W. K. C.]; Center for Molecular Genetics [W. K. C.], University of California, San Diego, California 92093-0688; Children's Hospital, San Diego, California 92123 [M. C. J.]; Department of Human Genetics, McGill University, Montreal, Quebec, H3G 1A4 Canada [G. E. G., A. S. T.]; The F. Clarke Fraser Clinical Genetics Unit, Montreal Children's Hospital, Montreal, Quebec, H3H 1P3 Canada [G. E. G., A. S. T.]; and Veterans Affairs Medical Center, La Jolla, California 92093 [C. R. B.]

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare hamartomatous polyposis condition with features of macrocephaly, intestinal juvenile polyposis, developmental delay, lipomas, and pigmentation spots of the male genitalia. An autosomal dominant pattern of inheritance exists in some families, but others appear as sporadic cases. Germ-line mutations in PTEN, a tyrosine phosphatase and putative tumor suppressor gene, have been demonstrated in two families with BRRS, and chromatin loss at the PTEN gene locus on chromosome 10q23 has been demonstrated in two BRRS patients. Germ-line mutations in PTEN have also been described in Cowden disease and in a small number of patients with juvenile polyposis syndrome. In an attempt to assess the nature of PTEN mutations in BRRS, we analyzed three sporadic BRRS patients for chromosome 10q23 deletion or PTEN germ-line mutations. All 3 patients demonstrated no loss of parental alleles at 15 chromosome 10q23 markers that encompassed the region of PTEN. In addition, analysis of mRNA and genomic DNA revealed no nonsense, missense, or insertion/deletion mutations of PTEN. Thus, other mechanisms besides mutation of PTEN must have occurred to cause BRRS in these patients. We speculate that BRRS and juvenile polyposis syndrome may have a heterogeneous etiology to cause their syndromes.

¹ Supported by Grant DK02433 from the USPHS National Institute of Digestive Diseases and Kidneys and Grant CA72851 from the National Cancer Institute, the "V" Foundation for Cancer Research, the Veterans Affairs Research Service, and the Robert Steel Foundation for Pediatric Cancer Research.

² To whom requests for reprints should be addressed, at Department of Medicine, University of California, San Diego, 4028 Basic Science Building, 9500 Gilman Drive, La Jolla, CA 92093-0688. Phone: (619) 822-0304; Fax: (619) 822-0301; E-mail: jcarethers@ucsd.edu.

Received 3/25/98. Accepted 5/13/98.

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