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Carney Complex, Peutz-Jeghers Syndrome, Cowden Disease, and Bannayan-Zonana Syndrome Share Cutaneous and Endocrine Manifestations, But Not Genetic Loci

Unit on Genetics and Endocrinology, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (C.A.S., L.S.K., S.E.T., D.J.T., C.G.), Bethesda, Maryland 20892; the Cardiology Division, Departments of Medicine and Cell Biology and Anatomy, Cornell University Medical College, The New York Hospital (C.T.B.), New York, New York 10021; Emeritus Staff, Mayo Clinic (J.A.C.), Rochester, Minnesota 55905; Dana-Farber Cancer Institute, Charles A. Dana Human Cancer Genetics Unit, Richard and Susan Smith Laboratories (D.J.M., C.E.), Boston, Massachusetts 02115; the Tumor Genetics Group, Nuffield Department of Clinical Medicine, University of Oxford, Wellcome Trust Center for Human Genetics (I.P.M.T.), Oxford, United Kingdom OX3 7HN; Institute of Cancer Research (R.S.H.), Sutton, Surrey, United Kingdom SM2 5NG; Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge (C.E.), Cambridge, United Kingdom CB2 2QQ; Wessex Clinical Genetics Service, Princess Ann Hospital (D.M.E., J.T.), Southampton, United Kingdom SO16 5YA; and the Division of Medical Genetics, Department of Genetics, Geneva University Medical School (J.-L.B., S.E.A.), 1211 Geneva, Switzerland

Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., D.Sc., Unit on Genetics and Endocrinology, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC1862, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov

Carney complex (CC), Peutz-Jeghers syndrome (PJS), Cowden disease (CD), and Bannayan-Zonana syndrome (BZS) share clinical features, such as mucocutaneous lentigines and multiple tumors (thyroid, breast, ovarian, and testicular neoplasms), and autosomal dominant inheritance. A genetic locus has been identified for CC on chromosome 2 (2p16), and the genes for PJS, CD, and BZS were recently identified; genetic heterogeneity appears likely in both CC and PJS. The genes for PJS and CD/BZS, STK11/LKB1 and PTEN, respectively, may act as tumor suppressors, because loss of heterozygosity (LOH) of the PJS and CD/BZS loci has been demonstrated in tumors excised from patients with these disorders. We studied 2 families with CC in whom the disease could not be shown to segregate with polymorphic markers from the 2p16 locus. Their members presented with lesions frequently seen in PJS and the other lentiginosis syndromes. We also tested 16 tumors and cell lines established from patients with CC for LOH involving the PJS and CD/BZS loci. DNA was extracted from peripheral blood, tumor cell lines, and tissues and subjected to PCR amplification with primers from microsatellite sequences flanking the STK11/LKB1 and PTEN genes on 19p13 and 10q23, respectively, and a putative PJS locus on 19q13. All loci were excluded as candidates in both families with LOD scores less than -2 and/or by haplotype analysis. LOH for these loci was not present in any of the tumors that were histologically identical to those seen in PJS. The overall rate of LOH for the PJS and CD/BZS loci in tumors from patients with CC was less than 10%. We conclude that despite substantial clinical overlap among CC, PJS, CD, and BZS, LOH for the STK11 and PTEN loci is an infrequent event in CC-related tumors. Linkage analysis excluded the PJS and CD/BZS loci on chromosomes 19 (19p13 and 19q13) and 10 (10q23) from harboring the gene defect(s) responsible for the phenotype in these 2 families.

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