FP11-6 Estrogen Excess Phenotype Associated With Loss of Heterozygosity of the STK11 Gene in the Testis of Two Boys With Peutz Jeghers Syndrome

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP11-Pediatric Endocrinology
Clinical
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:25 AM
Room 104 (Moscone Center)

Poster Board SAT-599
Kristy A Brown*1, Seungmin Ham2, Sarah Jayne Meachem3, Catherine Seut Choong4, Adrian K Charles5, Gareth S Baynam6, Timothy W Jones7, Nirukshi U Samarajeewa8 and Evan R Simpson9
1Prince Henry's Institute, Clayton VIC, Australia, 2Prince Henry's Institute, Clayton Victoria, Australia, 3Prince Henry's Inst Med Rsrch, Clayton VIC, Australia, 4Princess Margaret Hosp for Chi, Subiaco WA, Australia, 5Genetic Services of Western Australia, Australia, 6Princess Margaret Hospital for Children, Australia, 7Princess Margaret Hosp, Western Australia, Australia, 8Prince Henry's Institute, Australia, 9Prince Henry's Inst of Med Res, Clayton VIC, Australia
Peutz Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by the association of gastrointestinal harmatomatous polyps and mucocutaneous pigmentation which is due to mutations in the STK11 gene that encodes the LKB1 protein. PJS males may have estrogen excess manifesting as gynecomastia and an advanced bone age. We and the group of Santen have previously described an increase in testicular aromatase expression in PJS patients. However, the underlying mechanism has not yet been explored. The aim of this study was to characterize the role of LKB1 in regulating the expression of aromatase in the testes of two boys with PJS via signaling pathways involving pAMPK and CRTC1, CRTC2, and CRTC3. We studied testicular biopsies from two boys with STK11 mutations; a 13-year-old boy and an unrelated 4-year-old boy with prepubertal gynaecomastia and advanced bone age. Loss of heterozygosity of STK11 in Sertoli cells of abnormal cords of PJS testis samples, measured by the absence of LKB1 immunofluorescence staining, was associated with loss of p21 expression and decreased phosphorylation of AMPK, known downstream targets of LKB1, as well as the increased expression of aromatase.  The nuclear localization of the potent stimulator of aromatase CRTC3, which arises as a consequence of decreased activity of AMPK, was increased in cells where aromatase was detected. In conclusion, loss of heterozygosity of the STK11 gene leads to an increase in aromatase expression associated with increased CRTC3 nuclear localization, thereby providing a mechanism whereby PJS is associated with estrogen excess.

Nothing to Disclose: KAB, SH, SJM, CSC, AKC, GSB, TWJ, NUS, ERS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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