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Impact on Bone of an Estrogen Receptor- Gene Loss of Function Mutation

Department of Internal Medicine (E.P.S., R.M.C.), Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; South Dakota State University (B.S.), Ethel Austin Martin Program in Human Nutrition, Brookings, South Dakota 57007; Division of Endocrinology (B.E.B., M.J.A.), Children’s Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229; Laboratory of Reproductive and Developmental Toxicology (K.S.Ki., K.S.Ko.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; Department of Hematology and Oncology (K.S.Ki.), Emory University School of Medicine, Atlanta, Georgia 30322; Women’s Health & Musculoskeletal Biology (X.J.L.), Wyeth Research, Cambridge, Massachusetts 02140; National Institute of Dental and Craniofacial Research (M.F.Y.), Bethesda, Maryland 20892; Department of Medicine (N.S.F.), Johns Hopkins University, Baltimore, Maryland 21224; Division of Pediatric Endocrinology (G.R.F.), Schneider Children’s Hospital/Long Island Jewish Medical Center, New Hyde Park, New York 11042; and Department of Biochemistry & Child Health (D.B.L.), University of Missouri, Columbia, Missouri 65211

Address all correspondence and requests for reprints to: Eric P. Smith, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati College of Medicine, Vontz Center for Molecular Studies, 3125 Eden Avenue, Cincinnati, Ohio 45267-0547. E-mail: smithep{at}email.uc.edu.

Context: The kindred described is the only known instance of a germ line loss of function mutation of estrogen receptor (ER)-.

Objective: Our objective was to assess the impact of a loss of function mutation in the ER- gene on histomorphometry, bone volumetric density, bone geometry and skeletal growth, and ER- heterozygosity on spine density and adult height in an extended pedigree.

Design and Participants: A longitudinal follow-up of the propositus with homozygous loss of function mutation of ER- and single contact evaluation of the kindred were performed.

Main Outcome Measures: Iliac crest bone biopsy and peripheral quantitative computed tomography of propositus with serial measures of areal spine bone mineral density (aBMD) by dual-energy x-ray absorptiometry and bone age were performed. Members of pedigree were evaluated for ER- mutation carrier status and spine aBMD.

Results: Bone biopsy revealed marked osteopenia (cortex: 641 µm), low trabecular volume (10.6%), decreased thickness (76.2 µm), normal trabecular number, and low activation frequency (0.099/yr). Radial periosteal circumference was similar, endosteal circumference larger, and trabecular and cortical volumetric bone mineral density markedly lower (158 and 1092 mg/cm³, respectively) than controls. Spine aBMD at age 28.5 yr (0.745 g/cm²) decreased to 0.684 g/cm² (Z score –3.85) in 3.5 yr. Bone age advanced from 15–17.5 yr. Kindred analysis revealed that gene carriers had spine aBMD Z scores less than zero (P = 0.003), but carriers and nonmutant members were similar (–0.84 ± 0.26 vs. –0.64 ± 0.16).

Conclusion: Homozygous ER- disruption markedly affects bone growth, mineral content, and structure but not periosteal circumference. ER- heterozygosity appears to not impair spine aBMD.