Impact on Bone of an Estrogen Receptor-alpha Gene Loss of Function Mutation
CONTEXT: The kindred described is the only known instance of a germ line loss of function mutation of estrogen receptor (ER)-alpha.
OBJECTIVE: Our objective was to assess the impact of a loss of function mutation in the ER-alpha gene on histomorphometry, bone volumetric density, bone geometry and skeletal growth, and ER-alpha 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-alpha 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-alpha mutation carrier status and spine aBMD.
RESULTS: Bone biopsy revealed marked osteopenia (cortex: 641 microm), low trabecular volume (10.6%), decreased thickness (76.2 microm), 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/cm(3), respectively) than controls. Spine aBMD at age 28.5 yr (0.745 g/cm(2)) decreased to 0.684 g/cm(2) (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-alpha disruption markedly affects bone growth, mineral content, and structure but not periosteal circumference. ER-alpha heterozygosity appears to not impair spine aBMD.
The Journal of Clinical Endocrinology and Metabolism
DOI of Published Version
Smith, Eric P.; Specker, Bonny; Bachrach, Bert E.; Kimbro, K. S.; Li, X. J.; Young, Marian F.; Fedarko, Neal S.; Abuzzahab, M. J.; Frank, Graeme R.; Cohen, Robert M.; Lubahn, Dennis B.; and Korach, Kenneth S., "Impact on Bone of an Estrogen Receptor-alpha Gene Loss of Function Mutation" (2008). Ethel Austin Martin Program Publications. 53.