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, Korach Kenneth S
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, USA.
J Clin Endocrinol Metab. 2008 Aug;93(8):3088-96. doi: 10.1210/jc.2007-2397. Epub 2008 May 27.
The kindred described is the only known instance of a germ line loss of function mutation of estrogen receptor (ER)-alpha.
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.
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.
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.
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).
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.
所描述的家族是已知的雌激素受体（ER）-α种系功能丧失突变的唯一实例。
我们的目的是评估ER-α基因功能丧失突变对一个大家族中组织形态计量学、骨体积密度、骨几何形状和骨骼生长的影响，以及ER-α杂合性对脊柱密度和成人身高的影响。
对携带ER-α功能丧失纯合突变的先证者进行纵向随访，并对该家族进行单次接触评估。
对先证者进行髂嵴骨活检和外周定量计算机断层扫描，通过双能X线吸收法对脊柱面积骨密度（aBMD）进行系列测量，并评估骨龄。对家族成员进行ER-α突变携带者状态和脊柱aBMD评估。
骨活检显示明显的骨质减少（皮质：641微米）、低小梁体积（10.6%）、厚度降低（76.2微米）、小梁数量正常和低激活频率（0.099/年）。桡骨骨膜周长相似，骨内膜周长更大，小梁和皮质体积骨密度明显低于对照组（分别为158和1092毫克/立方厘米）。28.5岁时的脊柱aBMD（0.745克/平方厘米）在3.5年内降至0.684克/平方厘米（Z评分-3.85）。骨龄从15 - 17.5岁提前。家族分析显示，基因携带者的脊柱aBMD Z评分小于零（P = 0.003），但携带者和非突变成员相似（-0.84±0.26对-0.64±0.16）。
ER-α纯合缺失显著影响骨骼生长、矿物质含量和结构，但不影响骨膜周长。ER-α杂合性似乎不会损害脊柱aBMD。
