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

Objective: Our objective was to assess the impact of a loss of function mutation in the ER-α gene on histomorphometry, bone volumetric density, bone geometry and skeletal growth, and ER-α 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-α 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-α 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-α disruption markedly affects bone growth, mineral content, and structure but not periosteal circumference. ER-α heterozygosity appears to not impair spine aBMD.