Pregnancy-Associated Osteoporosis With a Heterozygous Deactivating LDL Receptor-Related Protein 5 (LRP5) Mutation and a Homozygous Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism
Version of Record online: 19 MAR 2014
© 2013 American Society for Bone and Mineral Research
Journal of Bone and Mineral Research
Volume 29, Issue 4, pages 922–928, April 2014
How to Cite
Cook, F. J., Mumm, S., Whyte, M. P. and Wenkert, D. (2014), Pregnancy-Associated Osteoporosis With a Heterozygous Deactivating LDL Receptor-Related Protein 5 (LRP5) Mutation and a Homozygous Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism. J Bone Miner Res, 29: 922–928. doi: 10.1002/jbmr.2095
- Issue online: 19 MAR 2014
- Version of Record online: 19 MAR 2014
- Accepted manuscript online: 7 SEP 2013 04:48AM EST
- Manuscript Accepted: 5 SEP 2013
- Manuscript Revised: 26 JUL 2013
- Manuscript Received: 22 MAY 2013
- Shriners Hospitals for Children, the Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund, the Hypophosphatasia Research Fund, and the Barnes-Jewish Hospital Foundation.
- OSTEOPOROSIS PSEUDOGLIOMA SYNDROME;
Pregnancy-associated osteoporosis (PAO) is a rare, idiopathic disorder that usually presents with vertebral compression fractures (VCFs) within 6 months of a first pregnancy and delivery. Spontaneous improvement is typical. There is no known genetic basis for PAO. A 26-year-old primagravida with a neonatal history of unilateral blindness attributable to hyperplastic primary vitreous sustained postpartum VCFs consistent with PAO. Her low bone mineral density (BMD) seemed to respond to vitamin D and calcium therapy, with no fractures after her next successful pregnancy. Investigation of subsequent fetal losses revealed homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism associated both with fetal loss and with osteoporosis (OP). Because her neonatal unilateral blindness and OP were suggestive of loss-of-function mutation(s) in the gene that encodes LDL receptor-related protein 5 (LRP5), LRP5 exon and splice site sequencing was also performed. This revealed a unique heterozygous 12-bp deletion in exon 21 (c.4454_4465del, p.1485_1488del SSSS) in the patient, her mother and sons, but not her father or brother. Her mother had a normal BMD, no history of fractures, PAO, ophthalmopathy, or fetal loss. Her two sons had no ophthalmopathy and no skeletal issues. Her osteoporotic father (with a family history of blindness) and brother had low BMDs first documented at ages ∼40 and 32 years, respectively. Serum biochemical and bone turnover studies were unremarkable in all subjects. We postulate that our patient's heterozygous LRP5 mutation together with her homozygous MTHFR polymorphism likely predisposed her to low peak BMD. However, OP did not cosegregate in her family with the LRP5 mutation, the homozygous MTHFR polymorphism, or even the combination of the two, implicating additional genetic or nongenetic factors in her PAO. Nevertheless, exploration for potential genetic contributions to PAO may explain part of the pathogenesis of this enigmatic disorder and identify some at-risk women. © 2013 American Society for Bone and Mineral Research.